Clinical expression of Menkes disease in females with normal karyotype.

Published online

Journal Article

BACKGROUND: Menkes Disease (MD) is a rare X-linked recessive fatal neurodegenerative disorder caused by mutations in the ATP7A gene, and most patients are males. Female carriers are mosaics of wild-type and mutant cells due to the random X inactivation, and they are rarely affected. In the largest cohort of MD patients reported so far which consists of 517 families we identified 9 neurologically affected carriers with normal karyotypes. METHODS: We investigated at-risk females for mutations in the ATP7A gene by sequencing or by multiplex ligation-dependent probe amplification (MLPA). We analyzed the X-inactivation pattern in affected female carriers, unaffected female carriers and non-carrier females as controls, using the human androgen-receptor gene methylation assay (HUMAR). RESULTS: The clinical symptoms of affected females are generally milder than those of affected boys with the same mutations. While a skewed inactivation of the X-chromosome which harbours the mutation was observed in 94% of 49 investigated unaffected carriers, a more varied pattern was observed in the affected carriers. Of 9 investigated affected females, preferential silencing of the normal X-chromosome was observed in 4, preferential X-inactivation of the mutant X chromosome in 2, an even X-inactivation pattern in 1, and an inconclusive pattern in 2. The X-inactivation pattern correlates with the degree of mental retardation in the affected females. Eighty-one percent of 32 investigated females in the control group had moderately skewed or an even X-inactivation pattern. CONCLUSION: The X- inactivation pattern alone cannot be used to predict the phenotypic outcome in female carriers, as even those with skewed X-inactivation of the X-chromosome harbouring the mutation might have neurological symptoms.

Full Text

Duke Authors

Cited Authors

  • Møller, LB; Lenartowicz, M; Zabot, M-T; Josiane, A; Burglen, L; Bennett, C; Riconda, D; Fisher, R; Janssens, S; Mohammed, S; Ausems, M; Tümer, Z; Horn, N; Jensen, TG

Published Date

  • January 22, 2012

Published In

Volume / Issue

  • 7 /

Start / End Page

  • 6 -

PubMed ID

  • 22264391

Pubmed Central ID

  • 22264391

Electronic International Standard Serial Number (EISSN)

  • 1750-1172

Digital Object Identifier (DOI)

  • 10.1186/1750-1172-7-6

Language

  • eng

Conference Location

  • England