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Case Report
Case Reports in Neurological Medicine
Volume 2015, Article ID 358605, 2 pages
Letter to the Editor

Is It a Pathogenic ATP7A Variation and Is It Menkes Disease?

Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Gammel Landevej 7, Glostrup, 2600 Copenhagen, Denmark

Received 4 May 2015; Accepted 1 June 2015

Academic Editor: Isabella Laura Simone

Copyright © 2015 Zeynep Tümer. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

This paper is a comment on “Menkes Disease Presenting with Epilepsia Partialis Continua.” While updating the LOVD (Leiden Open Variation Database) ATP7A mutation database ( I came across a case described by Rizk and colleagues and published in your journal [1].

Rizk and colleagues report a 17-month-old girl who was referred to their hospital with continuous right hand movements which developed suddenly at age of 14 months, regression of milestones, and repetitive episodes of hypothermia. She had hypotonia and constipation. Brain magnetic resonance imaging showed among others cortical and cerebral atrophy. EEG was abnormal and she was diagnosed with epilepsia partialis continua. Magnetic resonance angiography showed relatively tortuous but patent intracranial vessels, with appearance of “hair pin” sign. She had normal hair also with light microscopy. Blood copper and ceruloplasmin levels were normal. The patient was born full term and had normal birth measures. Genetic testing revealed presence of a heterozygous variation, c.1138G>A [p.(Val380Met)], and the authors concluded the diagnosis of Menkes disease (MD) in this patient.

Even though the clinical features of this female patient overlap with some of the features observed in Menkes disease patients, she lacks some of the major pathogenic criteria (such as reduced serum copper and ceruloplasmin levels, abnormal hair, hypopigmentation, and cutis laxa) (review in [2]) questioning the clinical diagnosis of Menkes disease, even though female patients may be less severely affected. Furthermore, the ATP7A variation identified is not convincing enough to establish a genetic diagnosis.

Firstly, this variation is described at least once in a healthy individual (rs149523862, dbSNP database of short genetic variations,, which questions its pathogenicity especially when taking into consideration that MD is a Mendelian disorder. This variation is a missense substitution in exon 4 of ATP7A proximal to but not within the 4th MBD (metal binding domain) of the ATP7A protein. Until now 70 different missense mutations in ATP7A have been described in 94 unrelated patients and none of these mutations were within the first 7 exons of ATP7A encoding the six MBDs [3]. It is generally believed that variations within these regions are more acceptable and do not necessarily lead to MD [3]. Furthermore, two commonly used and publicly available pathogenicity prediction methods, PhD-SNP ( and nsSNP analyser (, categorize this variation as neutral. Secondly, MD is an X-linked recessive disorder and manifesting heterozygotes are rare [4]. It is therefore extremely important to investigate the inheritance of this mutation and to perform X-inactivation studies before evaluating the clinical effect of this variation.

In conclusion, the clinical diagnosis of this patient and the pathogenicity of the identified ATP7A variation should be reevaluated.

Conflict of Interests

The author declares that there is no conflict of interests regarding the publication of this paper.


  1. T. Rizk, A. Mahmoud, T. Jamali, and S. Al-Mubarak, “Menkes disease presenting with epilepsia partialis continua,” Case Reports in Neurological Medicine, vol. 2014, Article ID 525784, 5 pages, 2014. View at Publisher · View at Google Scholar
  2. Z. Tümer and L. B. Møller, “Menkes disease,” European Journal of Human Genetics, vol. 18, no. 5, pp. 511–518, 2010. View at Publisher · View at Google Scholar · View at Scopus
  3. Z. Tümer, “An overview and update of ATP7A mutations leading to Menkes disease and occipital horn syndrome,” Human Mutation, vol. 34, no. 3, pp. 417–429, 2013. View at Publisher · View at Google Scholar · View at Scopus
  4. L. B. Møller, M. Lenartowicz, M. T. Zabot et al., “Clinical expression of Menkes disease in females with normal karyotype,” Orphanet Journal of Rare Diseases, vol. 7, no. 1, article 6, 2012. View at Publisher · View at Google Scholar · View at Scopus