Elsevier

Gene

Volume 505, Issue 2, 1 September 2012, Pages 266-268
Gene

X-inactivation in Fabry disease

https://doi.org/10.1016/j.gene.2012.06.013Get rights and content

Abstract

Background

Fabry disease is one of three X-linked lysosomal disorders. Because of X-chromosome inactivation (XCI), wherein there is (random) transcriptional silencing of one of the X‐chromosomes in each female cell, females are mosaic for the expression of (some) X-linked genes. Thus, based on penetrance and expression, some females heterozygous for Fabry disease are symptomatic but not to the same degree as hemizygous males. The purpose of this study was to ascertain whether skewed X-inactivation favoring the mutant α-galactosidase A allele exists in our cohort of female heterozygotes of Fabry disease.

Method

All patients were evaluated by physical examination and ascribed disease-specific severity sub-scores for each of the four categories (cardiac, renal, neurological, general) and a total score using the Mainz Severity Score Index (MSSI). Blood samples were drawn for enzymatic activity of α-galactosidase A and for DNA extraction for analysis for α-galactosidase A mutations. XCI ratios were determined from peripheral blood leukocyte samples. The X-chromosome inactivation ratio was determined in each heterozygote.

Results

Of 77 samples, only 18.2% were highly skewed (80/20). Only 14.3% of samples with nonsense mutations were highly skewed. There were no correlations between the XCI ratios and age, enzymatic activity of α-galactosidase A, MSSI sub-scores or total score, or with the clinical signs of cardiac involvement, neuropathic pain, or proteinuria.

Conclusion

These findings are comparable with others in Fabry disease, i.e., essentially the same as seen in normal non-elderly female population, raising the question of the mechanism underlying symptomatic phenotypic expression in heterozygous females with Fabry disease.

Highlights

► Most female Fabry heterozygotes are symptomatic but with later onset than males. ► Our findings confirm random X-inactivation in female carriers of Fabry mutations. ► X-inactivation may not play a role in X-linked Fabry disease.

Introduction

Fabry is a rare lysosomal disorder (Desnick et al., 2003) which results in multi-system involvement due to deficiency of the enzyme α-galactosidase A. The α-galactosidase A gene is located on the X‐chromosome with > 400 mostly private mutations described in patients globally a list of which is now available (Saito et al., 2011). The estimated incidence of Fabry disease was 1:117,000 based on live male births, but when considering heterozygotes, the incidence may be as high as 1:58,000 (Fuller et al., 2006); more recent screening efforts including more mutations will probably increase the incidence among hemizygous and heterozygous.

Accumulation of undegraded substrates, globotriaosyl-ceramide (Gb3) and deacylated globotriaosylsphingosine (lyso-Gb3) results in proteinuria and progressive renal disease, cardiac hypertrophy and vascular abnormalities, early stroke due to ischemia, angiokeratoma, corneal dystrophy, hypohidrosis, and acroparaesthesias (Mehta, 2009). These common signs and symptoms are noted in both male patients and female carriers; although the progression and severity may be attenuated in females so that they may present a decade or more later than males, their life expectancy is also reduced (Deegan et al., 2006). Fabry disease is one of three X-linked lysosomal disorders (Pinto et al., 2010) and the situation in female heterozygotes is apparently more comparable to that of female carriers of X-linked Danon disease (Boucek et al., 2011); symptomatic female carriers with X-linked Mucopolysaccharidosis II (MPS II; Hunter disease) are much more rare (de Camargo Pinto et al., 2011).

The majority of X-linked diseases produce symptomatic disease only in the males (Morey and Avner, 2010). However, by the molecular mechanism known as X-chromosome inactivation (XCI), wherein there is (random) transcriptional silencing of one of the X‐chromosomes in each female cell, females are mosaic for the expression of (some) X-linked genes. Thus, based on penetrance and expression, some female heterozygotes as in Fabry disease and Danon disease are symptomatic but not to the same degree as hemizygous males (heretofore termed “X-linked semi-dominant”), whereas in MPS II, most females are virtually unaffected (heretofore termed “X-linked recessive”). Although there are numerous biological events other than X-inactivation that may impact penetrance and expression in heterozygous females, X-inactivation cannot be disregarded as possibly having a major role in phenotypic expression.

In the case of Fabry disease, there have been conflicting results regarding the X-inactivation profiles of female heterozygotes. One study (Dobrovolny et al., 2005) had found that X-inactivation was a major factor in determining the clinical severity of female heterozygotes, whereas another study (Maier et al., 2006) showed that there was random X-inactivation in female heterozygotes of Fabry disease. The purpose of this study was to ascertain whether skewed X-inactivation favoring the mutant α-galactosidase A allele exists in our cohort of female heterozygotes of Fabry disease.

Section snippets

Methods

All patients were evaluated by physical examination and then ascribed disease-specific severity sub-scores for each of the four categories (cardiac, renal, neurological, general) and a total score using the Mainz Severity Score Index (MSSI; Whybra et al., 2004). Blood samples were drawn for enzymatic activity of α-galactosidase A which was also used initially for diagnostic purposes and for DNA extraction for analysis for α-galactosidase A mutations.

XCI ratios were determined from peripheral

Results

A total of 77 female heterozygotes were investigated: the characteristics of the cohort are noted in Table 1. Only 18.2% of the samples were highly skewed (80/20). The majority of samples (71.4%) exhibited a random XCI ratio. Only 3/21 (14.3%) samples with nonsense mutations were highly skewed.

There were a total of 61 different genotypes in this cohort. Table 2 presents the six most frequent genotypes as well the four examples of genotypes with deletions along with the respective enzyme levels

Discussion

The expectation for females heterozygous for X-linked diseases is that they will be virtually asymptomatic because of the input of the non-mutated allele. In Fabry disease, we now know that the vast majority of female heterozygotes will suffer the signs and symptoms of classic Fabry disease, albeit with a delay relative to male hemizygous patients. Non-random X-chromosome inactivation might underlie this phenomenon.

In our study, XCI was not found to be correlated with enzymatic levels nor with

Acknowledgements

The authors thank Prof. Arndt Rolfs (Albrecht-Kossel-Institute for Neuroregeneration (AKos) Medical Faculty, University Rostock) for providing the samples.

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Disclaimer: None of the authors has any conflicts of interest that may have impact on the results of this study.

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