Clinical expression of Menkes disease in females with normal karyotype

TY - JOUR

T1 - Clinical expression of Menkes disease in females with normal karyotype

AU - Møller, Lisbeth Birk

AU - Lenartowicz, Malgorzata

AU - Zabot, Marie-Therese

AU - Josiane, Arnaud

AU - Burglen, Lydie

AU - Bennett, Chris

AU - Riconda, Daniel

AU - Fisher, Richard

AU - Janssens, Sandra

AU - Mohammed, Shehla

AU - Ausems, Margreet

AU - Tümer, Zeynep

AU - Horn, Nina

AU - Jensen, Thomas G.

PY - 2012/1

Y1 - 2012/1

N2 - 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.

AB - 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.

KW - Adenosine Triphosphatases

KW - Cation Transport Proteins

KW - Chromosomes, Human, X

KW - Copper

KW - Female

KW - Gene Expression Regulation

KW - Humans

KW - Karyotype

KW - Male

KW - Menkes Kinky Hair Syndrome

KW - Mutation

KW - Phenotype

U2 - 10.1186/1750-1172-7-6

DO - 10.1186/1750-1172-7-6

M3 - Journal article

C2 - 22264391

SN - 1750-1172

VL - 7

SP - 6

JO - Orphanet Journal of Rare Diseases

JF - Orphanet Journal of Rare Diseases

ER -