CNS demyelination associated with copper deficiency and hyperzincemia

Case reports.

Patient 1.

A 45-year-old woman presented with symptoms of anemia since 1997, as well as persistent paresthesias in the lower extremities and difficulty ambulating. Previous hematologic evaluation at another hospital in December 1997 showed mild normocytic anemia with leukopenia. On admission to our medical center in January 1999, she had marked pallor and the tip of the spleen was palpable. Neurologic examination showed hyperactive reflexes, including a brisk jaw jerk, clonus at both ankles, extensor plantar responses, increased tone in both lower extremities, slow and clumsy rapid foot tapping, markedly decreased vibratory sense below the hips, and extremely ataxic gait. Her cognition was normal. There was no relevant family history. Laboratory data revealed marked normocytic anemia and neutropenia (table) but a normal platelet count (274 × 10³/μL). Bone marrow aspirate was remarkable for vacuolization of erythroid and granulocytic precursors and ring sideroblasts. Serum copper and ceruloplasmin levels were markedly reduced, whereas the serum zinc level was increased. Serum vitamin B₁₂, vitamin E, methylmalonic acid, and homocysteine levels as well as syphilis, human T-cell lymphotrophic virus type I, and HIV serologies were within normal limits or negative. CSF cell count, protein, oligoclonal bands, and Venereal Disease Research Laboratory results were normal or negative. Myelin basic protein was 0.7 (normal < 0.5) and IgG index was 15.5 mg/day (normal −9.9 to 3.3 mg/day). MRI of the brain showed multiple bilateral subcortical white matter lesions, more pronounced in the frontal areas, consistent with demyelination (figure 1). MRI of the thoracic and cervical spine was normal. No evidence of zinc ingestion or environmental exposure to zinc was found.

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Table Course of hematologic and biochemical data in two patients with copper deficiency and hyperzincemia

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Figure 1. Axial T2 weighted (A) and sagittal fluid-attenuated inversion recovery (B) brain MRI images showing white matter lesions in Patient 1. Note the frontal predominance of the lesions.

After treatment with oral copper acetate (2 mg/day), the hemogram returned to normal in 2 1/2 months (see the table); the serum zinc, however, increased further. Copper therapy was continued for 4 months, yet the neurologic problems persisted unchanged. Six months after oral copper supplementation was started, she noted moderate improvement of the sensory symptoms. One year after presentation the hemoglobin and white blood cell count values were still in the normal range, but the serum copper and ceruloplasmin levels had decreased to 16 μg/dL and 5 mg/dL, respectively. In September 2001, symptoms of anemia and laboratory data indicated hematologic relapse of copper deficiency (see the table). Neurologic findings and repeat MRI imaging of the brain were unchanged. Readministration of oral copper acetate led to prompt hematologic recovery, and the copper supplementation is being continued.

Patient 2.

A 45-year-old white man (reported previously2) presented in February 1999 with paresthesias in the hands and feet for 4 months, followed by progressive weakness, exertional dyspnea, and difficulty ambulating. On examination he had marked pallor and mild hepatosplenomegaly. Initial neurologic examination showed saccadic dysmetria, slow and clumsy toe tapping, decreased vibratory and joint position sense in the feet, brisk reflexes with extensor plantar responses, and marked truncal ataxia. CSF studies including oligoclonal bands, myelin basic protein, and IgG index were normal. Visual evoked responses were asymmetrically prolonged bilaterally, whereas brainstem evoked responses were normal. Brain MRI revealed demyelination involving the periventricular regions, corpus callosum, and cerebellar peduncles.2 Marked normocytic anemia and neutropenia due to documented copper deficiency responded to copper therapy, but the serum zinc level remained persistently high (see the table). No source for zinc ingestion was identified. With copper supplementation for the ensuing 4 months, the neurologic symptoms gradually improved. Ten months after presentation his coordination was markedly improved, and he was able to return to work as a truck driver. Residual neurologic findings were limited to mild saccadic dysmetria, mildly decreased vibratory and position sense in the lower extremities, brisk reflexes, and extensor plantar responses. At this time, the hemoglobin and white blood cell count values remained normal; however, serum copper and ceruloplasmin levels had decreased to 3.0 μg/dL and < 4.1 mg/dL, respectively, while the serum zinc remained elevated at 205 μg/dL.

In September 2001, hematologic relapse was evident, and the serum copper and zinc abnormalities persisted (see the table). Repeat brain MRI again showed extensive demyelination (figure 2), with no contrast enhancing lesions or obvious interval changes. Six weeks after reinstitution of copper therapy the hematologic and biochemical abnormalities were near normal without change in the serum zinc level.

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Figure 2. Axial T2 (A) and sagittal fast spin echo T2 weighted (B) brain MRI imaging showing widespread demyelinating lesions in Patient 2.

Discussion.

The features of the two patients described depict a novel syndrome, characterized by typical hematologic manifestations of copper deficiency, persistently increased serum zinc levels, and a concomitant demyelinating process of the CNS. Only one other similar case was recently reported,3 which differed from our patients in that the serum copper and ceruloplasmin levels were less severely depressed, serum zinc concentration was normal, and the demyelination was limited to the spinal cord.

Occurrence of copper deficiency in humans is well established but is encountered only under special circumstances, i.e., after prolonged parenteral or enteral feeding without copper supplement, after gastrectomy, following ingestion of excess zinc, and with use of copper chelating agents.1 Moreover, clinical manifestations heretofore consisted exclusively of anemia and neutropenia. On the other hand, Menkes disease, which can be associated with CNS demyelination, and several rare conditions of hypocupremia with neurologic abnormalities do not manifest anemia or neutropenia.4-6⇓⇓ Neuronal degeneration from nutritional copper deficiency has also been documented in ruminant animals, known as swayback.7 Assuming that the CNS demyelination in our patients was related to the copper abnormality, worsening of the neurologic features during relapse of hypocupremia was to be expected. Yet, no significant changes were detected. An explanation could be that in the adult individual a prolonged copper deficiency is required for demyelination to occur. This may be related to tissue-specific differences of blood cells and neurons in copper requirements, cell turnover, and the rate of response to copper deficiency. The patients’ full hematologic recovery on oral copper supplementation initially and after relapse off copper therapy supports an intestinal copper uptake abnormality as the primary defect.

The role of excess zinc in demyelination was considered in our previous brief report because of prior inferences made from epidemiologic studies suggesting that zinc may be a factor in the pathogenesis of MS.2,8⇓ However, familial hyperzincemia is not accompanied by clinical symptoms or abnormalities,9 and hyperzincemia in our patients is probably a secondary feature associated with the copper abnormality. It is possible that the neurologic manifestations observed, particularly in Patient 2, represent MS, although severe copper deficiency has not been shown to accompany this disorder.

We hypothesize that these cases have a derangement of copper uptake by the enterocyte that is somehow linked to increased uptake of zinc. Among candidate proteins with a functional defect may be a metallothionein, the Menkes protein, or the copper transporter Ctr1.10 In the case of metallothionein, alteration in its differential binding of copper and zinc may lead to greater retention of zinc and increased loss of copper, resembling the sequence of events observed after excessive zinc ingestion. Research focusing on the apparent impaired absorption of dietary copper and its relationship to zinc uptake, as well as elucidation of the role of copper in the pathogenesis of demyelination, will be relevant for this novel syndrome.