The mutation p.D313Y is associated with organ manifestation in Fabry disease

Abstract

Fabry disease (FD) is a multisystem lysosomal storage disorder caused by mutations in the GLA gene. The clinical significance of the mutation p.D313Y is still under debate. Retrospective chart analysis of clinical (neurological, cardiac, renal, and ophthalmological), genetic, and biochemical (lyso-globotriaosylsphingosine, lyso-Gb3; enzyme activity) data was performed in all our patients carrying the p.D313Y mutation. Fourteen patients from 5 families (10 female, 4 male; age range 10-51) were included. Symptoms and organ manifestations compatible with FD could be identified in 10 patients. Cerebrovascular events occurred in 4 females. Seven patients reported pain or acroparaesthesia. Cornea verticillata was found in 1 patient, mild retinal vascular tortuosity in 5 patients. Lyso-Gb3 was elevated in 2 females with cerebrovascular involvement. Classical cardiac, renal or skin manifestations could not be identified. The mutation p.D313Y in the GLA gene may lead to organ manifestations and elevation of the Fabry-specific biomarker lyso-Gb3. Neurological symptoms (stroke and pain) and ocular manifestations seem to be the leading findings. Annual routine visits are recommended for patients carrying the p.D313Y mutation. Enzyme replacement therapy might be considered in symptomatic patients.

Podocytopathies

“…Patients with Dent disease should be treated to avoid failure to thrive and kidney stones 64,65,206 . Similarly, patients with Fabry disease or cystinosis will likely benefit from early treatment, with enzyme replacement therapy or cysteamine depleting therapy, respectively 65,207 . Patients with pathogenetic mutations in exon 8 or 9 of WT1 will benefit from regular screening for Wilms tumour and some may undergo prophylactic nephrectomy 208 .…”

The D313Y genotype—Pathogenic mutation or polymorphism?

“…With great interest we have read the recent article by du Moulin et al, 1 formally challenging the "low-pathogenicity hypothesis" of the D313Y genotype in Fabry disease. Most important, the authors report cerebrovascular events in 4 of 14 subjects.…”

Diagnostic strategy for females suspected of Fabry disease

“…Due to random X‐inactivation, α‐Gal A activity in heterozygous females is not conclusive as women often present with normal enzyme levels, and potentially affected individuals might be missed. In contrast, primarily genetic testing leads to the identification of variants of unknown significance (VUS), and above all, to frequent benign variants, such as p.D313Y and p.A143T …”

“…In contrast, primarily genetic testing leads to the identification of variants of unknown significance (VUS), and above all, to frequent benign variants, such as p.D313Y and p.A143T. [6][7][8][9] In recent years, lyso-GL-3 has emerged as a useful biomarker in FD, [10][11][12][13][14][15][16] even allowing to differentiate between classic and later-onset FD. 17 However, lyso-GL-3 is not solely specific to FD, 18 so diagnosis cannot be based on lyso-GL-3 elevations alone.…”