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

We describe two female monozygotic (MZ) twins heterozygous for Fabry d isease, an X linked disorder resulting from the deficient activity of alpha-galactosidase A. While one of the twins was clinically affected, the other was asymptomatic. Enzymatic assay of alpha-galactosidase in blood leucocytes, skin fibroblasts, Epstein-Barr virus transformed ly mphoid cell lines, and hair follicles of the twins and their parents c onfirmed the heterozygous status of the twins and indicated that Fabry disease had occurred as a result of a de novo mutation. The son of th e unaffected twin sister was shown to be hemizygous. Molecular analysi s of the alpha-galactosidase A gene permitted the identification of an as yet undescribed point mutation at position 10182 of exon 5 which c auses an Asp to Asn substitution at codon 231. Single strand conformat ion polymorphism (SSCP) analysis again showed the heterozygous status of the twins and a normal pattern in their parents. The basis for the discordant expression of this de novo mutation in the twins was invest igated by studying their X inactivation status. Analysis of the inacti ve X specific methylation at the androgen receptor gene showed unbalan ced inactivation in the twins' fibroblasts and in opposite directions. While the maternally derived X chromosome was preferentially active i n the asymptomatic twin, the paternal X chromosome was active in the o ther, affected twin and was found in her hemizygotic nephew. These dat a suggest that the paternal X chromosome carries the de novo alpha-gal actosidase A mutation and that uneven X inactivation is the underlying mechanism for disease expression in this novel female MZ twin pair. T his is the first documented case of female twins discordant for Fabry disease.