Clinical expression of Menkes disease in females with normal karyotype

Lisbeth Birk Møller; Malgorzata Lenartowicz; Marie-Therese Zabot; Arnaud Josiane; Lydie Burglen; Chris Bennett; Daniel Riconda; Richard Fisher; Sandra Janssens; Shehla Mohammed; Margreet Ausems; Zeynep Tümer; Nina Horn; Thomas G. Jensen

doi:10.1186/1750-1172-7-6

Clinical expression of Menkes disease in females with normal karyotype

Lisbeth Birk Møller, Malgorzata Lenartowicz, Marie-Therese Zabot, Arnaud Josiane, Lydie Burglen, Chris Bennett, Daniel Riconda, Richard Fisher, Sandra Janssens, Shehla Mohammed, Margreet Ausems, Zeynep Tümer, Nina Horn, Thomas G. Jensen

Medical Genetics Program

24 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Orphanet Journal of Rare Diseases
Vol/bind	7
Sider (fra-til)	6
ISSN	1750-1172
DOI	https://doi.org/10.1186/1750-1172-7-6
Status	Udgivet - jan. 2012

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@article{fba775a6337942c2b17c9191ce35378b,

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. 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.",

keywords = "Adenosine Triphosphatases, Cation Transport Proteins, Chromosomes, Human, X, Copper, Female, Gene Expression Regulation, Humans, Karyotype, Male, Menkes Kinky Hair Syndrome, Mutation, Phenotype",

author = "M{\o}ller, {Lisbeth Birk} and Malgorzata Lenartowicz and Marie-Therese Zabot and Arnaud Josiane and Lydie Burglen and Chris Bennett and Daniel Riconda and Richard Fisher and Sandra Janssens and Shehla Mohammed and Margreet Ausems and Zeynep T{\"u}mer and Nina Horn and Jensen, {Thomas G.}",

year = "2012",

month = jan,

doi = "10.1186/1750-1172-7-6",

language = "English",

volume = "7",

pages = "6",

journal = "Orphanet Journal of Rare Diseases",

issn = "1750-1172",

publisher = "BioMed Central",

}

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 -

Clinical expression of Menkes disease in females with normal karyotype

Abstract

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