X‐chromosomal inactivation patterns in women with Fabry disease

Abstract

Background Although Fabry disease (FD) is an X‐linked lysosomal storage disorder caused by mutations in the α‐galactosidase A gene (GLA), women may develop severe symptoms. We investigated X‐chromosomal inactivation patterns (XCI) as a potential determinant of symptom severity in FD women. Patients and Methods We included 95 women with mutations in GLA (n = 18 with variants of unknown pathogenicity) and 50 related men, and collected mouth epithelial cells, venous blood, and skin fibroblasts for XCI analysis using the methylation status of the androgen receptor gene. The mutated X‐chromosome was identified by comparison of samples from relatives. Patients underwent genotype categorization and deep clinical phenotyping of symptom severity. Results 43/95 (45%) women carried mutations categorized as classic. The XCI pattern was skewed (i.e., ≥75:25% distribution) in 6/87 (7%) mouth epithelial cell samples, 31/88 (35%) blood samples, and 9/27 (33%) skin fibroblast samples. Clinical phenotype, α‐galactosidase A (GAL) activity, and lyso‐Gb3 levels did not show intergroup differences when stratified for X‐chromosomal skewing and activity status of the mutated X‐chromosome. Conclusions X‐inactivation patterns alone do not reliably reflect the clinical phenotype of women with FD when investigated in biomaterial not directly affected by FD. However, while XCI patterns may vary between tissues, blood frequently shows skewing of XCI patterns.

In vitro characterization of cells derived from a patient with the GLA variant c.376A>G (p.S126G) highlights a non-pathogenic role in Fabry disease

“…As reported before, phenotypic diversity occurs in patients sharing the same GLA variant [ 9 ]. In women, this might be ascribed to random X-inactivation and subsequent difference in cell-to-cell enzyme activity [ 45 , 73 ]. Since severe phenotypic variability was also found in men and even within one family [ 55 ], epigenetic modifications were proposed as an explanation [ 75 ].…”

Sex Differences in Anderson–Fabry Cardiomyopathy: Clinical, Genetic, and Imaging Analysis in Women

“…Depending on which X-chromosome is randomly ‘turned off’ or ‘turned on’, the expression of symptoms can vary across cells and organs within the same individual. However, classic measures of X-chromosome inactivation skewness may not fully capture disease manifestation: a study by Wagenhauser et al showed that X-inactivation patterns alone do not reliably reflect the clinical phenotype of women when assessed in biomaterial not directly affected by the disease [ 66 ]. Additionally, allele-specific DNA methylation at the GLA gene promoter could influence the mutated allele’s expression levels, thereby impacting disease onset and outcome [ 67 , 68 ].…”

Concurrent fabry disease and immunoglobulin a nephropathy: a case report

“…Because this mutation occurs on the X chromosome, females are heterozygous carriers. The non-random inactivation mechanism of X staining [ 8 ] renders female alpha-galactosidase enzyme activity values within the normal range or only slightly decreased, which may account for differences in the clinical presentation between men and women [ 9 ]. Symptoms of FD occur earlier (typically in childhood) and are more severe in male patients, whereas female carriers often have milder and less prominent symptoms that appear in adulthood.…”