Safety of intracerebroventricular copper histidine in adult rats.

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.

Functional copper transport explains neurologic sparing in occipital horn syndrome.

OBJECTIVE: A range of neurologic morbidity characterizes childhood-onset copper transport defects, including severe Menkes disease and milder occipital horn syndrome. Both phenotypes are caused by mutations in ATP7A, which encodes a copper-transporting adenosine triphosphatase, although defects causing occipital horn syndrome are rarely reported and nearly always involve exon-skipping (six of eight prior reports). Our objective was to characterize a novel occipital horn syndrome mutation (N1304S) not associated with aberrant splicing and to determine whether functional copper transport was associated with this allele. METHODS: We studied two brothers with typical occipital horn syndrome and used yeast complementation and timed growth assays, exploiting a Saccharomyces cerevisiae mutant strain, to assess in vitro N1304S copper transport. RESULTS: We documented that N1304S has approximately 33% residual copper transport, a result not inconsistent with a similar patient we reported with an exon-skipping mutation whose cells showed correctly spliced mRNA transcripts 36% of normal. CONCLUSION: These patients' mild neurologic phenotypes, together with our yeast complementation and growth experiments, imply that N1304S does not completely block copper transport to the developing brain early in life. The findings suggest that neurologic sparing in untreated occipital horn syndrome is associated with approximately 30% residual functional activity of ATP7A.