Menkes disease is an X-linked recessive disorder of copper transport caused by defects in a gene that encodes an evolutionarily conserved copper-transporting ATPase. In mammals, this gene product functions as an intracellular pump to transport copper into trans-Golgi spaces for incorporation into copper-requiring enzymes, and also mediates copper exodus from cells. The disorder presents in infancy with delayed development, failure to thrive, neurodegeneration, and premature death (typically by 3 years of age). Our work on this disorder includes development of rapid and reliable neurochemical and molecular techniques for very early diagnosis, efforts which dovetail with a clinical trial of very early copper histidine treatment for affected infants. We use cell biological, molecular, and biochemical approaches to characterize enrolled patients and to correlate with neurodevelopmental outcomes. Confocal imaging of patient fibroblasts is used to assess quantity and localization of mutant Menkes gene products. The blood-brain barrier poses a challenging treatment obstacle in many Menkes disease patients, and we hypothesized a molecular basis for treatment responsivity in the minority of patients (about 1 in 5) who respond successfully (normal neurodevelopmental outcomes) to early copper histidine. These patients have mutations that enable at least some residual copper transport to the developing brain. Consequently, we are developing alternative therapeutic approaches, including intrathecal copper administration, that bypass the blood-brain barrier. To assess safety and to determine a maximum tolerated dose (MTD), we began an animal protocol of intraventricular copper histidine using adult male rats. A maximum tolerated dose of 5 ?g has been established. Two weeks post-injection, some inflammatory changes are evident in the periventricular region regardless of dose, which do not appear to be clinically significant. Studies of chronic administration (i.e., weekly administration) of the MTD are in progress.
| Haddad, Marie Reine; Choi, Eun-Young; Zerfas, Patricia M et al. (2018) Cerebrospinal Fluid-Directed rAAV9-rsATP7A Plus Subcutaneous Copper Histidinate Advance Survival and Outcomes in a Menkes Disease Mouse Model. Mol Ther Methods Clin Dev 10:165-178 |
| Kaler, Stephen G (2016) Microbial peptide de-coppers mitochondria: implications for Wilson disease. J Clin Invest 126:2412-4 |
| Bandmann, Oliver; Weiss, Karl Heinz; Kaler, Stephen G (2015) Wilson's disease and other neurological copper disorders. Lancet Neurol 14:103-13 |
| Haddad, Marie Reine; Patel, Keyur D; Sullivan, Patricia H et al. (2014) Molecular and biochemical characterization of Mottled-dappled, an embryonic lethal Menkes disease mouse model. Mol Genet Metab 113:294-300 |
| Hicks, Julia D; Donsante, Anthony; Pierson, Tyler M et al. (2012) Increased frequency of congenital heart defects in Menkes disease. Clin Dysmorphol 21:59-63 |
| Huppke, Peter; Brendel, Cornelia; Korenke, Georg Christoph et al. (2012) Molecular and biochemical characterization of a unique mutation in CCS, the human copper chaperone to superoxide dismutase. Hum Mutat 33:1207-15 |
| Møller, Lisbeth B; Hicks, Julia D; Holmes, Courtney S et al. (2011) Diagnosis of copper transport disorders. Curr Protoc Hum Genet Chapter 17:Unit17.9 |
| Price, David J; Ravindranath, Thyyar; Kaler, Stephen G (2007) Internal jugular phlebectasia in Menkes disease. Int J Pediatr Otorhinolaryngol 71:1145-8 |
| Donsante, Anthony; Tang, Jingrong; Godwin, Sarah C et al. (2007) Differences in ATP7A gene expression underlie intrafamilial variability in Menkes disease/occipital horn syndrome. J Med Genet 44:492-7 |
| Lem, Kristen E; Brinster, Lauren R; Tjurmina, Olga et al. (2007) Safety of intracerebroventricular copper histidine in adult rats. Mol Genet Metab 91:30-6 |
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