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Background <p>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.</p> Case series <p>We report four related individuals with Fabry disease carrying the pathogenic <i>GLA</i> variant c.749&#xa0;A &gt; 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.</p> Conclusions <p>In this family, all clinically evaluated carriers of c.749&#xa0;A &gt; 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月15日

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  • Marija Stamenković,
  • Danijel Slavić,
  • Sonja Rajić,
  • Dragica Hajder,
  • Sanela Popović,
  • Predrag Jovićević,
  • Maša Jovićević,
  • Dejan Ćelić,
  • Željko Živanović

摘要

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.