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Is the alpha-galactosidase A variant p.Asp313Tyr (p.D313Y) pathogenic for Fabry disease? A systematic review

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The identification of pathogenic GLA variants plays a central role in the establishment of a definite Fabry disease (FD) diagnosis. We aimed to review and interpret the published data on the p.Asp313Tyr (p.D313Y) variant pathogenicity and clinical relevance. We performed a systematic review of peer-reviewed publications and case-reports on individuals and populations harbouring the p.Asp313Tyr variant. Overall, 35 studies were included in this review. We collected data regarding the clinical manifestations, alpha-galactosidase A enzyme activity, levels of the biomarkers globotriaosylceramide (Gb3 ) and sphingosine-globotriaosylceramide (lyso-Gb3 ) and histological findings of p.Asp313Tyr carriers. The prevalence of p.Asp313Tyr in populations at risk for FD (kidney, heart, neurologic disorders, or symptomatic populations) was calculated. We found high residual enzyme activity, low frequency of clinical features specific for FD, non-elevated lysoGb3 /Gb3 concentrations and lack of intracellular Gb3 accumulation in biopsies in the p.Asp313Tyr carriers. The prevalence of the variant in populations at risk for FD was comparable to the reported frequency in the general population. A possible higher frequency was only observed in neurologic disorders. p.Asp313Tyr can be classified as neutral or variant of unknown significance. Further investigations will be helpful to clarify a possible association between the variant and manifestations in the brain vessels.

Original languageEnglish
JournalJournal of Inherited Metabolic Disease
Volume43
Issue number5
Pages (from-to)922-933
Number of pages12
ISSN0141-8955
DOIs
Publication statusPublished - Sep 2020

    Research areas

  • D313Y, Fabry disease, GLA gene, mutation, variant

ID: 59998002