Uneven X inactivation in a female monozygotic twin pair with Fabry disease and discordant expression of a novel mutation in the alpha-galactosidase A gene.

Abstract

The basis for the discordant expression of this de novo mutation in the twins was investigated by studying their X inactivation status. Analysis of the inactive X specific methylation at the androgen receptor gene showed unbalanced inactivation in the twins' fibroblasts and in opposite directions. While the maternally derived X chromosome was preferentially active in the asymptomatic twin, the paternal X chromosome was active in the other, affected twin and was found in her hemizygotic nephew. These data suggest that the paternal X chromosome carries the de novo a-galactosidase A mutation and that uneven X inactivation is the underlying mechanism for disease expression in this novel female MZ twin pair. This is the first documented case of female twins discordant for Fabry disease.

Identification of a novelde novo mutation (G373D) in the ?-galactosidase A gene (GLA) in a patient affected with Fabry disease

“…Similarly, no mutation was found in the proband's siblings (three brothers and one sister). These results are at odds with the extremely low occurrence of de novo mutations in Fabry disease, which have been described only rarely (Madsen et al, 1995 ;Redonnet-Vernhet et al, 1996).…”

Prevalence of Fabry Disease in Female Patients With Late-Onset Hypertrophic Cardiomyopathy

“…Skewed X inactivation, a phenomenon by which the same X chromosome is silenced in most of or all the cells of a tissue, has been shown to be common in normal female subjects, and the X-inactivation pattern can vary widely between different tissues. [15][16][17] This variability makes inaccurate the extrapolation of the X-inactivation status from one tissue to another and explains the nearly normal values of blood ␣-Gal A activity in most (75%) of our female patients despite severe cardiac disease and the higher prevalence of isolated cardiac involvement compared with hemizygous males. The poor diagnostic role of blood ␣-Gal A activity (indicative of FD in only 25% of our cases) and the nonspecific contributions of noninvasive tools such as 2D echocardiography and cardiac MRI raise questions as to how Fabry cardiomyopathy can be detected in women with …”

Genetic or epigenetic difference causing discordance between monozygotic twins as a clue to molecular basis of mental disorders

“…19 Discordant phenotypes were reported in X-linked mental retardation, Duchenne type muscle dystrophy, 34,35 red-green color blindness, Hunter disease, 19 and Fabry's disease. 36 For example, in female MZ twins discordant for fragile X syndrome, the length of CGG repeat did not differ, but its methylation status was different. The normal allele of FMR-1 was methylated and inactivated in the affected twin, while mutant allele was methylated and inactivated in healthy twin.…”