Chapter 45 - Menkes disease and other ATP7A disorders

Abstract

Mutation of the copper transporter ATPase ATP7A, located in the trans-Golgi network and encoded by the X chromosome, causes the progressive copper deficiency disorder Menkes disease (MD) (also known as kinky hair disease), in addition to occipital horn syndrome and ATP7A-related distal motor neuropathy. ATP7A mediates intestinal Cu absorption to fulfill tissue requirements and prevents Cu over-accumulation. Regulation of ATP7A also contributes to Cu homeostasis in response to systemic Cu fluctuation. Basal levels of ATP7A are low in heart, spleen, and liver under Cu deficiency and administration of Cu restores normal ATP7A levels. In the intestine, ATP7A is regulated in the opposite manner, with decreases in systemic Cu increasing ATP7A and exogenous Cu increasing ATP7A, regulating Cu export into the circulation. The fundamental abnormality in the disease is thus the maldistribution of copper, which is unavailable as a cofactor of several enzymes including mitochondrial cytochrome c oxidase, lysyl oxidase, superoxide dismutase, dopamine beta-hydroxylase, and tyrosinase. Thus the main features of MD include mitochondrial respiratory chain dysfunction (complex IV deficiency), deficiency of collagen cross-links resulting in hair (pili torti and trichorrhexis nodosa) and vascular abnormalities (elongated cerebral vessels and subdural effusions), neuronal degeneration (markedly affecting Purkinje cells), and deficient melanin production dominate the disease manifestations. Affected neonates present with hypothermia, feeding difficulties, and seizures. The infants are pale and exhibit kinky hair. A variety of minimally symptomatic phenotypes, including ataxia or mental retardation have been recognized.