Method of treating fabry disease in patient having a mutation in the GLA gene

Abstract

To provide a method of treating fabry disease in a patient having a mutation in the GLA gene.SOLUTION: Provided are a method of treating a patient diagnosed with Fabry disease and a method of enhancing α-galactosidase A in a patient diagnosed with or suspected of having Fabry disease. Certain methods comprise administering to a patient a therapeutically effective dose of a pharmacological chaperone for α-galactosidase A. Here, the patient has a mutation in the nucleic acid sequence encoding α-galactosidase A. Also provided are a use of a pharmacological chaperone for the treatment of Fabry disease and a composition for use in the treatment of Fabry disease.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Principles and embodiments of the present invention relate generally to the use of pharmacological chaperones for the treatment of Fabry disease, particularly in patients with mutations or variants in the alpha-galactosidase (GLA) gene. [Background technology]

[0002] Many human diseases result from mutations that cause changes in the amino acid sequence of proteins, reducing their stability and preventing their proper folding. Proteins are generally folded within a specific region of the cell known as the endoplasmic reticulum (ER). Cells have quality control mechanisms that ensure proteins fold into their correct three-dimensional shape and then move from the ER to their appropriate destination within the cell, a process generally referred to as protein trafficking. Misfolded proteins are often initially retained in the ER and then eliminated by the quality control mechanisms. In some cases, misfolded proteins can accumulate in the ER before being eliminated. Retention of misfolded proteins in the ER can interfere with their proper trafficking, resulting in reduced biological activity and impairing cellular function, ultimately leading to disease. In addition, accumulation of misfolded proteins in the ER can cause various stresses on the cell, which can also contribute to cellular dysfunction and disease.

[0003] Such mutations can lead to lysosomal storage disorders (LSDs), characterized by lysosomal enzyme deficiencies due to mutations in genes encoding the lysosomal enzymes. The resulting disease causes pathological accumulation of the enzyme's substrates, including lipids, carbohydrates, and polysaccharides. While many different mutational genotypes exist associated with each LSD, many of these mutations are missense mutations that can lead to the production of less stable enzymes. These less stable enzymes are sometimes prematurely degraded by ER-associated degradation pathways, resulting in enzyme deficiencies in lysosomes and pathological accumulation of substrates. Such mutant enzymes are sometimes referred to in the relevant art as "folding mutants" or "conformational mutants."

[0004] Fabry disease is a rare neurodegenerative disorder caused by mutations in the GLA gene, which encodes the enzyme α-galactosidase A (α-Gal A). α-Gal A is required for glycosphingolipid metabolism. This mutation leads to the accumulation of the substrate globotriaosylceramide (GL-3) in various tissues and organs. Because the disease gene is encoded on the X chromosome, males with Fabry disease are hemizygous. Fabry disease is estimated to affect 1 in 40,000 and 1 in 60,000 men, with a lower incidence in women.

[0005] Several approaches to treating Fabry disease exist. One approved therapy for Fabry disease is enzyme replacement therapy (ERT), which typically involves intravenous infusion of a purified form of the corresponding wild-type protein. Two α-Gal A preparations are currently available for the treatment of Fabry disease: agalsidase alfa (Replagal®, Shire Human Genetic Therapies) and agalsidase beta (Fabrazyme®; Sanofi Genzyme Corporation). However, ERT has several drawbacks. One of the major complications of ERT is the rapid degradation of the injected protein, which leads to multiple, expensive, high-dose infusions. ERT also has several caveats, including the difficulty of large-scale production, purification, and storage of properly folded protein; the availability of glycosylated native protein; the development of anti-protein immune responses; and the inability of the protein to cross the blood-brain barrier and alleviate central nervous system pathology (i.e., low bioavailability). Additionally, replacement enzymes cannot penetrate the heart or kidney in sufficient quantities to reduce substrate accumulation in renal podocytes or cardiac myocytes, which is prominent in Fabry lesions.

[0006] Another therapeutic approach for certain enzyme deficiencies involves the use of small molecule inhibitors to reduce production of the natural substrate of the defective enzyme protein, thereby alleviating the pathology. This "substrate inhibition" approach has been described for approximately 40 classes of LSDs, including glycosphingolipid storage disorders in particular. The small molecule inhibitors proposed for use as therapy are specific for inhibiting enzymes involved in glycolipid synthesis, reducing the amount of cellular glycolipids that need to be degraded by the defective enzyme.

[0007] A third approach to treating Fabry disease is treatment with so-called pharmacological chaperones (PCs). Such PCs include small molecule inhibitors of α-Gal A, which can bind to α-Gal A and increase the stability of both the mutant enzyme and its wild-type counterpart. However, patients eligible for PC therapy must have an applicable mutation or variant that results in the production of a potent enzyme that is stabilized and folds into a conformation that allows trafficking out of the ER. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] “Remington's Pharmaceutical Sciences” by EW Martin, 18th Edition [Non-patent document 2] Ishii et al.,Biochem.Biophys.Res.Comm.1996;220:812-815 Summary of the Invention [Problem to be solved by the invention]

[0009] Therefore, even when Fabry disease is diagnosed by detecting deficient α-Gal A activity in plasma or peripheral white blood cells (WBCs), it is extremely difficult, if not impossible, to predict whether a particular Fabry patient will respond to treatment with PC. Therefore, there remains a need to identify new GLA mutations or variants that will respond to PC and to make available new treatment strategies for Fabry patients who carry such mutations or variants. [Means for solving the problem]

[0010] One aspect of the present invention relates to a method of treating a patient diagnosed with Fabry disease, comprising administering to the patient a therapeutically effective dose of a pharmacological chaperone of α-Gal A, wherein the patient has a missense mutation in the nucleic acid sequence encoding α-Gal A. In one or more embodiments, the mutation is N5D, N5K, P6L, P6Q, P6R, P6S, P6T, E7D, E7K, E7V, L8I, L8P, L8Q, H9L, H9Q, H9R, H9Y, L10M, L10P, L10Q, L10R, L10V, G11C, G11D, G11R, G11S, G11V, C12G, C12R, C12S, C12Y, A13E, A13G, L14F, L14H, L14V, R17C, R17G, R17H, R17P, R17S, F18I, F18L, A20G, L21H, V22A, V22F, V22I, V22L, S23P, S23T, W24S, D25H, I26N, P27A, P27L, P27S, P27T, G28E, G28R, G28W, A29G, A29P, A29V, R30G, L32M, L32Q, L32R, L32V, D33A, D33E, D33V, L36M, L36V, A37E, A37G, A37S, R38G, R38M, R38W, T39A, T39K, T39M, T39R, T39S, T41A, T41N, T41S, G43A, L45M, L45V, H46D, H46N, H46Q, E48A, F50Y, M51R, M51T, M51V, N53H, N53I, N53S, N53T, L54H, L54R, L54V, D55A, D55E, D55H, D55Y, C56W, E58K, E59A, E59D, E59G, E59Q, E59V, P60A, P60Q, P60R, D61E, D61V, S62A, S62C, S62F, S62P, S62Y, I64L, I64V, S65C, S65G, S65R, E66D, E66V, K67E, K67M, K67N, K67Q, K67T, L68I, F69I, F69Y, M70I, M70K, M70L, M70R, E71A, E71D, E71G, E71Q, E71V, M72L, M72T, A73S, A73T, E74D, E74G, E74K, E74V, L75F, L75P, M76V, V77I, V77L, S78L, S78P, E79A, E79D, E79G, E79K, E79Q, E79V, G80A, G80C, G80S,W81L、K82E、K82M、K82N、K82R、K82T、D83A、D83E、D83G、D83V、A84E、A84G、A84P、A84S、A84T、A84V、G85A、G85C、G85R、Y86F、E87G、Y88H、Y88N、L89V、I91F、I91L、I91M、I91S、M96L、M96T、A97D、A97S、A97T、P98H、P98L、P98R、Q99E、Q99L、Q99P、Q99R、D101A、D101E、D101G、D101H、D101V、S102A、S102P、S102T、G104A、G104D、G104S、R105G、R105I、R105K、R105T、L106H、L106I、L106P、L106V、Q107E、Q107H、Q107K、A108E、A108V、D109A、D109E、D109H、D109N、D109Y、P110T、F113V、F113Y、P114L、H115D、H115N、G116R、I117M、I117T、A121V、Y123D、Y123F、Y123N、Y123S、V124I、H125D、H125N、H125R、S126C、S126I、K127E、G128A、L129V、K130M、K130N、K130Q、L131V、I133L、I133T、I133V、A135E、A135G、A135S、A135T、D136A、D136N、D136V、V137A、V137D、V137G、V137I、V137L、G138A、N139H、N139I、N139K、N139Y、K140E、K140I、K140N、K140Q、K140R、T141S、A143E、A143G、G144A、G144C、G144R、G144S、F145C、F145L、F145V、F145Y、P146A、P146H、P146L、P146T、G147A、S148C、S148G、S148T、F149C、G150E、G150V、Y151C、Y151D、Y151S、Y152F、Y152S、D153A、D153H、D153N、D153V、D153Y、A156G、Q157E、Q157K、Q157L、Q157P、T158A、T158I、T158N、T158S、F159I、F159L、F159V、F159Y、A160G、A160S、A160T、A160V、D161H、D161N、D161V、D161Y、W162S、V164A、V164I、V164L、D165A、D165E、L166M、L166Q、L167I、F169C、F169L、F169V、F169Y、G171A、G171V、Y173C、Y173F、Y173H、Y173S、D175G、D175H、D175V、D175Y、S176C、S176R、L177F、L177M、L177S、L177V、L177W、E178A、E178G、E178K、E178Q、L180M、L180S、A181P、A181T、A181V、D182A、D182E、D182V、D182Y、Y184F、Y184H、Y184S、K185M、K185N、K185Q、K185T、H186D、H186L、H186N、H186Q、H186Y、M187L、S188A、S188C、S188F、S188P、S188T、S188Y、L189S、L189V、A190D、A190G、A190S、A190T、A190V、L191M、L191V、N192D、N192H、N192K、N192S、N192T、R193G、R193M、R193T、R193W、T194N、T194P、T194S、G195C、G195R、G195S、R196I、R196K、S197C、S197G、S197I、S197N、S197T、I198M、I198S、V199E、V199L、Y200N、Y200S、S201A、S201C、S201T、E203A、E203G、E203Q、W204S、L206F、L206H、L206I、L206R、L206V、Y207F、M208K、W209C、W209G、P210H、P210T、F211C、F211L、F211S、F211V、F211Y、Q212H、Q212P、K213E、K213Q、P214A、P214H、P214R、P214T、N215H、N215K、N215T、N215Y、Y216F、Y216H、Y216N、T217A、T217I、T217K、T217P、T217R、T217S、E218A、E218D、E218G、E218K、E218Q、E218V、I219F、I219M、I219S、R220L、Q221E、Q221H、Q221K、Q221L、Q221R、Y222C、Y222D、Y222H、Y222N、Y222S、N224H、R227G、N228H、N228I、N228T、F229I、F229S、F229Y、A230D、A230G、A230P、A230V、I232L、I232M、I232V、D233A、D233E、D233G、D233V、S235A、S235T、K237I、S238C、S238I、S238T、I239L、K240E、K240M、K240R、S241C、S241I、S241T、I242L、I242M、I242S、L243M、L243S、L243V、D244A、D244E、D244G、D244V、D244Y、W245C、T246A、T246I、T246K、T246R、S247A、S247F、S247T、S247Y、F248C、F248L、F248V、F248Y、N249D、N249H、N249I、N249S、N249T、N249Y、Q250E、Q250L、E251G、E251K、E251Q、E251V、R252G、I253F、I253N、I253V、V254A、V254D、V254F、V254G、D255A、D255E、D255H、D255N、D255V、D255Y、V256D、V256G、V256L、A257S、G258E、P259A、P259T、G260W、G261A、N263H、N263T、D264H、D264N、P265A、P265Q、M267L、M267V、L268F、L268I、V269L、I270L、I270S、I270V、N272D、F273Y、L275I、W277L、N278I、Q280L、Q280R、V281A、V281E、V281G、V281L、T282S、Q283E、Q283H、Q283L、M284I、M284L、A285G、A285T、A285V、L286F、L286H、L286V、A288G、A288S、A288V、I289L、I289T、I289V、A291G、A292G、A292S、L294F、L294I、L294V、F295I、F295S、F295V、F295Y、S297T、N298D、N298I、N298T、D299H、D299N、L300I、L300V、H302D、H302L、H302N、H302Y、I303S、S304I、Q306E、Q306L、Q306P、A307D、A307G、A307P、A307S、A307V、K308I、K308Q、<h2 style=";text-align:left;direction:ltr">K308R、A309D、A309T、L310I、L311I、Q312E、Q312K、Q312L、D313E、D313V、K314E、K314M、K314N、K314T、D315A、D315G、D315H、D315N、D315V、D315Y、V316 A、V316L、I317L、I317M、I317V、A318D、A318P、A318T、A318V、I319M、N320S、 N320T、Q321K、D322A、D322V、L324V、L324W、G325A、G325C、G325V、K326E、K32 6M、K326Q、K326R、K326T、Q327H、Q327P、Y329C、Y329D、Y329F、Y329H、Y329N、Q330E、Q330H、Q330K、L331H、L331P、L331R、L331V、R332G、R332I、R332S、R 332T、Q333E、Q333L、Q333P、G334R、G334V、D335A、D335E、D335G、D335V、D335Y、N336D、N336I、N336S、N336T、N336Y、F337C、F337L、F337V、F337Y、E338A、 E338D、E338G、V339M、E341A、E341Q、P343A、P343S、L344F、L344R、L344V、G346A、G346C、G346D、G346V、L347I、A348D、W349C、W349L、A350G、A350S、A350 T、A350V、V351A、V351E、A352S、A352T、M353K、M353L、M353T、I354R、N355D、 N355H、N355S、N355Y、R356L、Q357E、I359F、I359L、I359N、I359S、I359V、P36 2A、P362H、P362R、P362S、R363G、R363L、R363S、S364C、S364P、Y365D、Y365F、Y365N、Y365S、T366I、T366N、T366P、T366S、I367F、I367L、I367M、A368G、A 368P、V369A、V369F、V369G、V369I、V369L、A370D、A370G、A370P、A370T、A370V、S371C、S371T、G373A、G373C、K374E、K374I、K374R、K374T、G375R、V376E、<h2 style=";text-align:left;direction:ltr">V376G、V376L、V376M、A377G、A377P、A377S、A377T、N379D、N379I、N379K、N379T、P380A、P380H、P380R、P380T、A381D 、F383C、F383I、F383Y、I384F、I384M、I384T、T38、<h2 style=";text-align:left;direction:ltr"> 5I, Q386H, Q386K, Q386L, L387F, L387H, L387I, L387R, L388F, L388H, L388I, L388R, L388V, K391I, K391N, K391Q, K391R, R392G, R392K, R392M, R392W, K393E, K393N, K393Q, K393T, L394I, L394Q, L394R, G395R, F396 C, F396I, F396L, F396V, Y397C, Y397F, Y397H, Y397N, Y397S, E398G, E398Q, W399G, W399R, T400A, T400I, T4 00N, T400P, T400S, S401A, S401L, S401T, R402G, R402M, R402S, R402T, R402W, L403F, L403V, ​​R404G, R404I, R404K, R404S, R404T, S405G, H406D, H406L, H406Q, I407L, I407M, I407T, N408D, N408H, N408T, P409L, T410 S, G411A, G411C, G411V, T412A, T412I, T412S, V413F, V413G, V413I, L414F, L414V, L415H, L415I, Q416E, Q4 The missense mutations in the nucleic acid sequence encoding α-Gal A are 16H, Q416L, L417I, E418A, E418D, E418K, E418Q, N419I, N419S, N419T, N419Y, T420K, T420P, T420R, T420S, M421I, M421K, M421L, M421R, M421T, Q422P, M423I, M423K, M423L, M423T, S424L, L425F, D427N, or L429R. In various embodiments, these mutations are relative to SEQ ID NO: 2. An additional aspect of the invention relates to a pharmaceutical for treating a patient diagnosed with Fabry disease who has a missense mutation in a nucleic acid sequence encoding α-Gal A. In one or more embodiments, the mutation is as provided above. In various embodiments, these mutations are relative to SEQ ID NO: 2.

[0011] In some embodiments, the pharmacological chaperone or agent comprises migalastat or a salt thereof. In one or more embodiments, the dose of migalastat or a salt thereof is about 100 mg to about 150 mg free base equivalent (FBE). In some embodiments, the salt of migalastat is migalastat hydrochloride. In one or more embodiments, the dose is about 150 mg of migalastat hydrochloride every other day, or an equivalent dose of migalastat or a salt thereof other than hydrochloride. In some embodiments, migalastat or a salt thereof is administered orally or by injection. These embodiments may be combined with each other or with other embodiments of the invention, such as methods for enhancing α-Gal A in patients diagnosed with or suspected of having Fabry disease, embodiments relating to the use of a pharmacological chaperone of α-Gal A in the manufacture of a medicament for the treatment of patients diagnosed with Fabry disease or for use in the treatment of patients diagnosed with Fabry disease, and embodiments relating to applicable mutations, suitable PCs and their dosages, formulations and routes of administration.

[0012] Another aspect of the present invention relates to a method for enhancing a-Gal A in a patient diagnosed with or suspected of having Fabry disease. The method comprises administering a therapeutically effective dose of a pharmacological chaperone of a-Gal A to the patient, wherein the patient has a missense mutation in the nucleic acid sequence encoding a-Gal A. Accordingly, an additional aspect of the present invention relates to a pharmaceutical for enhancing a-Gal A in a patient diagnosed with or suspected of having Fabry disease who has a missense mutation in the nucleic acid sequence encoding a-Gal A. In one or more embodiments, the mutation is provided below.

[0013] In one or more embodiments, the mutation is N5D, N5K, P6L, P6Q, P6R, P6S, P6T, E7D, E7K, E7V, L8I, L8P, L8Q, H9L, H9Q, H9R, H9Y, L10M, L10P, L10Q, L10R, L10V, G11C, G11D, G11R, G11S, G11V, C12G, C12R, C12S, C12Y, A13E, A13G, L14F, L14H, L14V, R17C, R17G, R17H, R17P, R17S, F18I, F18L, A20G, L21H, V22A, V22F, V22I, V22L, S23P, S23T, W24S, D25H, I26N, P27A, P27L, P27S, P27T, G28E, G28R, G28W, A2 9G, A29P, A29V, R30G, L32M, L32Q, L32R, L32V, D33A, D33E, D33V, L36M, L36V, A37E, A37G, A37S, R38G, R38M, R38W, T39A, T39K, T39M, T39R, T39S, T41A, T4 1N, T41S, G43A, L45M, L45V, H46D, H46N, H46Q, E48A, F50Y, M51R, M51T, M51V, N53H, N53I, N53S, N53T, L54H, L54R, L54V, D55A, D55E, D55H, D55Y, C56W, E5 8K, E59A, E59D, E59G, E59Q, E59V, P60A, P60Q, P60R, D61E, D61V, S62A, S62C, S62F, S62P, S62Y, I64L, I64V, S65C, S65G, S65R, E66D, E66V, K67E, K67M, K6 7N, K67Q, K67T, L68I, F69I, F69Y, M70I, M70K, M70L, M70R, E71A, E71D, E71G, E71Q, E71V, M72L, M72T, A73S, A73T, E74D, E74G, E74K, E74V, L75F, L75P, M7 6V, V77I, V77L, S78L, S78P, E79A, E79D, E79G, E79K, E79Q, E79V, G80A, G80C, G80S, W81L, K82E, K82M, K82N, K82R, K82T, D83A, D83E, D83G, D83V, A84E, A8 4G, A84P, A84S, A84T, A84V, G85A, G85C, G85R, Y86F, E87G, Y88H, Y88N, L89V,I91F、I91L、I91M、I91S、M96L、M96T、A97D、A97S、A97T、P98H、P98L、P98R、Q99E、Q99L、Q99P、Q99R、D101A、D101E、D101G、D101H、D101V、S102A、S102P、S102T、G104A、G104D、G104S、R105G、R105I、R105K、R105T、L106H、L106I、L106P、L106V、Q107E、Q107H、Q107K、A108E、A108V、D109A、D109E、D109H、D109N、D109Y、P110T、F113V、F113Y、P114L、H115D、H115N、G116R、I117M、I117T、A121V、Y123D、Y123F、Y123N、Y123S、V124I、H125D、H125N、H125R、S126C、S126I、K127E、G128A、L129V、K130M、K130N、K130Q、L131V、I133L、I133T、I133V、A135E、A135G、A135S、A135T、D136A、D136N、D136V、V137A、V137D、V137G、V137I、V137L、G138A、N139H、N139I、N139K、N139Y、K140E、K140I、K140N、K140Q、K140R、T141S、A143E、A143G、G144A、G144C、G144R、G144S、F145C、F145L、F145V、F145Y、P146A、P146H、P146L、P146T、G147A、S148C、S148G、S148T、F149C、G150E、G150V、Y151C、Y151D、Y151S、Y152F、Y152S、D153A、D153H、D153N、D153V、D153Y、A156G、Q157E、Q157K、Q157L、Q157P、T158A、T158I、T158N、T158S、F159I、F159L、F159V、F159Y、A160G、A160S、A160T、A160V、D161H、D161N、D161V、D161Y、W162S、V164A、V164I、V164L、D165A、D165E、L166M、L166Q、L167I、F169C、F169L、F169V、F169Y、G171A、G171V、Y173C、Y173F、Y173H、Y173S、D175G、D175H、D175V、D175Y、S176C、S176R、L177F、L177M、L177S、L177V、L177W、E178A、E178G、E178K、E178Q、L180M、L180S、A181P、A181T、A181V、D182A、D182E、D182V、D182Y、Y184F、Y184H、Y184S、K185M、K185N、K185Q、K185T、H186D、H186L、H186N、H186Q、H186Y、M187L、S188A、S188C、S188F、S188P、S188T、S188Y、L189S、L189V、A190D、A190G、A190S、A190T、A190V、L191M、L191V、N192D、N192H、N192K、N192S、N192T、R193G、R193M、R193T、R193W、T194N、T194P、T194S、G195C、G195R、G195S、R196I、R196K、S197C、S197G、S197I、S197N、S197T、I198M、I198S、V199E、V199L、Y200N、Y200S、S201A、S201C、S201T、E203A、E203G、E203Q、W204S、L206F、L206H、L206I、L206R、L206V、Y207F、M208K、W209C、W209G、P210H、P210T、F211C、F211L、F211S、F211V、F211Y、Q212H、Q212P、K213E、K213Q、P214A、P214H、P214R、P214T、N215H、N215K、N215T、N215Y、Y216F、Y216H、Y216N、T217A、T217I、T217K、T217P、T217R、T217S、E218A、E218D、E218G、E218K、E218Q、E218V、I219F、I219M、I219S、R220L、Q221E、Q221H、Q221K、Q221L、Q221R、Y222C、Y222D、Y222H、Y222N、Y222S、N224H、R227G、N228H、N228I、N228T、F229I、F229S、F229Y、A230D、A230G、A230P、A230V、I232L、I232M、I232V、D233A、D233E、D233G、D233V、S235A、S235T、K237I、<h2 style=";text-align:left;direction:ltr">S238C、S238I、S238T、I239L、K240E、K240M、K240R、S241C、S241I、S241T、I2 42L、I242M、I242S、L243M、L243S、L243V、D244A、D244E、D244G、D244V、D244 Y、W245C、T246A、T246I、T246K、T246R、S247A、S247F、S247T、S247Y、F248C、F248L、F248V、F248Y、N249D、N249H、N249I、N249S、N249T、N249Y、Q250E、Q25 0L、E251G、E251K、E251Q、E251V、R252G、I253F、I253N、I253V、V254A、V254D 、V254F、V254G、D255A、D255E、D255H、D255N、D255V、D255Y、V256D、V256G、V 256L、A257S、G258E、P259A、P259T、G260W、G261A、N263H、N263T、D264H、D264N、P265A、P265Q、M267L、M267V、L268F、L268I、V269L、I270L、I270S、I270V、 N272D、F273Y、L275I、W277L、N278I、Q280L、Q280R、V281A、V281E、V281G、V281L、T282S、Q283E、Q283H、Q283L、M284I、M284L、A285G、A285T、A285V、L286 F、L286H、L286V、A288G、A288S、A288V、I289L、I289T、I289V、A291G、A292G、 A292S、L294F、L294I、L294V、F295I、F295S、F295V、F295Y、S297T、N298D、N29 8I、N298T、D299H、D299N、L300I、L300V、H302D、H302L、H302N、H302Y、I303S 、S304I、Q306E、Q306L、Q306P、A307D、A307G、A307P、A307S、A307V、K308I、K 308Q、K308R、A309D、A309T、L310I、L311I、Q312E、Q312K、Q312L、D313E、D313V、K314E、K314M、K314N、K314T、D315A、D315G、D315H、D315N、D315V、D315Y、<h2 style=";text-align:left;direction:ltr">V316A、V316L、I317L、I317M、I317V、A318D、A318P、A318T、A318V、I319M、N320S、N320T、Q321K、D322A、D322V、L324V、L324W、G325A、G325C、G325V、K326 E、K326M、K326Q、K326R、K326T、Q327H、Q327P、Y329C、Y329D、Y329F、Y329H、Y329N、Q330E、Q330H、Q330K、L331H、L331P、L331R、L331V、R332G、R332I、R33 2S、R332T、Q333E、Q333L、Q333P、G334R、G334V、D335A、D335E、D335G、D335V、D335Y、N336D、N336I、N336S、N336T、N336Y、F337C、F337L、F337V、F337Y、E 338A、E338D、E338G、V339M、E341A、E341Q、P343A、P343S、L344F、L344R、L344V、G346A、G346C、G346D、G346V、L347I、A348D、W349C、W349L、A350G、A350S、 A350T、A350V、V351A、V351E、A352S、A352T、M353K、M353L、M353T、I354R、N355D、N355H、N355S、N355Y、R356L、Q357E、I359F、I359L、I359N、I359S、I359 V、P362A、P362H、P362R、P362S、R363G、R363L、R363S、S364C、S364P、Y365D、 Y365F、Y365N、Y365S、T366I、T366N、T366P、T366S、I367F、I367L、I367M、A36 8G、A368P、V369A、V369F、V369G、V369I、V369L、A370D、A370G、A370P、A370T、A370V、S371C、S371T、G373A、G373C、K374E、K374I、K374R、K374T、G375R、V 376E、V376G、V376L、V376M、A377G、A377P、A377S、A377T、N379D、N379I、N379K、N379T、P380A、P380H、P380R、P380T、A381D、F383C、F383I、F383Y、I384F、I384M, I384T, T385I, Q386H, Q386K, Q386L, L387F, L387H, L387I , L387R, L388F, L388H, L388I, L388R, L388V, K391I, K391N, K391Q, K391R, R392G, R392K, R392M, R, 392W, K393E, K393N, K393Q, K393T, L394I, L394Q, L394R, G395R, F396C, F396I, F396L, F3 96V, Y397C, Y397F, Y397H, Y397N, Y397S, E398G, E398Q, W399G, W399R, T400A, T400I, T40 0N, T400P, T400S, S401A, S401L, S401T, R402G, R402M, R402S, R402T, R402W, L403F, L403 V, R404G, R404I, R404K, R404S, R404T, S405G, H406D, H406L, H406Q, I407L, I407M, I407T , N408D, N408H, N408T, P409L, T410S, G411A, G411C, G411V, T412A, T412I, T412S, V413F, V413G, V413I, L414F, L414V, L415H, L415I, Q416E, Q416H, Q416L, L417I, E418A, E418D, E In various embodiments, the mutations are 418K, E418Q, N419I, N419S, N419T, N419Y, T420K, T420P, T420R, T420S, M421I, M421K, M421L, M421R, M421T, Q422P, M423I, M423K, M423L, M423T, S424L, L425F, D427N, or L429R. In various embodiments, the mutations are relative to SEQ ID NO:2.

[0014] In some embodiments, the pharmacological chaperone comprises migalastat or a salt thereof. In one or more embodiments, the dose of migalastat or a salt thereof is about 100 mg to about 150 mg FBE. In some embodiments, the salt of migalastat is migalastat hydrochloride. In one or more embodiments, the dose is about 150 mg of migalastat hydrochloride every other day, or an equivalent dose of migalastat or a salt thereof other than hydrochloride. In some embodiments, migalastat or a salt thereof is administered orally or by injection. These embodiments may be combined with each other or with other embodiments of the invention, such as methods of treating patients with Fabry disease, embodiments relating to the use of a pharmacological chaperone of α-Gal A in the manufacture of a medicament for treating patients diagnosed with Fabry disease, or embodiments relating to a pharmacological chaperone of α-Gal A for use in treating patients diagnosed with Fabry disease, and embodiments relating to applicable mutations, suitable PCs and their dosages, formulations, and routes of administration.

[0015] Another aspect of the present invention relates to the use of a pharmacological chaperone of α-Gal A in the manufacture of a medicament for the treatment of a patient diagnosed with Fabry disease, wherein the patient has a missense mutation in the nucleic acid sequence encoding α-Gal A. In one or more embodiments, the mutation is N5D, N5K, P6L, P6Q, P6R, P6S, P6T, E7D, E7K, E7V, L8I, L8P, L8Q, H9L, H9Q, H9R, H9Y, L10M, L10P, L10Q, L10R, L10V, G11C, G11D, G11R, G11S, G11V, C12G, C12R, C12S, C12Y, A13E, A13G, L14F, L14H, L14V, R17C, R17G, R17H, R17P, R17S, F18I, F18L, A20G, L21H, V22A, V22F, V22I, V22L, S23P, S23T, W24S, D25H, I26N, P27A, P27L, P27S, P27T, G28E, G28R, G28W, A29G, A29P, A29V, R30G, L32M, L3 2Q, L32R, L32V, D33A, D33E, D33V, L36M, L36V, A37E, A37G, A37S, R38G, R38M, R38W, T39A, T39K, T39M, T39R, T39S, T41A, T41N, T41S, G43A, L45M, L45V, H46D, H46N, H46Q, E48A, F50Y, M51R, M51T, M51V, N53H, N53I, N53S, N53T, L54H, L54R, L54V, D55A, D55E, D55H, D55Y, C56W, E5 8K, E59A, E59D, E59G, E59Q, E59V, P60A, P60Q, P60R, D61E, D61V, S62A, S62C, S62F, S62P, S62Y, I64L, I64V, S65C, S65G, S65R, E66D, E66V, K67E, K67M, K67N, K67Q, K67T, L68I, F69I, F69Y, M70I, M70K, M70L, M70R, E71A, E71D, E71G, E71Q, E71V, M72L, M72T, A73S, A73T, E74D, E7 4G, E74K, E74V, L75F, L75P, M76V, V77I, V77L, S78L, S78P, E79A, E79D, E79G, E79K, E79Q, E79V, G80A, G80C, G80S, W81L, K82E, K82M, K82N,K82R、K82T、D83A、D83E、D83G、D83V、A84E、A84G、A84P、A84S、A84T、A84V、G85A、G85C、G85R、Y86F、E87G、Y88H、Y88N、L89V、I91F、I91L、I91M、I91S、M96L、M96T、A97D、A97S、A97T、P98H、P98L、P98R、Q99E、Q99L、Q99P、Q99R、D101A、D101E、D101G、D101H、D101V、S102A、S102P、S102T、G104A、G104D、G104S、R105G、R105I、R105K、R105T、L106H、L106I、L106P、L106V、Q107E、Q107H、Q107K、A108E、A108V、D109A、D109E、D109H、D109N、D109Y、P110T、F113V、F113Y、P114L、H115D、H115N、G116R、I117M、I117T、A121V、Y123D、Y123F、Y123N、Y123S、V124I、H125D、H125N、H125R、S126C、S126I、K127E、G128A、L129V、K130M、K130N、K130Q、L131V、I133L、I133T、I133V、A135E、A135G、A135S、A135T、D136A、D136N、D136V、V137A、V137D、V137G、V137I、V137L、G138A、N139H、N139I、N139K、N139Y、K140E、K140I、K140N、K140Q、K140R、T141S、A143E、A143G、G144A、G144C、G144R、G144S、F145C、F145L、F145V、F145Y、P146A、P146H、P146L、P146T、G147A、S148C、S148G、S148T、F149C、G150E、G150V、Y151C、Y151D、Y151S、Y152F、Y152S、D153A、D153H、D153N、D153V、D153Y、A156G、Q157E、Q157K、Q157L、Q157P、T158A、T158I、T158N、T158S、F159I、F159L、F159V、F159Y、A160G、A160S、A160T、A160V、D161H、D161N、D161V、D161Y、W162S、V164A、V164I、V164L、D165A、D165E、L166M、L166Q、L167I、F169C、F169L、F169V、F169Y、G171A、G171V、Y173C、Y173F、Y173H、Y173S、D175G、D175H、D175V、D175Y、S176C、S176R、L177F、L177M、L177S、L177V、L177W、E178A、E178G、E178K、E178Q、L180M、L180S、A181P、A181T、A181V、D182A、D182E、D182V、D182Y、Y184F、Y184H、Y184S、K185M、K185N、K185Q、K185T、H186D、H186L、H186N、H186Q、H186Y、M187L、S188A、S188C、S188F、S188P、S188T、S188Y、L189S、L189V、A190D、A190G、A190S、A190T、A190V、L191M、L191V、N192D、N192H、N192K、N192S、N192T、R193G、R193M、R193T、R193W、T194N、T194P、T194S、G195C、G195R、G195S、R196I、R196K、S197C、S197G、S197I、S197N、S197T、I198M、I198S、V199E、V199L、Y200N、Y200S、S201A、S201C、S201T、E203A、E203G、E203Q、W204S、L206F、L206H、L206I、L206R、L206V、Y207F、M208K、W209C、W209G、P210H、P210T、F211C、F211L、F211S、F211V、F211Y、Q212H、Q212P、K213E、K213Q、P214A、P214H、P214R、P214T、N215H、N215K、N215T、N215Y、Y216F、Y216H、Y216N、T217A、T217I、T217K、T217P、T217R、T217S、E218A、E218D、E218G、E218K、E218Q、E218V、I219F、I219M、I219S、R220L、Q221E、Q221H、Q221K、Q221L、Q221R、Y222C、Y222D、Y222H、Y222N、Y222S、N224H、R227G、N228H、N228I、N228T、F229I、F229S、F229Y、A230D、A230G、A230P、A230V、I232L、I232M、I232V、D233A、D233E、D233G、D233V、S235A、S235T、K237I、S238C、S238I、S238T、I239L、K240E、K240M、K240R、S241C、S241I、S241T、I242L、I242M、I242S、L243M、L243S、L243V、D244A、D244E、D244G、D244V、D244Y、W245C、T246A、T246I、T246K、T246R、S247A、S247F、S247T、S247Y、F248C、F248L、F248V、F248Y、N249D、N249H、N249I、N249S、N249T、N249Y、Q250E、Q250L、E251G、E251K、E251Q、E251V、R252G、I253F、I253N、I253V、V254A、V254D、V254F、V254G、D255A、D255E、D255H、D255N、D255V、D255Y、V256D、V256G、V256L、A257S、G258E、P259A、P259T、G260W、G261A、N263H、N263T、D264H、D264N、P265A、P265Q、M267L、M267V、L268F、L268I、V269L、I270L、I270S、I270V、N272D、F273Y、L275I、W277L、N278I、Q280L、Q280R、V281A、V281E、V281G、V281L、T282S、Q283E、Q283H、Q283L、M284I、M284L、A285G、A285T、A285V、L286F、L286H、L286V、A288G、A288S、A288V、I289L、I289T、I289V、A291G、A292G、A292S、L294F、L294I、L294V、F295I、F295S、F295V、F295Y、S297T、N298D、N298I、N298T、D299H、D299N、L300I、L300V、H302D、H302L、H302N、H302Y、I303S、S304I、Q306E、Q306L、Q306P、A307D、A307G、A307P、A307S、A307V、K308I、K308Q、K308R、A309D、A309T、<h2 style=";text-align:left;direction:ltr">L310I、L311I、Q312E、Q312K、Q312L、D313E、D313V、K314E、K314M、K314N、K314T、D315A、D315G、D315H、D315N、D315V、D315Y、V316A、V316L、I317L、I317 M、I317V、A318D、A318P、A318T、A318V、I319M、N320S、N320T、Q321K、D322A、 D322V、L324V、L324W、G325A、G325C、G325V、K326E、K326M、K326Q、K326R、K32 6T、Q327H、Q327P、Y329C、Y329D、Y329F、Y329H、Y329N、Q330E、Q330H、Q330K 、L331H、L331P、L331R、L331V、R332G、R332I、R332S、R332T、Q333E、Q333L、Q 333P、G334R、G334V、D335A、D335E、D335G、D335V、D335Y、N336D、N336I、N336S、N336T、N336Y、F337C、F337L、F337V、F337Y、E338A、E338D、E338G、V339M、 E341A、E341Q、P343A、P343S、L344F、L344R、L344V、G346A、G346C、G346D、G346V、L347I、A348D、W349C、W349L、A350G、A350S、A350T、A350V、V351A、V351 E、A352S、A352T、M353K、M353L、M353T、I354R、N355D、N355H、N355S、N355Y、R356L、Q357E、I359F、I359L、I359N、I359S、I359V、P362A、P362H、P362R、P36 2S、R363G、R363L、R363S、S364C、S364P、Y365D、Y365F、Y365N、Y365S、T366I、T366N、T366P、T366S、I367F、I367L、I367M、A368G、A368P、V369A、V369F、V 369G、V369I、V369L、A370D、A370G、A370P、A370T、A370V、S371C、S371T、G373A、G373C、K374E、K374I、K374R、K374T、G375R、V376E、V376G、V376L、V376M、A377G, A377P, A377S, A377T, N379D, N379I, N379K, N379T, P380A, P380H, P380R, P380T, A381D, F383C, F383I, F383Y, I384F, I384M, I384T, T385I, Q386H, Q386K, Q386, L, L387F, L387H, L387I, L387R, L388F, L388H, L388I, L388R, L388V, K391I, K391N, K391Q, K391R, R392G , R392K, R392M, R392W, K393E, K393N, K393Q, K393T, L394I, L394Q, L394R, G395R, F396C, F396I, F396L, F 396V, Y397C, Y397F, Y397H, Y397N, Y397S, E398G, E398Q, W399G, W399R, T400A, T400I, T400N, T400P, T4 00S, S401A, S401L, S401T, R402G, R402M, R402S, R402T, R402W, L403F, L403V, ​​R404G, R404I, R404K, R404 S, R404T, S405G, H406D, H406L, H406Q, I407L, I407M, I407T, N408D, N408H, N408T, P409L, T410S, G411A , G411C, G411V, T412A, T412I, T412S, V413F, V413G, V413I, L414F, L414V, L415H, L415I, Q416E, Q416H, Q 416L, L417I, E418A, E418D, E418K, E418Q, N419I, N419S, N419T, N419Y, T420K, T420P, T420R, T420S, M421I, M421K, M421L, M421R, M421T, Q422P, M423I, M423K, M423L, M423T, S424L, L425F, D427N, or L429R. In various embodiments, these mutations are relative to SEQ ID NO:2.

[0016] In some embodiments, the pharmacological chaperone comprises migalastat or a salt thereof. In one or more embodiments, the dose of migalastat or a salt thereof is about 100 mg to about 150 mg FBE. In some embodiments, the salt of migalastat is migalastat hydrochloride. In one or more embodiments, the dose is about 150 mg of migalastat hydrochloride every other day, or an equivalent dose of migalastat or a salt thereof other than hydrochloride. In some embodiments, migalastat or a salt thereof is administered orally or by injection. These embodiments may be combined with each other or with other embodiments of the invention, such as embodiments relating to methods of treating patients with Fabry disease, methods of enhancing α-Gal A in patients diagnosed with or suspected of having Fabry disease, or pharmacological chaperones of α-Gal A for use in treating patients diagnosed with Fabry disease, and embodiments relating to applicable mutations, suitable PCs and their dosages, formulations, and routes of administration.

[0017] Another aspect of the present invention relates to a pharmacological chaperone of α-Gal A for use in treating patients diagnosed with Fabry disease, wherein the patient has a missense mutation in the nucleic acid sequence encoding α-Gal A. In one or more embodiments, the mutation is N5D, N5K, P6L, P6Q, P6R, P6S, P6T, E7D, E7K, E7V, L8I, L8P, L8Q, H9L, H9Q, H9R, H9Y, L10M, L10P, L10Q, L10R, L10V, G11C, G11D, G11R, G11S, G11V, C12G, C12R, C12S, C12Y, A13E, A13G, L14F, L14H, L14V, R17C, R17G, R17H, R17P, R17S, F18I, F18L, A20G, L21H, V22A, V22F, V22I, V22L, S23P, S23T, W24S, D25H, I26N, P27A, P27L, P27S, P27T, G28E, G28R, G28W, A29G, A29P, A29V, R30G, L32M, L3 2Q, L32R, L32V, D33A, D33E, D33V, L36M, L36V, A37E, A37G, A37S, R38G, R38M, R38W, T39A, T39K, T39M, T39R, T39S, T41A, T41N, T41S, G43A, L45M, L45V, H46D, H46N, H46Q, E48A, F50Y, M51R, M51T, M51V, N53H, N53I, N53S, N53T, L54H, L54R, L54V, D55A, D55E, D55H, D55Y, C56W, E5 8K, E59A, E59D, E59G, E59Q, E59V, P60A, P60Q, P60R, D61E, D61V, S62A, S62C, S62F, S62P, S62Y, I64L, I64V, S65C, S65G, S65R, E66D, E66V, K67E, K67M, K67N, K67Q, K67T, L68I, F69I, F69Y, M70I, M70K, M70L, M70R, E71A, E71D, E71G, E71Q, E71V, M72L, M72T, A73S, A73T, E74D, E7 4G, E74K, E74V, L75F, L75P, M76V, V77I, V77L, S78L, S78P, E79A, E79D, E79G, E79K, E79Q, E79V, G80A, G80C, G80S, W81L, K82E, K82M, K82N,K82R、K82T、D83A、D83E、D83G、D83V、A84E、A84G、A84P、A84S、A84T、A84V、G85A、G85C、G85R、Y86F、E87G、Y88H、Y88N、L89V、I91F、I91L、I91M、I91S、M96L、M96T、A97D、A97S、A97T、P98H、P98L、P98R、Q99E、Q99L、Q99P、Q99R、D101A、D101E、D101G、D101H、D101V、S102A、S102P、S102T、G104A、G104D、G104S、R105G、R105I、R105K、R105T、L106H、L106I、L106P、L106V、Q107E、Q107H、Q107K、A108E、A108V、D109A、D109E、D109H、D109N、D109Y、P110T、F113V、F113Y、P114L、H115D、H115N、G116R、I117M、I117T、A121V、Y123D、Y123F、Y123N、Y123S、V124I、H125D、H125N、H125R、S126C、S126I、K127E、G128A、L129V、K130M、K130N、K130Q、L131V、I133L、I133T、I133V、A135E、A135G、A135S、A135T、D136A、D136N、D136V、V137A、V137D、V137G、V137I、V137L、G138A、N139H、N139I、N139K、N139Y、K140E、K140I、K140N、K140Q、K140R、T141S、A143E、A143G、G144A、G144C、G144R、G144S、F145C、F145L、F145V、F145Y、P146A、P146H、P146L、P146T、G147A、S148C、S148G、S148T、F149C、G150E、G150V、Y151C、Y151D、Y151S、Y152F、Y152S、D153A、D153H、D153N、D153V、D153Y、A156G、Q157E、Q157K、Q157L、Q157P、T158A、T158I、T158N、T158S、F159I、F159L、F159V、F159Y、A160G、A160S、A160T、A160V、D161H、D161N、D161V、D161Y、W162S、V164A、V164I、V164L、D165A、D165E、L166M、L166Q、L167I、F169C、F169L、F169V、F169Y、G171A、G171V、Y173C、Y173F、Y173H、Y173S、D175G、D175H、D175V、D175Y、S176C、S176R、L177F、L177M、L177S、L177V、L177W、E178A、E178G、E178K、E178Q、L180M、L180S、A181P、A181T、A181V、D182A、D182E、D182V、D182Y、Y184F、Y184H、Y184S、K185M、K185N、K185Q、K185T、H186D、H186L、H186N、H186Q、H186Y、M187L、S188A、S188C、S188F、S188P、S188T、S188Y、L189S、L189V、A190D、A190G、A190S、A190T、A190V、L191M、L191V、N192D、N192H、N192K、N192S、N192T、R193G、R193M、R193T、R193W、T194N、T194P、T194S、G195C、G195R、G195S、R196I、R196K、S197C、S197G、S197I、S197N、S197T、I198M、I198S、V199E、V199L、Y200N、Y200S、S201A、S201C、S201T、E203A、E203G、E203Q、W204S、L206F、L206H、L206I、L206R、L206V、Y207F、M208K、W209C、W209G、P210H、P210T、F211C、F211L、F211S、F211V、F211Y、Q212H、Q212P、K213E、K213Q、P214A、P214H、P214R、P214T、N215H、N215K、N215T、N215Y、Y216F、Y216H、Y216N、T217A、T217I、T217K、T217P、T217R、T217S、E218A、E218D、E218G、E218K、E218Q、E218V、I219F、I219M、I219S、R220L、Q221E、Q221H、Q221K、Q221L、Q221R、Y222C、Y222D、Y222H、Y222N、Y222S、N224H、R227G、N228H、N228I、N228T、F229I、F229S、F229Y、A230D、A230G、A230P、A230V、I232L、I232M、I232V、D233A、D233E、D233G、D233V、S235A、S235T、K237I、S238C、S238I、S238T、I239L、K240E、K240M、K240R、S241C、S241I、S241T、I242L、I242M、I242S、L243M、L243S、L243V、D244A、D244E、D244G、D244V、D244Y、W245C、T246A、T246I、T246K、T246R、S247A、S247F、S247T、S247Y、F248C、F248L、F248V、F248Y、N249D、N249H、N249I、N249S、N249T、N249Y、Q250E、Q250L、E251G、E251K、E251Q、E251V、R252G、I253F、I253N、I253V、V254A、V254D、V254F、V254G、D255A、D255E、D255H、D255N、D255V、D255Y、V256D、V256G、V256L、A257S、G258E、P259A、P259T、G260W、G261A、N263H、N263T、D264H、D264N、P265A、P265Q、M267L、M267V、L268F、L268I、V269L、I270L、I270S、I270V、N272D、F273Y、L275I、W277L、N278I、Q280L、Q280R、V281A、V281E、V281G、V281L、T282S、Q283E、Q283H、Q283L、M284I、M284L、A285G、A285T、A285V、L286F、L286H、L286V、A288G、A288S、A288V、I289L、I289T、I289V、A291G、A292G、A292S、L294F、L294I、L294V、F295I、F295S、F295V、F295Y、S297T、N298D、N298I、N298T、D299H、D299N、L300I、L300V、H302D、H302L、H302N、H302Y、I303S、S304I、Q306E、Q306L、Q306P、A307D、A307G、A307P、A307S、A307V、K308I、K308Q、K308R、A309D、A309T、<h2 style=";text-align:left;direction:ltr">L310I、L311I、Q312E、Q312K、Q312L、D313E、D313V、K314E、K314M、K314N、K314T、D315A、D315G、D315H、D315N、D315V、D315Y、V316A、V316L、I317L、I317 M、I317V、A318D、A318P、A318T、A318V、I319M、N320S、N320T、Q321K、D322A、 D322V、L324V、L324W、G325A、G325C、G325V、K326E、K326M、K326Q、K326R、K32 6T、Q327H、Q327P、Y329C、Y329D、Y329F、Y329H、Y329N、Q330E、Q330H、Q330K 、L331H、L331P、L331R、L331V、R332G、R332I、R332S、R332T、Q333E、Q333L、Q 333P、G334R、G334V、D335A、D335E、D335G、D335V、D335Y、N336D、N336I、N336S、N336T、N336Y、F337C、F337L、F337V、F337Y、E338A、E338D、E338G、V339M、 E341A、E341Q、P343A、P343S、L344F、L344R、L344V、G346A、G346C、G346D、G346V、L347I、A348D、W349C、W349L、A350G、A350S、A350T、A350V、V351A、V351 E、A352S、A352T、M353K、M353L、M353T、I354R、N355D、N355H、N355S、N355Y、R356L、Q357E、I359F、I359L、I359N、I359S、I359V、P362A、P362H、P362R、P36 2S、R363G、R363L、R363S、S364C、S364P、Y365D、Y365F、Y365N、Y365S、T366I、T366N、T366P、T366S、I367F、I367L、I367M、A368G、A368P、V369A、V369F、V 369G、V369I、V369L、A370D、A370G、A370P、A370T、A370V、S371C、S371T、G373A、G373C、K374E、K374I、K374R、K374T、G375R、V376E、V376G、V376L、V376M、A377G, A377P, A377S, A377T, N379D, N379I, N379K, N379T, P380A, P380H, P380R, P38 0T, A381D, F383C, F383I, F383Y, I384F, I384M, I384T, T385I, Q386H, Q386K, Q386L, , L387F, L387H, L387I, L387R, L388F, L388H, L388I, L388R, L388V, K391I, K391N, K391Q, K391R, R392G, R392K, R392M, R392W, K393E, K393N, K393Q, K393T, L394I, L394Q, L394R, G395R, F396C, F396I, F396L, F 396V, Y397C, Y397F, Y397H, Y397N, Y397S, E398G, E398Q, W399G, W399R, T400A, T400I, T400N, T400P, T4 00S, S401A, S401L, S401T, R402G, R402M, R402S, R402T, R402W, L403F, L403V, ​​R404G, R404I, R404K, R404 S, R404T, S405G, H406D, H406L, H406Q, I407L, I407M, I407T, N408D, N408H, N408T, P409L, T410S, G411A , G411C, G411V, T412A, T412I, T412S, V413F, V413G, V413I, L414F, L414V, L415H, L415I, Q416E, Q416H, Q 416L, L417I, E418A, E418D, E418K, E418Q, N419I, N419S, N419T, N419Y, T420K, T420P, T420R, T420S, M421I, M421K, M421L, M421R, M421T, Q422P, M423I, M423K, M423L, M423T, S424L, L425F, D427N, or L429R. In various embodiments, these mutations are relative to SEQ ID NO:2.

[0018] In some embodiments, the pharmacological chaperone comprises migalastat or a salt thereof. In one or more embodiments, the dose of migalastat or a salt thereof is about 100 mg to about 150 mg FBE. In some embodiments, the salt of migalastat is migalastat hydrochloride. In one or more embodiments, the dose is about 150 mg of migalastat hydrochloride every other day, or an equivalent dose of migalastat or a salt thereof other than hydrochloride. In some embodiments, migalastat or a salt thereof is administered orally or by injection. These embodiments may be combined with each other or with other embodiments of the invention, such as embodiments relating to methods of treating patients with Fabry disease, methods of enhancing α-Gal A in patients diagnosed with or suspected of having Fabry disease, or the use of a pharmacological chaperone of α-Gal A in the manufacture of a medicament for treating patients diagnosed with Fabry disease, as well as embodiments relating to applicable mutations, suitable PCs and their dosages, formulations, and routes of administration.

[0019] Another aspect of the invention relates to migalastat or a salt thereof for use in a method for treating Fabry disease in a human patient, wherein the patient has an α-galactosidase A mutation selected from the group consisting of the mutations provided in Table 2.

[0020] Another aspect of the present invention relates to a method of treating a patient diagnosed with Fabry disease, wherein the patient has a HEK assay-applicable mutation in α-galactosidase A disclosed in the Pharmacology Reference Table as disclosed herein. This aspect can have any of the features described in other aspects as disclosed herein.

[0021] Another aspect of the present invention relates to a method of enhancing α-galactosidase A in a patient diagnosed with or suspected of having Fabry disease, wherein the patient has a HEK assay-applicable mutation in α-galactosidase A disclosed in the Pharmacology Reference Table as disclosed herein. This aspect can have any of the features described in other aspects as disclosed herein.

[0022] Some embodiments relate to a method of treating Fabry disease in a subject. Mutational information corresponding to the subject is accessed. The mutational information identifies one or more α-galactosidase A mutations. Based on the mutational information, at least one of the mutations identified in Table 2 and / or N5D, N5K, P6L, P6Q, P6R, P6S, P6T, E7D, E7K, E7V, L8I, L8P, L8Q, H9L, H9Q, H9R, H9Y, L10M, L10P, L10Q, L10R, L10V, G11C, G11D, G11R, G11S, G11V, C12G, C12R, C12S, C12Y, A13E, A13G, L14F, L14H, L14V, R17C, R17G, R17H, R17P, R17C, R17G, R17H, R17P, R17C, R17D, R17K, R17V, L14F, L14H, L14V ...C, R17C, R17C, R17C, R17C, R17C, R17C, R17C, R17C, R17C, R17C, R17C, 7S, F18I, F18L, A20G, L21H, V22A, V22F, V22I, V22L, S23P, S23T, W24S, D25H, I26N, P27A, P27L, P27S, P27T, G28E, G28R, G28W, A29G, A29P, A 29V, R30G, L32M, L32Q, L32R, L32V, D33A, D33E, D33V, L36M, L36V, A37E, A37G, A37S, R38G, R38M, R38W, T39A, T39K, T39M, T39R, T39S, T41A, T41N, T41S, G43A, L45M, L45V, H46D, H46N, H46Q, E48A, F50Y, M51R, M51T, M51V, N53H, N53I, N53S, N53T, L54H, L54R, L54V, D55A, D55E, D55 H, D55Y, C56W, E58K, E59A, E59D, E59G, E59Q, E59V, P60A, P60Q, P60R, D61E, D61V, S62A, S62C, S62F, S62P, S62Y, I64L, I64V, S65C, S65G, S6 5R, E66D, E66V, K67E, K67M, K67N, K67Q, K67T, L68I, F69I, F69Y, M70I, M70K, M70L, M70R, E71A, E71D, E71G, E71Q, E71V, M72L, M72T, A73S, A 73T, E74D, E74G, E74K, E74V, L75F, L75P, M76V, V77I, V77L, S78L, S78P, E79A, E79D, E79G, E79K, E79Q, E79V, G80A, G80C, G80S, W81L, K82E,K82M、K82N、K82R、K82T、D83A、D83E、D83G、D83V、A84E、A84G、A84P、A84S、A84T、A84V、G85A、G85C、G85R、Y86F、E87G、Y88H、Y88N、L89V、I91F、I91L、I91M、I91S、M96L、M96T、A97D、A97S、A97T、P98H、P98L、P98R、Q99E、Q99L、Q99P、Q99R、D101A、D101E、D101G、D101H、D101V、S102A、S102P、S102T、G104A、G104D、G104S、R105G、R105I、R105K、R105T、L106H、L106I、L106P、L106V、Q107E、Q107H、Q107K、A108E、A108V、D109A、D109E、D109H、D109N、D109Y、P110T、F113V、F113Y、P114L、H115D、H115N、G116R、I117M、I117T、A121V、Y123D、Y123F、Y123N、Y123S、V124I、H125D、H125N、H125R、S126C、S126I、K127E、G128A、L129V、K130M、K130N、K130Q、L131V、I133L、I133T、I133V、A135E、A135G、A135S、A135T、D136A、D136N、D136V、V137A、V137D、V137G、V137I、V137L、G138A、N139H、N139I、N139K、N139Y、K140E、K140I、K140N、K140Q、K140R、T141S、A143E、A143G、G144A、G144C、G144R、G144S、F145C、F145L、F145V、F145Y、P146A、P146H、P146L、P146T、G147A、S148C、S148G、S148T、F149C、G150E、G150V、Y151C、Y151D、Y151S、Y152F、Y152S、D153A、D153H、D153N、D153V、D153Y、A156G、Q157E、Q157K、Q157L、Q157P、T158A、T158I、T158N、T158S、F159I、F159L、F159V、F159Y、A160G、A160S、A160T、A160V、D161H、D161N、D161V、D161Y、W162S、V164A、V164I、V164L、D165A、D165E、L166M、L166Q、L167I、F169C、F169L、F169V、F169Y、G171A、G171V、Y173C、Y173F、Y173H、Y173S、D175G、D175H、D175V、D175Y、S176C、S176R、L177F、L177M、L177S、L177V、L177W、E178A、E178G、E178K、E178Q、L180M、L180S、A181P、A181T、A181V、D182A、D182E、D182V、D182Y、Y184F、Y184H、Y184S、K185M、K185N、K185Q、K185T、H186D、H186L、H186N、H186Q、H186Y、M187L、S188A、S188C、S188F、S188P、S188T、S188Y、L189S、L189V、A190D、A190G、A190S、A190T、A190V、L191M、L191V、N192D、N192H、N192K、N192S、N192T、R193G、R193M、R193T、R193W、T194N、T194P、T194S、G195C、G195R、G195S、R196I、R196K、S197C、S197G、S197I、S197N、S197T、I198M、I198S、V199E、V199L、Y200N、Y200S、S201A、S201C、S201T、E203A、E203G、E203Q、W204S、L206F、L206H、L206I、L206R、L206V、Y207F、M208K、W209C、W209G、P210H、P210T、F211C、F211L、F211S、F211V、F211Y、Q212H、Q212P、K213E、K213Q、P214A、P214H、P214R、P214T、N215H、N215K、N215T、N215Y、Y216F、Y216H、Y216N、T217A、T217I、T217K、T217P、T217R、T217S、E218A、E218D、E218G、E218K、E218Q、E218V、I219F、I219M、I219S、R220L、Q221E、Q221H、Q221K、Q221L、Q221R、Y222C、Y222D、Y222H、Y222N、Y222S、N224H、R227G、N228H、N228I、N228T、F229I、F229S、F229Y、A230D、A230G、A230P、A230V、I232L、I232M、I232V、D233A、D233E、D233G、D233V、S235A、S235T、K237I、S238C、S238I、S238T、I239L、K240E、K240M、K240R、S241C、S241I、S241T、I242L、I242M、I242S、L243M、L243S、L243V、D244A、D244E、D244G、D244V、D244Y、W245C、T246A、T246I、T246K、T246R、S247A、S247F、S247T、S247Y、F248C、F248L、F248V、F248Y、N249D、N249H、N249I、N249S、N249T、N249Y、Q250E、Q250L、E251G、E251K、E251Q、E251V、R252G、I253F、I253N、I253V、V254A、V254D、V254F、V254G、D255A、D255E、D255H、D255N、D255V、D255Y、V256D、V256G、V256L、A257S、G258E、P259A、P259T、G260W、G261A、N263H、N263T、D264H、D264N、P265A、P265Q、M267L、M267V、L268F、L268I、V269L、I270L、I270S、I270V、N272D、F273Y、L275I、W277L、N278I、Q280L、Q280R、V281A、V281E、V281G、V281L、T282S、Q283E、Q283H、Q283L、M284I、M284L、A285G、A285T、A285V、L286F、L286H、L286V、A288G、A288S、A288V、I289L、I289T、I289V、A291G、A292G、A292S、L294F、L294I、L294V、F295I、F295S、F295V、F295Y、S297T、N298D、N298I、N298T、D299H、D299N、L300I、L300V、H302D、H302L、H302N、H302Y、I303S、S304I、Q306E、Q306L、Q306P、A307D、A307G、A307P、A307S、A307V、K308I、K308Q、K308R、A309D、<h2 style=";text-align:left;direction:ltr">A309T、L310I、L311I、Q312E、Q312K、Q312L、D313E、D313V、K314E、K314M、K314N、K314T、D315A、D315G、D315H、D315N、D315V、D315Y、V316A、V316L、I317 L、I317M、I317V、A318D、A318P、A318T、A318V、I319M、N320S、N320T、Q321K、D322A、D322V、L324V、L324W、G325A、G325C、G325V、K326E、K326M、K326Q、K32 6R、K326T、Q327H、Q327P、Y329C、Y329D、Y329F、Y329H、Y329N、Q330E、Q330H、Q330K、L331H、L331P、L331R、L331V、R332G、R332I、R332S、R332T、Q333E、Q 333L、Q333P、G334R、G334V、D335A、D335E、D335G、D335V、D335Y、N336D、N336I、N336S、N336T、N336Y、F337C、F337L、F337V、F337Y、E338A、E338D、E338G、 V339M、E341A、E341Q、P343A、P343S、L344F、L344R、L344V、G346A、G346C、G346D、G346V、L347I、A348D、W349C、W349L、A350G、A350S、A350T、A350V、V351 A、V351E、A352S、A352T、M353K、M353L、M353T、I354R、N355D、N355H、N355S、N355Y、R356L、Q357E、I359F、I359L、I359N、I359S、I359V、P362A、P362H、P36 2R、P362S、R363G、R363L、R363S、S364C、S364P、Y365D、Y365F、Y365N、Y365S、T366I、T366N、T366P、T366S、I367F、I367L、I367M、A368G、A368P、V369A、V 369F、V369G、V369I、V369L、A370D、A370G、A370P、A370T、A370V、S371C、S371T、G373A、G373C、K374E、K374I、K374R、K374T、G375R、V376E、V376G、V376L、V376M, A377G, A377P, A377S, A377T, N379D, N379I, N379K, N379T , P380A, P380H, P380R, P380T, A381D, F383C, F383I, F383Y, I384F, I384M, I384T, T385I, Q386H, Q, 386K, Q386L, L387F, L387H, L387I, L387R, L388F, L388H, L388I, L388R, L388V, K391I, K391N, K391Q, K391R, R392G, R392K, R392M, R392W, K393E, K393N, K393Q, K393T, L394I, L394Q, L394R, G395R, F396C, F396I, F396L, F396V, Y397C, Y397F, Y397H, Y397N, Y397S, E398G, E398Q, W399G, W399R, T400A, T400I, T400N, T400P, T400S, S401A, S401L, S401T, R402G, R402M, R402S, R402T, R402W, L403F, L403V, ​​R404G, R404I, R404K, R404S, R404T, S405G, H406D, H406L, H406Q, I407L, I407M, I407T, N408D, N408H, N408T, P409L, T410S, G411A, G411C, G411V , T412A, T412I, T412S, V413F, V413G, V413I, L414F, L414V, L415H, L415I, Q416E, Q416H, Q416L, L417I, E418A , E418D, E418K, E418Q, N419I, N419S, N419T, N419Y, T420K, T420P, T420R, T420S, M421I, M421K, M421L, M421R, M421T, Q422P, M423I, M423K, M423L, M423T, S424L, L425F, D427N, or L429R. In response to this determination, the subject is administered migalastat or a salt thereof.

[0023] At least one mutation involves amino acid residues 5-14, 17-18, 20-30, 32-33, 36-39, 41, 43, 45-46, 48, 50-51, 53-56, 58-62, 64-89, 91, 96-99, 101-102, 104-110, 113-117, 121, 123-131, 133, 135-141, 143-153, 156-162, 164-167, 169, 171, 173, 175-178, 180-182, 184-201, 203, 204, 206-222, 224, 227-230, 232-233, 234-235, 236-237, 238-239, 240-241, 242-243, 244-245, 246-247, 248-249, 249-250, 251-252, 252-253, 253-254, 255-256, 257-258, 259-260, 261-262, 262-263, 263-264, 264-265, 265-266, 266-267, 267-268, 269-270, 271-272, 273-274, 275-276, 277-278, may include one or more mutations at 233, 235, 237-261, 263-265, 267-270, 272-273, 275, 277-278, 280-286, 288-289, 291-292, 294-295, 297-300, 302-304, 306-322, 324-327, 329-339, 341, 343-344, 346-357, 359, 362-371, 373-377, 379-381, 383-388, 391-425, 427, or 429, or any combination thereof, where residues are numbered with respect to SEQ ID NO:2.

[0024] Determining that the subject has at least one mutation as identified in Table 2 may include initiating a query to a data store that identifies two or more mutations from the set of mutations identified in Table 2 and receiving query results that identify mutation information and also a representation of the at least one mutation in Table 2. The data store may further identify two or more mutations from another set of mutations (e.g., identified in Table 2). The data store may identify at least 10%, 25%, 50%, 75%, 90%, or 95% of the mutations as included in Table 1 and / or at least 10%, 25%, 50%, 75%, 90%, or 95% of the mutations as included in Table 2. The query may be initiated by accessing a particular web page hosted by a web server that controls the data store that identifies at least some of the mutations in Table 2. A query may be initiated by accessing a particular web page on the website; providing input at the particular web page that identifies at least a portion of the mutation information; and selecting an option at the web page that sends an electronic request to the web server to perform the query, the electronic request including a representation of the input. Query results may be received from the web server in response to the query and may be displayed on the particular web page or another web page on the website.

[0025] Migalastat or a salt thereof may be administered to a subject every other day. Administering migalastat or a salt thereof may include administering migalastat or a salt thereof at a dose of about 100 to about 150 mg free base equivalent; or administering migalastat or a salt thereof at about 123 mg free base equivalent. Migalastat or a salt thereof may enhance α-galactosidase A activity in a subject. The at least one mutation may include a HEK assay-compatible mutation in α-galactosidase A. Migalastat or a salt thereof may be administered orally or by injection.

[0026] In some embodiments, a computer-implemented method is provided. An electronic communication is received. The electronic communication corresponds to an identification of a particular mutation. A data store is queried with the identification of the particular mutation. The data store includes an identification of each of an applicable mutation set. Each of the applicable mutation sets corresponds to a mutation listed in Table 2. A result of the query is detected, the result indicating whether the particular mutation is represented in the applicable mutation set. Based on the response, an output is generated indicating the suitability of treating a patient with the particular mutation with migalastat or a migalastat salt. The output is transmitted.

[0027] The electronic communication may include an identification of the particular mutation in a first format, and the method may further include determining that the first format is different from a second format used by the data store; extracting one or more components from the identification; generating second identification based on the components, the second identification in the second format; transmitting the second identification; and receiving a second electronic communication indicating that the second identification corresponds to the first identification. The data store may be queried in response to receiving the second electronic communication. The data store may further include identification of another applicable mutation set. Each of the second applicable mutation sets corresponds to a mutation listed in Table 1, and the result may further indicate whether the particular mutation is represented in the second applicable mutation set. The result may include a binary indication of whether migalastat or a migalastat salt is a suitable treatment for the condition caused by the particular mutation. The identification of a particular mutation may correspond to an entry detected in a web page (generated at least in part based on web page data transmitted to a user device from which the electronic communication was received). The data store may identify at least 10%, at least 25%, at least 50%, at least 75%, or at least 90% of the mutations listed in Table 2.

[0028] In some embodiments, a computer-implemented method is provided. A dataset unit is accessed that stores a dataset identifying, for each mutation in a mutation set, the degree to which α-Gal A activity responds to migalastat or migalastat salt when the mutation is present. The mutation set includes one or more mutations listed in Table 2. A communication is received identifying one or more specific mutations. The dataset unit is queried using a representation of the one or more specific mutations. Results of the query are detected. The results indicate, for each of the one or more specific mutations, the degree to which α-Gal A activity responds to migalastat or migalastat salt when the specific mutation is present. A metric corresponding to the predicted effectiveness of treating patients with one or more specific mutations with migalastat or migalastat salt is determined. The metric is output.

[0029] The one or more specific mutations can include a plurality of specific mutations, and determining the metric includes identifying a minimum or maximum degree of response of α-Gal A activity to migalastat or migalastat salt among the plurality of specific mutations. The metric can be a binary indication of whether treatment with migalastat or migalastat salt is applicable to a condition associated with the one or more specific mutations. The metric can include a number, category, or descriptor indicating the predicted degree to which treatment with migalastat or migalastat salt is applicable to a condition associated with the one or more specific mutations. The query results can indicate that α-Gal A activity corresponding to a particular mutation does not respond to migalastat or migalastat salt as a result of the particular mutation not being detected in the dataset for the particular mutation(s). The mutation set can further include one or more mutations listed in Table 1. The one or more specific mutations can include a plurality of specific mutations, and determining the metric can include identifying a minimum or maximum response of α-Gal A activity to migalastat or a migalastat salt among the plurality of specific mutations.

[0030] In some examples, a method for treating Fabry disease in a subject is provided. Mutation information corresponding to the subject is accessed. The mutation information identifies one or more α-galactosidase A mutations. Based on the mutation information, it is determined that the subject has a mutation in which α-Gal A activity in a lysate prepared from HEK-293 cells transiently transfected with the mutant α-Gal A and incubated for 5 days in the presence of 10 μM migalastat is higher than a reference α-Gal A activity in another lysate prepared from other HEK-293 cells transiently transfected with the mutant α-Gal A and incubated for 5 days in the absence of 10 μM migalastat, and the mutant α-Gal A corresponds to this mutation. In response to this determination, migalastat or a salt thereof is administered to the subject.

[0031] α-Gal A activity may be defined as nanomoles of free 4-MU released per milligram of protein per hour. Determining may include determining that the subject has a mutation in which the α-Gal A activity is at least 1%, at least 5%, at least 10%, at least 25%, at least 50%, or at least 100% higher than a reference α-Gal A activity. Determining may include querying a data store for the identity of one or more α-galactosidase A mutations and receiving results of the query. The results may indicate that the data store contains a representation of the mutation. The results may include one or more values ​​associated with the representation of the mutation in the data store, and the method may further include comparing the one or more values, or a processed version thereof, to a predetermined threshold.

[0032] In some examples, a method is provided in which mutation information corresponding to a subject is accessed. The mutation information identifies one or more α-galactosidase A mutations. Based on the mutation information, it is determined that the subject has a mutation in which α-Gal A activity in a lysate prepared from HEK-293 cells transiently transfected with the mutant α-Gal A and incubated for 5 days in the presence of 10 μM migalastat is higher than a reference α-Gal A activity in another lysate prepared from another HEK-293 cell transiently transfected with the mutant α-Gal A and incubated for 5 days in the absence of 10 μM migalastat, and the mutant α-Gal A corresponds to the mutation. In response to this determination, an indication is output that the mutation is amenable to treatment with migalastat or a salt thereof.

[0033] α-Gal A activity may be defined as nanomoles of free 4-MU released per milligram of protein per hour. Determining may include determining that the subject has a mutation in which the α-Gal A activity is at least 1%, at least 5%, at least 10%, at least 25%, at least 50%, or at least 100% higher than a reference α-Gal A activity. Determining may include querying a data store for the identity of one or more α-galactosidase A mutations and receiving query results. The results may indicate that the data store contains a representation of the mutation. The results may include one or more values ​​associated with the representation of the mutation in the data store, and the method may further include comparing the one or more values, or a processed version thereof, to a predetermined threshold. The method may include receiving a first communication from the user device containing the mutation information, and outputting the instructions may include transmitting a second communication to the user device, the second communication including the instructions.

[0034] In some examples, a system is provided that includes one or more data processors and a non-transitory computer-readable storage medium storing instructions that, when executed on the one or more data processors, cause the one or more data processors to perform some or all of one or more of the methods disclosed herein. In some examples, a computer program product is provided that is tangibly embodied in the non-transitory machine-readable storage medium. The computer program product may include instructions configured to cause the one or more data processors to perform some or all of one or more of the methods disclosed herein.

[0035] Another aspect of the present invention relates to a method of diagnosing Fabry disease in a subject amenable to treatment with migastat or a salt thereof, the method comprising determining whether α-Gal A in a sample from the subject has an amino acid sequence containing at least one mutation as identified in Table 2; wherein if the α-Gal A in the sample from the subject has an amino acid sequence containing such a mutation, the subject has or is at risk of developing Fabry disease amenable to treatment with migastat or a salt thereof. In one or more embodiments, the subject has one or more symptoms of Fabry disease. In other embodiments, the subject does not have any symptoms of Fabry disease. In one or more embodiments, the subject is an infant. In one or more embodiments, the subject is male. In one or more embodiments, the subject is female. In one or more embodiments, the subject has a family history of Fabry disease. In one or more embodiments, the subject is the daughter of a male Fabry patient affected with the classic form.

[0036] Another aspect of the present invention relates to a method for identifying a subject with Fabry disease amenable to treatment with migastat or a salt thereof, the method comprising determining whether α-Gal A in a sample from the subject has an amino acid sequence containing at least one mutation as identified in Table 2; wherein if the α-Gal A in the sample from the subject has an amino acid sequence containing such a mutation, the subject has or is at risk of developing Fabry disease amenable to treatment with migastat or a salt thereof. In one or more embodiments, the subject has one or more symptoms of Fabry disease. In other embodiments, the subject does not have any symptoms of Fabry disease. In one or more embodiments, the subject is an infant. In one or more embodiments, the subject is male. In one or more embodiments, the subject is female. In one or more embodiments, the subject has a family history of Fabry disease. In one or more embodiments, the subject is the daughter of a male Fabry patient affected with the classic form.

[0037] Another aspect of the present invention relates to a method for diagnosing Fabry disease in a subject amenable to treatment with migastat or a salt thereof, the method comprising: determining whether a GLA gene in a sample from the subject contains a point mutation compared to the nucleic acid sequence of SEQ ID NO: 1; and if the GLA gene in the sample contains such a point mutation, determining whether the point mutation results in an α-Gal A amino acid mutation as identified in Table 2; wherein the point mutation results in an α-Gal A amino acid mutation as identified in Table 2, and the subject has or is at risk of developing Fabry disease amenable to treatment with migastat or a salt thereof. In other embodiments, the subject does not have any symptoms of Fabry disease. In one or more embodiments, the subject is an embryo. In one or more embodiments, the subject is an infant. In one or more embodiments, the subject is male. In one or more embodiments, the subject is female. In one or more embodiments, the subject has a family history of Fabry disease. In one or more embodiments, the subject is the daughter of a male Fabry patient affected with the classic form.

[0038] Another aspect of the present invention relates to a method for identifying a subject with Fabry disease amenable to treatment with migastat or a salt thereof, the method comprising: determining whether a GLA gene in a sample from the subject contains a point mutation compared to the nucleic acid sequence of SEQ ID NO: 1; and, if the GLA gene in the sample contains such a point mutation, determining whether the point mutation results in an α-Gal A amino acid mutation as identified in Table 2; wherein the point mutation results in an α-Gal A amino acid mutation as identified in Table 2, and the subject has or is at risk of developing Fabry disease amenable to treatment with migastat or a salt thereof. In other embodiments, the subject does not have any symptoms of Fabry disease. In one or more embodiments, the subject is an embryo. In one or more embodiments, the subject is an infant. In one or more embodiments, the subject is male. In one or more embodiments, the subject is female. In one or more embodiments, the subject has a family history of Fabry disease. In one or more embodiments, the subject is the daughter of a male Fabry patient affected with the classic form.

[0039] Various embodiments are listed below. It will be understood that the embodiments listed below can be combined not only as listed below, but in other suitable combinations within the scope of the present invention. [Brief explanation of the drawings]

[0040] [Figure 1A] The complete DNA sequence of the human wild-type GLA gene (SEQ ID NO: 1) is shown. [Figure 1B] The complete DNA sequence of the human wild-type GLA gene (SEQ ID NO: 1) is shown. [Figure 1C] The complete DNA sequence of the human wild-type GLA gene (SEQ ID NO: 1) is shown. [Figure 1D] The complete DNA sequence of the human wild-type GLA gene (SEQ ID NO: 1) is shown. [Figure 1E] The complete DNA sequence of the human wild-type GLA gene (SEQ ID NO: 1) is shown. [Figure 2]The wild-type α-Gal A protein (SEQ ID NO: 2) is shown. [Figure 3] The nucleic acid sequence encoding the wild-type α-Gal A protein (SEQ ID NO:3) is shown. [Figure 4A] 1 illustrates an exemplary interaction system for generating treatment classifications based on mutation data. [Figure 4B] FIG. 1 shows a schematic diagram of an exemplary mutation classifier system. [Figure 5] 1 illustrates an exemplary process for generating predictive metrics using mutation data. [Figure 6] 1 illustrates an exemplary process for generating predictive outputs using mutation data. [Figure 7] 1 illustrates an exemplary mutation representation used to facilitate evaluation of mutation-based effects. [Figure 8] 1 illustrates an exemplary interface for facilitating mutation-based treatment classification. DETAILED DESCRIPTION OF THE INVENTION

[0041] Before describing several example embodiments of the invention, it is to be understood that the invention is not limited to the details of construction or process steps set forth in the following description. The invention is capable of other embodiments and of being practiced or carried out in various ways.

[0042] As noted above, it is extremely difficult, if not impossible, to predict whether a particular Fabry patient will respond to treatment with PC. Currently, when evaluating a patient, it is necessary to first determine the specific mutation in α-Gal A and then test the patient's specific mutant form of α-Gal A in an assay that determines whether that mutation is amenable to treatment with migalastat. Migalastat eligibility testing is typically performed by someone other than the clinician evaluating the patient for treatment. This testing is time-consuming, delaying the initiation of treatment.

[0043] Accordingly, various aspects of the present invention relate to the identification of novel GLA mutations in Fabry patients that may respond to treatment with pharmacological chaperones. Other aspects of the present invention further relate to the treatment of those Fabry patients. For example, it has been unexpectedly discovered that the low α-Gal A activity resulting from the α-Gal A missense mutations shown in Table 2 can be increased when exposed to pharmacological chaperones, even though no patients with those particular mutations have been previously identified. Therefore, patients with these mutations are expected to respond to treatment with pharmacological chaperones.

[0044] Using the information in Table 2, further testing of the patient for PC applicability of α-Gal A is no longer necessary, thus preventing delays in treatment initiation. Instead, after determining the patient's specific mutation, the clinician can consult a list of α-Gal A mutations (e.g., including one or more mutations listed in Table 2) and, if the patient's mutation is on the list, treatment can be initiated immediately.

[0045] Identification of these novel mutations can also be used to determine whether a subject, including an embryo or newborn, is at risk for developing Fabry disease before symptoms appear. In one or more embodiments, the subject may be at risk for developing Fabry disease, such as by having a family history of Fabry disease.

[0046] definition The terms used herein generally have their ordinary meaning in the art, with respect to the present invention and in the specific context in which each term is used. Certain terms are discussed below or elsewhere in the specification to provide further guidance to the practitioner in describing the compositions and methods of the invention and how they may be made and used.

[0047] The term "Fabry disease" refers to an X-linked congenital abnormality of glycosphingolipid catabolism caused by deficient lysosomal α-Gal A activity. This defect leads to the accumulation of the substrate globotriaosylceramide ("GL-3," also known as Gb3 or ceramide trihexoside) and related glycosphingolipids in vascular endothelial lysosomes in the heart, kidney, skin, and other tissues. Another substrate for this enzyme is plasma globotriaosylsphingosine ("plasma lyso-Gb3").

[0048] A "carrier" is a female in whom one X chromosome contains a defective α-Gal A gene and one X chromosome contains a normal gene, and in which there is X chromosome inactivation of the normal allele in one or more cell types. Carriers are often diagnosed with Fabry disease.

[0049] "Patient" refers to a subject who has been diagnosed with or is suspected of having a particular disease. The patient may be a human or an animal.

[0050] "Fabry patient" refers to an individual with mutant α-Gal A, as further defined below, who has been diagnosed with or is suspected of having Fabry disease. The hallmark markers for Fabry disease can appear with equal prevalence in hemizygous male and female carriers, although females are typically affected with less severe disease.

[0051] Human α-galactosidase A (α-Gal A) refers to the enzyme encoded by the human GLA gene. The complete DNA sequence of α-Gal A, including introns and exons, is available under GenBank accession number X14448.1 and is shown in Figures 1A-1E (SEQ ID NO: 1). The human α-Gal A enzyme consists of 429 amino acids and is available under GenBank accession numbers X14448.1 and U78027 and is shown in Figure 2 (SEQ ID NO: 2). A nucleic acid sequence containing only the coding region (i.e., exons) of SEQ ID NO: 1 is shown in Figure 3 (SEQ ID NO: 3).

[0052] The term "mutant protein" includes proteins that have a mutation in the gene encoding the protein that prevents the protein from achieving a stable conformation under conditions normally present in the ER. Failure to achieve a stable conformation results in significant amounts of the enzyme not being transported to lysosomes but rather being degraded. Such mutations are sometimes referred to as "conformational mutants." Such mutations include, but are not limited to, missense mutations and in-frame small deletions and insertions.

[0053] As used herein in one embodiment, the term "mutant α-Gal A" includes α-Gal A with a mutation in the gene encoding α-Gal A that prevents the enzyme from achieving a stable conformation under conditions normally present in the ER. The inability to achieve a stable conformation results in significant amounts of the enzyme not being transported to lysosomes but rather being degraded.

[0054] As used herein, the term "specific pharmacological chaperone" ("SPC") or "pharmacological chaperone" ("PC") refers to any molecule, including small molecules, proteins, peptides, nucleic acids, carbohydrates, etc., that specifically binds to a protein and has one or more of the following effects: (i) promoting the formation of a stable molecular conformation of the protein; (ii) directing trafficking of the protein from the ER to another cellular site, preferably the native cellular site, i.e., preventing ER-associated degradation of the protein; (iii) preventing aggregation of misfolded proteins; and / or (iv) restoring or enhancing at least some wild-type function and / or activity to a protein. For example, a compound that specifically binds to α-Gal A means that it binds to and exerts a chaperone effect on that enzyme and not on a general group of related or unrelated enzymes. More specifically, the term does not refer to endogenous chaperones such as BiP or nonspecific agents, i.e., chemical chaperones, that demonstrate nonspecific chaperone activity toward various proteins, such as glycerol, DMSO, or heavy water. In one or more embodiments of the present invention, the PC can be a reversible competitive inhibitor. In one embodiment, the PC is migalastat or a salt thereof. In another embodiment, the PC is migalastat free base (e.g., 123 mg of migalastat free base). In yet another embodiment, the PC is a salt of migalastat (e.g., 150 mg of migalastat HCl).

[0055] A "competitive inhibitor" of an enzyme can refer to a compound that is structurally similar to the chemical and molecular structure of the enzyme substrate and binds to the enzyme at approximately the same location as the substrate. Thus, the inhibitor competes for the same active site as the substrate molecule, thus increasing the Km. Competitive inhibition is usually reversible if enough substrate molecules are available to displace the inhibitor; i.e., a competitive inhibitor can bind reversibly. Therefore, the amount of enzyme inhibition depends on the inhibitor concentration, the substrate concentration, and the relative affinities of the inhibitor and substrate for the active site.

[0056] As used herein, the term "specifically binds" refers to the interaction of a pharmacological chaperone with a protein, such as α-Gal A, specifically with amino acid residues in the protein that are directly involved in contact with the pharmacological chaperone. A pharmacological chaperone specifically binds to a target protein, e.g., α-Gal A, and exerts a chaperone effect on that protein, rather than on a general group of related or unrelated proteins. The amino acid residues in a protein that interact with a given pharmacological chaperone may or may not be within the "active site" of the protein. Specific binding can be assessed by routine binding assays or by structural studies, e.g., cocrystallization, NMR, etc. The active site of α-Gal A is the substrate-binding site.

[0057] "Deficient α-Gal A activity" refers to α-Gal A activity in cells from a patient that is below the normal range when compared (using the same method) with the activity of normal individuals who do not have or are not suspected of having Fabry disease or any other disease (particularly a hematological disorder).

[0058] As used herein, the terms "enhancing α-Gal A activity" or "increasing α-Gal A activity" refer to increasing the amount of α-Gal A in a stable conformation in cells contacted with an α-Gal A-specific pharmacological chaperone compared to the amount in cells (preferably of the same cell type or the same cells, e.g., at an earlier stage) that have not been contacted with the α-Gal A-specific pharmacological chaperone. The terms also refer to increasing α-Gal A trafficking to lysosomes in cells contacted with an α-Gal A-specific pharmacological chaperone compared to trafficking of α-Gal A not contacted with a pharmacological chaperone specific for that protein. These terms refer to both wild-type and mutant α-Gal A. In one embodiment, the increase in α-Gal A amount in cells is measured by measuring the hydrolysis of an artificial substrate in lysates from cells treated with PC. Increased hydrolysis is indicative of increased α-Gal A activity.

[0059] The term "α-Gal A activity" refers to the normal physiological function of wild-type α-Gal A in a cell. For example, α-Gal A activity includes the hydrolysis of GL-3.

[0060] A "responder" is an individual diagnosed with or suspected of having a lysosomal storage disorder, e.g., Fabry disease, whose cells respond to contact with PCs by exhibiting a sufficient increase in α-Gal A activity and / or alleviation of symptoms or enhancement of a surrogate marker, respectively. Non-limiting examples of enhanced Fabry surrogate markers include lyso-Gb3 and those disclosed in U.S. Patent Application Publication No. 2010-0113517, hereby incorporated by reference in its entirety.

[0061] Non-limiting examples of improvements in surrogate markers of Fabry disease disclosed in U.S. Patent Application Publication No. 2010 / 0113517 include increased α-Gal A levels or activity in cells (e.g., fibroblasts) and tissues; decreased GL-3 accumulation; decreased plasma concentrations of homocysteine ​​and vascular cell adhesion molecule-1 (VCAM-1); decreased GL-3 accumulation in cardiomyocytes and valvular fibrocytes; decreased plasma lyso-Gb3; decreased cardiac hypertrophy (especially the left ventricle), reduced valvular insufficiency and arrhythmias; reduced proteinuria; decreased urinary concentrations of lipids such as CTH, lactosylceramide, and ceramide and increased urinary concentrations of glucosylceramide and sphingomyelin; absence of lamellar inclusions (zebra bodies) in glomerular epithelial cells; improved renal function; reduced hypohidrosis; absence of angiokeratoma; and improvement in hearing abnormalities such as high-frequency sensorineural hearing loss, progressive hearing loss, sudden hearing loss, or tinnitus. Improvement of neurological symptoms includes prevention of transient ischemic attacks (TIA) or stroke; and reduction of neuropathic pain manifested as acroparesthesia (burning or tingling pain in the extremities). Another clinical marker that may determine Fabry disease is the prevalence of adverse cardiovascular symptoms. Common cardiac signs and symptoms in Fabry disease include left ventricular hypertrophy, valvular disease (especially mitral valve prolapse and / or regurgitation), premature coronary artery disease, angina, myocardial infarction, conduction abnormalities, arrhythmias, and congestive heart failure.

[0062] A dose that achieves one or more of the aforementioned responses is a "therapeutically effective dose."

[0063] The phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and typically do not produce adverse reactions when administered to humans. In some embodiments, as used herein, the term "pharmaceutically acceptable" means approved by a federal or state regulatory agency for use in animals, more particularly in humans, or listed in the United States Pharmacopeia or other generally recognized pharmacopeia. With respect to pharmaceutical carriers, the term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which a compound is administered. Such pharmaceutical carriers can be sterile liquids such as water and oils. Water or aqueous solutions, saline solutions, and aqueous dextrose and glycerol solutions are preferably utilized as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in (Non-Patent Document 1) or other editions.

[0064] As used herein, the term "isolated" means that the referenced material is removed from the environment in which it is normally found. Thus, isolated biological material can be free of cellular components, i.e., components of the cells in which the material is found or produced. In the case of nucleic acid molecules, isolated nucleic acids include PCR products, mRNA bands on gels, cDNA, or restriction fragments. In another embodiment, isolated nucleic acids are preferably excised from the chromosome in which they are found, and more preferably, when found in the chromosome, they are no longer connected to non-regulatory regions, non-coding regions, or other genes located upstream or downstream of the gene contained in the isolated nucleic acid molecule. In yet another embodiment, isolated nucleic acids lack one or more introns. Isolated nucleic acids include sequences inserted into plasmids, cosmids, artificial chromosomes, etc. Thus, in a specific embodiment, recombinant nucleic acids are isolated nucleic acids. An isolated protein can be associated with other proteins or nucleic acids, or both, to which it may be associated in a cell, or, if it is a membrane-bound protein, with the cell membrane. An isolated organelle, cell, or tissue is removed from the anatomical site in an organism in which it is found. An isolated material may, but need not, be purified.

[0065] The terms "about" and "approximately" are generally intended to refer to an acceptable degree of error for the measured quantity, given the nature or precision of the measurement. Typical exemplary degrees of error are within 20 percent (%), preferably within 10%, and more preferably within 5% of a given value or range of values. Alternatively, particularly in biological systems, the terms "about" and "approximately" can refer to values ​​within an order of magnitude of a given value, preferably within 10-fold or 5-fold, and more preferably within 2-fold. Numerical values ​​provided herein are approximate unless otherwise specified, i.e., the terms "about" or "approximately" can be implied even when not explicitly stated.

[0066] The term "enzyme replacement therapy" or "ERT" refers to the introduction of a non-naturally occurring purified enzyme into an individual deficient in such an enzyme. The administered protein can be obtained from natural sources or by recombinant expression (as described in more detail below). The term also refers to the introduction of a purified enzyme in an individual who would otherwise require or benefit from the administration of a purified enzyme, for example, an individual suffering from an enzyme deficiency. The introduced enzyme can be a purified recombinant enzyme made in vitro, or can be a protein purified from an isolated tissue or body fluid, such as placenta or animal milk, or purified from a plant.

[0067] As used herein, the term "free base equivalent" or "FBE" refers to the amount of migalastat present in migalastat or a salt thereof. In other words, the term "FBE" refers to either the amount of migalastat free base or the equivalent amount of migalastat free base provided by a salt of migalastat. For example, due to the weight of the hydrochloride salt, only 150 mg of migalastat hydrochloride provides the same amount of migalastat as 123 mg of migalastat in free base form. Other salts are expected to have different conversion factors depending on the molecular weight of the salt.

[0068] The term "migalastat" includes migalastat free base or a pharmaceutically acceptable salt thereof (eg, migalastat HCl), unless specifically indicated to the contrary.

[0069] The terms "mutation" and "variant" (e.g., as in "applicable mutation or variant") refer to a change in the nucleotide sequence of a gene or chromosome. These two terms referred to herein are typically used together—e.g., "mutation or variant"—to refer to the change in the nucleotide sequence described in the preceding sentence. If, for any reason, only one of these two terms is mentioned, the omitted term is intended to be included and should be understood as such. Furthermore, the terms "applicable mutation" and "applicable variant" refer to a mutation or variant to which PC therapy is applicable, such as a mutation to which migalastat therapy is applicable. A particular type of applicable mutation or variant is a "HEK assay-applicable mutation or variant," which is a mutation or variant that is determined to be applicable to migalastat therapy according to the criteria of the in vitro HEK assay described herein.

[0070] Fabry disease Fabry disease is a rare, progressive, severe, X-linked lysosomal storage disorder. Mutations in the GLA gene cause a deficiency of the lysosomal enzyme α-Gal A, which is required for glycosphingolipid metabolism. Decreased α-Gal A activity, beginning in early childhood, leads to the accumulation of glycosphingolipids, including GL-3 and plasma lyso-Gb3, leading to the symptoms and fatal sequelae of Fabry disease, including pain, gastrointestinal symptoms, renal failure, cardiomyopathy, cerebrovascular events, and premature death. Early initiation of therapy and lifelong treatment offers the opportunity to slow disease progression and extend life expectancy.

[0071] Fabry disease encompasses a range of disease severity and age of onset, but is traditionally divided into two major phenotypes, "classic" and "late-onset." The classic phenotype is primarily considered to be associated with males who have undetectable to low α-Gal A activity and early onset of renal, cardiac, and / or cerebrovascular symptoms. The late-onset phenotype is primarily considered to be associated with males who have higher residual α-Gal A activity and later onset of these disease symptoms. Heterozygous female carriers typically express the late-onset phenotype, but may also exhibit the classic phenotype depending on the pattern of X-chromosome inactivation.

[0072] Over 1,000 GLA mutations that cause Fabry disease have been identified. Approximately 60% are missense mutations that result in a single amino acid substitution in the α-Gal A enzyme. Missense GLA mutations often result in the production of abnormally folded, unstable forms of α-Gal A, the majority of which are associated with the classic phenotype. Normal cellular quality control mechanisms in the endoplasmic reticulum prevent these abnormal proteins from trafficking to lysosomes, targeting them for premature degradation and removal. Many missense mutant forms are targets of migalastat, an α-Gal A-specific pharmacological chaperone.

[0073] The clinical manifestations of Fabry disease range in severity and roughly correlate with a patient's residual α-GAL levels. The majority of patients currently receiving treatment are referred to as patients with classic Fabry disease, most of whom are men. These patients experience disease affecting various organs, including the kidneys, heart, and brain. Disease symptoms first appear in adolescence and progress in severity until death, typically in the patient's 30s or 40s. Several recent studies suggest that there are many undiagnosed men and women with various Fabry disease symptoms, such as cardiac or renal dysfunction and stroke, that usually first appear in adulthood. This type of Fabry disease, referred to as late-onset Fabry disease, tends to have higher residual α-GAL levels than patients with classic Fabry disease. Late-onset Fabry disease typically experiences its first disease symptoms in adulthood and often has disease symptoms localized to a single organ, such as left ventricular hypertrophy or progressive renal failure. In addition, late-onset Fabry disease can also present with strokes of unknown etiology.

[0074] Patients with Fabry disease have progressive renal dysfunction, and untreated individuals develop end-stage renal failure by their fourth decade. Deficiency of α-Gal A activity leads to the accumulation of GL-3 and related glycosphingolipids in many cell types, including those of the kidney. GL-3 accumulates in podocytes, distal tubules, and epithelial and tubular cells of the loop of Henle. Renal dysfunction can manifest as proteinuria and a reduced glomerular filtration rate.

[0075] Proper diagnosis of Fabry disease is challenging due to its rarity, involvement of multiple organs, and wide and heterogeneous age range of onset. Misdiagnosis is frequent due to low awareness among medical professionals. The diagnosis of Fabry disease is most often confirmed after a patient presents with symptoms, based on reduced α-Gal A activity in plasma or peripheral white blood cells (WBCs) in conjunction with mutation analysis. Diagnosis is even more challenging in females, due to unreliable enzymatic identification of carrier females due to random X-chromosome inactivation in some carrier cells. For example, some obligate carriers (daughters of classically affected men) have α-Gal A enzyme activity ranging from normal to very low activity. Because carriers may have normal α-Gal A enzyme activity in white blood cells, only identification of the α-Gal A mutation by genetic testing provides accurate carrier identification and / or diagnosis.

[0076] As described above, the age of onset, progression, and severity of Fabry disease depend, at least in part, on the rate of substrate accumulation, which correlates with enzyme activity in lysosomes. Therefore, the complete absence of residual activity can correspond to rapid substrate accumulation and thus to a severe form of the disease (with early onset and rapid progression). However, even a small amount of residual activity can be sufficient to degrade a large amount of substrate. This can lead to a milder form of the disease with later onset and slower progression due to a slowdown in substrate accumulation. Considering these factors, even a small increase in enzyme activity may be able to reduce the effects of a severe clinical phenotype. Data suggest that for most LSDs, an estimated 1% to 6% of normal activity is sufficient to delay or prevent disease onset or to reduce the severity of any resulting disease. Thus, even a small increase in activity can have a significant impact on substrate levels and, therefore, disease severity and rate of progression. Conversely, mutant lysosomal enzymes that are ineffective in vitro are also expected to be ineffective in vivo.

[0077] In one or more embodiments, a mutant or variant α-Gal A that is considered migalastat-applicable is defined as one that exhibits a relative increase (+10 μM migalastat) of 1.20-fold or greater over wild-type and an absolute increase (+10 μM migalastat) of 3.0% or greater when the mutant α-Gal A is expressed in HEK-293 cells (referred to as the "HEK assay") according to a Good Laboratory Practice (GLP) validated in vitro assay (the GLP HEK or migalastat applicability assay). Such mutations or variants are also referred to herein as "HEK assay-applicable" mutations or variants.

[0078] Prior screening methods have been provided to determine enzyme enhancement before treatment begins. For example, an assay using HEK-293 cells has been utilized in clinical trials to predict whether a given mutation will respond to pharmacological chaperone (e.g., migalastat) treatment. In this assay, a cDNA construct is generated. The corresponding α-Gal A mutant form is transiently expressed in HEK-293 cells. The cells are then incubated with migalastat (17 nM to 1 mM) for 4 to 5 days. α-Gal A levels are then measured in cell lysates using a synthetic fluorogenic substrate (4-MU-α-Gal) or by Western blot. This has been performed for known disease-causing missense or small in-frame insertion / deletion mutations. Mutations previously identified as responsive to PC (e.g., migalastat) using these methods are listed in U.S. Patent No. 8,592,362 (hereby incorporated by reference in their entirety).

[0079] HEK assay applicable mutations include at least those mutations listed in a pharmacology reference table (e.g., those listed in the U.S. or international package insert for a migalastat product, such as GALAFOLD®). As used herein, a "pharmacology reference table" refers to any publicly available written or electronic record, either contained in the package insert of a migalastat product (e.g., GALAFOLD®) or on a website accessible to healthcare providers, that conveys whether a particular mutation or variant is indicative of a response to migalastat (e.g., GALAFOLD®) PC therapy, and is not limited to written records presented in tabular format. In one embodiment of the present invention, therefore, a "pharmacology reference table" refers to any information repository containing one or more applicable mutations or variants. In another embodiment, a "pharmacology reference table" refers to an up-to-date repository of applicable mutations or variants, including novel mutations or variants disclosed herein (i.e., mutations presented in Table 2). Exemplary pharmacology reference tables for HEK assay applicable mutations can be found in the Summary of Formulation Characteristics and / or Prescribing Information for GALAFOLD® in the various countries where GALAFOLD® is approved for use, or on websites such as www.galafoldamenabilitytable.com or www.fabrygenevariantsearch.com (each of which is hereby incorporated by reference in its entirety).

[0080] An exemplary pharmacology reference table for HEK assay-eligible mutations is provided below in Table 1. In one or more embodiments, if double mutations are present on the same chromosome (male and female), the patient is considered HEK assay-eligible if the double mutations are present in one entry in Table 1 (e.g., D55V / Q57L). In some embodiments, if double mutations are present on different chromosomes (females only), the patient is considered HEK assay-eligible if either one of the individual mutations is present in Table 1.

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[0091] However, because treatment with migalastat is only applicable to certain mutations, it is necessary to identify novel mutations and determine whether migalastat therapy is applicable to such mutations. As described in the Examples below, several novel mutations have been identified and determined to be mutations applicable to migalastat therapy.

[0092] As described above, α-Gal A refers to the enzyme encoded by the human GLA gene. The coding sequence of the GLA gene consists of 1287 nucleotides. The human α-Gal A enzyme consists of 429 amino acid residues. To generate a list of all possible nonsynonymous missense mutations for GLA, each nucleotide in the coding sequence was individually replaced with three other nucleotides in the coding sequence, and the effect of each substitution on the protein sequence was examined.

[0093] If a codon change resulted in a protein sequence change due to a single amino acid residue substitution and the amino acid substitution had not been previously identified, the mutation was recorded and tested in the HEK assay. Mutations found to be applicable to the HEK assay were classified as theoretically applicable mutations. If multiple different nucleotide changes within a single codon resulted in the same amino acid residue substitution at that position, the protein sequence change was listed as a single entry with alternative nucleotide changes.

[0094] The theoretically applicable mutations identified include N5D, N5K, P6L, P6Q, P6R, P6S, P6T, E7D, E7K, E7V, L8I, L8P, L8Q, H9L, H9Q, H9R, H9Y, L10M, L10P, L10Q, L10R, L10V, G11C, G11D, G11R, G11S, G11V, C12G, C12R, C12S, C12Y, A13E, A13G, L14F, L14H, L14V, R17C, R17G, R17H, R17P, R17S, F18I, F18L, A20G, L21H, V22A, V22F, V22I, V22L, S 23P, S23T, W24S, D25H, I26N, P27A, P27L, P27S, P27T, G28E, G28R, G28W, A29 G, A29P, A29V, R30G, L32M, L32Q, L32R, L32V, D33A, D33E, D33V, L36M, L36V, A 37E, A37G, A37S, R38G, R38M, R38W, T39A, T39K, T39M, T39R, T39S, T41A, T41 N, T41S, G43A, L45M, L45V, H46D, H46N, H46Q, E48A, F50Y, M51R, M51T, M51V, N 53H, N53I, N53S, N53T, L54H, L54R, L54V, D55A, D55E, D55H, D55Y, C56W, E58 K, E59A, E59D, E59G, E59Q, E59V, P60A, P60Q, P60R, D61E, D61V, S62A, S62C, S62F, S62P, S62Y, I64L, I64V, S65C, S65G, S65R, E66D, E66V, K67E, K67M, K6 7N, K67Q, K67T, L68I, F69I, F69Y, M70I, M70K, M70L, M70R, E71A, E71D, E71G, E71Q, E71V, M72L, M72T, A73S, A73T, E74D, E74G, E74K, E74V, L75F, L75P, M7 6V, V77I, V77L, S78L, S78P, E79A, E79D, E79G, E79K, E79Q, E79V, G80A, G80C, G80S, W81L, K82E, K82M, K82N, K82R, K82T, D83A, D83E, D83G, D83V, A84E, A8 4G, A84P, A84S, A84T, A84V, G85A, G85C, G85R, Y86F, E87G, Y88H, Y88N, L89V,I91F、I91L、I91M、I91S、M96L、M96T、A97D、A97S、A97T、P98H、P98L、P98R、Q99E、Q99L、Q99P、Q99R、D101A、D101E、D101G、D101H、D101V、S102A、S102P、S102T、G104A、G104D、G104S、R105G、R105I、R105K、R105T、L106H、L106I、L106P、L106V、Q107E、Q107H、Q107K、A108E、A108V、D109A、D109E、D109H、D109N、D109Y、P110T、F113V、F113Y、P114L、H115D、H115N、G116R、I117M、I117T、A121V、Y123D、Y123F、Y123N、Y123S、V124I、H125D、H125N、H125R、S126C、S126I、K127E、G128A、L129V、K130M、K130N、K130Q、L131V、I133L、I133T、I133V、A135E、A135G、A135S、A135T、D136A、D136N、D136V、V137A、V137D、V137G、V137I、V137L、G138A、N139H、N139I、N139K、N139Y、K140E、K140I、K140N、K140Q、K140R、T141S、A143E、A143G、G144A、G144C、G144R、G144S、F145C、F145L、F145V、F145Y、P146A、P146H、P146L、P146T、G147A、S148C、S148G、S148T、F149C、G150E、G150V、Y151C、Y151D、Y151S、Y152F、Y152S、D153A、D153H、D153N、D153V、D153Y、A156G、Q157E、Q157K、Q157L、Q157P、T158A、T158I、T158N、T158S、F159I、F159L、F159V、F159Y、A160G、A160S、A160T、A160V、D161H、D161N、D161V、D161Y、W162S、V164A、V164I、V164L、D165A、D165E、L166M、L166Q、L167I、F169C、F169L、F169V、F169Y、G171A、G171V、Y173C、Y173F、Y173H、Y173S、D175G、D175H、D175V、D175Y、S176C、S176R、L177F、L177M、L177S、L177V、L177W、E178A、E178G、E178K、E178Q、L180M、L180S、A181P、A181T、A181V、D182A、D182E、D182V、D182Y、Y184F、Y184H、Y184S、K185M、K185N、K185Q、K185T、H186D、H186L、H186N、H186Q、H186Y、M187L、S188A、S188C、S188F、S188P、S188T、S188Y、L189S、L189V、A190D、A190G、A190S、A190T、A190V、L191M、L191V、N192D、N192H、N192K、N192S、N192T、R193G、R193M、R193T、R193W、T194N、T194P、T194S、G195C、G195R、G195S、R196I、R196K、S197C、S197G、S197I、S197N、S197T、I198M、I198S、V199E、V199L、Y200N、Y200S、S201A、S201C、S201T、E203A、E203G、E203Q、W204S、L206F、L206H、L206I、L206R、L206V、Y207F、M208K、W209C、W209G、P210H、P210T、F211C、F211L、F211S、F211V、F211Y、Q212H、Q212P、K213E、K213Q、P214A、P214H、P214R、P214T、N215H、N215K、N215T、N215Y、Y216F、Y216H、Y216N、T217A、T217I、T217K、T217P、T217R、T217S、E218A、E218D、E218G、E218K、E218Q、E218V、I219F、I219M、I219S、R220L、Q221E、Q221H、Q221K、Q221L、Q221R、Y222C、Y222D、Y222H、Y222N、Y222S、N224H、R227G、N228H、N228I、N228T、F229I、F229S、F229Y、A230D、A230G、A230P、A230V、I232L、I232M、I232V、D233A、D233E、D233G、D233V、S235A、S235T、K237I、<h2 style=";text-align:left;direction:ltr">S238C、S238I、S238T、I239L、K240E、K240M、K240R、S241C、S241I、S241T、I2 42L、I242M、I242S、L243M、L243S、L243V、D244A、D244E、D244G、D244V、D244 Y、W245C、T246A、T246I、T246K、T246R、S247A、S247F、S247T、S247Y、F248C、F248L、F248V、F248Y、N249D、N249H、N249I、N249S、N249T、N249Y、Q250E、Q25 0L、E251G、E251K、E251Q、E251V、R252G、I253F、I253N、I253V、V254A、V254D 、V254F、V254G、D255A、D255E、D255H、D255N、D255V、D255Y、V256D、V256G、V 256L、A257S、G258E、P259A、P259T、G260W、G261A、N263H、N263T、D264H、D264N、P265A、P265Q、M267L、M267V、L268F、L268I、V269L、I270L、I270S、I270V、 N272D、F273Y、L275I、W277L、N278I、Q280L、Q280R、V281A、V281E、V281G、V281L、T282S、Q283E、Q283H、Q283L、M284I、M284L、A285G、A285T、A285V、L286 F、L286H、L286V、A288G、A288S、A288V、I289L、I289T、I289V、A291G、A292G、 A292S、L294F、L294I、L294V、F295I、F295S、F295V、F295Y、S297T、N298D、N29 8I、N298T、D299H、D299N、L300I、L300V、H302D、H302L、H302N、H302Y、I303S 、S304I、Q306E、Q306L、Q306P、A307D、A307G、A307P、A307S、A307V、K308I、K 308Q、K308R、A309D、A309T、L310I、L311I、Q312E、Q312K、Q312L、D313E、D313V、K314E、K314M、K314N、K314T、D315A、D315G、D315H、D315N、D315V、D315Y、<h2 style=";text-align:left;direction:ltr">V316A、V316L、I317L、I317M、I317V、A318D、A318P、A318T、A318V、I319M、N320S、N320T、Q321K、D322A、D322V、L324V、L324W、G325A、G325C、G325V、K326 E、K326M、K326Q、K326R、K326T、Q327H、Q327P、Y329C、Y329D、Y329F、Y329H、Y329N、Q330E、Q330H、Q330K、L331H、L331P、L331R、L331V、R332G、R332I、R33 2S、R332T、Q333E、Q333L、Q333P、G334R、G334V、D335A、D335E、D335G、D335V、D335Y、N336D、N336I、N336S、N336T、N336Y、F337C、F337L、F337V、F337Y、E 338A、E338D、E338G、V339M、E341A、E341Q、P343A、P343S、L344F、L344R、L344V、G346A、G346C、G346D、G346V、L347I、A348D、W349C、W349L、A350G、A350S、 A350T、A350V、V351A、V351E、A352S、A352T、M353K、M353L、M353T、I354R、N355D、N355H、N355S、N355Y、R356L、Q357E、I359F、I359L、I359N、I359S、I359 V、P362A、P362H、P362R、P362S、R363G、R363L、R363S、S364C、S364P、Y365D、 Y365F、Y365N、Y365S、T366I、T366N、T366P、T366S、I367F、I367L、I367M、A36 8G、A368P、V369A、V369F、V369G、V369I、V369L、A370D、A370G、A370P、A370T、A370V、S371C、S371T、G373A、G373C、K374E、K374I、K374R、K374T、G375R、V 376E、V376G、V376L、V376M、A377G、A377P、A377S、A377T、N379D、N379I、N379K、N379T、P380A、P380H、P380R、P380T、A381D、F383C、F383I、F383Y、I384F、I384M, I384T, T385I, Q386H, Q386K, Q386L, L387F, L387H, L387I, L387R, L388F, L388H, L388I, L388R, L388V, K391I , K391N, K391Q, K391R, R392G, R392K, R392M, R39, 2W, K393E, K393N, K393Q, K393T, L394I, L394Q, L394R, G395R, F396C, F396I, F396L, F396 V, Y397C, Y397F, Y397H, Y397N, Y397S, E398G, E398Q, W399G, W399R, T400A, T400I, T400N , T400P, T400S, S401A, S401L, S401T, R402G, R402M, R402S, R402T, R402W, L403F, L403V, R404G, R404I, R404K, R404S, R404T, S405G, H406D, H406L, H406Q, I407L, I407M, I407T, N 408D, N408H, N408T, P409L, T410S, G411A, G411C, G411V, T412A, T412I, T412S, V413F, V4 13G, V413I, L414F, L414V, L415H, L415I, Q416E, Q416H, Q416L, L417I, E418A, E418D, E41 These mutations include 8K, E418Q, N419I, N419S, N419T, N419Y, T420K, T420P, T420R, T420S, M421I, M421K, M421L, M421R, M421T, Q422P, M423I, M423K, M423L, M423T, S424L, L425F, D427N, and L429R. These mutations, along with their corresponding nucleotide changes, are also presented in Table 2.

[0095] Thus, in one or more embodiments, migalastat is used to treat Fabry disease and / or enhance α-Gal A activity in patients with α-Gal A mutations selected from the group consisting of the mutations presented in Table 2. In various embodiments, these α-Gal A mutations relate to the amino acid sequence set forth in SEQ ID NO:2.

[0096] Exemplary nucleotide changes associated with these novel mutations are shown in Table 2 below.

[0097] TIFF2025137509000011.tif210170

[0098] TIFF2025137509000012.tif226170

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[0121] TIFF2025137509000035.tif225170

[0122] TIFF2025137509000036.tif225170

[0123] TIFF2025137509000037.tif33170

[0124] Thus, in various embodiments, migalastat is used to treat Fabry disease and / or enhance α-Gal A activity in patients with GLA mutations selected from the group consisting of nucleotide changes presented in Table 2. In various embodiments, these GLA mutations are with respect to the nucleic acid sequence set forth in SEQ ID NO:3.

[0125] Additional theoretically applicable mutations identified include V22G, A29D, D33H, N34H, G35A, R38S, N53K, N53Y, Q57R, F69L, G80V, Y88C, Y88S, M96V, Q107R, R112L, V124G, H125Y, I133M, and I133F. , A143V, Y152D, Y152N, D155E, A156S, Q157H, F159C, A160D, D165N, F169I, G17 1S, L180V, D182G, L189F, T194A, R196T, W204L, W204G, W209R, N215I, Y216S, I 219L, N224T, N228D, S238G, I239M, K240N, Q250K, A257V, A257T, P259Q, P259S , G271A, L275V, S276T, N278Y, M290V, M290T, A291S, I303T, I303V, K308E, L31 These mutations include 0V, N320H, D322H, P323T, Q330P, F337S, E338V, V339A, P343T, E358Q, G360A, G360R, G375A, P380L, K391E, R392T, L394P, N408Y, G411S, T412P, and N419D. These mutations, along with their corresponding nucleotide changes, are also presented in Table 3.

[0126] Thus, in one or more embodiments, migalastat is used to treat Fabry disease and / or enhance a-Gal A activity in patients with a-Gal A mutations selected from the group consisting of the mutations presented in Table 3. In various embodiments, these a-Gal A mutations are relative to the amino acid sequence set forth in SEQ ID NO:2.

[0127] Exemplary nucleotide changes associated with these novel mutations are shown in Table 3 below.

[0128] TIFF2025137509000038.tif66170

[0129] TIFF2025137509000039.tif225170

[0130] TIFF2025137509000040.tif225170

[0131] Thus, in various embodiments, migalastat is used to treat Fabry disease and / or enhance α-Gal A activity in patients with GLA mutations selected from the group consisting of nucleotide changes presented in Table 3. In various embodiments, these GLA mutations are relative to the nucleic acid sequence set forth in SEQ ID NO:3.

[0132] The applicable mutations presented in Tables 2 and 3 were originally procedural applicable mutations assessed by HEK assay, but some of these mutations have since been seen in subsequently identified patients. Thus, the mutations listed in Table 4 are now applicable mutations associated with patients, thus confirming that the procedural mutations described herein may subsequently be seen in patients and that such patients may be treated with migalastat.

[0133] TIFF2025137509000041.tif154170

[0134] TIFF2025137509000042.tif225170

[0135] TIFF2025137509000043.tif182170

[0136] In addition to the procedurally applicable mutations identified above in Tables 2 and 3, several novel mutations have been identified and determined to be mutations that are not applicable to migalastat therapy.

[0137] Mutations that were not found to be applicable to the HEK assay, as described above, were classified as procedurally inapplicable mutations. When multiple different nucleotide changes within a single codon lead to the same amino acid residue substitution at that position, the protein sequence change was listed as a single entry with the alternative nucleotide changes.

[0138] The theoretically inapplicable mutations identified include Q2E, Q2K, Q2L, Q2P, Q2R, Q2H, L3M, L3Q, L3R, R4G, R4W, R4K, R4T, R4M, R4S, N5I, N5Y, N5H, N5T, N5S, P6A, E7Q, E7A, E7G, L8R, L8V, H9D, H9P, H9N, G11A, C12F, C12W, A13S, A13V, L14R, L14I, A15V, A15S, L16R, L16I, L16F, R17L, F18V, F18Y, L19M, L19V, L19R, A20S, A20T, L21I, L21V, V22 D, S23A, S23C, S23Y, S23F, W24L, D25G, D25Y, D25A, D25E, D25V, D25N, I26F, I26L, I26M, I26S, I26T, I26V, P27H, P27R, G28A, G28V, A29S, A29T, R30I, R30 K, R30S, R30T, A31T, A31E, A31G, A31P, A31S, D33N, N34I, N34Y, R38K, R38T, T39P, P40T, T41P, G43C, W44G, W44L, W44R, W44S, L45Q, W47S, E48G, E48V, R49 H, F50I, F50L, F50S, F50V, M51L, C52F, L54I, D55N, C56R, Q57E, Q57H, Q57K, Q57P, E58A, E58G, E58Q, E58D, E58V, D61A, D61G, D61H, D61N, D61Y, S62T, C63 F, C63G, C63W, I64F, I64M, I64N, I64S, I64T, E66A, K67R, L68V, L68H, L68P, L68R, F69V, F69C, F69S, M70V, M70T, E71K, M72K, A73P, A73G, E74Q, E74A, L75 V, L75H, L75I, L75R, M76K, M76L, M76I, V77F, V77A, V77G, V77D, S78T, S78A, G80R, W81G, K82Q, D83Y, D83H, G85V, Y86N, Y86S, E87K, E87A, E87V, E87Q, Y88 F, L89I, C90F, C90G, C90S, I91V, I91N, D92A, D92E, D93A, D93H, C94R, C94W, W95R, M96K, M96R, A97G, P98A, P98S, P98T, Q99H, Q99K, R100G, R100I, R100S,D101N、D101Y、E103A、E103D、E103G、E103K、E103V、G104C、G104R、R105S、Q107P、A108G、A108P、A108S、D109V、P110H、P110S、Q111E、Q111H、Q111R、Q111K、Q111L、Q111P、R112P、F113C、P114A、P114H、P114S、P114T、P114R、H115L、H115P、H115Q、H115R、H115Y、G116W、G116A、G116E、I117F、I117L、I117N、I117V、R118G、R118P、R118S、R118L、R118H、Q119E、Q119H、Q119K、Q119L、Q119P、L120I、L120Q、L120R、A121S、A121D、A121G、N122D、N122H、N122I、N122K、N122S、N122T、N122Y、Y123H、V124L、V124A、V124F、H125Q、S126T、S126R、S126N、K127Q、K127T、K127R、K127I、K127N、G128R、G128V、L129M、L129Q、L129R、K130E、K130T、L131Q、L131I、L131R、G132W、G132V、I133S、Y134N、Y134C、Y134F、A135P、D136G、V137F、G138V、N139D、T141P、T141A、C142S、C142G、C142F、A143S、F145I、G147W、G147V、S148I、F149I、F149V、F149Y、F149L、F149S、G150A、G150R、Y151H、Y151N、Y151F、D153E、D153G、I154F、I154L、I154M、I154N、I154S、I154T、I154V、D155A、D155G、D155N、D155V、D155Y、A156P、Q157R、T158P、F159S、A160P、D161A、D161E、D161G、G163A、G163E、G163R、V164E、L166P、L166R、L167R、K168Q、K168E、K168I、K168T、D170A、D170E、D170Y、Y173D、Y173N、C174F、C174S、C174W、C174Y、D175A、S176G、S176I、S176N、S176T、E178D、E178V、N179D、N179H、N179I、N179K、N179S、N179T、N179Y、A181S、A181E、A181G、D182N、D182H、Y184D、K185R、H186R、M187K、L189M、L189W、A190P、L191R、N192Y、N192I、R193K、R193S、G195A、G195D、S197R、I198F、I198L、I198N、I198V、Y200D、Y200F、Y200H、C202F、C202G、C202S、P205A、P205H、Y207D、Y207N、M208I、M208L、M208T、M208V、W209L、W209S、P210A、P210R、F211I、Q212E、Q212K、Q212L、Q212R、K213T、I219V、R220G、Y222F、C223S、C223F、C223W、N224K、N224Y、N224I、H225N、H225Y、H225P、H225L、H225Q、W226G、W226S、W226L、R227L、N228Y、N228K、F229V、F229C、A230S、D231H、D231Y、D231A、D231E、I232N、I232F、D233N、D233H、D233Y、D234N、D234H、D234A、D234G、S235P、W236G、W236S、K237E、K237N、K237Q、K237R、K237T、I239K、I239R、I239V、K240Q、K240T、S241G、S241N、S241R、W245R、W245S、T246P、T246S、F248I、F248S、E251A、E251D、R252I、R252K、R252S、I253M、I253L、V254I、V254L、D255G、V256F、V256I、V256A、G258A、G260R、G260V、W262R、W262G、W262S、N263D、N263I、N263K、N263Y、D264E、D264G、P265T、D266G、M267K、L268V、V269G、I270F、I270N、G271R、N272H、N272Y、N272T、N272I、F273I、F273V、F273S、F273C、G274R、G274C、G274D、G274A、L275P、L275R、S276C、S276I、S276R、W277R、<h2 style=";text-align:left;direction:ltr">W277S、N278H、N278D、N278T、N278S、N278K、Q279L、Q279P、Q280E、Q280P、V281I、T282P、Q283K、M284R、M284K、A285S、L286I、L286R、L286P、W287S、A288 T、I289N、I289M、M290R、M290K、A291D、A291V、A292D、P293R、F295L、M296R、 M296K、S297P、S297Y、S297A、N298Y、D299A、D299V、D299Y、L300R、H302P、H30 2Q、H302R、I303L、I303M、S304G、S304C、S304R、P305A、P305H、P305L、P305R 、P305S、P305T、Q306H、Q306K、Q306R、K308T、A309G、A309S、L310H、L310P、L 311H、D313H、D313N、D313A、K314Q、K314R、D315E、A318G、A318S、I319S、I319L、I319V、I319N、N320D、Q321P、D322Y、D322G、P323A、P323H、P323L、P323S、 L324M、L324F、L324S、Q327R、Y329S、Q330L、L331I、L331F、R332K、Q333H、Q333K、G334A、D335H、D335N、N336H、N336K、F337I、E338Q、V339L、W340G、W340 L、W340S、W340C、E341V、E341G、P343R、P343H、L344I、L344H、S345L、S345T、S345A、G346S、G346R、L347V、L347S、L347F、A348T、A348S、A348G、A348V、W34 9G、A350D、V351I、V351L、V351G、M353I、M353V、M353R、I354M、I354L、I354V 、I354T、N355I、N355T、Q357L、Q357P、Q357H、Q357R、Q357K、E358V、I359M、G 360V、G361V、S364T、S364A、S364Y、S364F、Y365C、Y365H、T366A、I367V、I367N、I367T、I367S、A368S、A368E、A368V、V369D、A370S、S371A、S371F、S371P、S371Y, L372M, L372V, G373V, K374N, K374Q, G375V, V376A, A377V, C378F, C378G, C378W, N379H, N379S, N379Y, P38 0S, A381P, A381S, A381T, A381G, A381V, C382F, C382G, C382S, F383L, F383S, F383V, I384L, I384S, I384V, T385K, T385R, T385S, Q386E, Q386R, L387P, L387V, P389H, P389S, P389T, V390A, V390E, V390G, V390L, R392S, K393M, K39 3R, L394V, G395V, G395W, F396S, Y397D, E398D, E398V, W399C, W399L, S401P, R402K, L403I, S405C, S405I, S405N, S405T, H406N, H406P, H406Y, N408I, N408K, N408S, P409H, P409R, T410R, G411R, V413A, V413D, V413L, L414M, L41 4W, L415R, L415V, Q416K, Q416R, L417Q, L417V, E418V, N419H, N419K, T420A, T420I, Q422E, Q422H, Q422K, Q422L, These mutations, along with their corresponding nucleotide changes, include Q422R, M423R, M423V, S424A, S424P, S424T, L425I, L425S, L425V, K426E, K426Q, K426T, K426I, K426N, K426R, D427A, D427H, D427Y, D427E, D427G, D427V, L428F, L428S, L428I, L428V, L429I, L429V, L429F, L429H, and L429P. These mutations are also presented in Table 5.

[0139] Exemplary nucleotide changes associated with these novel mutations are shown in Table 5 below.

[0140] TIFF2025137509000044.tif121170

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[0163] The non-applicable mutations presented in Table 5 were originally procedural non-applicable mutations assessed by the HEK assay, but some of these mutations have since been seen in subsequently identified patients. Thus, the mutations listed in Table 6 are now applicable mutations associated with patients, thus confirming that the procedural mutations described herein may subsequently be seen in patients.

[0164] TIFF2025137509000067.tif130170

[0165] TIFF2025137509000068.tif224170

[0166] TIFF2025137509000069.tif125170

[0167] Additionally, various embodiments of the present invention provide PCs for the treatment of Fabry disease in patients with a mutation in the gene encoding α-Gal A, wherein the patient is identified as having a missense mutation in human α-Gal A encoded by the nucleic acid sequence set forth in SEQ ID NO:1 and / or SEQ ID NO:3. Another aspect of the present invention relates to methods for treating patients diagnosed with Fabry disease. In one or more embodiments, the method comprises administering to the patient a therapeutically effective dose of a PC of α-Gal A. In further embodiments, the patient has a missense mutation in the nucleic acid sequence encoding α-Gal A. Another aspect of the present invention relates to methods for enhancing α-Gal A in patients diagnosed with or suspected of having Fabry disease. In one or more embodiments, the method comprises administering to the patient a therapeutically effective dose of a PC of α-Gal A, wherein the patient has a mutant α-Gal A encoded by a nucleic acid sequence having a missense mutation compared to SEQ ID NO:1 and / or SEQ ID NO:3. Details of these uses and methods, as well as further embodiments, are set forth below. Any of the embodiments relating to methods of treating patients with Fabry disease, methods of increasing α-Gal A in patients diagnosed with or suspected of having Fabry disease, use of a pharmacological chaperone of α-Gal A in the manufacture of a medicament for the treatment of patients diagnosed with Fabry disease, or relating to a pharmacological chaperone of α-Gal A for use in the treatment of patients diagnosed with Fabry disease, where the patient is identified as having a missense mutation in human α-Gal A encoded by the nucleic acid sequence set forth in SEQ ID NO:1 and / or SEQ ID NO:3, can be combined with any of the other embodiments of the invention, such as embodiments relating to PC and suitable dosages thereof.

[0168] In one or more embodiments, the patient may have other mutations in their GLA gene. For example, there may be mutations in intron regions, which may or may not affect the resulting α-Gal A enzyme. Thus, in one or more embodiments, the patient has a mutant α-Gal A encoded by a nucleic acid sequence having at least 95, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% identity to SEQ ID NO:1. Additionally, the patient may have one or more additional mutations in the coding region of the GLA gene. Thus, in one or more embodiments, the patient has a mutant α-Gal A encoded by a nucleic acid sequence having at least 95, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% identity to SEQ ID NO:3. Additionally, in one or more embodiments, the patient has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 30 mutations compared to SEQ ID NO: 1 or SEQ ID NO: 3. It is also noted that because various amino acids are encoded by multiple nucleic acid sequences, some nucleic acid mutations in SEQ ID NO: 1 or SEQ ID NO: 3 may not result in a change in the amino acid of the resulting protein. Again, any of these embodiments can be combined with any of the other embodiments of the invention, such as those relating to applicable mutations, PCs, and their suitable dosages.

[0169] In various embodiments, a pharmacology reference table is provided that includes one or more of the mutations disclosed herein. In one or more embodiments, the pharmacology reference table includes one or more of the mutations from Table 2. In one or more embodiments, the pharmacology reference table includes all of the mutations from Table 2. In one or more embodiments, the pharmacology reference table includes one or more of the mutations from Table 1. In one or more embodiments, the pharmacology reference table includes all of the mutations from Table 1. In one or more embodiments, the pharmacology reference table includes one or more of the mutations from Table 1 and one or more of the mutations from Table 2. In one or more embodiments, the pharmacology reference table includes one or more of the mutations from Table 1 and all of the mutations from Table 2. In one or more embodiments, the pharmacology reference table includes all of the mutations from Table 1 and all of the mutations from Table 2.

[0170] As described above, the pharmacology reference table can be any publicly available paper or electronic record. In one or more embodiments, the pharmacology reference table is a paper record. In one or more embodiments, the pharmacology reference table is provided in the package insert of a migalastat product, such as a migalastat product approved by the United States or other regulatory agency for the treatment of Fabry disease. In one or more embodiments, the pharmacology reference table is provided in the GALAFOLD® package insert. In one or more embodiments, the pharmacology reference table is an electronic record. In one or more embodiments, the pharmacology reference table is provided on a website. In one or more embodiments, the website relates to migalastat products, such as a migalastat product approved by the United States or other regulatory agency for the treatment of Fabry disease. In one or more embodiments, the pharmacology reference table is provided at www.galafoldamenabilitytable.com. In one or more embodiments, the pharmacology reference table is provided at www.fabrygenevariantsearch.com.

[0171] Various embodiments also relate to a data store comprising a pharmacology reference table as described herein. Such a data store may include an electronic search function for determining whether a particular mutation is included in the pharmacology reference table. In one or more embodiments, the data store and optional search function are provided on a website. In one or more embodiments, the data store and optional search function are provided on an electronic storage medium. Examples of such electronic storage medium include, but are not limited to, a compact disc (CD), a digital versatile disc (DVD), a hard drive, and a flash drive.

[0172] Pharmacological Chaperones Binding of small molecule inhibitors of LSD-related enzymes can increase the stability of both mutant and corresponding wild-type enzymes (see U.S. Patent Nos. 6,274,597; 6,583,158; 6,589,964; 6,599,919; 6,916,829; and 7,141,582, all of which are incorporated herein by reference). Specifically, administration of small molecule derivatives of glucose and galactose, which are specific and selective competitive inhibitors of several target lysosomal enzymes, effectively increased the stability of the enzymes in cells in vitro, thereby increasing the trafficking of the enzymes to lysosomes. Therefore, increasing the amount of enzymes in lysosomes is expected to increase the hydrolysis of the enzyme substrates. The original theory behind this strategy was as follows: because mutant enzyme proteins are unstable in the ER (Non-Patent Document 2), they are delayed in the normal transport pathway (ER → Golgi apparatus → endosomes → lysosomes) and are prematurely degraded. Therefore, compounds that bind to and increase the stability of mutant enzymes may act as "chaperones" for the enzyme, increasing the amount that can exit the ER and be transported to lysosomes. In addition, because the folding and trafficking of some wild-type proteins are incomplete, and in some cases up to 70% of some wild-type proteins are degraded before reaching their final cellular location, chaperones can be used to stabilize wild-type enzymes, thereby increasing the amount of enzyme that can exit the ER and be transported to lysosomes.

[0173] In one or more embodiments, the pharmacological chaperone comprises migalastat or a salt thereof. The compound migalastat, also known as 1-deoxygalactonojirimycin (1-DGJ) or (2R,3S,4R,5S)-2-(hydroxymethyl)piperidine-3,4,5-triol, is a compound having the following chemical formula: TIFF2025137509000070.tif51170

[0174] As discussed herein, pharmaceutically acceptable salts of migalastat can also be used in the present invention.When a salt of migalastat is used, the dosage of the salt will be adjusted so that the patient receives a dose of migalastat equivalent to the amount that the patient would receive if migalastat free base was used.An example of a pharmaceutically acceptable salt of migalastat is migalastat HCl. TIFF2025137509000071.tif56170

[0175] Migalastat is a low-molecular-weight iminosugar and an analog of the terminal galactose of GL-3. In vitro and in vivo pharmacological studies have demonstrated that migalastat acts as a pharmacological chaperone, binding with high affinity, selectivity, and reversibility to the active site of wild-type α-Gal A and specific mutant forms of α-Gal A. Binding of migalastat stabilizes these mutant forms of α-Gal A in the endoplasmic reticulum and promotes their proper trafficking to lysosomes, where its dissociation allows α-Gal A to reduce levels of GL-3 and other substrates.

[0176] In a specific embodiment, the PC comprises migalastat or a salt thereof. In a further embodiment, the PC comprises migalastat hydrochloride.

[0177] Any of these PCs for α-Gal A may be used in combination with other embodiments of the invention, such as methods for treating patients with Fabry disease, methods for enhancing α-Gal A in patients diagnosed with or suspected of having Fabry disease, embodiments relating to the use of a pharmacological chaperone of α-Gal A in the manufacture of a medicament for the treatment of patients diagnosed with Fabry disease or for use in the treatment of patients diagnosed with Fabry disease, and embodiments relating to suitable doses of PC, applicable mutations, and to the treatment of Fabry patients with specific mutations in the nucleic acid sequence encoding α-Gal A.

[0178] Dosing, Formulation and Administration In one or more embodiments, a Fabry patient is administered migalastat or a salt thereof once every other day (also referred to as "QOD"). In various embodiments, the doses described herein relate to migalastat hydrochloride or an equivalent dose of migalastat or a salt thereof other than the hydrochloride salt. In some embodiments, these doses relate to the free base of migalastat. In alternative embodiments, these doses relate to a salt of migalastat. In further embodiments, the salt of migalastat is migalastat hydrochloride. The administration of migalastat or a salt of migalastat is referred to herein as "migalastat therapy."

[0179] An effective amount of migalastat or a salt thereof can range from about 100 mg FBE to about 150 mg FBE. Exemplary doses include about 100 mg FBE, about 105 mg FBE, about 110 mg FBE, about 115 mg FBE, about 120 mg FBE, about 123 mg FBE, about 125 mg FBE, about 130 mg FBE, about 135 mg FBE, about 140 mg FBE, about 145 mg FBE, or about 150 mg FBE.

[0180] It is again noted that 150 mg of migalastat hydrochloride is equivalent to 123 mg of the free base form of migalastat. Thus, in one or more embodiments, the dose is 150 mg of migalastat hydrochloride administered once every other day, or an equivalent dose of migalastat or a salt thereof other than the hydrochloride salt. As indicated above, this dose is referred to as 123 mg FBE of migalastat. In a further embodiment, the dose is 150 mg of migalastat hydrochloride administered once every other day. In other embodiments, the dose is 123 mg of migalastat free base administered once every other day.

[0181] In various embodiments, the effective amount is about 122 mg, about 128 mg, about 134 mg, about 140 mg, about 146 mg, about 150 mg, about 152 mg, about 159 mg, about 165 mg, about 171 mg, about 177 mg, or about 183 mg of migalastat hydrochloride.

[0182] Thus, in various embodiments, migalastat therapy comprises administering 150 mg of migalastat hydrochloride every other day, such as 123 mg FBE once every other day.

[0183] Administration of migalastat or a salt thereof can be over a period of time. In one or more embodiments, migalastat or a salt thereof is administered for a duration of at least 28 days, e.g., at least 30, 60, or 90 days, or at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 20, 24, 30, or 36 months, or at least 1, 2, 3, 4, or 5 years. In various embodiments, the migalastat therapy is long-term migalastat therapy for at least 6 months, e.g., at least 6, 7, 8, 9, 10, 11, 12, 16, 20, 24, 30, or 36 months, or at least 1, 2, 3, 4, or 5 years.

[0184] The administration of migalastat or a salt thereof according to the present invention can be in a formulation suitable for any route of administration, but is preferably administered in an oral dosage form such as a tablet, capsule, or solution. As an example, a patient is orally administered capsules each containing 150 mg of migalastat hydrochloride or an equivalent dose of migalastat or a salt thereof other than hydrochloride.

[0185] In some embodiments, the PC (e.g., migalastat or a salt thereof) is administered orally. In one or more embodiments, the PC (e.g., migalastat or a salt thereof) is administered by injection. The PC may be accompanied by a pharmaceutically acceptable carrier, which may depend on the method of administration.

[0186] In one or more embodiments, the PC (e.g., migalastat or a salt thereof) is administered as monotherapy and can be in a form suitable for any route of administration, such as orally in tablet or capsule or liquid form or in a sterile aqueous solution for injection, etc. In other embodiments, the PC is provided as a lyophilized powder that is added to the replacement enzyme formulation during or immediately after reconstitution to prevent enzyme aggregation in vitro prior to administration.

[0187] When a PC (e.g., migalastat or a salt thereof) is formulated for oral administration, tablets or capsules can be prepared by conventional means with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets can be coated by methods well known in the art. Liquid preparations for oral administration can take the form of, for example, solutions, syrups, or suspensions, or can be prepared as a dry preparation for constitution with water or another suitable vehicle before use. Such liquid formulations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid). The formulations may also contain buffer salts, flavoring agents, coloring agents, and sweetening agents, as appropriate. Formulations for oral administration may also be suitably formulated to give controlled release of the active chaperone compound.

[0188] Pharmaceutical formulations of PC (e.g., migastat or its salts) suitable for parenteral / injectable use generally include sterile aqueous solutions (where water soluble) or dispersions for the extemporaneous preparation of sterile injectable solutions or dispersions, and sterile powders. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. The prevention of microbial action can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, benzyl alcohol, sorbic acid, and the like. In many cases, it will be advisable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0189] Sterile injectable solutions are prepared by blending the required amount of purified enzyme (if present) and PC (e.g., migalastat or its salts) in an appropriate solvent with various other ingredients as enumerated above, as needed, followed by filtration or terminal sterilization. Generally, dispersions are prepared by blending the various sterilized active ingredients in a sterile vehicle containing the basic dispersion medium and the other required ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying, which yield a powder of the active ingredient plus any additional desired ingredients from a previously sterile-filtered solution thereof.

[0190] The formulation may contain an excipient. Pharmaceutically acceptable excipients that may be included in the formulation include buffers, such as citrate buffer, phosphate buffer, acetate buffer, bicarbonate buffer, amino acids, urea, alcohols, ascorbic acid, and phospholipids; proteins such as serum albumin, collagen, and gelatin; salts such as EDTA or EGTA and sodium chloride; liposomes; polyvinylpyrrolidone; sugars such as dextran, mannitol, sorbitol, and glycerol; propylene glycol and polyethylene glycol (e.g., PEG-4000, PEG-6000); glycerol; glycine or other amino acids; and lipids. Buffer systems used with the formulation include citrate, acetate, bicarbonate, and phosphate buffers. Phosphate buffers are a preferred embodiment.

[0191] The route of administration of the chaperone compound can be oral or parenteral, including intravenous, subcutaneous, intra-arterial, intraperitoneal, intraocular, intramuscular, buccal, rectal, intravaginal, intraorbital, intracerebral, intradermal, intracranial, intraspinal, intraventricular, intrathecal, intracisternal, intravesicular, intrapulmonary, intranasal, transmucosal, transdermal, or by inhalation.

[0192] Administration of the chaperone compound in the parenteral formulations described above can be by periodic injection of a bolus of the formulation, or can be administered by intravenous or intraperitoneal administration from an external (e.g., an IV bag) or internal (e.g., a bioerodible implant) reservoir.

[0193] The embodiments relating to pharmaceutical formulations and administration may be combined with any of the other embodiments of the invention, such as embodiments relating to methods of treating patients with Fabry disease, embodiments relating to the use of a pharmacological chaperone for α-Gal A to manufacture a medicament for the treatment of patients diagnosed with Fabry disease, or embodiments relating to a pharmacological chaperone for α-Gal A for use in the treatment of patients diagnosed with Fabry disease, and embodiments relating to applicable mutations, PCs and suitable dosages thereof.

[0194] In one or more embodiments, the PC (e.g., migalastat or a salt thereof) is administered in combination with ERT. ERT increases the amount of protein by exogenously introducing a wild-type or biologically functional enzyme via infusion. As discussed above, this therapy has been developed for many genetic disorders, including LSDs such as Fabry disease. After infusion, the exogenous enzyme is assumed to be taken up by tissues via nonspecific or receptor-specific mechanisms. Generally, uptake efficiency is not high, and the circulation time of exogenous proteins is short. In addition, exogenous proteins are unstable, subject to rapid intracellular degradation, and there is also the possibility of adverse immune reactions with subsequent treatment. In one or more embodiments, a chaperone is administered simultaneously with the replacement enzyme (e.g., replacement α-Gal A). In some embodiments, the chaperone is formulated with the replacement enzyme (e.g., replacement α-Gal A).

[0195] Throughout this specification, the phrases "one embodiment," "particular embodiment," "various embodiments," "one or more embodiments," or "an embodiment" mean that the particular features, structures, materials, or characteristics described in connection with that embodiment are included in at least one embodiment of the invention. Thus, the appearance of phrases such as "in one or more embodiments," "particular embodiment," "various embodiments," "in one embodiment," or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment of the invention. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments.

[0196] Although the invention herein has been described with reference to detailed embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It will be apparent to those skilled in the art that various modifications and variations can be made in the method and apparatus of the present invention without departing from the spirit and scope of the invention. Therefore, it is intended that the present invention cover such modifications and variations provided they come within the scope of the appended claims and their equivalents. [Example]

[0197] Example: Effect of migalastat on α-Gal A mutations α-Gal A activity was measured in lysates prepared from HEK-293 cells transiently transfected with the indicated mutant forms of α-Gal A and incubated for 5 days in the absence or presence of 10 μM migalastat. α-Gal A activity is expressed as nanomoles of free 4-MU released per milligram of protein per hour (nmol / mg / hr). Baseline α-Gal A activity and α-Gal A activity after incubation with 10 μM migalastat were further expressed as a percentage of baseline wild-type α-Gal A activity (%WT). The wild-type α-Gal A activity used to calculate these percentages was the average activity measured in lysates from wild-type transfected cells incubated in the absence of migalastat, measured in parallel.

[0198] The results of α-Gal A activity testing for the novel mutations presented in Table 2 are shown in Table 7 below.

[0199] TIFF2025137509000072.tif207170

[0200] TIFF2025137509000073.tif216170

[0201] TIFF2025137509000074.tif216170

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[0227] In Table 7, mean ± standard error of the mean (SEM) values ​​were calculated. nmol / mg / hr indicates "nanomoles of free 4-MU released per mg of protein per hour." WT indicates "wild type." NC indicates "not calculable." N / A indicates "not applicable."

[0228] Baseline and 10 μM migalastat α-Gal A activity: Differences in α-Gal A activity between lysates incubated in the absence or presence of 10 μM migalastat were determined using a one-tailed Mann-Whitney U test; an increase at 10 μM migalastat of p<0.05 was considered significant. "BLD" indicates that the mean α-Gal A activity was below the limit of detection (<142 nmol / mg / hr).

[0229] Baseline α-Gal A activity (%WT) = (α-Gal A activity in mutant-transfected cell lysates without migalastat ÷ α-Gal A activity in wild-type-transfected cell lysates without migalastat) × 100.

[0230] 10 μM migalastat α-Gal A activity (%WT) = (α-Gal A activity in mutant transfected cell lysates incubated with 10 μM migalastat ÷ α-Gal A activity in wild-type transfected cell lysates without migalastat) × 100.

[0231] Absolute increase (%WT) = 10 μM migalastat α-Gal A activity (%WT) minus baseline α-Gal A activity (%WT).

[0232] Relative increase is 10 μM migalastat α-Gal A activity in mutant-transfected cell lysates divided by baseline α-Gal A activity in mutant-transfected cell lysates incubated without migalastat.

[0233] As can be seen from Table 7, the novel α-Gal A mutations listed in Table 2 demonstrated in vitro responses to incubation with migalastat that met the applicability criteria. Thus, patients with these mutations are likely treatable with migalastat therapy as described herein.

[0234] In some examples, a set of electronic components may communicate to determine a predicted outcome of using migalastat or a migalastat salt based on mutation data representing one or more mutations. The predicted outcome may be based, for example, on whether the mutations represented in the mutation data are identified in the data store and / or which data values ​​are associated with the identifying information in the data store.

[0235] 4 illustrates an exemplary interaction system 400 for generating a treatment classification based on mutation data. The illustrated components (e.g., systems) may communicate with each other through one or more networks (e.g., the Internet, a wide area network, a local area network, an internet or short-range connection).

[0236] The interaction system 400 may include a provider system 405 that may be associated with a provider providing medical care to a subject. Providers may include (for example) doctors, nurses, clinics, hospitals, etc. Subjects may include individuals (e.g., male or female) diagnosed or presumptively diagnosed with Fabry disease and / or diagnosed or presumptively diagnosed with a disorder related to α-Gal A activity. The provider system 405 may collect subject data corresponding to data from various sources. For example, some subject data may be collected locally as a result of information provided directly to the provider by the subject, such as demographic information, symptom profile, and / or treatment history. Some subject data may be initially collected and / or detected by a clinical laboratory system 410, such as urine culture data (e.g., indicating whether proteinuria, albuminuria, or lyso-Gb3 accumulation was detected in a urine sample from the subject) and / or blood test data (e.g., characterizing the activity of the α-galactosidase A enzyme and / or indicating whether Lyso-Gb3 accumulation was detected in a blood sample from the subject). Some subject data may have been collected by a sequencing system 415 that may sequence one or more genes and / or detect one or more mutations. For example, the GLA gene may be sequenced, and a mutation detection analysis may be performed to identify any mutations in the GLA gene (e.g., any single nucleotide polymorphisms or structural mutations). The sequencing system 415 may identify and / or describe the mutations as nucleotide mutations, protein sequence mutations, etc.

[0237] In some examples, the donor system 405 sends a subject's data request (e.g., along with the subject's identifier) ​​directly to the laboratory system 410 and / or the sequencing system 415, optionally along with an indication that the subject has authorized the donor to use the data (e.g., authorization granted by signature). In some examples, one or both of the laboratory system 410 and the sequencing system 415 transmit the subject data to a collaborative access control system 420 that controls and manages a central (e.g., remote and / or cloud-based) subject data store 425. The access control system 420 may perform data aggregation, synchronization, and authorization processes. For example, the access control system 420 may use whitelisting, blacklisting, cryptographic verification, and / or account verification techniques to determine whether to update the subject data store 425 based on data from a given system and / or whether to send requested data from the subject data store 425 to a given system. For example, the access control system 420 may require the use of a personal information link (supported by a shared secret key) between the provider system and the access control system in order to send any subject data to the provider system. As another example, the data synchronization process may—upon detection of inconsistent data—delete the old data value and use the new data value, store each of the old and new data values, assign trust to one or both of the old and new data values ​​(e.g., based on the trustworthiness of the data source, the extent to which the data value is represented in the patient population), etc.

[0238] The provider system 405 may send a request to the mutation classification system 430 to generate a predictive metric or predictive output for a subject. The request may include or be accompanied by at least a portion of the subject data, such as sequence data (e.g., corresponding to one or more genes) and / or mutation data (e.g., corresponding to one or more genes).

[0239] The predictive metric and / or predictive output may be predictive of whether and / or how effective a given treatment is likely to be in treating, delaying, and / or preventing a particular condition. For example, the predictive metric and / or predictive output may be predictive of whether and / or how effective administration of migalastat or a migalastat salt (e.g., generally at a particular dosage and / or via a particular route of administration) will be in treating Fabry disease.

[0240] The mutation classifier system 430 may, in some examples, include a web server 432, at least one data processor 433, and a non-transitory computer-readable storage medium 434. The web server 432 provides a web page that accepts input identifying mutation data. The web page may not require input of subject-identifying data. In some examples, the web page may be configured such that only the input fields for accepting subject-related data accept sequence data and / or mutation data. In some examples, the web page is configured to allow uploading of a file identifying a sequence. In some examples, the web page is configured to include an input component that accepts text input identifying a mutation. The web page may identify a format in which the mutation identification information should be expressed and / or a file format to be used for uploading the sequence data.

[0241] Upon receiving a communication corresponding to a predictive metric and / or predictive output request, the mutation classifier system 430 can determine whether the mutation identification information (and / or the uploaded sequence file) is in the correct format. In some embodiments, the determination of the appropriate format is performed by the data processor 433. For example, the format may require that a nucleotide mutation include a prefix letter (“c”) followed by a period (or this may be an optional component). The format may further require that the mutation identify the wild-type nucleotide, the nucleotide number, and the mutant nucleotide. The format may require (or allow) a ">" symbol and / or a particular order. For example, the allowed or required format may include the following components in the following order: (optionally “c.”), the nucleotide number, the wild-type nucleotide, ">", and the mutant nucleotide. As another example, the allowed or required format may include the following components in the following order: (optionally “c.”), the wild-type nucleotide, the nucleotide number, and the mutant nucleotide.

[0242] In some examples, if the mutation identifying information is not in a required or permitted format, the mutation classifier system 430 may return an error indication via the web server 432. In some examples, if the mutation identifying information provided in a first format is not in a required or permitted format, the mutation classifier system 430 may generate one or more suggested identifying information in a second format based on the input and transmit the suggested identifying information to be utilized by the provider system 205 (e.g., presented on a web page), so that one of the suggested identifying information in the second format can be selected or the suggested identifying information can guide subsequent input. The suggested identifying information in the second format may be generated by the data processor 433 by detecting numeric and / or alphabetic characters in the initial input in the first format and recognizing them in a manner consistent with the permitted or required format (and, for example, by adding or removing one or more characters such as "." or ">"). In examples where sequence data is received, the mutation classifier system 430 may identify one or more mutations by comparing the sequence to a reference sequence.

[0243] The mutation classifier system 430 and data processor 433 can query the applicable mutation data storage medium 435 with a representation of one or more mutations to obtain data corresponding to a predicted outcome of using each of one or more treatments by a subject having one or more mutations. The outcome can relate (for example) to efficacy and / or a low incidence of adverse effects. The one or more treatments can include migalastat or a migalastat salt. The outcome can include or be based on an observed outcome, such as one generated based on human or animal studies in which a treatment is administered to a subject having a mutation and the condition (e.g., the state of the condition, such as the state of Fabry disease) is monitored. Alternatively or additionally, the outcome can include or be based on a theoretical outcome, which can be based on in vitro experiments that indicate whether and / or to what extent administering an agent corresponding to the treatment to cells having the mutation will have a desired effect (e.g., increased α-Gal activity). In some examples, the applicable mutation data storage medium 435 indicates whether in vivo experiments / tests have been performed and analyzed (e.g., compared to only in vitro data or no data). In some examples, both in vivo and in vitro data are available for at least some of the mutations, and this paired data may be used to derive scaling factors and / or conversion functions for normalizing the data and / or converting the in vitro-based data to another scale.

[0244] The data processor 433 can retrieve query results from the applicable mutation data storage medium 435 and determine whether the query results indicate that one or more mutations are applicable to a given treatment.

[0245] The results of a given query may include one or more of: an indication as to whether the obtained data corresponds to in vivo data or to theoretical data (e.g., in vitro-based data); an indication as to whether the treatment is predicted to be effective given the frequency of mutations identified by the input; and / or a predicted magnitude (e.g., of efficacy, time course, or frequency of adverse events) of administering the treatment given the frequency of mutations identified by the input. The indication as to whether the treatment is predicted to be effective may include a binary indicator. A binary indicator may be determined based on whether the magnitude of the desired effect (as observed in in vivo or in vitro testing) exceeds a predetermined magnitude threshold (e.g., the median or mean of the treated and untreated data sets differs by at least 80%, 50%, 30%, 10%, or 5%), whether the p-value corresponding to the desired effect is below a predetermined p-value threshold (e.g., 0.1, 0.05, 0.02, 0.01, or 0.005), and / or whether the confidence value corresponding to the desired effect is below a predetermined confidence threshold (e.g., 70%, 80%, 90%, 95%, 98%, or 99%). A binary indicator may be determined based on whether the magnitude of the undesired effect (as observed in in vivo or in vitro testing) is below a predetermined magnitude threshold (e.g., the median or mean of the treated and untreated data sets differ by less than 80%, 50%, 30%, 10%, or 5%), whether the p-value corresponding to the undesired effect is above a predetermined p-value threshold (e.g., 0.1, 0.05, 0.02, 0.01, or 0.005), and / or whether the confidence value corresponding to the undesired effect is above a predetermined confidence threshold (e.g., 70%, 80%, 90%, 95%, 98%, or 99%). The predicted magnitude may correspond to a subtractive or multiplicative difference between the mean or median of the untreated and treated groups.

[0246] Additionally, the data processor 433 may generate an output indicating the applicability of a given treatment to one or more mutations, which output may be transmitted to and provided by the web server 432 and / or the provider system 205.

[0247] In some examples, the request corresponds to multiple mutations. The applicable mutation data storage medium 435 need not necessarily contain data corresponding to every possible mutation combination. Thus, the mutation classifier system 430 and data processor 433 may separately acquire data corresponding to each individual mutation. In some examples, the mutation classifier system 430 and data processor 433 then select data corresponding to a single mutation. The single mutation may correspond (for example) to the mutation with the most positive (e.g., consistent with a metric indicating the highest predicted efficacy and / or the lowest predicted adverse effect frequency or magnitude), the most negative, or the midpoint result among the multiple mutations. In some examples, individual mutations in the applicable mutation data storage medium 435 are assigned a rank, where a single mutation is identified as the mutation and selected as having the lowest relative rank (a lower rank is better than a higher rank). The rank may represent how dominant a mutation is in influencing disease treatment outcomes.

[0248] In some examples, one or more classifications are assigned to each of one or more mutations and / or to the collective mutation set (e.g., if multiple are identified in the input). For example, in some examples, the applicable mutation dataset 435 may identify one or more classifications for each represented mutation. The classification may correspond to (for example) a predicted magnitude of efficacy, a prediction as to whether a treatment is likely to result in any efficacy, a timescale of any efficacy, a predicted magnitude of adverse events, and / or a prediction as to whether a treatment is likely to result in any adverse events. In some examples, the classification corresponds to converting the numerical value of a single variable into a category of the same variable (using one or more thresholds). In some examples, the classification converts values ​​of multiple variables (e.g., corresponding to two or more of a predicted magnitude of efficacy, a predicted frequency of occurrence of the efficacy, a predicted magnitude of adverse events, and a predicted frequency of occurrence of adverse events) into a single variable. The clustering transformation function may be defined based on (for example) a clustering algorithm, component analysis (e.g., principal component analysis or independent component analysis), a neural network, and / or user input. The classifications may be represented in applicable mutation data storage medium 435 and / or determined by mutation classifier system 430. For example, applicable mutation data storage medium 435 may associate each mutation with one or more classifications, or applicable mutation data storage medium 435 may associate each mutation with one or more values ​​(e.g., numeric, binary, or even categorical values), which mutation classifier system 430 may process to identify the classifications.

[0249] Data store controller system 450 can control what data is included in applicable mutation data storage medium 435. For example, data store controller system 450 can authorize, receive, and evaluate communications indicative of experimental and / or test results from in vivo testing system 455 and / or in vitro testing system 460. The authorization process can include (for example) whitelisting the system and / or ensuring required authentication information is provided. In vivo testing system 455 can be configured to (for example) evaluate data corresponding to clinical trials (e.g., Phase I, Phase II, or Phase III trials) or data corresponding to experiments conducted on animals (human or non-human). In some examples, authorization information can further be used to resolve any data conflicts. For example, if multiple in vivo testing systems 455 submit conflicting results regarding whether (or how effective) a given treatment is when a particular mutation is detected, data store controller system 450 may use a priority list to determine which of the in vivo testing systems 455 to control. Data conflicts may be resolved by prioritizing test data (for example) performed according to clinical trial protocols, performed on humans, performed on mammals, and / or most recently performed. In vitro testing system 460 may be configured to evaluate data corresponding to (for example) cell culture experiments.

[0250] Upon receiving the results, the provider system 405 may (but need not) further process the results by considering additional subject data (e.g., unrelated to the genetic sequence data). Based on the results (and any additional data), the provider system 405 can identify an appropriate treatment strategy for the subject. The treatment may be selected as the treatment associated with the highest predicted efficacy (e.g., its mean, median, or probability), the lowest predicted incidence of adverse events (e.g., its mean, median, or probability), or a combination thereof. In some examples, the provider system 405 sends an order (e.g., a prescription) for the given treatment to the pharmacy system 465. The subject or another entity may administer the treatment to the patient.

[0251] FIG. 5 illustrates an exemplary process for generating predictive metrics using mutation data. Process 500 may be performed (for example) by mutation classifier system 430. Process 500 begins at block 505, where a dataset unit is accessed that stores a dataset identifying the degree of responsiveness to a particular type of treatment for each mutation in a mutation set. The degree of responsiveness may indicate (for example) the predicted magnitude of efficacy, the predicted frequency of efficacy, the predicted magnitude of adverse events, and / or the predicted frequency of adverse events. The type of treatment may include (for example) treatment with migalastat or migalastat salt. The degree of responsiveness may be limited to a particular subject group (e.g., having a given disease state and / or a mutation in a particular gene). The dataset may be derived from in vivo (e.g., human and / or non-human; primate and / or non-primate; mammalian and / or non-mammalian) studies and / or in vitro studies. The dataset may be accessed from one or more local or remote data stores.

[0252] At block 510, a communication is received identifying one or more specific mutations. For example, the specific mutations may include one or more nucleotide mutations and / or one or more protein mutations. The specific mutations may correspond to one or more genes. The communication may be received over a network and may have been generated in response to providing input on a web page. The specific mutations may correspond to a particular subject and may have been identified based on input from (for example) the subject, from the donor, and / or from a sequencing system.

[0253] At block 515, the dataset is queried with a representation of one or more specific mutations. The dataset may be local or remote to the computer system performing the query. The query may correspond to a request for data indicating the effect of administering a specific treatment to subjects with one, some, or all of the specific mutations. The query may (but need not) specify a specific treatment.

[0254] The dataset may include or be based on experimental data indicating whether or how much a particular treatment increases α-Gal A activity. More specifically, α-Gal A activity (e.g., mean or median activity) may be determined for wild-type cells; each of a set of mutant cells; and each of a set of treated mutant cells (treated with a particular treatment). The dataset may include each of these values. The dataset may include, for each of the mutant sets, a ratio or percentage comparing the α-Gal activity of the mutant cells (having the mutation) to the α-Gal activity of wild-type cells and / or a ratio or percentage comparing the α-Gal activity of the treated mutant cells to the α-Gal activity of wild-type cells.

[0255] The dataset may include, for each of the mutation sets, the absolute difference between the α-Gal activity of the treated mutant cells and the α-Gal activity of the untreated mutant cells and / or the absolute difference between the relative α-Gal activity (as compared to the wild-type instance) of the treated mutant cells and the relative α-Gal activity of the untreated mutant cells. The dataset may include, for each of the mutation sets, the relative difference calculated by subtracting the α-Gal activity of the untreated mutant cells from the α-Gal activity of the treated mutant cells, or by subtracting the relative α-Gal activity of the untreated mutant cells from the relative α-Gal activity (as compared to the wild-type instance) of the treated mutant cells.

[0256] The dataset may include, for each of the mutation sets, a categorical or binary indicator determined based on one of the aforementioned activity values, e.g., the activity change variable Δ is 治療済み,突然変異体 / activity WT -Active 未治療,突然変異体 / activity WT where activity is α-Gal activity. Categories may be defined as Δ≦1, 1<Δ≦5, 5<Δ≦10, 10<Δ≦20, and 20<Δ. As another example, a binary indicator can be set to "applicable" when Δ > threshold and "not applicable" when Δ≦threshold (e.g., where threshold is set to 1.0, 2.0, 5.0, or 10.0).

[0257] As another example, the activity change variable Δ is 100% x activity 治療済み,突然変異体 / activity 未治療,突然変異体 The categories may be defined as Δ≦100%, 100%<Δ≦105%, 105%<Δ≦110%, 110%<Δ≦150%, and 150%<Δ. As another example, a binary indicator may be set to "applicable" when Δ > threshold and "not applicable" when Δ≦threshold (e.g., where the threshold is set to 100%, 101%, 105%, or 110%).

[0258] In block 520, one or more results to the query may be detected. The query results may indicate the applicability of each of one or more treatments (e.g., migalastat and / or migalastat salts) to subjects with particular mutations. The query results may indicate the frequency and / or magnitude of the predicted effectiveness of administering the treatment and / or the incidence of adverse events. The query results may include a binary indication (e.g., indicating whether a particular treatment is applicable to each of the particular mutations) and / or a numeric or categorical value that more specifically indicates the applicability of a particular treatment to each of the particular mutations.

[0259] In some examples, the query results identify α-Gal A activity metrics associated with mutant, treated cells; mutant, untreated cells; and / or wild-type cells and / or absolute or relative differences between two or more of such cell types.

[0260] In block 525, a metric corresponding to the predicted effect of administering a treatment (e.g., a specific identified treatment) to a subject with a specific mutation is determined. The metric may include one or more query results and / or processed versions thereof. For example, a relative or absolute difference between α-Gal A activity in treated mutant cells compared to untreated mutant cells can be calculated (e.g., activity is absolute or relative to wild-type activity). Furthermore, the numerical result (or processed version thereof) can be converted into a categorical or binary metric. Furthermore, if multiple specific mutations are identified, the metric may be the maximum, minimum, mean, or median of the mutation-specific results. The metric may include the frequency and / or magnitude of the predicted effectiveness of administering the treatment and / or the incidence of adverse events.

[0261] At block 530, the metrics are output. Outputting the metrics may include (for example) transmitting the metrics to a provider system or subject device where they are displayed via an interface. Alternatively or additionally, outputting the metrics may include locally presenting and / or storing the metrics (e.g., associated with the subject's identifier and / or for a particular mutation).

[0262] In some cases, the metric itself indicates and / or is accompanied by an indication as to whether the metric is based on theoretical data and / or in vitro data. For example, a metric generated based on in vivo human data indicating that a treatment is effective in treating a given condition for a given mutation may be expressed differently than a metric generated solely based on in vitro or simulation data indicating similar efficacy in a similar context. Thus, in some cases, four possible metrics are available: applicable to treatment based on in vivo data; not applicable to treatment based on in vivo data; applicable to treatment based on in vitro data; and not applicable to treatment based on in vitro data. In some cases, the variable type differs between instances supported by in vivo data and other instances. For example, a metric may be a binary indicator when supported by in vivo data, but may be a categorical or numeric value in other cases.

[0263] 6 shows an exemplary process for generating a predictive output using mutation data. Process 600 may be performed by (for example) a mutation classifier system 430 including a web server 432, a data processor 433, and a storage medium 434. Process 600 begins at block 605, where an electronic communication corresponding to the identification of one or more specific mutations is received by the web server 432. This communication may be received as (for example) an HTTP request received in interaction with a web page. The specific mutations may (but need not) correspond to one or more specific genes.

[0264] At block 610, the applicable mutation data store is queried by the data processor 433 with specific mutation identification information. The applicable mutation data store may be local or remote to the computer system sending the query. The query may correspond to a request for data indicating the effect of administering a specific treatment to subjects with (one, some, or all) specific mutations. The query may (but need not) specify a specific treatment. The applicable mutation data storage medium 435 may include one or more data types and / or characteristics as described with respect to the data set queried at block 515 of process 500.

[0265] In some examples, applicable mutation data storage medium 435 selectively lists and / or stores data about mutations for which a given treatment (e.g., migalastat or migalastat salts) has been determined to be applicable. For example, a mutation may be selectively identified for inclusion in the applicable mutation data store when in vivo data indicates that the treatment is effective when the mutation is present and / or when in vitro data indicates that administering the treatment to cells having the mutation produces a desired effect (e.g., an increase in absolute α-Gal A activity by at least a threshold amount compared to untreated instances, or an increase in α-Gal A activity relative to wild-type instances compared to untreated mutant instances by at least a threshold amount).

[0266] At block 615, one or more results to the query may be detected by the data processor 433. The query result may indicate whether a particular treatment is applicable to a particular mutation (or each of a plurality of identified particular mutations). The query result may indicate whether there is a representation of the particular mutation in the applicable mutation data store, and / or the query result may include one or more values ​​associated with the identified particular mutation in the applicable mutation data store (e.g., indicating the effect of the treatment when the particular treatment is administered and / or indicating the type of experiment or test used to identify such effect).

[0267] At block 620, one or more outputs indicating the suitability of one or more treatments for subjects with specific mutations are generated by the data processor 433. The outputs can include or be generated based on query results. For example, if multiple specific mutations are being evaluated, the output can include query results or maximum, average, median, or minimum results for each of the specific mutations. By way of example, the output can indicate that multiple specific mutations collectively are amenable to treatment if the query results indicate that at least one of the specific mutations individually is amenable to treatment. The outputs can be numeric, binary, and / or categorical. In some examples, the numeric and / or categorical inputs represent increasing suitability as the predicted frequency and / or predicted magnitude of a benefit increases and / or as the predicted frequency and / or predicted magnitude of an adverse event increases.

[0268] In block 625, the output is sent by the data processor 433 to the web server 432 or the provider system 205. For example, the output can be sent to the provider system or the target device where it is displayed via an interface.

[0269] Figure 7 shows exemplary mutation representations used to facilitate evaluation of mutation-based effects. For example, two different formats for representing nucleotide mutations are presented. Each includes the wild-type amino acid (first amino acid) and mutant amino acid (second amino acid) and amino acid position. Thus, detecting whether a given character or string corresponds to an alphabetic character, a numeric character, a multi-digit number, etc., can indicate which of the above fields (if any) are represented by that character or string. This determination can facilitate automated or suggested mutation format conversions. The third column presents representations of various protein sequence mutations, which further convey the wild-type and mutant proteins and positions.

[0270] FIG. 8 shows an exemplary interface for facilitating mutation-based treatment classification. The illustrated interface provides information indicating the format in which mutations should be identified. In the illustrated example, the searched mutations do not conform to that format. The returned results suggest multiple mutation representations that may correspond to the input. The methods, systems, and devices discussed above are examples. Various configurations may omit, substitute, or add various procedures or components, as appropriate. For example, in alternative configurations, the methods may be performed in a different order than described, and / or various steps may be added, omitted, and / or combined. Also, features described with respect to particular configurations may be combined in various other configurations. Different aspects and elements of such configurations may be similarly combined. Also, technology evolves, and therefore many of the elements are examples and do not limit the scope of the disclosure or the claims.

[0271] In this description, specific details are provided to provide a thorough understanding of example aspects, including implementation aspects. However, the aspects may be practiced without these specific details. For example, well-known circuits, processes, algorithms, structures, and techniques are shown without unnecessary detail to avoid obscuring the aspects. This description merely provides example aspects and does not limit the scope, applicability, or configuration of the claims. Rather, the foregoing description of the aspects will provide one of ordinary skill in the art with a description of enablement requirements for practicing the described techniques. Various changes in the function and arrangement of elements may be made without departing from the spirit or scope of the present disclosure.

[0272] Also, aspects may be described as a process that is illustrated as a schematic flowchart or block diagram. While each operation may be described as a sequential process, many of these operations may be performed in parallel or simultaneously. In addition, the order of operations may be rearranged. A process may have additional operations not included in the figures. Furthermore, these method examples may be implemented by hardware, software, firmware, middleware, microcode, hardware description languages, or any combination thereof. When implemented in software, firmware, middleware, or microcode, the program code or code segments to perform the necessary tasks may be stored in a non-transitory computer-readable medium, such as a storage medium. A processor may perform the described tasks.

[0273] While several exemplary embodiments have been described, various modifications, alternative constructions, and equivalents may be used without departing from the spirit of this disclosure. For example, the above elements may be components of a larger system, where other rules may take precedence or the application of the technology may otherwise vary. Also, several actions may occur before, during, or after the above elements are considered. Therefore, the above description does not constrain the scope of the claims.

[0274] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to a "user" includes a plurality of such users, reference to "the processor" includes reference to one or more processors and equivalents thereof known to those skilled in the art, and so forth.

[0275] Also, the words "comprise," "including," "contain," "containing," "include," "comprises," and "includes," when used in this specification and the claims that follow, are intended to specify the presence of stated features, integers, components, or operations, but they do not exclude the presence or addition of one or more other features, integers, components, operations, acts, or groups.

[0276] The patents and scientific literature referred to herein establish knowledge available to those skilled in the art. All U.S. patents and published or unpublished U.S. patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are hereby incorporated by reference. All other published references, documents, articles and scientific literature cited herein are hereby incorporated by reference.

[0277] While the present invention has been particularly shown and described with reference to preferred embodiments thereof, those skilled in the art will understand that various changes in form and detail may be made therein without departing from the scope of the invention as encompassed by the appended claims. [Explanation of symbols]

[0278] 405 Provider System 410 Clinical Testing Systems 415 Sequencing System 420 Access Control System 425 Target Data 430 Mutation Classifier System 435 applicable mutation data 450 Data Store Controller System 455 In Vivo Test System 460 In Vitro Testing System 465 Pharmacy System 500 processes 505 Block 510 blocks 515 blocks 520 blocks 525 blocks 530 blocks 600 processes 605 Block 610 Block 615 blocks 620 Block 625 blocks

Claims

1. 1. A method of treating Fabry disease in a subject, comprising: accessing mutation information corresponding to the subject, the mutation information identifying one or more α-galactosidase A mutations; determining, based on the mutation information, that the subject has at least one mutation as identified in Table 2; and administering migalastat or a salt thereof to said subject determined to have at least one mutation as identified in Table 2. A method comprising:

2. Determining that the subject has at least one mutation as identified in Table 2 includes: initiating a query to the data store to identify two or more mutations from the mutation set identified in Table 2; and receiving the mutation information and also a query result identifying a representation of the at least one mutation in Table 2; The method of claim 1 , comprising:

3. The method of claim 2 , wherein the data store further identifies two or more mutations from another mutation set identified in Table 1.

4. 4. The method of claim 2 or 3, wherein the data store comprises at least 50% of the mutation set identified in Table 2.

5. 5. The method of claim 2, wherein the query is initiated by accessing a specific web page hosted by a web server that controls a data store that identifies at least some of the mutations in Table 2.

6. The inquiry is Accessing certain web pages on the Website; providing an input at the particular web page identifying at least a portion of the mutation information; and selecting an option on the web page to send to a web server an electronic request for performance of the query, the electronic request including a representation of the input; Initiated by; The method of any one of claims 2 to 4, wherein the query results are received from the web server in response to the query and displayed on the particular web page or another web page on the website.

7. The at least one mutation may be at amino acid residues 5-14, 17-18, 20-30, 32-33, 36-39, 41, 43, 45-46, 48, 50-51, 53-56, 58-62, 64-89, 91, 96-99, 101-102, 104-110, 113-117, 121, 123-131, 133, 135-141, 143-153, 156-162, 164-167, 169, 171, 173, 175-178, 180-182, 184-201, 203, 204, 206-222, 224, 227-230, 232-233, 235, 7. The method of any one of claims 1-6, comprising one or more mutations at 237-261, 263-265, 267-270, 272-273, 275, 277-278, 280-286, 288-289, 291-292, 294-295, 297-300, 302-304, 306-322, 324-327, 329-339, 341, 343-344, 346-357, 359, 362-371, 373-377, 379-381, 383-388, 391-425, 427, 429, or any combination thereof, wherein the residues are numbered with respect to SEQ ID NO:

2.

8. 7. The method of any one of claims 1 to 6, wherein the at least one mutation comprises one or more mutations at amino acid residues 5-14, 17-18, 20-30, 32-33, 36-39, 41, 43, 45-46, 48, 50-51, 53-56, 58-62, 64-89, 91, 96-99 of α-galactosidase A, or any combination thereof, wherein the residues are numbered with respect to SEQ ID NO:

2.

9. 7. The method of any one of claims 1 to 6, wherein the at least one mutation comprises one or more mutations at amino acid residues 101-102, 104-110, 113-117, 121, 123-131, 133, 135-141, 143-153, 156-162, 164-167, 169, 171, 173, 175-178, 180-182, 184-201 of α-galactosidase A, or any combination thereof, wherein the residues are numbered with respect to SEQ ID NO:

2.

10. 7. The method of any one of claims 1 to 6, wherein the at least one mutation comprises one or more mutations at amino acid residues 203, 204, 206-222, 224, 227-230, 232-233, 235, 237-261, 263-265, 267-270, 272-273, 275, 277-278, 280-286, 288-289, 291-292, 294-295, 297-300 of α-galactosidase A, or any combination thereof, wherein the residues are numbered with respect to SEQ ID NO:

2.

11. 7. The method of any one of claims 1 to 6, wherein the at least one mutation comprises one or more mutations at amino acid residues 302-304, 306-322, 324-327, 329-339, 341, 343-344, 346-357, 359, 362-371, 373-377, 379-381, 383-388 of α-galactosidase A, or any combination thereof, wherein the residues are numbered with respect to SEQ ID NO:

2.

12. 7. The method of any one of claims 1 to 6, wherein the at least one mutation comprises one or more mutations at amino acid residues 391 to 425, 427, 429, or any combination thereof, of α-galactosidase A, the residues being numbered with respect to SEQ ID NO:

2.

13. The at least one mutation is mutations at amino acid residue 5, including N5D or N5K; a mutation at amino acid residue 6, including P6L, P6Q, P6R, P6S, or P6T; mutations at amino acid residue 7, including E7D, E7K, and E7V; mutations at amino acid residue 8, including L8I, L8P, and L8Q; mutations at amino acid residue 9, including H9L, H9Q, H9R, or H9Y; a mutation at amino acid residue 10, including L10M, L10P, L10Q, L10R, or L10V; a mutation at amino acid residue 11, including G11C, G11D, G11R, G11S, or G11V; a mutation at amino acid residue 12, including C12G, C12R, C12S, or C12Y; mutations at amino acid residue 13, including A13E or A13G; a mutation at amino acid residue 14, including L14F, L14H, or L14V; a mutation at amino acid residue 17, including R17C, R17G, R17H, R17P, or R17S; a mutation at amino acid residue 18, including F18I or F18L; mutations at amino acid residue 20, including A20G; mutations at amino acid residue 21, including L21H; a mutation at amino acid residue 22, including V22A, V22F, V22I, or V22L; mutations at amino acid residue 23, including S23P or S23T; a mutation at amino acid residue 24, including W24S; or Mutations at amino acid residue 25, including D25H wherein the residues are numbered with respect to SEQ ID NO:

2.

14. The at least one mutation is mutations at amino acid residue 26, including I26N; a mutation at amino acid residue 27, including P27A, P27L, P27S, or P27T; a mutation at amino acid residue 28, including G28E, G28R, or G28W; a mutation at amino acid residue 29, including A29G, A29P, or A29V; Mutations at amino acid residue 30, including R30G; a mutation at amino acid residue 32, including L32M, L32Q, L32R, or L32V; a mutation at amino acid residue 33, including D33A, D33E, or D33V; mutations at amino acid residue 36, including L36M or L36V; a mutation at amino acid residue 37, including A37E, A37G, or A37S; a mutation at amino acid residue 38, including R38G, R38M, or R38W; a mutation at amino acid residue 39, including T39A, T39K, T39M, T39R, or T39S; a mutation at amino acid residue 41, including T41A, T41N, or T41S; mutations at amino acid residue 43, including G43A; a mutation at amino acid residue 45, including L45M or L45V; mutations at amino acid residue 46, including H46D, H46N, or H46Q; a mutation at amino acid residue 48, including E48A; or Mutations at amino acid residue 50, including F50Y wherein the residues are numbered with respect to SEQ ID NO:

2.

15. The at least one mutation is a mutation at amino acid residue 51, including M51R, M51T, or M51V; a mutation at amino acid residue 53, including N53H, N53I, N53S, or N53T; a mutation at amino acid residue 54, including L54H, L54R, or L54V; a mutation at amino acid residue 55, including D55A, D55E, D55H, or D55Y; mutations at amino acid residue 56, including C56W; mutations at amino acid residue 58, including E58K; a mutation at amino acid residue 59, including E59A, E59D, E59G, E59Q, or E59V; a mutation at amino acid residue 60, including P60A, P60Q, or P60R; a mutation at amino acid residue 61, including D61E or D61V; a mutation at amino acid residue 62, including S62A, S62C, S62F, S62P, or S62Y; a mutation at amino acid residue 64, including I64L or I64V; a mutation at amino acid residue 65, including S65C, S65G, or S65R; a mutation at amino acid residue 66, including E66D or E66V; a mutation at amino acid residue 67, including K67E, K67M, K67N, K67Q, or K67T; mutations at amino acid residue 68, including L68I; mutations at amino acid residue 69, including F69I or F69Y; a mutation at amino acid residue 70, including M70I, M70K, M70L, or M70R; a mutation at amino acid residue 71, including E71A, E71D, E71G, E71Q, or E71V; a mutation at amino acid residue 72, including M72L or M72T; a mutation at amino acid residue 73, including A73S or A73T; A mutation at amino acid residue 74, including E74D, E74G, E74K, or E74V; or Mutations at amino acid residue 75, including L75F or L75P wherein the residues are numbered with respect to SEQ ID NO:

2.

16. The at least one mutation is mutations at amino acid residue 76, including M76V; a mutation at amino acid residue 77, including V77I or V77L; mutations at amino acid residue 78, including S78L or S78P; a mutation at amino acid residue 79, including E79A, E79D, E79G, E79K, E79Q, or E79V; a mutation at amino acid residue 80, including G80A, G80C, or G80S; mutations at amino acid residue 81, including W81L; a mutation at amino acid residue 82, including K82E, K82M, K82N, K82R, or K82T; a mutation at amino acid residue 83, including D83A, D83E, D83G, or D83V; a mutation at amino acid residue 84, including A84E, A84G, A84P, A84S, A84T, or A84V; a mutation at amino acid residue 85, including G85A, G85C, or G85R; mutations at amino acid residue 86, including Y86F; mutations at amino acid residue 87, including E87G; mutations at amino acid residue 88, including Y88H or Y88N; mutations at amino acid residue 89, including L89V; a mutation at amino acid residue 91, including I91F, I91L, I91M, or I91S; mutations at amino acid residue 96, including M96L or M96T; a mutation at amino acid residue 97, including A97D, A97S, or A97T; a mutation at amino acid residue 98, including P98H, P98L, or P98R; or Mutations at amino acid residue 99, including Q99E, Q99L, Q99P, or Q99R wherein the residues are numbered with respect to SEQ ID NO:

2.

17. The at least one mutation is mutations at amino acid residue 101, including D101A, D101E, D101G, D101H, D101V; a mutation at amino acid residue 102, including S102A, S102P, or S102T; a mutation at amino acid residue 104, including G104A, G104D, or G104S; a mutation at amino acid residue 105, including R105G, R105I, R105K, or R105T; a mutation at amino acid residue 106, including L106H, L106I, L106P, or L106V; a mutation at amino acid residue 107, including Q107E, Q107H, or Q107K; a mutation at amino acid residue 108, including A108E or A108V; a mutation at amino acid residue 109, including D109A, D109E, D109H, D109N, or D109Y; mutations at amino acid residue 110, including P110T; a mutation at amino acid residue 113, including F113V or F113Y; mutations at amino acid residue 114, including P114L; a mutation at amino acid residue 115, including H115D or H115N; a mutation at amino acid residue 116, including G116R; a mutation at amino acid residue 117, including I117M or I117T; mutations at amino acid residue 121, including A121V; a mutation at amino acid residue 123, including Y123D, Y123F, Y123N, or Y123S; a mutation at amino acid residue 124, including V124I; or Mutations at amino acid residue 125, including H125D, H125N, or H125R wherein the residues are numbered with respect to SEQ ID NO:

2.

18. The at least one mutation is a mutation at amino acid residue 126, including S126C or S126I; mutations at amino acid residue 127, including K127E; mutations at amino acid residue 128, including G128A; a mutation at amino acid residue 129, including L129V; a mutation at amino acid residue 130, including K130M, K130N, or K130Q; mutations at amino acid residue 131, including L131V; a mutation at amino acid residue 133, including I133L, I133T, or I133V; a mutation at amino acid residue 135, including A135E, A135G, A135S, or A135T; a mutation at amino acid residue 136, including D136A, D136N, or D136V; a mutation at amino acid residue 137, including V137A, V137D, V137G, V137I, or V137L; mutations at amino acid residue 138, including G138A; a mutation at amino acid residue 139, including N139H, N139I, N139K, or N139Y; a mutation at amino acid residue 140, including K140E, K140I, K140N, K140Q, or K140R; mutations at amino acid residue 141, including T141S; a mutation at amino acid residue 143, including A143E or A143G; a mutation at amino acid residue 144, including G144A, G144C, G144R, or G144S; a mutation at amino acid residue 145, including F145C, F145L, F145V, or F145Y; a mutation at amino acid residue 146, including P146A, P146H, P146L, or P146T; mutations at amino acid residue 147, including G147A; a mutation at amino acid residue 148, including S148C, S148G, or S148T; a mutation at amino acid residue 149, including F149C; or Mutations at amino acid residue 150, including G150E or G150V wherein the residues are numbered with respect to SEQ ID NO:

2.

19. The at least one mutation is a mutation at amino acid residue 151, including Y151C, Y151D, or Y151S; a mutation at amino acid residue 152, including Y152F or Y152S; a mutation at amino acid residue 153, including D153A, D153H, D153N, D153V, or D153Y; mutations at amino acid residue 156, including A156G; a mutation at amino acid residue 157, including Q157E, Q157K, Q157L, or Q157P; a mutation at amino acid residue 158, including T158A, T158I, T158N, or T158S; a mutation at amino acid residue 159, including F159I, F159L, F159V, or F159Y; a mutation at amino acid residue 160, including A160G, A160S, A160T, or A160V; a mutation at amino acid residue 161, including D161H, D161N, D161V, or D161Y; mutations at amino acid residue 162, including W162S; a mutation at amino acid residue 164, including V164A, V164I, or V164L; a mutation at amino acid residue 165, including D165A or D165E; a mutation at amino acid residue 166, including L166M or L166Q; mutations at amino acid residue 167, including L167I; a mutation at amino acid residue 169, including F169C, F169L, F169V, or F169Y; a mutation at amino acid residue 171, including G171A or G171V; a mutation at amino acid residue 173, including Y173C, Y173F, Y173H, or Y173S; or Mutations at amino acid residue 175, including D175G, D175H, D175V, or D175Y wherein the residues are numbered with respect to SEQ ID NO:

2.

20. The at least one mutation is a mutation at amino acid residue 176, including S176C or S176R; a mutation at amino acid residue 177, including L177F, L177M, L177S, L177V, or L177W; a mutation at amino acid residue 178, including E178A, E178G, E178K, or E178Q; a mutation at amino acid residue 180, including L180M or L180S; a mutation at amino acid residue 181, including A181P, A181T, or A181V; a mutation at amino acid residue 182, including D182A, D182E, D182V, or D182Y; a mutation at amino acid residue 184, including Y184F, Y184H, or Y184S; a mutation at amino acid residue 185, including K185M, K185N, K185Q, or K185T; a mutation at amino acid residue 186, including H186D, H186L, H186N, H186Q, or H186Y; mutations at amino acid residue 187, including M187L; a mutation at amino acid residue 188, including S188A, S188C, S188F, S188P, S188T, or S188Y; a mutation at amino acid residue 189, including L189S or L189V; a mutation at amino acid residue 190, including A190D, A190G, A190S, A190T, or A190V; a mutation at amino acid residue 191, including L191M or L191V; a mutation at amino acid residue 192, including N192D, N192H, N192K, N192S, or N192T; a mutation at amino acid residue 193, including R193G, R193M, R193T, or R193W; a mutation at amino acid residue 194, including T194N, T194P, or T194S; a mutation at amino acid residue 195, including G195C, G195R, or G195S; mutations at amino acid residue 196, including R196I or R196K; a mutation at amino acid residue 197, including S197C, S197G, S197I, S197N, or S197T; a mutation at amino acid residue 198, including I198M or I198S; a mutation at amino acid residue 199, including V199E or V199L; or Mutations at amino acid residue 200, including Y200N or Y200S wherein the residues are numbered with respect to SEQ ID NO:

2.

21. The at least one mutation is a mutation at amino acid residue 201, including S201A, S201C, or S201T; a mutation at amino acid residue 203, including E203A, E203G, or E203Q; a mutation at amino acid residue 204, including W204S; a mutation at amino acid residue 206, including L206F, L206H, L206I, L206R, or L206V; mutations at amino acid residue 207, including Y207F; mutations at amino acid residue 208, including M208K; a mutation at amino acid residue 209, including W209C or W209G; a mutation at amino acid residue 210, including P210H or P210T; a mutation at amino acid residue 211, including F211C, F211L, F211S, F211V, or F211Y; a mutation at amino acid residue 212, including Q212H or Q212P; mutations at amino acid residue 213, including K213E or K213Q; a mutation at amino acid residue 214, including P214A, P214H, P214R, or P214T; a mutation at amino acid residue 215, including N215H, N215K, N215T, or N215Y; a mutation at amino acid residue 216, including Y216F, Y216H, or Y216N; a mutation at amino acid residue 217, including T217A, T217I, T217K, T217P, T217R, or T217S; a mutation at amino acid residue 218, including E218A, E218D, E218G, E218K, E218Q, or E218V; a mutation at amino acid residue 219, including I219F, I219M, or I219S; mutations at amino acid residue 220, including R220L; a mutation at amino acid residue 221, including Q221E, Q221H, Q221K, Q221L, or Q221R; a mutation at amino acid residue 222, including Y222C, Y222D, Y222H, Y222N, or Y222S; or Mutations at amino acid residue 224, including N224H wherein the residues are numbered with respect to SEQ ID NO:

2.

22. The at least one mutation is mutations at amino acid residue 227, including R227G; a mutation at amino acid residue 228, including N228H, N228I, or N228T; a mutation at amino acid residue 229, including F229I, F229S, or F229Y; a mutation at amino acid residue 230, including A230D, A230G, A230P, or A230V; a mutation at amino acid residue 232, including I232L, I232M, or I232V; a mutation at amino acid residue 5, including D233A, D233E, D233G, or D233V; a mutation at amino acid residue 235, including S235A or S235T; mutations at amino acid residue 237, including K237I; a mutation at amino acid residue 238, including S238C, S238I, or S238T; mutations at amino acid residue 239, including I239L; a mutation at amino acid residue 240, including K240E, K240M, or K240R; a mutation at amino acid residue 241, including S241C, S241I, or S241T; a mutation at amino acid residue 242, including I242L, I242M, or I242S; a mutation at amino acid residue 243, including L243M, L243S, or L243V; a mutation at amino acid residue 244, including D244A, D244E, D244G, D244V, or D244Y; mutations at amino acid residue 245, including W245C; a mutation at amino acid residue 246, including T246A, T246I, T246K, or T246R; a mutation at amino acid residue 247, including S247A, S247F, S247T, or S247Y; a mutation at amino acid residue 248, including F248C, F248L, F248V, or F248Y; a mutation at amino acid residue 249, including N249D, N249H, N249I, N249S, N249T, or N249Y; Mutations at amino acid residue 250, including Q250E or Q250L wherein the residues are numbered with respect to SEQ ID NO:

2.

23. The at least one mutation is a mutation at amino acid residue 251, including E251G, E251K, E251Q, or E251V; mutations at amino acid residue 252, including R252G; a mutation at amino acid residue 253, including I253F, I253N, or I253V; a mutation at amino acid residue 254, including V254A, V254D, V254F, or V254G; a mutation at amino acid residue 255, including D255A, D255E, D255H, D255N, D255V, or D255Y; a mutation at amino acid residue 256, including V256D, V256G, or V256L; mutations at amino acid residue 257, including A257S; mutations at amino acid residue 258, including G258E; a mutation at amino acid residue 259, including P259A or P259T; a mutation at amino acid residue 260, including G260W; mutations at amino acid residue 261, including G261A; a mutation at amino acid residue 263, including N263H or N263T; a mutation at amino acid residue 264, including D264H or D264N; a mutation at amino acid residue 265, including P265A or P265Q; a mutation at amino acid residue 267, including M267L or M267V; a mutation at amino acid residue 268, including L268F or L268I; mutations at amino acid residue 269, including V269L; a mutation at amino acid residue 270, including I270L, I270S, or I270V; mutations at amino acid residue 272, including N272D; a mutation at amino acid residue 273, including F273Y; or Mutations at amino acid residue 275, including L275I wherein the residues are numbered with respect to SEQ ID NO:

2.

24. The at least one mutation is mutations at amino acid residue 277, including W277L; mutations at amino acid residue 278, including N278I; a mutation at amino acid residue 280, including Q280L or Q280R; a mutation at amino acid residue 281, including V281A, V281E, V281G, or V281L; mutations at amino acid residue 282, including T282S; a mutation at amino acid residue 283, including Q283E, Q283H, or Q283L; a mutation at amino acid residue 284, including M284I or M284L; a mutation at amino acid residue 285, including A285G, A285T, or A285V; a mutation at amino acid residue 286, including L286F, L286H, or L286V; a mutation at amino acid residue 288, including A288G, A288S, or A288V; a mutation at amino acid residue 289, including I289L, I289T, or I289V; mutations at amino acid residue 291, including A291G; a mutation at amino acid residue 292, including A292G or A292S; a mutation at amino acid residue 294, including L294F, L294I, or L294V; a mutation at amino acid residue 295, including F295I, F295S, F295V, or F295Y; mutations at amino acid residue 297, including S297T; mutations at amino acid residue 298, including N298D, N298I, or N298T; a mutation at amino acid residue 299, including D299H or D299N; or Mutations at amino acid residue 300, including L300I or L300V wherein the residues are numbered with respect to SEQ ID NO:

2.

25. The at least one mutation is a mutation at amino acid residue 302, including H302D, H302L, H302N, or H302Y; mutations at amino acid residue 303, including I303S; mutations at amino acid residue 304, including S304I; a mutation at amino acid residue 306, including Q306E, Q306L, or Q306P; a mutation at amino acid residue 307, including A307D, A307G, A307P, A307S, or A307V; a mutation at amino acid residue 308, including K308I, K308Q, or K308R; a mutation at amino acid residue 309, including A309D or A309T; mutations at amino acid residue 310, including L310I; mutations at amino acid residue 311, including L311I; a mutation at amino acid residue 312, including Q312E, Q312K, or Q312L; a mutation at amino acid residue 313, including D313E or D313V; a mutation at amino acid residue 314, including K314E, K314M, K314N, or K314T; a mutation at amino acid residue 315, including D315A, D315G, D315H, D315N, D315V, or D315Y; a mutation at amino acid residue 316, including V316A or V316L; a mutation at amino acid residue 317, including I317L, I317M, or I317V; a mutation at amino acid residue 318, including A318D, A318P, A318T, or A318V; mutations at amino acid residue 319, including I319M; a mutation at amino acid residue 320, including N320S or N320T; mutations at amino acid residue 321, including Q321K; a mutation at amino acid residue 322, including D322A or D322V; a mutation at amino acid residue 324, including L324V or L324W; or Mutations at amino acid residue 325, including G325A, G325C, or G325V wherein the residues are numbered with respect to SEQ ID NO:

2.

26. The at least one mutation is a mutation at amino acid residue 326, including K326E, K326M, K326Q, K326R, or K326T; a mutation at amino acid residue 327, including Q327H or Q327P; a mutation at amino acid residue 329, including Y329C, Y329D, Y329F, Y329H, or Y329N; a mutation at amino acid residue 330, including Q330E, Q330H, or Q330K; a mutation at amino acid residue 331, including L331H, L331P, L331R, or L331V; a mutation at amino acid residue 332, including R332G, R332I, R332S, or R332T; a mutation at amino acid residue 333, including Q333E, Q333L, Q333P, or G334R; a mutation at amino acid residue 334, including G334V; a mutation at amino acid residue 335, including D335A, D335E, D335G, D335V, or D335Y; a mutation at amino acid residue 336, including N336D, N336I, N336S, N336T, or N336Y; a mutation at amino acid residue 337, including F337C, F337L, F337V, or F337Y; a mutation at amino acid residue 338, including E338A, E338D, or E338G; mutations at amino acid residue 339, including V339M; mutations at amino acid residue 341, including E341A, E341Q; a mutation at amino acid residue 343, including P343A or P343S; a mutation at amino acid residue 344, including L344F, L344R, or L344V; a mutation at amino acid residue 346, including G346A, G346C, G346D, or G346V; mutations at amino acid residue 347, including L347I; mutations at amino acid residue 348, including A348D; a mutation at amino acid residue 349, including W349C or W349L; or Mutations at amino acid residue 350, including A350G, A350S, A350T, and A350V wherein the residues are numbered with respect to SEQ ID NO:

2.

27. The at least one mutation is a mutation at amino acid residue 351, including V351A or V351E; a mutation at amino acid residue 352, including A352S or A352T; a mutation at amino acid residue 353, including M353K, M353L, or M353T; mutations at amino acid residue 354, including I354R; a mutation at amino acid residue 355, including N355D, N355H, N355S, or N355Y; mutations at amino acid residue 356, including R356L; mutations at amino acid residue 357, including Q357E; a mutation at amino acid residue 359, including I359F, I359L, I359N, I359S, or I359V; a mutation at amino acid residue 362, including P362A, P362H, P362R, or P362S; a mutation at amino acid residue 363, including R363G, R363L, or R363S; a mutation at amino acid residue 364, including S364C or S364P; a mutation at amino acid residue 365, including Y365D, Y365F, Y365N, or Y365S; a mutation at amino acid residue 366, including T366I, T366N, T366P, or T366S; a mutation at amino acid residue 367, including I367F, I367L, or I367M; a mutation at amino acid residue 368, including A368G or A368P; a mutation at amino acid residue 369, including V369A, V369F, V369G, V369I, or V369L; a mutation at amino acid residue 370, including A370D, A370G, A370P, A370T, or A370V; a mutation at amino acid residue 371, including S371C or S371T; a mutation at amino acid residue 373, including G373A or G373C; a mutation at amino acid residue 374, including K374E, K374I, K374R, or K374T; or Mutations at amino acid residue 375, including G375R wherein the residues are numbered with respect to SEQ ID NO:

2.

28. The at least one mutation is a mutation at amino acid residue 376, including V376E, V376G, V376L, or V376M; a mutation at amino acid residue 377, including A377G, A377P, A377S, or A377T; a mutation at amino acid residue 379, including N379D, N379I, N379K, or N379T; a mutation at amino acid residue 380, including P380A, P380H, P380R, or P380T; mutations at amino acid residue 381, including A381D; a mutation at amino acid residue 383, including F383C, F383I, or F383Y; a mutation at amino acid residue 384, including I384F, I384M, or I384T; mutations at amino acid residue 385, including T385I; a mutation at amino acid residue 386, including Q386H, Q386K, or Q386L; a mutation at amino acid residue 387, including L387F, L387H, L387I, or L387R; a mutation at amino acid residue 388, including L388F, L388H, L388I, L388R, or L388V; a mutation at amino acid residue 391, including K391I, K391N, K391Q, or K391R; a mutation at amino acid residue 392, including R392G, R392K, R392M, or R392W; a mutation at amino acid residue 393, including K393E, K393N, K393Q, or K393T; a mutation at amino acid residue 394, including L394I, L394Q, or L394R; a mutation at amino acid residue 395, including G395R; a mutation at amino acid residue 396, including F396C, F396I, F396L, or F396V; a mutation at amino acid residue 397, including Y397C, Y397F, Y397H, Y397N, or Y397S; or a mutation at amino acid residue 398, including E398G or E398Q; a mutation at amino acid residue 394, including W399G or W399R; Mutations at amino acid residue 400, including T400A, T400I, T400N, T400P, or T400S wherein the residues are numbered with respect to SEQ ID NO:

2.

29. The at least one mutation is a mutation at amino acid residue 401, including S401A, S401L, or S401T; a mutation at amino acid residue 402, including R402G, R402M, R402S, R402T, or R402W; a mutation at amino acid residue 403, including L403F or L403V; a mutation at amino acid residue 404, including R404G, R404I, R404K, R404S, or R404T; mutations at amino acid residue 405, including S405G; a mutation at amino acid residue 406, including H406D, H406L, or H406Q; a mutation at amino acid residue 407, including I407L, I407M, or I407T; a mutation at amino acid residue 408, including N408D, N408H, or N408T; a mutation at amino acid residue 409, including P409L; mutations at amino acid residue 410, including T410S; a mutation at amino acid residue 411, including G411A, G411C, or G411V; a mutation at amino acid residue 412, including T412A, T412I, or T412S; a mutation at amino acid residue 413, including V413F, V413G, or V413I; a mutation at amino acid residue 414, including L414F or L414V; a mutation at amino acid residue 415, including L415H or L415I; a mutation at amino acid residue 416, including Q416E, Q416H, or Q416L; mutations at amino acid residue 417, including L417I; a mutation at amino acid residue 418, including E418A, E418D, E418K, or E418Q; a mutation at amino acid residue 419, including N419I, N419S, N419T, or N419Y; a mutation at amino acid residue 420, including T420K, T420P, T420R, or T420S; a mutation at amino acid residue 421, including M421I, M421K, M421L, M421R, or M421T; a mutation at amino acid residue 422, including Q422P; a mutation at amino acid residue 423, including M423I, M423K, M423L, or M423T; mutations at amino acid residue 424, including S424L; mutations at amino acid residue 425, including L425F; a mutation at amino acid residue 427, including D427N; or Mutations at amino acid residue 429, including L429R wherein the residues are numbered with respect to SEQ ID NO:

2.

30. 30. The method of any one of claims 1 to 29, wherein administering migalastat or a salt thereof comprises administering migalastat or a salt thereof to the subject every other day.

31. 31. The method of any one of claims 1 to 30, wherein administering migalastat or a salt thereof comprises administering to the subject a dose of about 100 to about 150 mg free base equivalent of the migalastat or a salt thereof.

32. 32. The method of any one of claims 1 to 31, wherein administering migalastat or a salt thereof comprises administering to the subject a dose of about 123 mg free base equivalent of the migalastat or a salt thereof.

33. The method of any one of claims 1 to 32, wherein the migalastat or a salt thereof enhances α-galactosidase A activity in the subject.

34. 34. The method of any one of claims 1 to 33, wherein the at least one mutation comprises a HEK assay-applicable mutation in α-galactosidase A.

35. The method of any one of claims 1 to 34, wherein the migalastat or a salt thereof is administered orally.

36. The method of any one of claims 1 to 34, wherein the migalastat or a salt thereof is administered by injection.

37. receiving an electronic communication corresponding to the identification of the specific mutation; querying a data storage medium with the identification of the particular mutation, the data storage medium including an identification of each of a set of applicable mutations, each of the set of applicable mutations corresponding to a mutation listed in Table 2; detecting a result of the query, the result indicating whether there is a representation of the particular mutation in the applicable mutation set; generating an output based on the response that indicates the suitability of treating the subject having the particular mutation with migalastat or a migalastat salt; and transmitting said output; 10. A computer-implemented method comprising:

38. The electronic communication includes the identification of the specific mutation in a first format, and the method further comprises: determining that the first format is different from a second format used by the data store; extracting one or more components from said identification information; generating second identification information based on the components, the second identification information being in the second format; transmitting said second identification information; and receiving a second electronic communication indicating that the second identification information corresponds to the first identification information, the data storage medium being queried in response to receiving the second electronic communication; 38. The method of claim 37, further comprising:

39. 39. The method of claim 37 or 38, wherein the data storage medium further includes identification information of a second applicable mutation set, each of the second applicable mutation set corresponding to a mutation listed in Table 1, and the result further indicates whether there is a representation of the particular mutation in the second applicable mutation set.

40. 40. The method of any one of claims 37 to 39, wherein the result comprises a binary indication as to whether migalastat or a migalastat salt is a suitable treatment for the condition caused by the particular mutation.

41. transmitting web page data to a user device, wherein the electronic communication is received from the user device, the web page data corresponds to a web page, and the identification of the specific mutation corresponds to an input detected on the web page. The method of any one of claims 37 to 40, further comprising:

42. 42. The method of any one of claims 37 to 41, wherein the data storage medium identifies at least 90% of the mutations listed in Table 2.

43. one or more data processors; A non-transitory computer-readable storage medium that, when executed on the one or more data processors, receiving an electronic communication corresponding to the identification of the specific mutation; querying a data storage medium with the identification of the particular mutation, the data storage medium including an identification of each of a set of applicable mutations, each of the set of applicable mutations corresponding to a mutation listed in Table 2; detecting a result of the query, the result indicating whether there is a representation of the particular mutation in the applicable mutation set; generating an output based on the response that indicates the suitability of treating the subject having the particular mutation with migalastat or a migalastat salt; and transmitting said output; a non-transitory computer-readable storage medium storing instructions that cause the one or more data processors to perform actions including: A system including:

44. The electronic communication includes the identification of the specific mutation in a first format, and the action is: determining that the first format is different from a second format used by the data store; extracting one or more components from said identification information; generating second identification information based on the components, the second identification information being in the second format; transmitting said second identification information; and receiving a second electronic communication indicating that the second identification information corresponds to the first identification information, the data storage medium being queried in response to receiving the second electronic communication; 44. The system of claim 43, further comprising:

45. 45. The system of claim 43 or 44, wherein the data storage medium further includes identification information of a second applicable mutation set, each of the second applicable mutation set corresponding to a mutation listed in Table 1, and the results further indicate whether there is a representation of the particular mutation in the second applicable mutation set.

46. 46. ​​The system of any one of claims 43 to 45, wherein the result comprises a binary indication as to whether migalastat or a migalastat salt is a suitable treatment for the condition caused by the particular mutation.

47. The action is transmitting web page data to a user device, wherein the electronic communication is received from the user device and the identification of the specific mutation corresponds to an input detected on the web page. The system of any one of claims 43 to 46, further comprising:

48. 48. The system of any one of claims 43 to 47, wherein the data storage medium identifies at least 90% of the mutations listed in Table 2.

49. receiving an electronic communication corresponding to the identification of the specific mutation; querying a data storage medium with the identification of the particular mutation, the data storage medium including an identification of each of a set of applicable mutations, each of the set of applicable mutations corresponding to a mutation listed in Table 2; detecting a result of the query, the result indicating whether there is a representation of the particular mutation in the applicable mutation set; generating an output based on the response that indicates the suitability of treating the subject having the particular mutation with migalastat or a migalastat salt; and transmitting said output; 1. A computer program product tangibly embodied in a non-transitory machine-readable storage medium comprising instructions configured to cause one or more data processors to perform actions including:

50. The electronic communication includes the identification of the specific mutation in a first format, and the action is: determining that the first format is different from a second format used by the data store; extracting one or more components from said identification information; generating second identification information based on the components, the second identification information being in the second format; transmitting said second identification information; and receiving a second electronic communication indicating that the second identification information corresponds to the first identification information, the data storage medium being queried in response to receiving the second electronic communication; 50. The computer program product of claim 49, further comprising:

51. 51. The computer program product of claim 49 or 50, wherein the data storage medium further includes identification information of a second applicable mutation set, each of the second applicable mutation set corresponding to a mutation listed in Table 1, and the result further indicates whether there is a representation of the particular mutation in the second applicable mutation set.

52. 52. The computer program product of any one of claims 49 to 51, wherein the result comprises a binary indication as to whether migalastat or a migalastat salt is a suitable treatment for the condition caused by the particular mutation.

53. The action is transmitting web page data to a user device, wherein the electronic communication is received from the user device and the identification of the specific mutation corresponds to an input detected on the web page.

53. A computer program product according to any one of claims 49 to 52, further comprising:

54. 54. The computer program product of any one of claims 49 to 53, wherein the data storage medium identifies at least 90% of the mutations listed in Table 2.

55. accessing a data storage medium storing a dataset unit that stores a dataset identifying, for each mutation in a mutation set, the degree of response of α-Gal A activity to migalastat or a migalastat salt when the mutation is present, wherein the mutation set includes one or more mutations listed in Table 2; receiving a communication identifying one or more specific mutations; querying the data storage medium with a representation of the one or more particular mutations; detecting, for each particular mutation of the one or more particular mutations, a result of said query indicative of the degree of response of α-Gal A activity to migalastat or a migalastat salt when said particular mutation is present; Determining a metric corresponding to the predicted efficacy of treating a subject with the one or more specific mutations with migalastat or a migalastat salt; and outputting said metrics; 10. A computer-implemented method comprising:

56. 56. The computer-implemented method of claim 55, wherein the one or more specific mutations comprise a plurality of specific mutations, and determining the metric comprises identifying a minimum or maximum value for the degree of response of α-Gal A activity to migalastat or a migalastat salt among the plurality of specific mutations.

57. 57. The computer-implemented method of claim 55 or 56, wherein the metric is a binary indication as to whether treatment with migalastat or a migalastat salt is applicable to the condition associated with the one or more particular mutations.

58. 58. The computer-implemented method of any one of claims 55 to 57, wherein the metric comprises a number, category, or descriptor indicating the predicted degree to which treatment with migalastat or a migalastat salt is applicable to the condition associated with the one or more particular mutations.

59. 59. The computer-implemented method of any one of claims 55-58, wherein the results of the query indicate, for a particular one of the one or more particular mutations and as a result of not detecting the particular mutation in the dataset, that the α-Gal A activity corresponding to the particular mutation is not responsive to migalastat or a migalastat salt.

60. 60. The computer-implemented method of any one of claims 55 to 59, wherein the mutation set further comprises one or more mutations listed in Table 1.

61. 61. The computer-implemented method of any one of claims 55-60, wherein the one or more specific mutations comprise a plurality of specific mutations, and determining the metric comprises identifying a minimum or maximum value for the degree of response of α-Gal A activity to migalastat or a migalastat salt among the plurality of specific mutations.

62. one or more data processors; A non-transitory computer-readable storage medium that, when executed on the one or more data processors, accessing a dataset unit that stores a dataset identifying, for each mutation in a mutation set, the degree of response of α-Gal A activity to migalastat or migalastat salt when the mutation is present, wherein the mutation set includes one or more mutations listed in Table 2; receiving a communication identifying one or more specific mutations; querying the dataset unit with a representation of the one or more particular mutations; detecting, for each particular mutation of the one or more particular mutations, a result of said query indicative of the degree of response of α-Gal A activity to migalastat or a migalastat salt when said particular mutation is present; Determining a metric corresponding to the predicted efficacy of treating a subject with the one or more specific mutations with migalastat or a migalastat salt; and outputting said metrics; a non-transitory computer-readable storage medium storing instructions that cause the one or more data processors to perform actions including: A system including:

63. 63. The system of claim 62, wherein the one or more specific mutations comprise a plurality of specific mutations, and determining the metric comprises identifying a minimum or maximum value for the degree of response of α-Gal A activity to migalastat or a migalastat salt among the plurality of specific mutations.

64. 64. The system of claim 62 or 63, wherein the metric is a binary indication as to whether treatment with migalastat or a migalastat salt is applicable to the condition associated with the one or more particular mutations.

65. 65. The system of any one of claims 62-64, wherein the metric comprises a number, category, or descriptor indicating the predicted degree to which treatment with migalastat or a migalastat salt is applicable to the condition associated with the one or more particular mutations.

66. 66. The system of any one of claims 62-65, wherein the results of the query indicate, for a particular one of the one or more particular mutations and as a result of not detecting the particular mutation in the dataset, that the α-Gal A activity corresponding to the particular mutation is not responsive to migalastat or a migalastat salt.

67. 67. The system of any one of claims 62 to 66, wherein the mutation set further comprises one or more mutations listed in Table 1.

68. 68. The system of any one of claims 62-67, wherein the one or more specific mutations comprise a plurality of specific mutations, and determining the metric comprises identifying a minimum or maximum value for the degree of response of α-Gal A activity to migalastat or a migalastat salt among the plurality of specific mutations.

69. accessing a dataset unit that stores a dataset identifying, for each mutation in a mutation set, the degree of response of α-Gal A activity to migalastat or migalastat salt when the mutation is present, wherein the mutation set includes one or more mutations listed in Table 2; receiving a communication identifying one or more specific mutations; querying the dataset unit with a representation of the one or more particular mutations; detecting, for each particular mutation of the one or more particular mutations, a result of said query indicative of the degree of response of α-Gal A activity to migalastat or a migalastat salt when said particular mutation is present; Determining a metric corresponding to the predicted efficacy of treating a subject with the one or more specific mutations with migalastat or a migalastat salt; and outputting said metrics; 1. A computer program product tangibly embodied in a non-transitory machine-readable storage medium comprising instructions configured to cause one or more data processors to perform actions including:

70. 70. The computer program product of claim 69, wherein the one or more specific mutations comprise a plurality of specific mutations, and determining the metric comprises identifying a minimum or maximum value for the degree of response of α-Gal A activity to migalastat or a migalastat salt among the plurality of specific mutations.

71. 71. The computer program product of claim 69 or 70, wherein the metric is a binary indication as to whether treatment with migalastat or a migalastat salt is applicable to the condition associated with the one or more particular mutations.

72. 72. The computer program product of any one of claims 69 to 71, wherein the metric comprises a number, category, or descriptor indicating the predicted degree to which treatment with migalastat or a migalastat salt is applicable to the condition associated with the one or more particular mutations.

73. 73. The computer program product of any one of claims 69-72, wherein the results of the query indicate, for a particular one of the one or more particular mutations and as a result of not detecting the particular mutation in the dataset, that the α-Gal A activity corresponding to the particular mutation is unresponsive to migalastat or a migalastat salt.

74. 74. The computer program product of any one of claims 69 to 73, wherein the mutation set further comprises one or more mutations listed in Table 1.

75. 75. The computer program product of any one of claims 69-74, wherein the one or more specific mutations comprise a plurality of specific mutations, and determining the metric comprises identifying a minimum or maximum value for the degree of response of α-Gal A activity to migalastat or a migalastat salt among the plurality of specific mutations.

76. 1. A method of treating Fabry disease in a subject, comprising: accessing mutation information corresponding to the subject, the mutation information identifying one or more α-galactosidase A mutations; determining, based on the mutation information, that the subject has a mutation such that α-Gal A activity in a lysate prepared from HEK-293 cells transiently transfected with a mutant α-Gal A and incubated for 5 days in the presence of 10 μM migalastat is higher than a reference α-Gal A activity in another lysate prepared from another HEK-293 cell transiently transfected with the mutant α-Gal A and incubated for 5 days in the absence of 10 μM migalastat, wherein the mutant α-Gal A corresponds to the mutation; and administering migalastat or a salt thereof to said subject in response to said determining. A method comprising:

77. 77. The method of claim 76, wherein the α-Gal A activity is defined as nanomoles of free 4-MU released per milligram of protein per hour.

78. 78. The method of claim 76 or 77, wherein said determining comprises determining that said subject has a mutation in which the α-Gal A activity is at least 1% higher than the reference α-Gal A activity.

79. 78. The method of claim 76 or 77, wherein said determining comprises determining that said subject has a mutation in which the α-Gal A activity is at least 5% higher than the reference α-Gal A activity.

80. 78. The method of claim 76 or 77, wherein said determining comprises determining that said subject has a mutation in which the α-Gal A activity is at least 10% higher than the reference α-Gal A activity.

81. 78. The method of claim 76 or 77, wherein said determining comprises determining that said subject has a mutation in which the α-Gal A activity is at least 20% greater than the reference α-Gal A activity.

82. The said decision: querying a data storage medium for the identity of said one or more α-galactosidase A mutations; receiving results of said query; 82. The method of any one of claims 76 to 81, comprising:

83. 83. The method of claim 82, wherein the result indicates that the data store contains a representation of the mutation.

84. 83. The method of claim 82, wherein the results include one or more values ​​associated with a representation of the mutation in the data store, the method further comprising comparing the one or more values, or processed versions thereof, to a predetermined threshold.

85. accessing mutation information corresponding to the subject, wherein the mutation information identifies one or more α-galactosidase A mutations; determining, based on the mutation information, that the subject has a mutation such that α-Gal A activity in a lysate prepared from HEK-293 cells transiently transfected with a mutant α-Gal A and incubated for 5 days in the presence of 10 μM migalastat is higher than a reference α-Gal A activity in another lysate prepared from another HEK-293 cell transiently transfected with the mutant α-Gal A and incubated for 5 days in the absence of 10 μM migalastat, wherein the mutant α-Gal A corresponds to the mutation; and and in response to said determining, outputting an indication that said mutation is amenable to treatment with migalastat or a salt thereof. A method comprising:

86. 86. The method of claim 85, wherein the α-Gal A activity is defined as nanomoles of free 4-MU released per milligram of protein per hour.

87. 87. The method of claim 85 or 86, wherein said determining comprises determining that said subject has a mutation in which the α-Gal A activity is at least 1% higher than the reference α-Gal A activity.

88. 87. The method of claim 85 or 86, wherein said determining comprises determining that said subject has a mutation in which the α-Gal A activity is at least 5% higher than the reference α-Gal A activity.

89. 87. The method of claim 85 or 86, wherein said determining comprises determining that said subject has a mutation in which the α-Gal A activity is at least 10% higher than the reference α-Gal A activity.

90. 87. The method of claim 85 or 86, wherein said determining comprises determining that said subject has a mutation in which the α-Gal A activity is at least 20% greater than the reference α-Gal A activity.

91. The said decision: querying a data storage medium for the identity of the one or more α-galactosidase A mutations; and receiving results of said query; 91. The method of any one of claims 85 to 90, comprising:

92. 92. The method of claim 91, wherein the result indicates that the data store contains a representation of the mutation.

93. 92. The method of claim 91 , wherein the results include one or more values ​​associated with a representation of the mutation in the data store, the method further comprising comparing the one or more values, or processed versions thereof, to a predetermined threshold.

94. receiving a first communication from a user device that includes the mutation information; further comprising:

94. The method of any one of claims 85 to 93, wherein outputting the instruction comprises transmitting a second communication to the user device, the second communication including the instruction.

95. one or more data processors; A non-transitory computer-readable storage medium that, when executed on the one or more data processors, accessing mutation information corresponding to the subject, wherein the mutation information identifies one or more α-galactosidase A mutations; determining, based on the mutation information, that the subject has a mutation such that α-Gal A activity in a lysate prepared from HEK-293 cells transiently transfected with a mutant α-Gal A and incubated for 5 days in the presence of 10 μM migalastat is higher than a reference α-Gal A activity in another lysate prepared from another HEK-293 cell transiently transfected with the mutant α-Gal A and incubated for 5 days in the absence of 10 μM migalastat, wherein the mutant α-Gal A corresponds to the mutation; and and in response to said determining, outputting an indication that said mutation is amenable to treatment with migalastat or a salt thereof. a non-transitory computer-readable storage medium storing instructions that cause the one or more data processors to perform actions including: A system including:

96. 96. The system of claim 95, wherein the α-Gal A activity is defined as nanomoles of free 4-MU released per milligram of protein per hour.

97. 97. The system of claim 95 or 96, wherein said determining comprises determining that said subject has a mutation in which α-Gal A activity is at least 1% higher than said reference α-Gal A activity.

98. 97. The system of claim 95 or 96, wherein said determining comprises determining that said subject has a mutation in which α-Gal A activity is at least 5% higher than said reference α-Gal A activity.

99. 97. The system of claim 95 or 96, wherein said determining comprises determining that said subject has a mutation in which α-Gal A activity is at least 10% higher than said reference α-Gal A activity.

100. 97. The system of claim 95 or 96, wherein said determining comprises determining that said subject has a mutation in which α-Gal A activity is at least 20% higher than said reference α-Gal A activity.

101. The said decision: querying a data storage medium for the identity of the one or more α-galactosidase A mutations; and receiving results of said query; The system of any one of claims 95 to 100, comprising:

102. 102. The system of claim 101, wherein the result indicates that the data store includes a representation of the mutation.

103. 102. The system of claim 101, wherein the results include one or more values ​​associated with a representation of the mutation in the data store, and the actions further include comparing the one or more values, or processed versions thereof, to a predetermined threshold.

104. The action is receiving a first communication from a user device that includes the mutation information; further comprising:

104. The system of any one of claims 95 to 103, wherein outputting the instruction comprises transmitting a second communication to the user device, the second communication including the instruction.

105. accessing mutation information corresponding to the subject, wherein the mutation information identifies one or more α-galactosidase A mutations; determining, based on the mutation information, that the subject has a mutation such that α-Gal A activity in a lysate prepared from HEK-293 cells transiently transfected with a mutant α-Gal A and incubated for 5 days in the presence of 10 μM migalastat is higher than a reference α-Gal A activity in another lysate prepared from another HEK-293 cell transiently transfected with the mutant α-Gal A and incubated for 5 days in the absence of 10 μM migalastat, wherein the mutant α-Gal A corresponds to the mutation; and and in response to said determining, outputting an indication that said mutation is amenable to treatment with migalastat or a salt thereof.

1. A computer program product tangibly embodied in a non-transitory machine-readable storage medium comprising instructions configured to cause one or more data processors to perform actions including:

106. 106. The computer program product of claim 105, wherein the α-Gal A activity is defined as nanomoles of free 4-MU released per milligram of protein per hour.

107. 107. The computer program product of claim 105 or 106, wherein said determining comprises determining that the subject has a mutation in which the α-Gal A activity is at least 1% higher than the reference α-Gal A activity.

108. 107. The computer program product of claim 105 or 106, wherein said determining comprises determining that the subject has a mutation in which the α-Gal A activity is at least 5% higher than the reference α-Gal A activity.

109. 107. The computer program product of claim 105 or 106, wherein said determining comprises determining that the subject has a mutation in which the α-Gal A activity is at least 10% higher than the reference α-Gal A activity.

110. 107. The computer program product of claim 105 or 106, wherein said determining comprises determining that the subject has a mutation in which the α-Gal A activity is at least 20% higher than the reference α-Gal A activity.

111. The said decision: querying a data storage medium for the identity of the one or more α-galactosidase A mutations; and receiving results of said query; A computer program product according to any one of claims 105 to 110, comprising:

112. 112. The computer program product of claim 111, wherein the result indicates that the data store includes a representation of the mutation.

113. 112. The computer program product of claim 111, wherein the results include one or more values ​​associated with the representation of the mutation in the data store, and the actions further include comparing the one or more values ​​or processed versions thereof to a predetermined threshold.

114. The action is receiving a first communication from a user device that includes the mutation information; further comprising:

114. The computer program product of any one of claims 105 to 113, wherein outputting the instruction comprises transmitting a second communication to the user device, the second communication including the instruction.

115. 1. A method of treating Fabry disease in a human patient in need thereof, comprising administering a therapeutically effective dose of migalastat or a salt thereof to the patient, wherein the patient has an α-galactosidase A mutation selected from the group consisting of the mutations provided in Table 2.

116. 1. A method of enhancing α-galactosidase A in a patient diagnosed with or suspected of having Fabry disease, comprising administering a therapeutically effective dose of migalastat or a salt thereof to the patient, wherein the patient has an α-galactosidase A mutation selected from the group consisting of the mutations provided in Table 2.

117. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of N5D, N5K, P6L, P6Q, P6R, P6S, P6T, E7D, E7K, E7V, L8I, L8P, L8Q, H9L, H9Q, H9R, H9Y, L10M, L10P and L10Q.

118. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of L10R, L10V, G11C, G11D, G11R, G11S, G11V, C12G, C12R, C12S, C12Y, A13E, A13G, L14F, L14H, L14V, R17C, R17G, R17H and R17P.

119. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of R17S, F18I, F18L, A20G, L21H, V22A, V22F, V22I, V22L, S23P, S23T, W24S, D25H, I26N, P27A, P27L, P27S, P27T, G28E and G28R.

120. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of G28W, A29G, A29P, A29V, R30G, L32M, L32Q, L32R, L32V, D33A, D33E, D33V, L36M, L36V, A37E, A37G, A37S, R38G, R38M and R38W.

121. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of T39A, T39K, T39M, T39R, T39S, T41A, T41N, T41S, G43A, L45M, L45V, H46D, H46N, H46Q, E48A, F50Y, M51R, M51T, M51V and N53H.

122. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of N53I, N53S, N53T, L54H, L54R, L54V, D55A, D55E, D55H, D55Y, C56W, E58K, E59A, E59D, E59G, E59Q, E59V, P60A, P60Q and P60R.

123. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of D61E, D61V, S62A, S62C, S62F, S62P, S62Y, I64L, I64V, S65C, S65G, S65R, E66D, E66V, K67E, K67M, K67N, K67Q, K67T and L68I.

124. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of F69I, F69Y, M70I, M70K, M70L, M70R, E71A, E71D, E71G, E71Q, E71V, M72L, M72T, A73S, A73T, E74D, E74G, E74K, E74V and L75F.

125. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of L75P, M76V, V77I, V77L, S78L, S78P, E79A, E79D, E79G, E79K, E79Q, E79V, G80A, G80C, G80S, W81L, K82E, K82M, K82N and K82R.

126. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of K82T, D83A, D83E, D83G, D83V, A84E, A84G, A84P, A84S, A84T, A84V, G85A, G85C, G85R, Y86F, E87G, Y88H, Y88N, L89V and I91F.

127. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of I91L, I91M, I91S, M96L, M96T, A97D, A97S, A97T, P98H, P98L, P98R, Q99E, Q99L, Q99P, Q99R, D101A, D101E, D101G, D101H and D101V.

128. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of S102A, S102P, S102T, G104A, G104D, G104S, R105G, R105I, R105K, R105T, L106H, L106I, L106P, L106V, Q107E, Q107H, Q107K, A108E, A108V and D109A.

129. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of D109E, D109H, D109N, D109Y, P110T, F113V, F113Y, P114L, H115D, H115N, G116R, I117M, I117T, A121V, Y123D, Y123F, Y123N, Y123S, V124I and H125D.

130. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of H125N, H125R, S126C, S126I, K127E, G128A, L129V, K130M, K130N, K130Q, L131V, I133L, I133T, I133V, A135E, A135G, A135S, A135T, D136A and D136N.

131. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of D136V, V137A, V137D, V137G, V137I, V137L, G138A, N139H, N139I, N139K, N139Y, K140E, K140I, K140N, K140Q, K140R, T141S, A143E, A143G and G144A.

132. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of G144C, G144R, G144S, F145C, F145L, F145V, F145Y, P146A, P146H, P146L, P146T, G147A, S148C, S148G, S148T, F149C, G150E, G150V, Y151C and Y151D.

133. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of Y151S, Y152F, Y152S, D153A, D153H, D153N, D153V, D153Y, A156G, Q157E, Q157K, Q157L, Q157P, T158A, T158I, T158N, T158S, F159I, F159L and F159V.

134. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of F159Y, A160G, A160S, A160T, A160V, D161H, D161N, D161V, D161Y, W162S, V164A, V164I, V164L, D165A, D165E, L166M, L166Q, L167I, F169C and F169L.

135. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of F169V, F169Y, G171A, G171V, Y173C, Y173F, Y173H, Y173S, D175G, D175H, D175V, D175Y, S176C, S176R, L177F, L177M, L177S, L177V, L177W and E178A.

136. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of E178G, E178K, E178Q, L180M, L180S, A181P, A181T, A181V, D182A, D182E, D182V, D182Y, Y184F, Y184H, Y184S, K185M, K185N, K185Q, K185T and H186D.

137. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of H186L, H186N, H186Q, H186Y, M187L, S188A, S188C, S188F, S188P, S188T, S188Y, L189S, L189V, A190D, A190G, A190S, A190T, A190V, L191M and L191V.

138. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of N192D, N192H, N192K, N192S, N192T, R193G, R193M, R193T, R193W, T194N, T194P, T194S, G195C, G195R, G195S, R196I, R196K, S197C, S197G and S197I.

139. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of S197N, S197T, I198M, I198S, V199E, V199L, Y200N, Y200S, S201A, S201C, S201T, E203A, E203G, E203Q, W204S, L206F, L206H, L206I, L206R and L206V.

140. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of Y207F, M208K, W209C, W209G, P210H, P210T, F211C, F211L, F211S, F211V, F211Y, Q212H, Q212P, K213E, K213Q, P214A, P214H, P214R, P214T and N215H.

141. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of N215K, N215T, N215Y, Y216F, Y216H, Y216N, T217A, T217I, T217K, T217P, T217R, T217S, E218A, E218D, E218G, E218K, E218Q, E218V, I219F and I219M.

142. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of I219S, R220L, Q221E, Q221H, Q221K, Q221L, Q221R, Y222C, Y222D, Y222H, Y222N, Y222S, N224H, R227G, N228H, N228I, N228T, F229I, F229S and F229Y.

143. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of A230D, A230G, A230P, A230V, I232L, I232M, I232V, D233A, D233E, D233G, D233V, S235A, S235T, K237I, S238C, S238I, S238T, I239L, K240E and K240M.

144. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of K240R, S241C, S241I, S241T, I242L, I242M, I242S, L243M, L243S, L243V, D244A, D244E, D244G, D244V, D244Y, W245C, T246A, T246I, T246K and T246R.

145. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of S247A, S247F, S247T, S247Y, F248C, F248L, F248V, F248Y, N249D, N249H, N249I, N249S, N249T, N249Y, Q250E, Q250L, E251G, E251K, E251Q and E251V.

146. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of R252G, I253F, I253N, I253V, V254A, V254D, V254F, V254G, D255A, D255E, D255H, D255N, D255V, D255Y, V256D, V256G, V256L, A257S, G258E and P259A.

147. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of P259T, G260W, G261A, N263H, N263T, D264H, D264N, P265A, P265Q, M267L, M267V, L268F, L268I, V269L, I270L, I270S, I270V, N272D, F273Y and L275I.

148. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of W277L, N278I, Q280L, Q280R, V281A, V281E, V281G, V281L, T282S, Q283E, Q283H, Q283L, M284I, M284L, A285G, A285T, A285V, L286F, L286H and L286V.

149. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of A288G, A288S, A288V, I289L, I289T, I289V, A291G, A292G, A292S, L294F, L294I, L294V, F295I, F295S, F295V, F295Y, S297T, N298D, N298I and N298T.

150. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of D299H, D299N, L300I, L300V, H302D, H302L, H302N, H302Y, I303S, S304I, Q306E, Q306L, Q306P, A307D, A307G, A307P, A307S, A307V, K308I and K308Q.

151. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of K308R, A309D, A309T, L310I, L311I, Q312E, Q312K, Q312L, D313E, D313V, K314E, K314M, K314N, K314T, D315A, D315G, D315H, D315N, D315V and D315Y.

152. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of V316A, V316L, I317L, I317M, I317V, A318D, A318P, A318T, A318V, I319M, N320S, N320T, Q321K, D322A, D322V, L324V, L324W, G325A, G325C and G325V.

153. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of K326E, K326M, K326Q, K326R, K326T, Q327H, Q327P, Y329C, Y329D, Y329F, Y329H, Y329N, Q330E, Q330H, Q330K, L331H, L331P, L331R, L331V and R332G.

154. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of R332I, R332S, R332T, Q333E, Q333L, Q333P, G334R, G334V, D335A, D335E, D335G, D335V, D335Y, N336D, N336I, N336S, N336T, N336Y, F337C and F337L.

155. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of F337V, F337Y, E338A, E338D, E338G, V339M, E341A, E341Q, P343A, P343S, L344F, L344R, L344V, G346A, G346C, G346D, G346V, L347I, A348D and W349C.

156. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of W349L, A350G, A350S, A350T, A350V, V351A, V351E, A352S, A352T, M353K, M353L, M353T, I354R, N355D, N355H, N355S, N355Y, R356L, Q357E and I359F.

157. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of I359L, I359N, I359S, I359V, P362A, P362H, P362R, P362S, R363G, R363L, R363S, S364C, S364P, Y365D, Y365F, Y365N, Y365S, T366I, T366N and T366P.

158. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of T366S, I367F, I367L, I367M, A368G, A368P, V369A, V369F, V369G, V369I, V369L, A370D, A370G, A370P, A370T, A370V, S371C, S371T, G373A and G373C.

159. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of K374E, K374I, K374R, K374T, G375R, V376E, V376G, V376L, V376M, A377G, A377P, A377S, A377T, N379D, N379I, N379K, N379T, P380A, P380H and P380R.

160. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of P380T, A381D, F383C, F383I, F383Y, I384F, I384M, I384T, T385I, Q386H, Q386K, Q386L, L387F, L387H, L387I, L387R, L388F, L388H, L388I and L388R.

161. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of L388V, K391I, K391N, K391Q, K391R, R392G, R392K, R392M, R392W, K393E, K393N, K393Q, K393T, L394I, L394Q, L394R, G395R, F396C, F396I and F396L.

162. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of F396V, Y397C, Y397F, Y397H, Y397N, Y397S, E398G, E398Q, W399G, W399R, T400A, T400I, T400N, T400P, T400S, S401A, S401L, S401T, R402G and R402M.

163. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of R402S, R402T, R402W, L403F, L403V, ​​R404G, R404I, R404K, R404S, R404T, S405G, H406D, H406L, H406Q, I407L, I407M, I407T, N408D, N408H and N408T.

164. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of P409L, T410S, G411A, G411C, G411V, T412A, T412I, T412S, V413F, V413G, V413I, L414F, L414V, L415H, L415I, Q416E, Q416H, Q416L, L417I and E418A.

165. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of E418D, E418K, E418Q, N419I, N419S, N419T, N419Y, T420K, T420P, T420R, T420S, M421I, M421K, M421L, M421R, M421T, Q422P, M423I, M423K and M423L.

166. 117. The method of claim 115 or 116, wherein the mutation is selected from the group consisting of M423T, S424L, L425F, D427N and L429R.

167. 167. The method of any one of claims 115 to 166, wherein the migalastat or a salt thereof is administered to the patient every other day.

168. 168. The method of any one of claims 115-167, wherein the patient is administered about 100 to about 150 mg free base equivalent of the migalastat or salt thereof every other day.

169. 169. The method of any one of claims 115 to 168, wherein the patient is administered about 123 mg free base equivalent of the migalastat or salt thereof every other day.

170. 170. The method of any one of claims 115-169, wherein the patient is administered about 123 mg of migalastat free base every other day.

171. 170. The method of any one of claims 115 to 169, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day.

172. The method of any one of claims 115 to 171, wherein the migalastat or a salt thereof enhances α-galactosidase A activity.

173. 173. The method of any one of claims 115 to 172, wherein the mutation is disclosed in a pharmacology reference table.

174. The method of claim 173, wherein the pharmacological reference table is provided in the package insert for a migalastat product approved for the treatment of Fabry disease.

175. 174. The method of claim 173, wherein the pharmacology reference table is provided in the GALAFOLD (registered trademark) package insert.

176. 174. The method of claim 173, wherein the pharmacology reference table is provided on a website.

177. 177. The method of claim 176, wherein the website is one or more of www.galafoldamenabilitytable.com or www.fabrygenevariantsearch.com.

178. 178. The method of any one of claims 115 to 177, wherein the migalastat or a salt thereof is administered orally.

179. 178. The method of any one of claims 115 to 177, wherein the migalastat or a salt thereof is administered by injection.

180. 180. The method of any one of claims 115 to 179, wherein the patient is male.

181. 180. The method of any one of claims 115 to 179, wherein the patient is female.

182. 1. A method of treating Fabry disease in a human patient in need thereof, comprising administering a therapeutically effective dose of migalastat or a salt thereof to said patient, said patient having a HEK assay-applicable mutation in α-galactosidase A disclosed in a pharmacology reference table, said pharmacology reference table including one or more mutations from Table 2.

183. 1. A method for enhancing α-galactosidase A in a patient diagnosed with or suspected of having Fabry disease, comprising administering a therapeutically effective dose of migalastat or a salt thereof to the patient, wherein the patient has a HEK assay-applicable mutation in α-galactosidase A disclosed in a pharmacology reference table, the pharmacology reference table including one or more mutations from Table 2.

184. 184. The method of claim 182 or 183, wherein the pharmacology reference table includes all of the mutations from Table 2.

185. 185. The method of any one of claims 182 to 184, wherein the pharmacology reference table comprises one or more mutations from Table 1.

186. 186. The method of any one of claims 182 to 185, wherein said pharmacology reference table comprises all of said mutations from Table 1.

187. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of N5D, N5K, P6L, P6Q, P6R, P6S, P6T, E7D, E7K, E7V, L8I, L8P, L8Q, H9L, H9Q, H9R, H9Y, L10M, L10P and L10Q.

188. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of L10R, L10V, G11C, G11D, G11R, G11S, G11V, C12G, C12R, C12S, C12Y, A13E, A13G, L14F, L14H, L14V, R17C, R17G, R17H and R17P.

189. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of R17S, F18I, F18L, A20G, L21H, V22A, V22F, V22I, V22L, S23P, S23T, W24S, D25H, I26N, P27A, P27L, P27S, P27T, G28E and G28R.

190. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of G28W, A29G, A29P, A29V, R30G, L32M, L32Q, L32R, L32V, D33A, D33E, D33V, L36M, L36V, A37E, A37G, A37S, R38G, R38M and R38W.

191. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of T39A, T39K, T39M, T39R, T39S, T41A, T41N, T41S, G43A, L45M, L45V, H46D, H46N, H46Q, E48A, F50Y, M51R, M51T, M51V and N53H.

192. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of N53I, N53S, N53T, L54H, L54R, L54V, D55A, D55E, D55H, D55Y, C56W, E58K, E59A, E59D, E59G, E59Q, E59V, P60A, P60Q and P60R.

193. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of D61E, D61V, S62A, S62C, S62F, S62P, S62Y, I64L, I64V, S65C, S65G, S65R, E66D, E66V, K67E, K67M, K67N, K67Q, K67T and L68I.

194. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of F69I, F69Y, M70I, M70K, M70L, M70R, E71A, E71D, E71G, E71Q, E71V, M72L, M72T, A73S, A73T, E74D, E74G, E74K, E74V and L75F.

195. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of L75P, M76V, V77I, V77L, S78L, S78P, E79A, E79D, E79G, E79K, E79Q, E79V, G80A, G80C, G80S, W81L, K82E, K82M, K82N and K82R.

196. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of K82T, D83A, D83E, D83G, D83V, A84E, A84G, A84P, A84S, A84T, A84V, G85A, G85C, G85R, Y86F, E87G, Y88H, Y88N, L89V and I91F.

197. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of I91L, I91M, I91S, M96L, M96T, A97D, A97S, A97T, P98H, P98L, P98R, Q99E, Q99L, Q99P, Q99R, D101A, D101E, D101G, D101H and D101V.

198. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of S102A, S102P, S102T, G104A, G104D, G104S, R105G, R105I, R105K, R105T, L106H, L106I, L106P, L106V, Q107E, Q107H, Q107K, A108E, A108V and D109A.

199. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of D109E, D109H, D109N, D109Y, P110T, F113V, F113Y, P114L, H115D, H115N, G116R, I117M, I117T, A121V, Y123D, Y123F, Y123N, Y123S, V124I and H125D.

200. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of H125N, H125R, S126C, S126I, K127E, G128A, L129V, K130M, K130N, K130Q, L131V, I133L, I133T, I133V, A135E, A135G, A135S, A135T, D136A and D136N.

201. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of D136V, V137A, V137D, V137G, V137I, V137L, G138A, N139H, N139I, N139K, N139Y, K140E, K140I, K140N, K140Q, K140R, T141S, A143E, A143G and G144A.

202. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of G144C, G144R, G144S, F145C, F145L, F145V, F145Y, P146A, P146H, P146L, P146T, G147A, S148C, S148G, S148T, F149C, G150E, G150V, Y151C and Y151D.

203. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of Y151S, Y152F, Y152S, D153A, D153H, D153N, D153V, D153Y, A156G, Q157E, Q157K, Q157L, Q157P, T158A, T158I, T158N, T158S, F159I, F159L and F159V.

204. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of F159Y, A160G, A160S, A160T, A160V, D161H, D161N, D161V, D161Y, W162S, V164A, V164I, V164L, D165A, D165E, L166M, L166Q, L167I, F169C and F169L.

205. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of F169V, F169Y, G171A, G171V, Y173C, Y173F, Y173H, Y173S, D175G, D175H, D175V, D175Y, S176C, S176R, L177F, L177M, L177S, L177V, L177W and E178A.

206. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of E178G, E178K, E178Q, L180M, L180S, A181P, A181T, A181V, D182A, D182E, D182V, D182Y, Y184F, Y184H, Y184S, K185M, K185N, K185Q, K185T and H186D.

207. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of H186L, H186N, H186Q, H186Y, M187L, S188A, S188C, S188F, S188P, S188T, S188Y, L189S, L189V, A190D, A190G, A190S, A190T, A190V, L191M and L191V.

208. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of N192D, N192H, N192K, N192S, N192T, R193G, R193M, R193T, R193W, T194N, T194P, T194S, G195C, G195R, G195S, R196I, R196K, S197C, S197G and S197I.

209. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of S197N, S197T, I198M, I198S, V199E, V199L, Y200N, Y200S, S201A, S201C, S201T, E203A, E203G, E203Q, W204S, L206F, L206H, L206I, L206R and L206V.

210. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of Y207F, M208K, W209C, W209G, P210H, P210T, F211C, F211L, F211S, F211V, F211Y, Q212H, Q212P, K213E, K213Q, P214A, P214H, P214R, P214T and N215H.

211. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of N215K, N215T, N215Y, Y216F, Y216H, Y216N, T217A, T217I, T217K, T217P, T217R, T217S, E218A, E218D, E218G, E218K, E218Q, E218V, I219F and I219M.

212. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of I219S, R220L, Q221E, Q221H, Q221K, Q221L, Q221R, Y222C, Y222D, Y222H, Y222N, Y222S, N224H, R227G, N228H, N228I, N228T, F229I, F229S and F229Y.

213. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of A230D, A230G, A230P, A230V, I232L, I232M, I232V, D233A, D233E, D233G, D233V, S235A, S235T, K237I, S238C, S238I, S238T, I239L, K240E and K240M.

214. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of K240R, S241C, S241I, S241T, I242L, I242M, I242S, L243M, L243S, L243V, D244A, D244E, D244G, D244V, D244Y, W245C, T246A, T246I, T246K and T246R.

215. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of S247A, S247F, S247T, S247Y, F248C, F248L, F248V, F248Y, N249D, N249H, N249I, N249S, N249T, N249Y, Q250E, Q250L, E251G, E251K, E251Q and E251V.

216. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of R252G, I253F, I253N, I253V, V254A, V254D, V254F, V254G, D255A, D255E, D255H, D255N, D255V, D255Y, V256D, V256G, V256L, A257S, G258E and P259A.

217. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of P259T, G260W, G261A, N263H, N263T, D264H, D264N, P265A, P265Q, M267L, M267V, L268F, L268I, V269L, I270L, I270S, I270V, N272D, F273Y and L275I.

218. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of W277L, N278I, Q280L, Q280R, V281A, V281E, V281G, V281L, T282S, Q283E, Q283H, Q283L, M284I, M284L, A285G, A285T, A285V, L286F, L286H and L286V.

219. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of A288G, A288S, A288V, I289L, I289T, I289V, A291G, A292G, A292S, L294F, L294I, L294V, F295I, F295S, F295V, F295Y, S297T, N298D, N298I and N298T.

220. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of D299H, D299N, L300I, L300V, H302D, H302L, H302N, H302Y, I303S, S304I, Q306E, Q306L, Q306P, A307D, A307G, A307P, A307S, A307V, K308I and K308Q.

221. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of K308R, A309D, A309T, L310I, L311I, Q312E, Q312K, Q312L, D313E, D313V, K314E, K314M, K314N, K314T, D315A, D315G, D315H, D315N, D315V and D315Y.

222. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of V316A, V316L, I317L, I317M, I317V, A318D, A318P, A318T, A318V, I319M, N320S, N320T, Q321K, D322A, D322V, L324V, L324W, G325A, G325C and G325V.

223. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of K326E, K326M, K326Q, K326R, K326T, Q327H, Q327P, Y329C, Y329D, Y329F, Y329H, Y329N, Q330E, Q330H, Q330K, L331H, L331P, L331R, L331V and R332G.

224. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of R332I, R332S, R332T, Q333E, Q333L, Q333P, G334R, G334V, D335A, D335E, D335G, D335V, D335Y, N336D, N336I, N336S, N336T, N336Y, F337C and F337L.

225. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of F337V, F337Y, E338A, E338D, E338G, V339M, E341A, E341Q, P343A, P343S, L344F, L344R, L344V, G346A, G346C, G346D, G346V, L347I, A348D and W349C.

226. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of W349L, A350G, A350S, A350T, A350V, V351A, V351E, A352S, A352T, M353K, M353L, M353T, I354R, N355D, N355H, N355S, N355Y, R356L, Q357E and I359F.

227. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of: I359L, I359N, I359S, I359V, P362A, P362H, P362R, P362S, R363G, R363L, R363S, S364C, S364P, Y365D, Y365F, Y365N, Y365S, T366I, T366N and T366P.

228. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of T366S, I367F, I367L, I367M, A368G, A368P, V369A, V369F, V369G, V369I, V369L, A370D, A370G, A370P, A370T, A370V, S371C, S371T, G373A and G373C.

229. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of K374E, K374I, K374R, K374T, G375R, V376E, V376G, V376L, V376M, A377G, A377P, A377S, A377T, N379D, N379I, N379K, N379T, P380A, P380H and P380R.

230. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of P380T, A381D, F383C, F383I, F383Y, I384F, I384M, I384T, T385I, Q386H, Q386K, Q386L, L387F, L387H, L387I, L387R, L388F, L388H, L388I and L388R.

231. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of L388V, K391I, K391N, K391Q, K391R, R392G, R392K, R392M, R392W, K393E, K393N, K393Q, K393T, L394I, L394Q, L394R, G395R, F396C, F396I and F396L.

232. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of F396V, Y397C, Y397F, Y397H, Y397N, Y397S, E398G, E398Q, W399G, W399R, T400A, T400I, T400N, T400P, T400S, S401A, S401L, S401T, R402G and R402M.

233. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of R402S, R402T, R402W, L403F, L403V, ​​R404G, R404I, R404K, R404S, R404T, S405G, H406D, H406L, H406Q, I407L, I407M, I407T, N408D, N408H and N408T.

234. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of P409L, T410S, G411A, G411C, G411V, T412A, T412I, T412S, V413F, V413G, V413I, L414F, L414V, L415H, L415I, Q416E, Q416H, Q416L, L417I and E418A.

235. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of E418D, E418K, E418Q, N419I, N419S, N419T, N419Y, T420K, T420P, T420R, T420S, M421I, M421K, M421L, M421R, M421T, Q422P, M423I, M423K and M423L.

236. 187. The method of any one of claims 182 to 186, wherein the mutation is selected from the group consisting of M423T, S424L, L425F, D427N and L429R.

237. 237. The method of any one of claims 182 to 236, wherein the migalastat or a salt thereof is administered to the patient every other day.

238. 238. The method of any one of claims 182 to 237, wherein the patient is administered about 100 to about 150 mg free base equivalent of the migalastat or salt thereof every other day.

239. 239. The method of any one of claims 182 to 238, wherein the patient is administered about 123 mg free base equivalent of the migalastat or salt thereof every other day.

240. 240. The method of any one of claims 182-239, wherein the patient is administered about 123 mg of migalastat free base every other day.

241. 240. The method of any one of claims 182 to 239, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day.

242. The method of any one of claims 182 to 241, wherein the migalastat or a salt thereof enhances α-galactosidase A activity.

243. 243. The method of any one of claims 182 to 242, wherein the pharmacology reference table is provided in the package insert for a migalastat product approved for the treatment of Fabry disease.

244. 244. The method of any one of claims 182 to 243, wherein the pharmacology reference table is provided in the GALAFOLD® package insert.

245. The method of any one of claims 182 to 243, wherein the pharmacology reference table is provided on a website.

246. 246. The method of any one of claims 182-245, wherein the website is one or more of www.galafoldamenabilitytable.com or www.fabrygenevariantsearch.com.

247. The method of any one of claims 182 to 246, wherein the migalastat or a salt thereof is administered orally.

248. The method of any one of claims 182 to 246, wherein the migalastat or a salt thereof is administered by injection.

249. The method of any one of claims 182 to 248, wherein the patient is male.

250. The method of any one of claims 182 to 248, wherein the patient is female.

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