Fabry disease in mainland China is now mapped through the largest single-centre cohort to date, clarifying how α-galactosidase A deficiency, genotype and sex jointly sculpt the clinical spectrum. Retrospective analysis of 311 genetically confirmed individuals (200 males, 111 females) collected between 2012 and 2022 reveals that 76% present the classical phenotype and 24% the late-onset variant, with male predominance in the former (72%) and female skewing in the latter (62%). Limb pain (67%), hypohidrosis (63%), proteinuria (51%) and angiokeratomas (46%) emerge as the cardinal complaints, followed by renal (58%), cardiovascular (55%) and neuro-psychiatric (58%) involvement. Eye and ear lesions are also common, yet their frequency diverge sharply between sexes and phenotypes.
Males consistently harbour lower residual enzyme activity (median 0.29 μmol/L/h) than females (3.57 μmol/L/h), and classical patients cluster at ≤ 5% of normal activity, whereas late-onset cases span 3–30%. Organ involvement mirrors this gradient: ≤ 5% activity associates with 89 % acroparesthesia, 81% hypohidrosis, 74% renal disease and 67% cardiac involvement, while > 5% activity halves these rates and confines late-onset patients chiefly to renal and cardiovascular domains. In females, enzyme activity poorly predicts burden, underscoring the impact of skewed X-inactivation and other epigenetic modifiers.
Next-generation sequencing of 163 patients identifies 95 distinct GLA variants, with exon 5 hosting the largest share (18%). Missense mutations dominate (62%), followed by nonsense (17%), frameshift (14%) and splice variants (5%). Truncating lesions trend toward slightly lower enzyme levels than non-truncating ones, yet the difference is not significant, and neither genotype class dictates phenotype severity across sexes or age strata. Even the recurrent c.334C>T (p.R112C) mutation, carried by nine unrelated males and one female, demonstrates intrafamilial heterogeneity: some carriers develop multiorgan failure before age 30, others remain oligosymptomatic into the sixth decade.
Taken together, the data reinforce sex and residual α-Gal A activity—not genotype alone—as the primary determinants of clinical trajectory in Chinese Fabry patients. Males with classical disease face the highest risk of early multiorgan damage, whereas females and late-onset males present milder, organ-limited phenotypes despite genetic overlap. Routine enzyme assays remain indispensable for males, but genotype-guided surveillance is equally critical for females, given the unpredictable expression pattern.
Frontiers of Medicine
Experimental study
Not applicable
Correlation of enzyme activities and genotype with clinical manifestations in Chinese patients of different sexes with classical and late-onset Fabry disease
9-Jun-2025