Female Fabry disease patients and X-chromosome inactivation

Abstract

Fabry disease is an X-linked inherited lysosomal storage disorder caused by mutations in the gene encoding α-galactosidase A (GLA). Once it was thought to affect only hemizygous males. Over the last fifteen years, research has shown that most females carrying mutated allele also develop symptoms, demonstrating a wide range of disease severity, from a virtually asymptomatic to more classical profile, with cardiac, renal, and cerebrovascular manifestations. This variable expression in females is thought to be influenced by the process of X-chromosome inactivation (XCI). The aim of this study was to assess severity of the clinical phenotype, to analyze XCI patterns, and to estimate their effect on disease manifestation in twelve female Fabry disease patients from five unrelated Polish families. Our analyses revealed that patients presented with the broad range of disease expression - from mild to severe, and their clinical involvement did not correlate with XCI profiles. Female carriers of the mutation in the GLA gene with the random XCI may present with the wide range of disease signs and symptoms. Thus, XCI is not a main factor in the phenotype variability of Fabry disease manifestation in heterozygous females.

Results of Fabry Disease Screening in Male Pre-End Stage Renal Disease Patients with Unknown Etiology Found Through the Platform of a Chronic Kidney Disease Education Program in a Northern Taiwan Medical Center

“…Tanakahashi N et al reported that a middle-aged woman with normal GLA enzyme activity was diagnosed with FD by kidney pathology [34]. For a heterozygous female, X chromosome inactivation means there is no clear association between clinical symptoms and GLA enzyme activity [35]. In female FD patients, the enzymatic activity can be normal or slightly lower.…”

Storage diseases with hypertrophic cardiomyopathy phenotype

“…Variants in this gene can affect enzyme synthesis, folding, degradation, trafficking or activity, leading to inability to degrade Gb3. Males have low or absent enzyme activity, but as a result of the lyonization process (transcriptional inactivation of one of the X chromosomes in some cells during embryogenesis) may present with atypical forms and a wide spectrum of signs and symptoms ( Figure 12 ), depending on enzyme’s activity preservation or absence among the different organs and tissues 49 .…”

De novo mutation and skewed X‐inactivation in girl with BCAP31 ‐related syndrome

“…XCI status has been used to explain the wide spectrum of phenotypes observed (from asymptomatic to severe) in some X‐linked diseases in women, depending on the degree of silencing of the normal allele (Echevarria et al, 2016; Elstein, Schachamorov, Beeri, & Altarescu, 2012; Fahim et al, 2019; Juchniewicz et al, 2018). For example, the severity scores and progression phenomena in X‐linked Fabry disease caused by α‐Gal deficiency had significant correlation with XCI ratio in female patients (Echevarria et al, 2016; Elstein et al, 2012; Juchniewicz et al, 2018). Given the recent observation that skewed XCI is common in the general female population (Shvetsova et al, 2019), female patients with clinical features of an X‐linked recessive disorder and one copy of the mutated gene should be screened for skewed XCI.…”