Menkes disease (MD) is a fatal X-linked multisystem disease caused by mutations in ATP7A. In this study, clinical and genetic analysis was performed in 24 male MD patients. Development delay, seizures, kinky coarse hair, and dystonia were found in 24, 22, 24, and 24 patients, respectively. Serum ceruloplasmin/copper tested in 19 patients was low. Abnormal classic features of MD presented in the MRI/MRA of 19 patients. Seventeen mutations of ATP7A were identified in 22 patients. Twelve were novel mutations including three small deletion/insertion, one missense mutation, two nonsense mutations, three splicing-site mutations, and three gross deletions. Twenty-two patients were genetically diagnosed; neither point mutation nor deletion/duplication was found in two of them. c.2179G > A found in five patients might be a hot-spot mutation. Prenatal molecular diagnosis was performed for five unrelated fetuses (1 female and 4 male), which found four fetuses to be wild type and one male carried the same mutation as the proband. This study of the largest sample of Chinese MD patients examined to date discovered the unique phenotype and genotype spectrum in Chinese patients with 12 novel mutations of ATP7A, and that c.2179G > A might be a hot-spot mutation in MD patients. Five successful prenatal diagnosis contributed important information for MD families.
Menkes disease ATP7AMutations Prenatal diagnosis
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We thank all the patients and their families for their cooperation. We also thank Helene Lawler revising the manuscript. This research was supported by the grants from The National Key Research and Development Program of China (No. 2016YFC0901500 (2016YFC0901505), The National Key Research Project“12-5” (No:2012BAI09B04), Beijing key laboratory of molecular diagnosis and study on pediatric genetic diseases (No:Z141107004414036).
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Conflict of interest
The authors declare no conflict of interest.
Bahi-Buisson N, Kaminska A, Nabbout R et al (2006) Epilepsy in Menkes disease: analysis of clinical stages [J]. Epilepsia 47(2):380–386CrossRefPubMedGoogle Scholar
Bindu PS, Sinha S, Taly AB et al (2007) Menkes syndrome presenting as myoclonic seizures: neuroimaging and EEG observations [J]. J Child Neurol 22(4):452–455CrossRefPubMedGoogle Scholar
Bryndorf T, Christensen B, Xiang Y et al (1994) Prenatal diagnosis by fluorescence in situ hybridization on chorionic villus cells: nonsignificance of maternal cell contamination [J]. Fetal Diagn Ther 9(2):73–76CrossRefPubMedGoogle Scholar
Caminsky N, Mucaki E J, Rogan P K. 2014 Interpretation of mRNA splicing mutations in genetic disease: review of the literature and guidelines for information-theoretical analysis [J]. F1000Res 3: 282.Google Scholar
Chelly J, Tumer Z, Tonnesen T et al (1993) Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein[J]. Nat Genet 3(1):14–19CrossRefPubMedGoogle Scholar
Danks DM, Campbell PE, Stevens BJ et al (1972) Menkes's kinky hair syndrome. An inherited defect in copper absorption with widespread effects [J]. Pediatrics 50(2):188–201PubMedGoogle Scholar
Das S, Whitney S, Taylor J et al (1995) Prenatal diagnosis of Menkes disease by mutation analysis [J]. J Inherit Metab Dis 18(3):364–365CrossRefPubMedGoogle Scholar
Faerber EN, Grover WD, Defilipp GJ et al (1989) Cerebral MR of Menkes kinky-hair disease [J]. AJNR Am J Neuroradiol 10(1):190–192PubMedGoogle Scholar
Heydorn K, Damsgaard E, Horn N (1999) Accumulated experience with prenatal diagnosis of Menkes disease by neutron activation analysis of chorionic villi specimens [J]. Biol Trace Elem Res 71-72:551–561CrossRefPubMedGoogle Scholar
Horn N (1983) Menkes' X-linked disease: prenatal diagnosis and carrier detection [J]. J Inherit Metab Dis 6(Suppl 1):59–62CrossRefPubMedGoogle Scholar
Horn N, Tonnesen T, Tumer Z (1992) Menkes disease: an X-linked neurological disorder of the copper metabolism [J]. Brain Pathol 2(4):351–362CrossRefPubMedGoogle Scholar
Menkes JH, Alter M, Steigleder GK et al (1962) A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration[J]. Pediatrics 29:764–779PubMedGoogle Scholar
Mercer JF, Livingston J, Hall B et al (1993) Isolation of a partial candidate gene for Menkes disease by positional cloning [J]. Nat Genet 3(1):20–25CrossRefPubMedGoogle Scholar
Nomura S, Nozaki S, Hamazaki T et al (2014) PET imaging analysis with 64Cu in disulfiram treatment for aberrant copper biodistribution in Menkes disease mouse model [J]. J Nucl Med 55(5):845–851CrossRefPubMedGoogle Scholar
Prasad AN, Levin S, Rupar CA et al (2011) Menkes disease and infantile epilepsy [J]. Brain and Development 33(10):866–876CrossRefPubMedGoogle Scholar
Schlief ML, Gitlin JD (2006) Copper homeostasis in the CNS: a novel link between the NMDA receptor and copper homeostasis in the hippocampus [J]. Mol Neurobiol 33(2):81–90CrossRefPubMedGoogle Scholar
Schlief ML, West T, Craig AM et al (2006) Role of the Menkes copper-transporting ATPase in NMDA receptor-mediated neuronal toxicity [J]. Proc Natl Acad Sci U S A 103(40):14919–14924CrossRefPubMedPubMedCentralGoogle Scholar
Schrijver I, Cherny SC, Zehnder JL (2007) Testing for maternal cell contamination in prenatal samples: a comprehensive survey of current diagnostic practices in 35 molecular diagnostic laboratories [J]. J Mol Diagn 9(3):394–400CrossRefPubMedPubMedCentralGoogle Scholar
Sfaello I, Castelnau P, Blanc N et al (2000) Infantile spasms and Menkes disease [J]. Epileptic Disord 2(4):227–230PubMedGoogle Scholar
Stojilkovic-Mikic T, Mann K, Docherty Z et al (2005) Maternal cell contamination of prenatal samples assessed by QF-PCR genotyping [J]. Prenat Diagn 25(1):79–83CrossRefPubMedGoogle Scholar
Tang J, Donsante A, Desai V et al (2008) Clinical outcomes in Menkes disease patients with a copper-responsive ATP7A mutation, G727R[J]. Mol Genet Metab 95(3):174–181CrossRefPubMedPubMedCentralGoogle Scholar
Verrotti A, Cusmai R, Darra F et al (2014a) Epilepsy in Menkes disease: an electroclinical long-term study of 28 patients [J]. Epilepsy Res 108(9):1597–1603CrossRefPubMedGoogle Scholar
Verrotti A, Carelli A, Coppola G (2014b) Epilepsy in children with Menkes disease: a systematic review of literature [J]. J Child Neurol 29(12):1757–1764CrossRefPubMedGoogle Scholar
Verrotti A, Cusmai R, Darra F et al (2014c) Epilepsy in Menkes disease: an electroclinical long-term study of 28 patients [J]. Epilepsy Res 108(9):1597–1603CrossRefPubMedGoogle Scholar
Vulpe C, Levinson B, Whitney S et al (1993) Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase[J]. Nat Genet 3(1):7–13CrossRefPubMedGoogle Scholar
Wang Q, Ding Y, Wang JM et al (2014) [Clinical and ATP7A gene analysis of three infants with Menkes disease and prenatal diagnosis for a fetus at risk] [J]. Zhongguo Dang Dai Er Ke Za Zhi 16(6):624–628PubMedGoogle Scholar