Journal of Inherited Metabolic Disease

, Volume 33, Issue 5, pp 583–589 | Cite as

Molecular correlates of epilepsy in early diagnosed and treated Menkes disease

  • Stephen G. KalerEmail author
  • Clarissa J. Liew
  • Anthony Donsante
  • Julia D. Hicks
  • Susumu Sato
  • Jacquelyn C. Greenfield
Original Article


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 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



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.


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Copyright information

© US Government 2010

Authors and Affiliations

  • Stephen G. Kaler
    • 1
    • 3
    Email author
  • Clarissa J. Liew
    • 2
  • Anthony Donsante
    • 1
  • Julia D. Hicks
    • 1
  • Susumu Sato
    • 2
  • Jacquelyn C. Greenfield
    • 2
  1. 1.Unit on Human Copper Metabolism, Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaUSA
  2. 2.EEG Section, National Institute of Neurological Disorders and StrokeNational Institutes of HealthBethesdaUSA
  3. 3.National Institutes of HealthBethesdaUSA

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