Pathology, clinical features and treatments of congenital copper metabolic disorders--focus on neurologic aspects.

Genetic disorders of copper metabolism, including Menkes kinky hair disease (MD), occipital horn syndrome (OHS) and Wilson's disease (WD) are reviewed with a focus on the neurological aspects. MD and OHS are X-linked recessive disorders characterized by a copper deficiency. Typical features of MD, such as neurologic disturbances, connective tissue disorders and hair abnormalities, can be explained by the abnormally low activity of copper-dependent enzymes. The current standard-of-care for treatment of MD is parenteral administration of copper-histidine. When the treatment is initiated in newborn babies, neurologic degeneration can be prevented, but delayed treatment is considerably less effective. Moreover, copper-histidine treatment does not improve connective tissue disorders. Novel treatments targeting neurologic and connective tissue disorders need to be developed. OHS is the mildest form of MD and is characterized by connective tissue abnormalities. Although formal trials have not been conducted for OHS, OHS patients are typically treated in a similar manner to MD. WD is an autosomal recessive disorder characterized by the toxic effects of chronic exposure to high levels of copper. Although the hepatic and nervous systems are typically most severely affected, initial symptoms are variable, making an early diagnosis difficult. Because early treatments are often critical, especially in patients with neurologic disorders, medical education efforts for an early diagnosis should target primary care physicians. Chelating agents and zinc are effective for the treatment of WD, but neurologic symptoms become temporarily worse just after treatment with chelating agents. Neurologic worsening in patients treated with tetrathiomolybdate has been reported to be lower than rates of neurologic worsening when treating with other chelating agents.