Overlapping Dilemma Involving the New Great Imposter

Introduction: Fabry disease (FD) is a rare X linked lysosomal storage disorder due to alpha-galactosidase A (GLA) gene mutation causing intracellular glycosphingolipid accumulation. The renal manifestations are proteinuria, chronic kidney disease (CKD), hypertension, Fanconi syndrome and renal sinus cysts. We present a case of woman with history of long-standing diabetes mellitus (DM) referred for proteinuria of 1.5 g/dL diagnosed with FD. Case Description: A 48-year-old woman with history of well controlled type 2 DM of 10-year duration on metformin and empagliflozin, presumed Stickler syndrome, hypertension on losartan and amlodipine, arthritis referred to nephrology for worsening albuminuria. She had hand and feet pain aggravated by exercise and heat, hearing loss, alternating constipation and diarrhea, and fatigue for a decade. Family history was positive for valvular heart disease in her mother and cleft palate in father. Physical examination was unremarkable other than cleft palate. Labs revealed normal kidney function, proteinuria, no microscopic hematuria and unremarkable serologies. Imaging studies showed left ventricular hypertrophy and unremarkable kidneys. Kidney gene panel testing revealed heterozygous pathogenic variant c.679C>T (p. Arg227*) GLA gene consistent with FD. The genetic testing for Stickler syndrome was negative. Her plasma globotriaosylsphingosine (Lyso-Gb3) level was elevated at 3 ng/mL (reference range is below 0.3 ng/mL). With initiation of enzyme replacement therapy (ERT), albuminuria improved (Table 1), fatigue and gastrointestinal symptoms resolved. Family genetic testing revealed son with FD. Discussion: Nephrologists should consider genetic testing in men and women with at least one of the clinical features of FD such as acroparesthesia, irritable bowel syndrome, arrhythmias, cutaneous vascular lesions, hypo or anhidrosis, stroke of unknown etiology, proteinuria, and CKD of unknown etiology. Due to rarity of FD, patients are often misdiagnosed with other conditions such as in our patient whose proteinuria was initially attributed to DM and presumed Stickler syndrome. Prompt diagnosis is important as family genetic testing and timely ERT can improve the overall outcome in FD. Albuminuria and proteinuria trend - Lab test 4 years prior to FD diagnosis At the time of FD diagnosis Enzyme replacement therapy initiation(4 months after FD diagnosis) 1 year after FD diagnosis Urine albumin creatinine ratio (mg/g) 861 1000 916 568 Urine protein creatinine ratio (g/g) Not done 1.3 1.48 1.1 FD - Fabry disease