Metal Storage Disorders: Inherited Disorders of Copper and Manganese Metabolism and Movement Disorders

Copper Metabolism and Transport, Deficiency, and Toxicity Copper is one of the six transition metals that have important biochemical roles in humans, particularly in catalysis and electron transport [1, 2]. Because it can exist in two redox states (Cu/Cu), it can participate in redox reactions involving transfer of an electron, but if it builds up it can also generate potentially toxic reactive oxygen species by Fenton chemistry. Examples of copper in redox enzymes include: complex IV of the mitochondrial respiratory chain, copper–zinc superoxide dismutase, ceruloplasmin (ferroxidase), lysyl oxidase, dopamine betahydroxylase, and tyrosinase. Copper is present in many foods and in drinking water. The content is particularly high in organ meats (e.g. liver), shellfish, chocolate, nuts, and mushrooms. The content in food may be increased by cooking in copper-containing vessels. Copper absorption is reduced by gastric bypass surgery and this can lead to a myelopathy [3]. Copper is transported into the enterocyte via the CTR1 transporter. Export from the enterocyte is regulated by the copper-transporting ATPase, ATP7A. This protein is synthesized in the endoplasmic reticulum and resides in the trans-Golgi network, but, as intracellular copper levels rise, it translocates to the basolateral membrane where it allows copper export into the plasma. Mutations in ATP7A give rise to generalized copper deficiency, deficient activity of copper enzymes, and the symptoms of Menkes syndrome and variants [4]. On arriving at the liver, copper is taken up through CTR1 at the basolateral membrane and rising copper levels lead to translocation of ATP7B from the trans-Golgi network to the apical membrane where the copper is excreted into the bile canaliculus [4]. ATP7B is also required for the secretion of copper bound to ceruloplasmin from the liver into plasma. Mutations in ATP7B (Wilson disease) cause an accumulation of copper in the liver with reduced plasma concentrations of ceruloplasmin and ceruloplasminbound copper (normally the major fraction of plasma copper). As the disease progresses, levels of free copper in the plasma increase; urinary copper excretion is higher than normal. Copper deposition in the basal ganglia of the brain is responsible for the movement disorder, copper deposition in Descemet’s membrane at the corneoscleral junction in the eye give rise to Kayser–Fleischer rings, copper deposition in the kidneys can cause a tubulopathy, and high free plasma copper can cause hemolysis. Within the cell, chaperones are important in conveying copper to copper-dependent enzymes such as copper–zinc superoxide dismutase (chaperone: CCS) and complex IV of the respiratory chain (chaperones: SCO1 and SCO2). SCO1mutations in the mouse lead to severe cellular copper deficiency because, in addition to its role in complex IV assembly, SCO1 is required for expression of CTR1 and hence copper uptake [5].