Silent Symptoms, Serious Findings: Fabry Disease in a Heterozygous Woman

Introduction: Fabry disease (FD) is a lysosomal storage disorder caused by a deficiency of alpha-galactosidase A (α-Gal A). It affects many organs, including the kidneys. It is X-linked recessive, thus usually unexpected in female carriers. We present a case of a female carrier with albuminuria and classic FD findings on kidney biopsy. Case Description: A 34-year-old woman with a history of attention deficit hyperactivity disorder (ADHD) and obesity was referred for evaluation after microalbuminuria (87 mg/g) was detected during routine insurance testing. Her family history was notable for her mother having end-stage kidney disease and hypertrophic cardiomyopathy. Genetic testing revealed a heterozygous Y207X truncating pathogenic mutation in the GLA gene. The same mutation was also seen in her mother. A subsequent kidney biopsy showed features suggestive of FD (Figure 1). The patient reported occasional tinnitus and decreased exercise tolerance but lacked other manifestations of FD. Cardiac and brain imaging were unremarkable, and she was initially managed conservatively. Two years later, she developed hypertension and worsening albuminuria, peaking at 396 mg/g. In addition to an ACE inhibitor, agalsidase beta was initiated to slow the progression of kidney disease. Discussion: Fabry disease typically causes severe symptoms in hemizygous males due to X-linked recessive inheritance. Females exhibit variable expression due to random X-chromosome inactivation, resulting in severe manifestations in some. In our patient, the Y207X mutation led to premature termination of GLA protein expression, resulting in a nonfunctional protein. Genetic results alone do not predict severity; thus, close monitoring and early treatment are essential to prevent complications.