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Review
. 2021 Jul 17;22(14):7663.
doi: 10.3390/ijms22147663.

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

Emanuela Viggiano  1 , Luisa Politano  2
Affiliations
Review

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

Emanuela Viggiano et al. Int J Mol Sci. .

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.

Keywords: Fabry disease; X chromosome inactivation; carriers.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Pattern of XCI in healthy females. Each tissue of females is a mosaic of cells, including cells (white circle) in which the paternal X chromosome is activated (Xpa) and the maternal X chromosome is inactivated (Xmi) and cells (grey circle) in which the maternal X chromosome is activated (Xma) and the paternal X chromosome is inactivated (Xpi).
Figure 2
Figure 2
Example of cellular mosaicism in a female carrier of X-linked disease. The figure represents an example of (a) a random XCI pattern with the same percentage of cells expressing the paternal (white) mutated X chromosome (Xp•) and the maternal (grey) X chromosome (Xm) (on the left); (b) a skewed XCI pattern with a higher percentage of cells expressing the maternal X chromosome that determines the absence of symptoms or a skewed XCI pattern with a higher percentage of cells expressing the Xp• that determines the presence of symptoms (in the center); (c) an extremely skewed XCI with a higher percentage of cells expressing the maternal X chromosome that determines the absence of symptoms or an extremely skewed XCI pattern with a higher percentage of cells expressing the Xp• that determines the presence of symptoms (on the right). a = activated; i = inactivated.
Figure 3
Figure 3
Flow chart.
Figure 4
Figure 4
Forest plots for skewed versus random XCI in mild and moderate-severe symptomatic Fabry carriers. Heterogeneity I2 = 65.43%, p = 0.055.
Figure 5
Figure 5
Forest plots for skewed versus random XCI in symptomatic Fabry carriers at cardiac level. Heterogeneity I2 = 0.0%, p = 0.609.
See this image and copyright information in PMC

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