Menkes Disease and Other Disorders Related to ATP7A

Abstract The ATP7A-related disorders are a heterogeneous group of diseases resulting from ATP7A (Menkes ATPase) dysfunction. They have varying phenotypes and clinical diseases, depending on the underlying genetic mutations. Some ensue from direct changes in the gene that encodes the ATP7A protein. The severity of the mutations can affect the phenotype expressed. If the mutations are severe loss-of-function mutations, the result is a lethal neurodevelopmental and systemic disease with low copper and reduced cuproenzymes activity (Menkes disease). If the mutations are milder, such as with leaky splice junction defects, some copper transport is possible and the phenotype is less severe, as in occipital horn syndrome. Two unique missense mutations that do not impair the copper transport function of ATP7A but rather its trafficking, cause a motor neuron-specific illness that develops gradually, with no evidence of abnormal copper metabolism. ATP7A function can also be affected by mutations outside of its coding gene, such as in MEDNIK and Huppke–Brendel syndromes. The resulting defects in intracellular localization of the ATP7A (and ATP7B) pump(s) can impair normal copper transport function.