About Prof. Chen Nan
Prof. Chen Nan is a distinguished nephrologist at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, specialising in chronic kidney disease, glomerulonephritis, and renal replacement therapy. She has led landmark national studies on IgA nephropathy and kidney fibrosis, established China's largest hereditary nephropathy biobank, and developed the multimodal clinical-pathological-genetic-enzymatic diagnostic platform that reduced the average time to diagnosis of Fabry disease from five years to under one year. Her team produced the Chinese Expert Consensus on Fabry Disease Management, enabling enzyme replacement therapy to be included in China's national reimbursement catalogue. She is a Foreign Associate of the French National Academy of Medicine and recipient of the International Society of Nephrology Pioneer Award.
Case Overview
Mr. Zhou (pseudonym), a 38-year-old man, was referred to Prof. Chen Nan with a six-year history of unexplained proteinuria (urine PCR 1.8 g/g), progressive renal impairment (eGFR declining from 82 to 54 mL/min/1.73m² over four years), episodic burning pain in the hands and feet since adolescence, and a family history of his father reaching end-stage renal disease at 52 and a paternal uncle with early-onset stroke. A prior renal biopsy had been reported as focal segmental glomerulosclerosis (FSGS); corticosteroid treatment had produced no benefit. Prof. Chen Nan's multimodal diagnostic platform — clinical phenotyping, renal biopsy re-review with electron microscopy, alpha-galactosidase A (GLA) enzyme activity assay, and GLA gene sequencing — established the diagnosis of Fabry disease within six weeks: electron microscopy revealed pathognomonic zebra bodies in podocytes and tubular cells; GLA enzyme activity was markedly reduced at 0.8 nmol/hr/mg protein (normal ≥45); and GLA gene sequencing identified a hemizygous pathogenic variant. Enzyme replacement therapy (agalsidase beta) was initiated. At two-year follow-up, eGFR had stabilised (52 mL/min/1.73m²), proteinuria had reduced to 0.9 g/g, and neuropathic pain had decreased in frequency and severity. Family cascade screening identified two affected male relatives, one of whom was pre-symptomatic and commenced ERT before any renal impairment developed. Mr. Zhou reflected: "Six years of tests and no answer. Prof. Chen's team found the diagnosis in six weeks. Knowing what it is — and knowing there is a treatment — changed everything for me and for my family."
Diagnostic Workup
Renal biopsy re-review with electron microscopy identified the pathognomonic ultrastructural finding of Fabry disease: lamellar lysosomal inclusions (zebra bodies) in podocytes, mesangial cells, endothelial cells, and tubular epithelial cells. The original FSGS diagnosis had been made on light microscopy alone, without electron microscopy, missing this finding. GLA enzyme activity assay confirmed markedly reduced activity at 0.8 nmol/hr/mg protein (reference ≥45). GLA gene sequencing identified a hemizygous pathogenic variant in exon 5, enabling family cascade screening. Cardiac assessment (ECG, echocardiography, cardiac MRI) identified mild left ventricular hypertrophy consistent with early Fabry cardiomyopathy. Neurological assessment confirmed small fibre neuropathy on skin punch biopsy. Ophthalmological assessment identified cornea verticillata on slit-lamp examination. Multidisciplinary review — nephrology, cardiology, neurology, and ophthalmology — confirmed the diagnosis, staged organ involvement, and established the ERT initiation and surveillance plan.
Prof. Chen's diagnostic assessment: The original FSGS report was not wrong on light microscopy — there was focal segmental scarring. But FSGS is a pattern, not a diagnosis, and in a young man with acral pain since adolescence, a family history of early renal failure and stroke, and steroid-resistant proteinuria, the obligation is to look further. Electron microscopy makes the diagnosis visible: the zebra bodies are pathognomonic. The enzyme assay and gene sequencing confirm it. This patient had been living with an undiagnosed treatable disease for six years. The diagnostic platform exists precisely to prevent that.
Treatment Strategy and Course
Diagnosis: Fabry Disease (GLA hemizygous pathogenic variant, markedly reduced alpha-galactosidase A activity) with renal involvement (proteinuria, CKD Stage G3a), early cardiomyopathy, small fibre neuropathy, and cornea verticillata — 6-year diagnostic delay.
Treatment principle: enzyme replacement therapy to address the underlying enzymatic deficiency, combined with renoprotective therapy, multiorgan surveillance, and family cascade screening to identify and treat affected relatives before organ damage develops.
- ERT initiation: Agalsidase beta 1 mg/kg IV every two weeks; well tolerated with no infusion-related reactions; continued as outpatient biweekly infusions
- Renoprotective therapy: ACE inhibitor for proteinuria reduction; blood pressure target <130/80 mmHg; dietary protein restriction; SGLT2 inhibitor added at month three
- Multiorgan surveillance: Nephrology: eGFR and urine PCR every three months; Cardiology: annual echocardiography and cardiac MRI; Neurology: annual neuropathy assessment; Ophthalmology: annual slit-lamp examination
- Family cascade screening: GLA sequencing for all first-degree relatives; two affected males identified — one symptomatic (commenced ERT), one pre-symptomatic (commenced ERT before renal impairment); female carriers enrolled in surveillance
- Two-year follow-up: eGFR stable at 52 mL/min/1.73m²; proteinuria reduced from 1.8 to 0.9 g/g; neuropathic pain reduced; left ventricular hypertrophy stable; ERT well tolerated; patient returned to full-time work
Prof. Chen's clinical reflection: The two-year result — stable eGFR, reduced proteinuria, improved neuropathic symptoms — reflects what ERT can achieve when started before irreversible organ damage. This patient had six years of diagnostic delay; he still has meaningful renal reserve, and ERT has stabilised it. The pre-symptomatic relative identified through cascade screening and started on ERT before any renal impairment — that is the outcome the diagnostic platform is ultimately designed to achieve: finding the disease before the organ is lost.
Expert Commentary — Prof. Chen Nan
1. Fabry Disease: The Diagnostic Challenge and the Cost of Delay
Fabry disease is an X-linked lysosomal storage disorder caused by pathogenic GLA variants, resulting in deficient alpha-galactosidase A activity and progressive accumulation of globotriaosylceramide (Gb3) in the kidney, heart, and nervous system. Estimated prevalence is 1 in 40,000–117,000, but it is substantially underdiagnosed: the average time from symptom onset to diagnosis has historically been five years or more, during which progressive and largely irreversible organ damage accumulates. The diagnostic challenge arises from non-specific early symptoms — acral pain, hypohidrosis, gastrointestinal symptoms — and from the fact that FSGS on light microscopy, common in Fabry nephropathy, does not distinguish Fabry disease from other FSGS causes without electron microscopy. Prof. Chen Nan's multimodal platform integrates clinical phenotyping, electron microscopy, enzyme assay, and genetic sequencing — reducing average time to diagnosis to under one year with 98% diagnostic accuracy in the Ruijin Hospital hereditary nephropathy cohort.
2. The Multimodal Diagnostic Platform
Accurate diagnosis of hereditary nephropathy requires integration of modalities no single test can replace. Clinical phenotyping identifies the pattern of multiorgan involvement that raises diagnostic suspicion. Renal biopsy with electron microscopy is the pathological cornerstone: zebra bodies are pathognomonic and present even in early disease. GLA enzyme activity assay provides biochemical confirmation — markedly reduced in affected males, variable in female carriers, making genetic testing essential for carrier identification. GLA gene sequencing establishes the molecular diagnosis, enables genotype-phenotype correlation, and is the prerequisite for cascade screening. The integration of these four modalities in a coordinated pathway enables diagnosis within weeks rather than years.
3. CKD Progression in Fabry Disease: ERT, Renoprotection, and Early Intervention
Without treatment, eGFR declines at 3–5 mL/min/1.73m² per year in affected males, with end-stage renal disease typically in the fourth to sixth decade. ERT — agalsidase alfa or beta, IV every two weeks — replaces the deficient enzyme, reduces Gb3 accumulation, and stabilises or slows eGFR decline when initiated before significant renal fibrosis. The critical determinant of ERT efficacy is the degree of existing fibrosis at treatment initiation: patients with eGFR above 60 and minimal fibrosis show the greatest benefit; those with advanced fibrosis show attenuated response. This is the strongest argument for early diagnosis, early ERT, and cascade screening of family members who can be treated before any renal impairment develops. ACE inhibitors or ARBs reduce proteinuria and slow eGFR decline independently of ERT; emerging evidence supports SGLT2 inhibitors in CKD of any aetiology.
How CMCS Shanghai Coordinated This Case
CMCS Shanghai supported Mr. Zhou and his family throughout the diagnostic, treatment, and surveillance pathway at Ruijin Hospital, including: priority consultation coordination with Prof. Chen Nan's nephrology and hereditary nephropathy team; bilingual interpretation across all nephrology, cardiology, neurology, and ophthalmology consultations; bilingual explanation of the Fabry disease diagnosis, multimodal findings, ERT plan, and multiorgan surveillance programme; coordination of renal biopsy re-review, GLA enzyme assay, GLA gene sequencing, cardiac MRI, skin punch biopsy, and ophthalmological assessment with bilingual results communication; bilingual ERT consent; biweekly ERT infusion day coordination; family cascade screening coordination including genetic counselling and ERT initiation for affected relatives; and ongoing surveillance scheduling.
For international patients with unexplained proteinuria, progressive renal impairment, or a family history of early kidney failure — particularly where a hereditary cause has not been excluded — Prof. Chen Nan's team at Ruijin Hospital offers access to one of China's most experienced hereditary nephropathy diagnostic and treatment programmes. CMCS ensures that expertise is accessible — in the patient's language, with every step coordinated and communicated clearly.
This case report is de-identified and published for educational purposes. All clinical details have been anonymized in accordance with patient privacy standards. CMCS Shanghai is a medical concierge service and does not provide direct medical care.
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