EARLY COPPER THERAPY IN CLASSIC MENKES DISEASE PATIENTS WITH A NOVEL SPLICING MUTATION

To correlate genotype with response to early copper histidine therapy in Menkes disease, an X-linked disorder of copper transport, we perfor med mutational analysis in 2 related males who began treatment at the age of 10 days and prenatally at 32 weeks' gestation, respectively. A G to T transversion at the -1 exonic position of a splice donor site w as identified, predicting a glutamine to histidine substitution at cod on 724 of the Menkes copper-transporting ATPase gene. The Q724H mutati on disrupts proper splicing and generates five mutant transcripts that skip from one to four exons. None of these transcripts is predicted t o encode a functional copper transport protein. Copper histidine treat ment normalized circulating copper and ceruloplasmin levels but did no t improve the baseline deficiency of dopamine-beta-hydroxylase, a copp er-dependent enzyme. At the age of 36 months, the first patient was li ving and had neurodevelopmental abilities ranging from 10 to 15 months . The second patient also showed delayed neurodevelopment and died of pulmonary complications at the age of 51/2 months. We conclude that ea rly copper histidine therapy does not normalize neurological outcome i n patients with the Q724H splicing mutation, and suggest that preserva tion of some residual Menkes ATPase activity may be a general prerequi site for significant clinical efficacy from such treatment.