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Clinical expression of Menkes disease in females with normal karyotype

Lisbeth Birk Møller1*, Malgorzata Lenartowicz2, Marie-Therese Zabot3, Arnaud Josiane4, Lydie Burglen5, Chris Bennett6, Daniel Riconda7, Richard Fisher8, Sandra Janssens9, Shehla Mohammed10, Margreet Ausems11, Zeynep Tümer1, Nina Horn1 and Thomas G Jensen12

Author Affiliations

1 Center of Applied Human Genetics, Kennedy Center, Gl. Landevej 7, 2600 Glostrup, Denmark

2 Department of Genetics and Evolution, Institute of Zoology, Jagiellonian University, Ingardena 6, 30-060 Krakow, Poland

3 Cellular Biotechnology center - GHE - Hospices Civils de Lyon - France

4 Grenoble University Hospital, BP217, 38043 Grenoble cedex 9, France and INSERM U884, 38041 Grenoble, France

5 Service de génétique et Centre de référence des maladies congénitales du cervelet, APHP, Hôpital Trousseau, Paris, France

6 Yorkshire Regional Clinical Genetics Service, Ward 10, Floor 3, Chapel Allerton Hospital, Harehills Lane, Leeds LS7 4SA UK

7 Hughes Center for Fetal Diagnostics Winnie Palmer Hospital, 83W. Miller St. Orlando, Florida, USA

8 Teesside Genetics Unit, Northern Genetics Service, James Cook University Hospital, Marton Road, Middlesbrough TS4 3BW, UK

9 Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium

10 Clinical Genetics, 7th Floor Borough Wing, Guy's Hospital. London SE1 9RT, UK

11 Department of Medical Genetics, University Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands

12 Department of Human Genetics, University of Aarhus, Denmark

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Orphanet Journal of Rare Diseases 2012, 7:6  doi:10.1186/1750-1172-7-6

Published: 22 January 2012



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.


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).


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.


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.