Favorably skewed X-inactivation accounts for neurological sparing in female carriers of Menkes disease

Clin Genet. 2011 Feb;79(2):176-82. doi: 10.1111/j.1399-0004.2010.01451.x.


Classical Menkes disease is an X-linked recessive neurodegenerative disorder caused by mutations in ATP7A, which is located at Xq13.1-q21. ATP7A encodes a copper-transporting P-type ATPase and plays a critical role in development of the central nervous system. With rare exceptions involving sex chromosome aneuploidy or X-autosome translocations, female carriers of ATP7A mutations are asymptomatic except for subtle hair and skin abnormalities, although the mechanism for this neurological sparing has not been reported. We studied a three-generation family in which a severe ATP7A mutation, a 5.5-kb genomic deletion spanning exons 13 and 14, segregated. The deletion junction fragment was amplified from the proband by long-range polymerase chain reaction and sequenced to characterize the breakpoints. We screened at-risk females in the family for this junction fragment and analyzed their X-inactivation patterns using the human androgen-receptor (HUMARA) gene methylation assay. We detected the junction fragment in the proband, two obligate heterozygotes, and four of six at-risk females. Skewed inactivation of the X chromosome harboring the deletion was noted in all female carriers of the deletion (n = 6), whereas random X-inactivation was observed in all non-carriers (n = 2). Our results formally document one mechanism for neurological sparing in female carriers of ATP7A mutations. Based on review of X-inactivation patterns in female carriers of other X-linked recessive diseases, our findings imply that substantial expression of a mutant ATP7A at the expense of the normal allele could be associated with neurologic symptoms in female carriers of Menkes disease and its allelic variants, occipital horn syndrome, and ATP7A-related distal motor neuropathy.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Adult
  • Cation Transport Proteins / genetics
  • Chromosomes, Human, X / genetics
  • Copper-Transporting ATPases
  • Female
  • Gene Deletion
  • Genetic Testing
  • Heterozygote
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Menkes Kinky Hair Syndrome / genetics*
  • Pedigree
  • X Chromosome Inactivation / genetics*
  • Young Adult


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