Fabry disease: The α-galactosidase A (GLA) c.427G&gt;A (A143T) mutation, effect of the 5′-10C&gt;T polymorphism

Desnick, Robert J.; Doheny, Dana; Chen, Brenden; Yu, Chunli; Nazarenko, Irina; Lee, Beom-Hee; Atherton, Andrea M.; Montel, R.; Singh, Asha; Kadirvel, Senkottuvelan

doi:10.1016/j.ymgme.2014.12.067

Cited by 7 publications

(5 citation statements)

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“…38 In addition, -10C>T is associated with reduced GLA expression and, consequently, mildly reduced α-galactosidase A activity (reduced by approximately 15-20% but not in disease range). 39 Therefore, -10C>T is likely to be a disease modifier when associated with a pathogenic variant. Of note, symptomatic -10C>T variant patients have been administered ERT, resulting in apparent reduction in neuropathic pain and increased physical activity 38 .…”

Section: %mentioning

confidence: 99%

Is it Fabry disease?

Schiffmann¹,

Fuller

Clarke

et al. 2016

Genetics in Medicine

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Fabry disease is caused by mutations in the GLA gene that lower α-galactosidase A activity to less than 25-30% of the mean normal level. Several GLA variants have been identified that are associated with relatively elevated residual α-galactosidase A. The challenge is to determine which GLA variants can cause clinical manifestations related to Fabry disease. Here, we review the various types of GLA variants and recommend that pathogenicity be considered only when associated with elevated globotriaosylceramide in disease-relevant organs and tissues as analyzed by mass spectrometry. This criterion is necessary to ensure that very costly and specific therapy is provided only when appropriate.Genet Med 18 12, 1181-1185.

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Section: %mentioning

confidence: 99%

Is it Fabry disease?

Schiffmann¹,

Fuller

Clarke

et al. 2016

Genetics in Medicine

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“…As in many diseases multiple additional genetic and epigenetic factors are likely to ameliorate or exacerbate the impact of each Fabry mutation, and hence underlie the significant heterogeneity of disease. For example, in FD patients with the p.A143T GLA mutation, the 10C>T polymorphism in the 5 0 untranslated region of GLA has been shown to reduce alpha-galactosidase activity (Desnick et al 2015). This could partially explain the pathogenic variability seen in this mutation.…”

Section: Discussionmentioning

confidence: 99%

Elevated Lyso-Gb3 Suggests the R118C GLA Mutation Is a Pathological Fabry Variant

Talbot

Nicholls

2018

JIMD Reports

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Background: Fabry disease (FD), an X-linked lysosomal storage disease, results from an a-galactosidase A deficiency and altered sphingolipid metabolism. An accumulation of globotriaosylsphingosine (lyso-Gb3) likely triggers the pathological cascade leading to disease phenotype. The pathogenic significance of several Fabry mutations including the R118C a-galactosidase (GLA) gene variant has been disputed. We describe three members of the same family with the R118C variant, each having documented clinical signs of FD, low residual enzyme levels, and an elevated lyso-Gb3 in one heterozygote. Determining the clinical significance of each GLA gene variant remains an ongoing challenge, with potential for inadequate treatment if the diagnosis of FD is missed. Elevated lyso-Gb3 has been shown to be the most reliable noninvasive marker of clinically relevant GLA variants. While the R118C variant will likely lead to a milder phenotype, additional genetic, epigenetic, and environmental factors can ameliorate or exacerbate the expression and impact on the resultant phenotype and associated complications. Patients affected with this variant warrant closer review and better management of disease risk factors. Abbreviations aGal Alpha-galactosidase A FD Fabry disease Gb3 Globotriaosylceramide GLA Gene encoding a-galactosidase Lyso Gb3 Globotriaosylsphingosine

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“…The A143T variant, which has an allele frequency of ~0.1% in the European (non‐Finnish) population in gnomAD (Karczewski et al, 2020), was previously reported in association with both classic and late‐onset Fabry symptoms (De Brabander et al, 2013; Eng et al, 1997; Gaggl, El‐Hadi, Aigner, & Sunder‐Plassmann, 2016; Valtola et al, 2020). However, more recently, this variant is suggested to be a disease modifier (Desnick et al, 2015; Godel et al, 2020; Terryn et al, 2013) or benign pseudodeficiency after multiple studies observing this variant in male and female patients with residual enzyme function and normal plasma lyso‐Gb3 (LGB3) levels (Lenders et al, 2016) and absence of Gb3 deposits in biopsies of affected tissue (Terryn et al, 2013). At the time of this publication, the Clinvar entry (RCV000011495.28) (Landrum et al, 2018) for A143T cites conflicting interpretations of pathogenicity, with listed classifications from submitting laboratories ranging from pathogenic to likely benign.…”

Section: Introductionmentioning

confidence: 99%

Newborn screening for Fabry disease in Oregon: Approaching the iceberg of A143T and variants of uncertain significance

Viall

Dennis

Yang

2022

American J of Med Genetics Pt C

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Fabry disease newborn screening (NBS) has been ongoing in Oregon for over 41 months by first-tier enzyme quantitation and second-tier DNA testing. During that period the majority of abnormal referrals received (34/60) were for the presence of the controversial c.427G > A (p.Ala143Thr) aka A143T and the majority of non-A143T referrals were for other variants of uncertain significance (17/60) resulting in at least 32 infants with an inconclusive case outcome even after clinical evaluation and/or diagnostic testing. To date there has been no significant family history or onset of symptoms in individuals with an inconclusive outcome. Based on our experience, we have developed a framework for approaching A143T and other variants of uncertain clinical significance in an attempt to balance sensitivity with the unnecessary medicalization of healthy infants.

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Fabry disease: The α-galactosidase A (GLA) c.427G>A (A143T) mutation, effect of the 5′-10C>T polymorphism

Cited by 7 publications

References 0 publications

Is it Fabry disease?

Is it Fabry disease?

Elevated Lyso-Gb3 Suggests the R118C GLA Mutation Is a Pathological Fabry Variant

Newborn screening for Fabry disease in Oregon: Approaching the iceberg of A143T and variants of uncertain significance

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