Cooper concentration of liver tissue under cooper histidin therapy in a patient with Menkes disease

X-linked Menkes disease (OMIM 309400) is a neurodegenerative disease with an estimated incidence of 1 in 300.000 births. The gene locus has been identified in the region Xq12-q13. Mutations cause a defect in a copper transporting ATPase (ATP7A) leading to deranged function of a variety of copper dependent enzymes in the brain, liver, kidneys and intestinal tract. To date parenterally administered copper histidine is the only causative treatment but may induce copper overload of the liver followed by liver cirrhosis. We report on a now 11 year old patient, who was diagnosed with Menkes disease at the age of 11 months by decreased serum copper concentrations of 35µg/dl (normal range 39–79µg/dl). Molecular analysis of the ATP7A gene revealed a G666R missense mutation. From the age of 16 months onward he received a copper histidine therapy subcutaneously every other day, starting with 0.2ml and increasing to 2.3ml per injection over time. 1ml of manufactured sterile solution contained 5.4mg copper chloride and 102mg of histidine. Dosage of copper histidine was adjusted to keep his serum copper values in a low normal range. D-penicillamine, 150mg orally, was given every alternate day to eliminate free copper from serum. During the 9-year follow up period 6 needle liver biopsies were performed in general anaesthesia and determination of copper concentrations performed by mass spectrometry. Copper concentration in liver tissue prior to onset of treatment was normal and remained within the normal range (<50µg/g dry weight), except on one occasion after the first year of treatment (156µg/g). Light microscopy of liver tissue did not show any histological changes during the whole observational period. Our data support, that copper histidine treatment was safe with regard to the risk of copper induced liver cirrhosis over a long treatment period in this patient. Nevertheless clinical benefit was limited to partial control of seizures and did not alter the overall course of the disease.