Acquired, as well as inherited, forms of abnormal copper homeostasis are implicated in neurologic dysfunction (Desai and Kaler, 2008). Menkes disease (MD), a prototypical genetic syndrome of defective copper transport, is characterized by low brain copper levels, infantile neurodegeneration, and premature death. The condition is caused by mutations in ATP7A, an X-linked copper transporter gene. The occipital horn syndrome is a milder allelic variant, associated with leaky ATP7A splice junction mutations, in which autonomic dysfunction predominates. Recently, we identified several families with motor neuron disease resembling Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis that are caused by novel missense mutations in the carboxyl half of ATP7A. These conditions are the consequence of mild loss-of-function defects that appear to affect intracellular trafficking of ATP7A. Thus, the phenotypic spectrum of ATP7A mutations has expanded; discovery of these new allelic variants indicates a previously unappreciated role for ATP7A in motor neuron maintenance and function.