Clinical expression of Menkes disease in females with normal karyotype

Orphanet J Rare Dis. 2012 Jan 22;7:6. doi: 10.1186/1750-1172-7-6.

Abstract

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.

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism
  • Chromosomes, Human, X
  • Copper / metabolism
  • Copper-Transporting ATPases
  • Female
  • Gene Expression Regulation / physiology
  • Humans
  • Karyotype*
  • Male
  • Menkes Kinky Hair Syndrome / pathology*
  • Mutation
  • Phenotype

Substances

  • Cation Transport Proteins
  • Copper
  • Adenosine Triphosphatases
  • ATP7A protein, human
  • Copper-Transporting ATPases