Case Report: Concurrent Fabry disease, IgA nephropathy and undifferentiated connective tissue disease in a female with normal enzyme activity.
The diagnosis of Fabry disease (FD) in heterozygous females remains clinically challenging, as random X-chromosome inactivation frequently leads to preserved α-galactosidase A (α-Gal A) activity and absence of classic clinical stigmata. While concurrent FD and IgA nephropathy (IgAN) is a rare comorbidity predominantly reported in East Asian females, its overlap with systemic autoimmune conditions such as undifferentiated connective tissue disease (UCTD) has not been documented. The shared immunopathogenic mechanisms linking lysosomal sphingolipid storage, immune-mediated glomerular injury, and systemic autoimmunity remain poorly understood.
A 44-year-old Chinese woman presented with facial and lower limb edema, proteinuria (2.772 g/24h), and microscopic hematuria. She lacked classic FD manifestations, and both plasma α-Gal A activity (4.31 μmol/L/h) and lyso-Gb3 (0.52 ng/mL) were normal. Renal biopsy confirmed IgAN (Lee grade III, M1E1S1T0-C0) but electron microscopy incidentally identified pathognomonic lamellated zebra bodies in podocytes. GLA gene sequencing identified a heterozygous c.593T>C (p.Ile198Thr) mutation, confirming FD. Serologic workup revealed high-titer ANA (1:1000) and anti-SSA positivity, fulfilling UCTD criteria.
The patient declined enzyme replacement therapy and received renoprotective regimens combined with hydroxychloroquine. At 6-month follow-up, renal function remained stable and no new UCTD manifestations occurred. Family screening identified her son as a hemizygous GLA carrier.
This case highlights that routine electron microscopy during renal biopsy is critical for detecting occult FD in females with normal enzyme activity, and is consistent with a biologically plausible hypothesis of Gb3-driven immune dysregulation as a potential shared link among FD, IgAN, and systemic autoimmunity, which requires further validation in larger cohorts and functional studies.
A 44-year-old Chinese woman presented with facial and lower limb edema, proteinuria (2.772 g/24h), and microscopic hematuria. She lacked classic FD manifestations, and both plasma α-Gal A activity (4.31 μmol/L/h) and lyso-Gb3 (0.52 ng/mL) were normal. Renal biopsy confirmed IgAN (Lee grade III, M1E1S1T0-C0) but electron microscopy incidentally identified pathognomonic lamellated zebra bodies in podocytes. GLA gene sequencing identified a heterozygous c.593T>C (p.Ile198Thr) mutation, confirming FD. Serologic workup revealed high-titer ANA (1:1000) and anti-SSA positivity, fulfilling UCTD criteria.
The patient declined enzyme replacement therapy and received renoprotective regimens combined with hydroxychloroquine. At 6-month follow-up, renal function remained stable and no new UCTD manifestations occurred. Family screening identified her son as a hemizygous GLA carrier.
This case highlights that routine electron microscopy during renal biopsy is critical for detecting occult FD in females with normal enzyme activity, and is consistent with a biologically plausible hypothesis of Gb3-driven immune dysregulation as a potential shared link among FD, IgAN, and systemic autoimmunity, which requires further validation in larger cohorts and functional studies.