X Chromosome Inactivation in Carriers of Fabry Disease: Review and Meta-Analysis.

Emanuela Viggiano,Luisa Politano

doi:10.3390/ijms22147663

Abstract

Anderson-Fabry disease is an X-linked inborn error of glycosphingolipid catabolism caused by a deficiency of α-galactosidase A. The incidence ranges between 1: 40,000 and 1:117,000 of live male births. In Italy, an estimate of incidence is available only for the north-western Italy, where it is of approximately 1:4000. Clinical symptoms include angiokeratomas, corneal dystrophy, and neurological, cardiac and kidney involvement. The prevalence of symptomatic female carriers is about 70%, and in some cases, they can exhibit a severe phenotype. Previous studies suggest a correlation between skewed X chromosome inactivation and symptoms in carriers of X-linked disease, including Fabry disease. In this review, we briefly summarize the disease, focusing on the clinical symptoms of carriers and analysis of the studies so far published in regards to X chromosome inactivation pattern, and manifesting Fabry carriers. Out of 151 records identified, only five reported the correlation between the analysis of XCI in leukocytes and the related phenotype in Fabry carriers, in particular evaluating the Mainz Severity Score Index or cardiac involvement. The meta-analysis did not show any correlation between MSSI or cardiac involvement and skewed XCI, likely because the analysis of XCI in leukocytes is not useful for predicting the phenotype in Fabry carriers.

Highlights

Lyso-Gb3 is involved in the vasculopathy, as it induces the proliferation of smooth muscle cells that is associated with hypertrophy and myocardial arterial walls and fibrosis, in vitro [20,21,22]
The classical form of Fabry disease develops in childhood or adolescence, usually with endothelial dysfunction leading to angiokeratomas, and corneal dystrophy, that represent the physical stigmata of the disease [35]
In the Fabry Outcome Survey (FOS), which included 545 patients belonging to 157 families from nine European countries, a highly significant positive correlation was found between the age at entry into FOS and the FOS Severity Index as well as between the age at entry into FOS and the number of affected organs (p < 0.001) in males with GLA missense mutations, irrespective of whether the change in the amino acid side chain predicted in the α-gal protein was classified as a conservative or non-conservative change [57]