Epilepsy is a major feature of Menkes disease, an X-linked recessive infantile neurodegenerative disorder caused by mutations in ATP7A, which produces a copper-transporting ATPase. Three prior surveys indicated clinical seizures and electroencephalographic (EEG) abnormalities in a combined 27 of 29 (93%) symptomatic Menkes disease patients diagnosed at 2 months of age or older. To assess the influence of earlier, presymptomatic diagnosis and treatment on seizure semiology and brain electrical activity, we evaluated 71 EEGs in 24 Menkes disease patients who were diagnosed and treated with copper injections in early infancy (≤6 weeks of age), and whose ATP7A mutations we determined. Clinical seizures were observed in only 12.5% (3/24) of these patients, although 46% (11/24) had at least one abnormal EEG tracing, including 50% of patients with large deletions in ATP7A, 50% of those with small deletions, 60% of those with nonsense mutations, and 57% of those with canonical splice junction mutations. In contrast, five patients with mutations shown to retain partial function, either via some correct RNA splicing or residual copper transport capacity, had neither clinical seizures nor EEG abnormalities. Our findings suggest that early diagnosis and treatment improve brain electrical activity and decrease seizure occurrence in classical Menkes disease irrespective of the precise molecular defect. Subjects with ATP7A mutations that retain some function seem particularly well protected by early intervention against the possibility of epilepsy.
Respiratory Syncytial Virus Status Epilepticus Infantile Spasm Copper Transport Clinical Seizure
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This study was supported by the NIH intramural research program. We thank the participating subjects and their parents, and gratefully acknowledge Maryellen Rechen and the nursing staffs of the Pediatric Inpatient, Day Hospital, and Outpatient units at the NIH Clinical Center for their expert patient care.
Bahi-Buisson N, Kaminska A, Nabbout R et al (2006) Epilepsy in Menkes disease: analysis of clinical stages. Epilepsia 47:380–386CrossRefPubMedGoogle Scholar
Danks DM et al (1972) Menkes’ kinky hair syndrome: an inherited defect in copper absorption with widespread effects. Pedatrics 50:188–201Google Scholar
Desai V, Donsante A, Swoboda KJ, Martensen M, Thompson J, Kaler SG et al (2010) Favorably skewed X-inactivation accounts for neurological sparing in female carriers of Menkes disease. Clin Genet Apr 19 doi:10.1111/j.1399-0004.2010.01451.x
El Meskini R, Crabtree KL, Cline LB et al (2007) ATP7A (Menkes protein) functions in axonal targeting and synaptogenesis. Mol Cell Neurosci 34:409–421CrossRefPubMedGoogle Scholar
Friedman E, Harden A, Koivikko M, Pampiglione G (1978) Menkes’ disease: neurophysiological aspects. J Neurol Neurosurg Psychiatry 41:505–510CrossRefPubMedGoogle Scholar
Grange DK, Kaler SG, Albers GM, Petterchak JA, Thorpe CM, DeMello DE (2005) Severe bilateral panlobular emphysema and pulmonary arterial hypoplasia: unusual manifestations of Menkes disease. Am J Med Genet A 139A:151–155CrossRefPubMedGoogle Scholar
Horn N, Tønnesen T, Tümer Z (1992) Menkes disease: an X-linked neurological disorder of the copper metabolism. Brain Pathol 2:351–362CrossRefPubMedGoogle Scholar
Kaler SG (1994) Menkes disease. In: Barness LA (ed) Advances in pediatrics, volume 41. C.V. Mosby, St. Louis, pp 263–304Google Scholar
Kaler SG (1998) Diagnosis and therapy of Menkes syndrome, a genetic form of copper deficiency. Am J Clin Nutr 67(5 Suppl):1029S–1034SPubMedGoogle Scholar
Kaler SG (2010) Small copper complexes for treatment of acquired and inherited copper deficiency syndromes. Chapter 14. In: Thoene JG (ed) Small molecule therapy for genetic disease. Cambridge University Press, New York (in press)Google Scholar
Kaler SG, Goldstein DS, Holmes CS et al (1993a) Plasma and cerebrospinal fluid neurochemical pattern in Menkes disease. Ann Neurol 33:171–175CrossRefPubMedGoogle Scholar
Kaler SG, Gahl WA, Berry SA et al (1993b) Predictive value of plasma catecholamine levels in neonatal detection of Menkes disease. J Inherit Metab Dis 16:907–908CrossRefPubMedGoogle Scholar
Kaler SG, Gallo LK, Proud VK et al (1994) Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus. Nat Genet 8:195–202CrossRefPubMedGoogle Scholar
Kaler SG, Buist NR, Holmes CS et al (1995) Early copper therapy in classic Menkes disease with a novel splicing mutation. Ann Neurol 38:921–928CrossRefPubMedGoogle Scholar
Kaler SG, Das S, Levinson B et al (1996) Successful early copper therapy in Menkes disease associated with a mutant transcript containing a small in-frame deletion. Biochem Mol Med 57:37–46CrossRefPubMedGoogle Scholar
Kaler SG, Holmes CS, Goldstein DS et al (2008) Neonatal diagnosis and treatment of Menkes disease. N Engl J Med 358:605–614CrossRefPubMedGoogle Scholar
Kaler SG, Tang J, Donsante A, Kaneski CR (2009) Translational read-through of a nonsense mutation in ATP7A impacts treatment outcome in Menkes disease. Ann Neurol 65:108–113CrossRefPubMedGoogle Scholar
Kennerson ML, Nicholson GA, Kaler SG et al (2010) Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy. Am J Hum Genet 86:343–352CrossRefPubMedGoogle Scholar
Liu PC, McAndrew PE, Kaler SG (2002) Rapid and robust screening of the Menkes disease/occipital horn syndrome gene. Genet Testing 6:255–260CrossRefGoogle Scholar
Neville B (2007) Epileptic encephalopathy. Ann Indian Acad Neurol 10:3–6Google Scholar