PLASMA AND CEREBROSPINAL-FLUID NEUROCHEMICAL PATTERN IN MENKES DISEASE

Menkes disease is a neurodegenerative disorder of copper metabolism. B ecause the enzyme dopamine-beta-hydroxylase requires copper to catalyz e the conversion of dopamine to norepinephrine, we reasoned that patie nts with Menkes disease would have a neurochemical pattern similar to that seen in patients with congenital absence of dopamine-beta-hydroxy lase, i.e., high levels of dopamine, the dopamine metabolite dihydroxy phenylacetic acid (DOPAC), and the catecholamine precursor dihydroxyph enylalanine (DOPA), and low levels of norepinephrine and its neuronal metabolite dihydroxyphenylglycol (DHPG). We measured plasma and cerebr ospinal fluid (CSF) levels of catechols in 10 patients ranging in age from 9 days to 27 months. In contrast to patients with congenital abse nce of dopamine-beta-hydroxylase, norepinephrine levels were normal in plasma of 4 Menkes patients and in CSF of all 10 patients. However, t he ratios of DOPA: DHPG and DOPAC: DHPG in plasma and CSF of Menkes pa tients were invariably increased beyond the ranges of control values. These neurochemical findings indicate partial deficiency of dopamine-b eta-hydroxylase in Menkes patients, with compensatory increases in cat echolamine biosynthesis in sympathetic nerves and in the brain. Increa sed tyrosine hydroxylation and increased exocytotic release of norepin ephrine may be responsible for preservation of plasma and CSF norepine phrine levels in Menkes patients. The abnormal neurochemical pattern, including high ratios of DOPA: DHPG and DOPAC: DHPG, may serve as a bi ochemical marker for Menkes disease and provide a baseline against whi ch the influence of proposed therapies can be judged.