Fabry disease

Description

An X-linked lysosomal storage disorder caused by deficiency of alpha-galactosidase A, leading to progressive accumulation of globotriaosylceramide (Gb3) in vascular endothelium and multiple organs

X-linked, so classically presents with full severity in hemizygous males; heterozygous females can also be significantly affected (unlike many other X-linked conditions) due to X-inactivation patterns, though typically with a later onset and more variable severity

Gb3 accumulation in vascular endothelium and tissue causes progressive vasculopathy and organ dysfunction - kidneys (progressive CKD), heart (left ventricular hypertrophy, arrhythmia), and CNS (stroke, particularly at a younger age than typical)
Classic phenotype presents in childhood/adolescence with acroparaesthesia (burning hand/foot pain, often heat-triggered), angiokeratomas (small dark red skin lesions), hypohidrosis, and corneal opacities (cornea verticillata) - before progressing to major organ involvement in adulthood
An attenuated/late-onset phenotype (residual enzyme activity) can present later in life with isolated cardiac or renal involvement, without the classic childhood features

Alpha-galactosidase A enzyme activity assay (reliably diagnostic in males; can be normal in some female carriers, given X-inactivation variability) + genetic testing (GLA gene) - both used together, particularly in females where enzyme activity alone may be insufficient
Elevated plasma/urine Gb3 (and the related biomarker lyso-Gb3) supports diagnosis and is used for monitoring
Screening relatives once a proband is identified is important given the X-linked inheritance pattern and the possibility of an attenuated presentation in other family members

Enzyme replacement therapy (agalsidase alfa/beta) - reduces Gb3 accumulation and can stabilise or slow progression of renal/cardiac disease, most effective if started before irreversible organ damage
Oral chaperone therapy (migalastat) - an alternative for patients with an amenable GLA variant, stabilising residual enzyme activity
Symptomatic management: neuropathic pain control for acroparaesthesia, standard CKD and cardiac disease management alongside disease-specific therapy

Chronic kidney disease (a leading cause of morbidity if untreated), stroke at a young age, left ventricular hypertrophy/cardiomyopathy, corneal verticillata (a specific, often incidentally noted sign)

Earlier diagnosis and treatment (before irreversible organ damage, particularly renal fibrosis) produces substantially better long-term outcomes - diagnostic delay is common given the non-specific early symptoms (pain, GI symptoms) that are often misattributed to other causes for years

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