Neurological
Cytochrome c oxidase
There have been several hypotheses about the role of copper and some of its neurological manifestations. Some suggest that disruptions in cytochrome c oxidase, also known as Complex IV, of the electron transport chain is responsible for the spinal cord degeneration. Methylation cycle
Another hypothesis is that copper deficiency myelopathy is caused by disruptions in the methylation cycle. The methylation cycle causes a transfer of a methyl group (-CH3) from methyltetrahydrofolate to a range of macromolecules by the suspected copper dependent enzyme methionine synthase. This cycle is able to produce purines, which are a component of DNA nucleotide bases, and also myelin proteins. The spinal cord is surrounded by a layer of protective protein coating called myelin (see figure). When this methionine synthase enzyme is disrupted, the methylation decreases and myelination of the spinal cord is impaired. This cycle ultimately causes myelopathy. Hematological cause
Iron transportation
The anemia caused by copper deficiency is thought to be caused by impaired iron transport. Hephaestin is a copper containing ferroxidase enzyme located in the duodenal muscosa that oxidizes iron and facilitates its transfer across the basolateral membrane into circulation. Another iron transporting enzyme is ceruloplasmin. This enzyme is required to mobilize iron from the reticuloendothelial cell to plasma. Ceruloplasmin also oxidizes iron from its ferrous state to the ferric form that is required for iron binding. Impairment in these copper dependent enzymes that transport iron may cause the secondary iron deficiency anemia.
Unlike most cases of myelodysplastic syndrome, the bone marrow aspirate in copper deficiency characteristically shows cytoplasmic vacuoles within red and white cell precursors, and karyotyping in cases of copper deficiency does not reveal cytogenetic features characteristic of myelodysplastic syndrome.Anemia and neutropenia typically resolve within six weeks of copper replacement. Neurological symptoms
Copper deficiency can cause a wide variety of neurological problems including myelopathy, peripheral neuropathy, and optic neuropathy. Myelopathy
Copper deficiency myelopathy in humans was discovered and first described by Schleper and Stuerenburg in 2001. They described a patient with a history of gastrectomy and partial colonic resection who presented with severe tetraparesis and painful paraesthesias and who was found on imaging to have dorsomedial cervical cord T2 hyperintensity. Upon further analysis, it was found that the patient had decreased levels of serum coeruloplasmin, serum copper, and CSF copper. The patient was treated with parenteral copper and the patients paraesthesias did resolve. Since this discovery, there has been heightened and increasing awareness of copper-deficiency myelopathy and its treatment, and this disorder has been reviewed by Kumar. Patients typically present difficulty walking (gait difficulty) caused by sensory ataxia (irregular muscle coordination) due to dorsal column dysfunction or degeneration of the spinal cord (myelopathy). Patients with ataxic gait have problems balancing and display an unstable wide walk. They often feel tremors in their torso, causing sideways jerks and lunges.In brain MRI, there is often an increased T2 signalling at the posterior columns of the spinal cord in patients with myelopathy caused by copper deficiency.