Fishing for Zebras: Catching Fabry Disease with Pretransplant Genetic Testing

Introduction: Fabry Disease (FD) is a rare X-linked lysosomal storage disorder whose diagnosis can be particularly challenging in women, who often present atypically. Case Description: A 43-year-old woman with ESRD attributed to hypertension and fibromuscular dysplasia (FMD) presented to renal clinic for pre-transplant evaluation. She had hypertension since age 20, complicated by hemorrhagic stroke at age 33 and an admission for hypertensive urgency at age 34, during which she was told she had FMD based on right renal atrophy and distal right renal artery stenosis, treated with balloon angioplasty. Unfortunately her eGFR declined rapidly over 4 years from 52 to 10 ml/min/1.73m2 without explanation on serology and “no evidence of fibromuscular dysplasia” or re-stenosis on repeat MRA. She started dialysis in 2019 at age 39. Her medical history was also notable for incidental ischemic strokes seen on imaging, memory impairment, complete heart block in 2022, and systolic heart failure in 2024. Due to the patient’s early-onset renal disease (in combination with her cardiac and neurologic history), the transplant nephrologist ordered a kidney gene panel. This revealed a heterozygous, “likely-pathogenic” galactosidase alpha (GLA) gene mutation c.1018T>A (p.Trp340Arg), consistent with FD. She was referred to Medical Genetics who elicited a history of hypohidrosis and diarrhea, but no neuropathic pain, skin lesions, vision/hearing impairment, or known family history of FD. However, her son had neuropathy and her brother died young from heart failure. Enzyme levels showed accumulation of globotriaosylsphingosine (LysoGb3) and she subsequently started enzyme replacement therapy. Family testing revealed the same mutation in her daughter. Discussion: FD demands a high index of suspicion and low threshold for genetic testing in patients with early-onset kidney disease, especially in the setting of cardiac and neurologic manifestations. Panels to identify genetic causes of CKD are now recommended in KDIGO’s recent 2024 CKD evaluation guidelines. Patients with FD stand to benefit as more nephrologists gain access to this testing and can cast a wide net to catch heterozygous or atypical cases earlier. Furthermore, ESRD is not too late to test and drastically improve outcomes for patients and their family members.