Classical
Menkes disease is an X-linked recessive
neurodegenerative disorder caused by mutations in a
P-type ATPase (ATP7A) that normally delivers
copper to the developing central nervous system. Infants with large deletions, or other mutations in ATP7A that incapacitate
copper transport to the brain, show poor clinical outcomes and subnormal brain
copper despite early subcutaneous
copper histidine (CuHis)
injections. These findings suggest a need for direct central nervous system approaches in such patients. To begin to evaluate an aggressive but potentially useful new strategy for metabolic improvement of this disorder, we studied the acute and chronic effects of CuHis administered by intracerebroventricular (ICV) injection in healthy adult rats. Magnetic resonance imaging (MRI) after ICV CuHis showed diffuse T(1)-signal enhancement, indicating wide brain distribution of
copper after ICV administration, and implying the utility of this paramagnetic
metal as a MRI
contrast agent. The maximum tolerated dose (MTD) of CuHis, defined as the highest dose that did not induce overt toxicity, growth retardation, or reduce lifespan, was 0.5mcg. Animals receiving multiple infusions of this MTD showed increased brain
copper concentrations, but no significant differences in activity, behavior, and somatic growth, or brain histology compared to saline-injected controls. Based on estimates of the brain
copper deficit in
Menkes disease patients, CuHis doses 10-fold lower than the MTD found in this study may restore proper brain
copper concentration. Our results suggest that ICV CuHis administration have potential as a novel treatment approach in
Menkes disease infants with severe mutations. Future trials of direct CNS
copper administration in mouse models of
Menkes disease will be informative.