Hereditary lysosomal storage disorder · KIMS Secunderabad
Fabry Disease — A Hereditary Metabolic Disorder That Progressively Damages the Kidneys
Fabry disease (Anderson-Fabry disease) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene encoding the enzyme alpha-galactosidase A (alpha-GalA). The enzyme deficiency causes progressive accumulation of glycosphingolipids — primarily globotriaosylceramide (Gb3) — within the lysosomes of cells throughout the body: kidney tubular cells and podocytes, cardiac myocytes, dorsal root ganglion neurons, endothelial cells, and smooth muscle cells. The progressive accumulation of Gb3 causes multisystem organ damage — the kidneys, heart, and nervous system are the organs most critically affected.
Fabry disease is rare — estimated at 1 in 40,000 to 1 in 117,000 in the general population, though the frequency may be higher in India given the large population size. It is significantly under-diagnosed because its early symptoms (neuropathic pain, heat intolerance, skin rash) are non-specific and the connection to kidney disease becomes apparent only years later. The clinical significance of identifying Fabry disease is high: enzyme replacement therapy (ERT) — agalsidase alfa or agalsidase beta — slows the progression of kidney, cardiac, and neurological disease when started early.
Clinical features — multisystem involvement by decade
Childhood and teens
Neuropathic pain — burning or lancinating pain in the hands and feet (acroparaesthesias), often triggered by fever, exercise, or temperature changes. Heat and cold intolerance. Hypohydrosis (reduced sweating). Angiokeratomas — small dark red-purple skin lesions in the 'bathing trunk' distribution (lower abdomen, groin, buttocks). Corneal verticillata — whorled opacities visible on slit-lamp examination — pathognomonic of Fabry disease.
20s and 30s
Proteinuria — the earliest renal manifestation. Haematuria (microscopic). Declining eGFR beginning. Cardiovascular: left ventricular hypertrophy, arrhythmias, conduction defects.
30s and 40s (males) · 40s and 50s (females)
Progressive CKD leading to ESRD — typically requiring kidney transplant or dialysis by 40s in untreated classical males. Stroke (from endothelial Gb3 accumulation causing arterial thrombosis). Hearing loss. Cardiac failure from hypertrophic cardiomyopathy.
Female carriers
Variable expression — from almost asymptomatic (corneal verticillata only) to severe multisystem disease similar to affected males. Previously thought to be 'carriers' with no significant disease — now recognised that up to 70% of female carriers develop significant symptoms and organ damage.
Diagnosis at KIMS
Alpha-galactosidase A enzyme activity
The primary diagnostic test in males. Leukocyte alpha-GalA enzyme activity is measured in peripheral blood. In classically affected males, enzyme activity is severely reduced (below 1% of normal). In females, enzyme activity may be normal or borderline (because random X-inactivation in some cells preserves some enzyme function) — genetic testing is required for definitive diagnosis in females.
GLA gene mutation analysis — definitive diagnosis
Sequencing of the GLA gene identifies the specific mutation. Essential for: diagnosing female carriers who may have normal enzyme activity, confirming the diagnosis in males with borderline enzyme activity (particularly late-onset variants with residual enzyme function), and enabling cascade genetic testing of family members.
Plasma lyso-Gb3 (lyso-globotriaosylsphingosine)
A biomarker that is elevated in most Fabry disease patients — including female carriers. Useful for supporting the diagnosis, monitoring treatment response, and identifying carriers who have normal enzyme activity on standard testing.
Kidney biopsy with LM + IF + EM at KIMS
The kidney biopsy findings are highly characteristic on EM — the pathognomonic 'zebra bodies' (osmiophilic multilamellar inclusions in lysosomes, resembling zebra stripes in cross-section) in podocytes and tubular cells. EM is the single most diagnostically specific test for Fabry disease on biopsy. LM shows podocyte vacuolisation and tubular cell vacuolisation. The kidney biopsy in Fabry disease is primarily performed when the diagnosis is uncertain (to avoid misclassifying Fabry nephropathy as FSGS or other causes of proteinuria) and to assess the degree of fibrosis before initiating ERT.
Echocardiogram and cardiac MRI
Left ventricular hypertrophy (LVH) is present in the majority of adult Fabry patients — the most common cardiac manifestation. Cardiac gadolinium enhancement on MRI identifies fibrosis. Holter monitoring for arrhythmias.
Treatment — enzyme replacement therapy (ERT)
Agalsidase alfa (Replagal) or agalsidase beta (Fabrazyme)
Both are recombinant human alpha-galactosidase A enzymes administered by IV infusion every 2 weeks. ERT reduces plasma Gb3 and tissue Gb3 levels, reduces the rate of CKD progression, reduces cardiac LV mass, and reduces neuropathic pain. ERT is most effective when started before significant irreversible end-organ damage (FSGS on kidney biopsy, cardiac fibrosis on MRI, established CKD). ERT does not cure Fabry disease — it slows progression. Infusion reactions (fever, chills, chest tightness) occur in approximately 20% of patients and are managed with pre-medication (antihistamines, paracetamol, steroids) and slower infusion rates.
Migalastat (Galafold) — oral chaperone therapy
An oral pharmacological chaperone that stabilises specific (amenable) alpha-GalA mutations — allowing the enzyme to fold correctly and transit to the lysosome where it can function. Approved for patients with amenable GLA mutations — approximately 50% of known mutations are amenable. Migalastat is taken every other day orally. A significant advance over IV ERT for suitable patients — oral dosing every 48 hours is far more convenient than fortnightly IV infusions.
ACE inhibitors or ARBs
For proteinuria reduction and kidney protection — standard nephroprotective therapy alongside ERT.
Kidney transplant
For Fabry ESRD — the transplanted kidney does not develop Fabry disease (the donor kidney produces normal alpha-GalA). ERT is continued post-transplant to prevent accumulation in non-renal organs (heart, nervous system).
Fabry disease is among the most important rare genetic kidney diseases to diagnose because the treatment is disease-modifying and best started before advanced organ damage. Any young adult (below 40) with unexplained CKD, LVH, neuropathic pain, and unexplained stroke — particularly if male — should be tested for Fabry disease with leukocyte alpha-GalA enzyme activity and GLA gene sequencing. At KIMS, this workup is available through the glomerular disease and genetic nephrology programme.
Book a Genetic Nephrology Assessment for Fabry Disease at KIMS. Call 040-4488-5000
Frequently Asked Questions — Fabry Disease
Fabry disease is a hereditary condition where the body lacks a specific enzyme — alpha-galactosidase A — that normally breaks down a fatty substance called globotriaosylceramide (Gb3). Without this enzyme, Gb3 accumulates in cells throughout the body — particularly in the kidneys, heart, blood vessels, and nervous system. Over decades, the accumulation of Gb3 progressively damages these organs: the kidneys develop proteinuria and eventually kidney failure; the heart develops thickening of the heart muscle; the blood vessels are prone to clotting (causing stroke); and the nervous system causes pain and hearing loss. The condition is X-linked — it is caused by a mutation on the X chromosome and affects males more severely than females.
No — though classical Fabry disease is more severe in males (who have only one X chromosome and therefore no normal copy of the GLA gene). Females — who have two X chromosomes and therefore carry one normal and one mutated copy — were historically considered 'carriers' with no significant disease. Current evidence shows this is incorrect: up to 70% of female carriers develop significant symptoms and organ damage, including kidney disease, cardiac hypertrophy, neuropathic pain, and stroke. The severity in females is variable — from minimal symptoms to a course nearly as severe as in males — depending on which cells preferentially express the normal vs mutated X chromosome (random X-inactivation). Female carriers should be evaluated and monitored as potentially affected individuals, not dismissed as asymptomatic carriers.
Zebra bodies are the pathognomonic EM finding of Fabry disease in kidney biopsy specimens — named for their appearance on electron microscopy. They are lamellar osmiophilic inclusions within lysosomes of podocytes and tubular cells — concentric layers of Gb3 lipid that stack to produce alternating dark and light bands under the electron microscope, resembling the stripes of a zebra. No other condition produces this specific ultrastructural appearance, making the zebra body finding on EM essentially diagnostic of Fabry disease. EM is performed in-house at KIMS's NABL-accredited laboratory, making this diagnosis available locally without outsourcing.
Not with currently available treatments — enzyme replacement therapy (ERT) and migalastat slow the progression of organ damage but do not remove the Gb3 already accumulated in tissues, do not correct the underlying genetic mutation, and must be continued indefinitely. Gene therapy for Fabry disease is in early clinical trials and represents the most promising path to a cure — but is not yet clinically available. Kidney transplant for Fabry ESRD is a major advance — the transplanted kidney does not develop Fabry disease — but systemic Gb3 accumulation continues to affect the heart, nervous system, and vasculature, requiring continued ERT post-transplant.
KIMS Secunderabad — Dr. Aswini Dutt T (glomerular disease subspecialty), leukocyte alpha-GalA enzyme activity, GLA gene sequencing, plasma lyso-Gb3, kidney biopsy with EM (zebra body identification in-house), echocardiogram and cardiac MRI coordination, ERT infusion (agalsidase alfa and beta), migalastat assessment for amenable mutations, ACE inhibitor kidney protection protocol, transplant evaluation for Fabry ESRD. NABH and NABL accredited. Call 040-4488-5000.