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

• Published in: Journal of medical genetics 1996-08, Vol.33 (8), p.682-688
• Main Authors: Redonnet-Vernhet, I, Ploos van Amstel, J K, Jansen, R P, Wevers, R A, Salvayre, R, Levade, T
• Format: Article
• Language: English
• Subjects: Adult; alpha-Galactosidase - genetics; alpha-Galactosidase - metabolism; Biological and medical sciences; Cells, Cultured; DNA Methylation; Dosage Compensation, Genetic; Errors of metabolism; Fabry Disease - enzymology; Fabry Disease - genetics; Female; Fibroblasts - enzymology; Genes - genetics; Hair Follicle; Heterozygote; Humans; Leukocytes - enzymology; Lipids (lysosomal enzyme disorders, storage diseases); Male; Medical sciences; Metabolic diseases; Molecular Sequence Data; Pedigree; Point Mutation - genetics; Polymorphism, Single-Stranded Conformational; Receptors, Androgen - genetics; Twins, Monozygotic - genetics
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.33.8.682

We describe two female monozygotic (MZ) twins heterozygous for Fabry disease, 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 lymphoid cell lines, and hair follicles of the twins and their parents confirmed the heterozygous status of the twins and indicated that Fabry disease had occurred as a result of a de novo mutation. The son of the unaffected twin sister was shown to be hemizygous. Molecular analysis of the alpha-galactosidase A gene permitted the identification of an as yet undescribed point mutation at position 10182 of exon 5 which causes an Asp to Asn substitution at codon 231. Single strand conformation 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 d 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 alpha-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.