Abstract
BackgroundFabry disease is a multisystemic lysosomal storage disorder caused by the impairment of α-galactosidase A. The incidence of this rare disease is underestimated due to delayed diagnosis. Moreover, the management of the identified subjects is often complicated by the detection of variants of unclear diagnostic interpretation, usually identified in screening studies. We performed an observational study based on biochemical and genetic analysis of 805 dried blood spot samples from patients with clinical symptoms or family history of this pathology, which were collected from 109 Spanish hospitals, all over the country.ResultsWe identified 77 new diagnosed patients with mutations related to classical Fabry disease, as well as 2 subjects with c.374A > T; p.His125Leu, a possible new mutation that need to be confirmed. Additionally, we detected 8 subjects carrying genetic variants possibly linked to late onset Fabry disease (p.Arg118Cys and p.Ala143Thr), 4 cases with polymorphism p.Asp313Tyr and 36 individuals with single nucleotide polymorphisms in intronic regions of GLA. Five of the identified mutations (c.431delG; c.1182delA; c.374A > T; c.932 T > C; c.125 T > A; c.778G > A), which were associated with a classical phenotype have not been previously described. Moreover 3 subjects presenting complex haplotypes made up by the association of intronic variants presented impaired levels of GLA transcripts and Gb3 deposits in skin biopsy.ConclusionsEnzymatic screening for Fabry Disease in risk population (2 or more clinical manifestations or family history of the disease) helped to identify undiagnosed patients and unravel the impairment of GLA expression in some subjects with complex haplotypes.
Highlights
Fabry disease is a multisystemic lysosomal storage disorder caused by the impairment of α-galactosidase A
Enzymatic activity was measured in 805 dried blood spots samples (DBS) samples of 479 males and 326 females; among them, GLA sequencing was performed in male patients with activity lower than 2.6 μmol/Lh and in all female subjects
We identified a family of 2 subjects (1 male and 1 female), who presented with clinical features compatible with the classic form of Fabry Disease (FD), and carry a newly described variant in GLA (c.374A > T;p.His125Leu), which need to be further studied to confirm its pathogenic status
Summary
Fabry disease is a multisystemic lysosomal storage disorder caused by the impairment of α-galactosidase A The incidence of this rare disease is underestimated due to delayed diagnosis. It was originally reported that the incidence of FD is of 1:117,000 [9] for the general population; pilot studies performed in asymptomatic newborns estimated an incidence ranging between 1:3000 and 1: 7000 live births [10, 11] These data and the results of several screening studies performed in patients with medical conditions of diverse etiology (i.e. stroke, renal failure, ventricular hypertrophy) [4, 12, 13] highlight the large number of undetected FD patients, who are probably still unidentified or misdiagnosed
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