A multigenerational fabry disease case caused by a <i>de novo</i> GLA mutation: Diagnostic delay, phenotypic variability, and the impact of early detection.

Abstract

Fabry disease (FD) is a rare X-linked lysosomal storage disorder characterized by α-galactosidase A deficiency, marked phenotypic heterogeneity, and frequent diagnostic delay. We report a multigenerational family with Fabry disease caused by a <i>de novo</i> GLA (α-galactosidase A gene) mutation in a female patient, affecting two adult sons and an infant granddaughter. The index patient, a 25-year-old male, experienced neuropathic pain, recurrent unexplained fever, gastrointestinal symptoms, anhidrosis, and cerebrovascular events for more than a decade prior to diagnosis. Cardiac hypertrophy, cornea verticillata, and ischemic cerebral lesions were detected. His mother showed neurological and cardiac involvement and was confirmed to carry a <i>de novo</i> GLA mutation. The younger brother presented a milder phenotype without cardiac or ocular involvement. Early cascade genetic screening enabled diagnosis of an affected infant at 6 months of age. Enzyme replacement therapy (ERT) was initiated in all adult patients, leading to symptomatic improvement, although cerebrovascular events persisted in the index case. This case series highlights the pronounced intrafamilial phenotypic variability of Fabry disease and underscores the need to consider FD even in the absence of a positive family history. Early genetic screening, including prenatal and early postnatal testing, is critical to reduce diagnostic delay and optimize long-term clinical outcomes.