Correlation of enzyme activities and genotype with clinical manifestations in Chinese patients of different sexes with classical and late-onset Fabry disease

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.