title: Neurodevelopment and brain growth in classic Menkes disease is influenced by age and symptomatology at initiation of copper treatment.
abstract: Menkes disease is an X-linked recessive disorder of brain copper metabolism caused by mutations in an essential mammalian copper transport gene, ATP7A. Untreated affected individuals suffer failure to thrive and neurodevelopmental delays that usually commence at 6-8 weeks of age. Death by age three years is typical. While provision of working copies of ATP7A to the brain by viral vectors is a promising strategy under development, the only treatment currently available is subcutaneous copper injections. These can normalize circulating blood levels and may replete brain copper depending on the molecular context, e.g., the severity of ATP7A mutation and potential presence of mosaicism. In this paper, we summarize somatic growth and neurodevelopmental outcomes for 60 subjects enrolled in a recently concluded phase I/II clinical trial of copper histidine for Menkes disease (ClinicalTrials.gov Identifier: NCT00001262). Primary outcomes indicate highly statistically significant improvements in gross motor, fine motor/adaptive, personal-social, and language neurodevelopment in the cohort of subjects who received early treatment prior to onset of symptoms (n=35). Correlating with these findings, quantitative parameters of somatic growth indicated statistically significant greater growth in head circumference for the initially asymptomatic group, whereas weight and height/length at age three years (or at time of death) did not differ significantly. Mortality at age 3 was higher (50%) in subjects older and symptomatic when treatment commenced compared to the asymptomatic group (28.6%). We conclude that early copper histidine for Menkes disease is safe and efficacious, with treatment outcomes influenced by the timing of intervention, and ATP7A mutation.
authors.affiliation: Section on Translational Neuroscience; Molecular Medicine Program, NICHD, Porter Neuroscience Research Center II, Building 35, Room 2D-971, 35A Convent Drive, MSC 3754, National Institutes of Health, Bethesda, MD 20892-3754, United States. Electronic address: kalers@mail.nih.gov.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Kaler
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D001921:Brain / Q000254:growth & development* / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics; D002675:Child, Preschool; D003300:Copper / Q000627:therapeutic use*; D000073840:Copper-Transporting ATPases; D005260:Female; D006801:Humans; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D009154:Mutation
chemical_list: D027682:Cation Transport Proteins; D003300:Copper; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases
keywords: ATP7A; Brain growth; Copper; Menkes disease; Neurodevelopment