Chronological observations of histological changes, cytochrome oxidase activity and copper level in the brain of the postnatal brindled mouse.

Neuropathological and enzyme-histochemical studies were performed on brindled mouse hemizygotes (BMs) and normal littermates at the age of 2 days, 7 days, 11 days and 14 days, together with an investigation of their tissue copper levels. A greatly increased copper concentration was confirmed in the kidney and intestine and a greatly reduced concentration in the liver and brain of BMs. The copper concentration in the brain increased gradually with age in the normal littermates, whereas this did not occur in BMs. There was no significant difference in the tissue copper concentration between the cerebrum and the cerebellum-brainstem in BMs or in normal littermates. Light and electron microscopy of the BM brain revealed progressive neuronal degeneration in association with increased mitochondrial changes (ballooning and crista disintegration). Enzyme histochemical examinations demonstrated a progressive comparative decrease (i.e., an increased difference from normal) of cytochrome oxidase activity in the BM brain. These data suggest that progressive degeneration of the brain in Menkes' disease is attributable to mitochondrial degeneration caused by a comparative decrease of both copper concentration and cytochrome oxidase activity in the brain.