Genotype: A Crucial but Not Unique Factor Affecting the Clinical Phenotypes in Fabry Disease

Abstract

Numerous α-galactosidase A (α-gal A) gene (GLA) mutations have been identified in Fabry disease (FD), but studies on genotype-phenotype correlation are limited. This study evaluated the features of GLA gene mutations and genotype-phenotype relationship in Chinese FD patients. Gene sequencing results, demographic information, clinical history, and laboratory findings were collected from 73 Chinese FD patients. Totally 47 mutations were identified, including 23 novel mutations which might be pathogenic. For male patients, those with frameshift and nonsense mutations presented the classical FD, whereas those with missense mutations presented both of classical and atypical phenotypes. Interestingly, two male patients with missense mutation p.R356G from two unrelated families, and two with p.R301Q from one family presented different phenotypes. A statistically significant association was found between the levels of α-gal A enzyme activity and ocular changes in males, though no significant association was found between residual enzyme activity level and genotype or clinical phenotypes. For female patients, six out of seven with frameshift mutations and one out of nine with missense mutation presented the classical FD, and α-gal A activity in those patients was found to be significantly lower than that of patients with atypical phenotypes (13.73 vs. 46.32 nmol/ml/h/mg). Our findings suggest that the α-gal A activity might be associated with the clinical severity in female patients with FD. But no obvious associations between activity level of α-gal A and genotype or clinical phenotypes were found for male patients.

Characterization of Classical and Nonclassical Fabry Disease: A Multicenter Study

“…However, the considerable variation in disease course, even within genotypes, should be taken into account. 17 Most studies on the natural course of FD are from the pre-ERT era. 12,13 Although not explicitly stated, the subjects in these studies were most likely to have a classical phenotype, because awareness and screening studies led to a marked increase in the identification of patients with nonclassical FD.…”

Different renal phenotypes in related adult males with Fabry disease with the same classic genotype

“…Renal variability has been documented recently in a large cohort of Chinese patients, and in particular in a family with the R301Q mutation, but this is now considered to be a late‐onset variant (Pan et al. ).…”

“…More recently, in four Italian pedigrees, several cases of interfamilial variability have been documented, but some males already had albuminuria and their age was not indicated (Rigoldi et al 2014). Renal variability has been documented recently in a large cohort of Chinese patients, and in particular in a family with the R301Q mutation, but this is now considered to be a late-onset variant (Pan et al 2016).…”

“…; Pan et al. ). By contrast, a different renal phenotype between adult male patients belonging to the same family, but without any clinical sign of renal damage, has not been described yet.…”

“…Although, some of these are associated with a classic phenotype and others to a late-onset phenotype, genotype/phenotype correlation is still controversial. Across the same family, variability in the phenotype has been often documented between female members but also among male patients with late-onset mutations, and between male patients with severe or mild renal involvement (Redonnet-Vernhet et al 1996;Veronik et al 2004;Rigoldi et al 2014;Pan et al 2016). By contrast, a different renal phenotype between adult male patients belonging to the same family, but without any clinical sign of renal damage, has not been described yet.…”