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.