Neurological phenotype in Fabry disease: case series with GLA missense variant c.749 A > C (p.Gln250Pro)

Background Fabry disease (FD) is an X-linked lysosomal enzymopathy resulting from deficient alpha-galactosidase A (α-Gal A) activity, leading to the accumulation of glycosphingolipids. Neurological manifestations of Fabry disease markedly diminish quality of life and may present suddenly or gradually, spanning a spectrum from painful small-fiber neuropathy to severe cerebrovascular events in both males and females. Case series We report four related individuals with Fabry disease carrying the pathogenic GLA variant c.749 A > C (p.Gln250Pro): two hemizygous males presented with recurrent brainstem strokes, cerebral small-vessel disease (SVD), acral neuropathic pain, and hearing loss; their heterozygous mother exhibited cerebral SVD, also acral neuropathic pain consistent with small fiber neuropathy (in addition she had electrophysiologically documented mild large fiber sensorimotor polyneuropathy); and an 18-year-old heterozygous niece was neurologically asymptomatic but had cornea verticillata and a short PR interval on ECG, with normal neurophysiological and neurosonological studies. Conclusions In this family, all clinically evaluated carriers of c.749 A > C (p.Gln250Pro), demonstrated either symptomatic or subclinical neurological involvement, predominantly cerebral SVD and suspected small-fiber neuropathy. These observations support systematic neurological and neuroimaging assessment in Fabry disease patients, even in the absence of neurological symptoms.