title: Molecular correlates of epilepsy in early diagnosed and treated Menkes disease.
abstract: 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.
authors.affiliation: Unit on Human Copper Metabolism, Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1853, USA. kalers@mail.nih.gov
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Kaler
authors.forename: Clarissa J
authors.initials: CJ
authors.lastname: Liew
authors.forename: Anthony
authors.initials: A
authors.lastname: Donsante
authors.forename: Julia D
authors.initials: JD
authors.lastname: Hicks
authors.forename: Susumu
authors.initials: S
authors.lastname: Sato
authors.forename: Jacquelyn C
authors.initials: JC
authors.lastname: Greenfield
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics*; D016009:Chi-Square Distribution; D003300:Copper / Q000008:administration & dosage; D000073840:Copper-Transporting ATPases; D004252:DNA Mutational Analysis; D019587:Dietary Supplements; D042241:Early Diagnosis; D004569:Electroencephalography; D004827:Epilepsy / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007279:Injections, Subcutaneous; D008396:Maryland; D007706:Menkes Kinky Hair Syndrome / Q000150:complications / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology / Q000628:therapy; D009154:Mutation; D010641:Phenotype; D011237:Predictive Value of Tests; D016896:Treatment Outcome
chemical_list: D027682:Cation Transport Proteins; D003300:Copper; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases