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Updated: Jun 10, 2026
Lipidomics and Transcriptomics in Neurological Diseases
Published on: March 18, 2022
Molecular correlates of epilepsy in early diagnosed and treated Menkes disease
Stephen G Kaler1, Clarissa J Liew, Anthony Donsante
1Unit 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
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.
Insights
Early diagnosis and treatment of Menkes disease significantly reduce clinical seizures and improve brain electrical activity (EEG) in infants. This intervention is effective regardless of the specific ATP7A gene mutation, offering protection against epilepsy.
Area of Science:
- Genetics
- Neuroscience
- Pediatric Neurology
Background:
- Menkes disease is an X-linked neurodegenerative disorder characterized by copper transport defects due to ATP7A gene mutations.
- Epilepsy and EEG abnormalities are common in symptomatic Menkes disease patients diagnosed later in infancy.
- Early diagnosis and intervention are crucial for managing neurodegenerative conditions.
Purpose of the Study:
- To evaluate the impact of early, presymptomatic diagnosis and copper treatment on seizure occurrence and EEG findings in Menkes disease.
- To determine if the type of ATP7A mutation influences the effectiveness of early intervention on neurological outcomes.
- To assess the long-term effects of early treatment on brain electrical activity in affected infants.
Main Methods:
- Analysis of 71 electroencephalograms (EEGs) from 24 Menkes disease patients diagnosed and treated with copper injections within the first six weeks of life.
- Correlation of clinical seizure data and EEG abnormalities with specific ATP7A mutation types (large deletions, small deletions, nonsense, splice junction, and partial function mutations).
- Comparison of neurological findings in early-treated patients versus historical data of later-diagnosed symptomatic patients.
Main Results:
- Only 12.5% of early-diagnosed and treated patients experienced clinical seizures, a significant reduction compared to historical data.
- Despite low seizure rates, 46% of patients exhibited abnormal EEG findings, varying by mutation type (e.g., 60% for nonsense mutations).
- Patients with ATP7A mutations retaining partial function showed no clinical seizures or EEG abnormalities with early intervention.
Conclusions:
- Early diagnosis and copper treatment markedly decrease seizure incidence and improve brain electrical activity in Menkes disease, irrespective of the specific ATP7A mutation.
- While early intervention protects against epilepsy, EEG abnormalities may persist in some patients depending on the molecular defect.
- ATP7A mutations that allow for residual copper transport or RNA splicing offer significant protection against epilepsy when combined with early treatment.
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