title: Clinical expression of Menkes disease in females with normal karyotype.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center of Applied Human Genetics, Kennedy Center, Gl, Landevej 7, Glostrup, Denmark. lbm@kennedy.dk
authors.forename: Lisbeth Birk
authors.initials: LB
authors.lastname: Møller
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Lenartowicz
authors.forename: Marie-Therese
authors.initials: MT
authors.lastname: Zabot
authors.forename: Arnaud
authors.initials: A
authors.lastname: Josiane
authors.forename: Lydie
authors.initials: L
authors.lastname: Burglen
authors.forename: Chris
authors.initials: C
authors.lastname: Bennett
authors.forename: Daniel
authors.initials: D
authors.lastname: Riconda
authors.forename: Richard
authors.initials: R
authors.lastname: Fisher
authors.forename: Sandra
authors.initials: S
authors.lastname: Janssens
authors.forename: Shehla
authors.initials: S
authors.lastname: Mohammed
authors.forename: Margreet
authors.initials: M
authors.lastname: Ausems
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Tümer
authors.forename: Nina
authors.initials: N
authors.lastname: Horn
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Jensen
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D041321:Chromosomes, Human, X; D003300:Copper / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D059785:Karyotype; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000473:pathology*; D009154:Mutation; D010641:Phenotype
chemical_list: D027682:Cation Transport Proteins; D003300:Copper; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases