Impaired Copper and Iron Metabolism in Blood Cells and Muscles of Patients Affected by Copper Deficiency Myeloneuropathy.

Abstract AIMS: Severe copper deficiency leads to a treatable multisystem disease characterized by anaemia and degeneration of spinal cord and nerves, but its mechanisms have not been investigated in humans. We tested whether copper deficit leads to alterations in fundamental copper dependent proteins and in iron metabolism in blood cells and muscles of patients affected by copper deficiency myeloneuropathy, and if these metabolic abnormalities are associated with compensatory mechanisms for copper maintenance. METHODS: We evaluated the expression of critical copper-enzymes, of iron-related proteins, and copper chaperones and transporters in blood and muscles from five copper deficient patients presenting with subacute sensory ataxia, muscle paralysis, steatosis, and variable anaemia. Severe copper deficiency was caused by chronic zinc intoxication in all of the patients, with an additional history of gastrectomy in two cases. RESULTS: The antioxidant enzyme SOD1 and subunit 2 of cytochrome c oxidase were significantly decreased in blood cells and in muscles of copper-deficient patients compared to controls. In muscle, the iron storage protein ferritin was dramatically reduced despite normal serum ferritin, and the expression of the heme-proteins cytochrome c and myoglobin was impaired. Muscle expression of the copper transporter CTR1 and of the copper chaperone CCS, were strikingly increased, while antioxidant protein 1 was diminished. CONCLUSIONS: Critical copper-dependent enzymes involved in antioxidant defenses, in mitochondrial energy production, and in iron metabolism are affected in blood cells and muscles of patients with profound copper deficiency leading to myeloneuropathy. Homeostatic mechanisms are strongly activated to increase intracellular copper retention.