Letter to the Editor Is It a Pathogenic ATP7A Variation and Is It Menkes Disease? Zeynep Tümer Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Gammel Landevej 7, Glostrup, 2600 Copenhagen, Denmark Correspondence should be addressed to Zeynep T¨ umer; zeynep.tumer@regionh.dk Received 4 May 2015; Accepted 1 June 2015 Academic Editor: Isabella Laura Simone Copyright © 2015 Zeynep T¨ umer. Tis 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. Tis paper is a comment on “Menkes Disease Presenting with Epilepsia Partialis Continua.” While updating the LOVD (Leiden Open Variation Database) ATP7A mutation data- base (https://grenada.lumc.nl/LOVD2/MD/home.php) 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 hypother- mia. She had hypotonia and constipation. Brain magnetic resonance imaging showed among others cortical and cere- bral 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. Te 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]) ques- tioning the clinical diagnosis of Menkes disease, even though female patients may be less severely afected. Furthermore, the ATP7A variation identifed 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, http://www.ncbi.nlm.nih.gov/SNP/), which ques- tions its pathogenicity especially when taking into consider- ation that MD is a Mendelian disorder. Tis 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 diferent missense mutations in ATP7A have been described in 94 unrelated patients and none of these mutations were within the frst 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 com- monly used and publicly available pathogenicity predic- tion methods, PhD-SNP (http://snps.biofold.org/phd-snp/ phd-snp.html) and nsSNP analyser (http://snpanalyzer.uthsc .edu/), 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 inves- tigate the inheritance of this mutation and to perform X- inactivation studies before evaluating the clinical efect of this variation. In conclusion, the clinical diagnosis of this patient and the pathogenicity of the identifed ATP7A variation should be reevaluated. Conflict of Interests Te author declares that there is no confict of interests regarding the publication of this paper. Hindawi Publishing Corporation Case Reports in Neurological Medicine Volume 2015, Article ID 358605, 2 pages http://dx.doi.org/10.1155/2015/358605