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Copper Deficiency Myelopathy

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Copper Deficiency Myelopathy OBSERVATION Copper Deficiency Myelopathy Neeraj Kumar, MD; Brian Crum, MD; Ronald C. Petersen, MD, PhD; Steven A. Vernino, MD, PhD; J. Eric Ahlskog, PhD, MD Background: In humans, Menkes disease is the well- Results: All patients had evidence of posterior column recognized neurological disorder due to inherited cop- dysfunction clinically and on somatosensory evoked po- per deficiency. Myelopathy due to acquired copper de- tential studies. Two had a signal change in the posterior ficiency is not a well-recognized entity in humans, column on magnetic resonance imaging of the spinal cord. although myelopathy due to copper deficiency is well documented in some animal species. Conclusion: Patients presenting with otherwise unex- plained myelopathies should have their serum cerulo- Patients: We describe 3 patients who developed a pro- plasmin level measured. gressive spastic-ataxic gait with proprioceptive deficits. All patients had a severe reduction in serum ceruloplas- min and copper levels. Arch Neurol. 2004;61:762-766 OPPER DEFICIENCY IN RUMI- injections. Despite subsequent vitamin B12 nants is known to cause a normalization, his neurological illness pro- progressive ataxic my- gressed. At the age of 26 years, he had un- elopathy (“swayback”).1 In dergone partial gastric resection for pep- humans, Menkes disease is tic ulcer disease. Cthe well-recognized childhood neurologi- His neurological examination re- cal disorder due to inherited copper mal- sults revealed lower limb spasticity, gen- absorption. The literature on the neurologi- eralized hyperreflexia, ankle clonus, and cal manifestations of acquired copper extensor plantar responses. There was deficiency in human adults is limited,2-6 al- decreased perception of touch, pinprick, though the hematologic manifestations are and position over the toes and fingers; his well described.7 vibratory sense was reduced at the knees Copper is a key constituent of vari- and distally. He required assistance to ous metalloenzymes, has an important role ambulate. in mitochondrial metabolism, and is im- His vitamin B12 level was elevated, and portant for the structure and function of there was a slight decrease in the hemo- the nervous system. We describe 3 pa- globin level (Table). Normal investiga- tients with a myelopathy related to cop- tion results were found for electrolytes, cre- per deficiency. atinine, homocysteine, methylmalonic acid, folate, antinuclear antibody, and thy- REPORT OF CASES roid-stimulating hormone levels; immu- noelectrophoresis; the paraneoplastic PATIENT 1 panel; and human immunodeficiency vi- rus and human T-lymphotropic virus 1 se- A 72-year-old man was referred for an rological tests. Nerve conduction studies 8-month history of gait ataxia. His illness showed a mild sensorimotor axonal poly- started with foot numbness, ascending over neuropathy. Tibial and median somato- 4 months to involve the lower limbs. Hand sensory evoked potentials were mark- numbness developed a few weeks after the edly abnormal, with evidence of impaired foot numbness. Increasing gait unsteadi- conduction in central proprioceptive path- From the Department of ness paralleled these symptoms. A mildly ways. Spine magnetic resonance imaging Neurology, Mayo Clinic, Mayo reduced vitamin B12 level of 181 pg/mL (MRI) showed an increased T2 signal in Foundation, Rochester, Minn. (134 pmol/L) was treated with vitamin B12 the dorsal aspect of the cord from verte- (REPRINTED) ARCH NEUROL / VOL 61, MAY 2004 WWW.ARCHNEUROL.COM 762 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Summary of the Clinical Features of the 3 Patients* Patient No. Feature† 12 3 Age, y 72 49 46 Sex Male Female Female Duration of symptoms, mo 8 18 6 Vitamin B12 level, pg/mL Ͼ2000 378 404 Methylmalonic acid level, µmol/L 0.10 0.13 0.17 Hemoglobin level, g/dL 12.5 14.0 12.6 Serum copper level, µg/dL 18 11 24 Serum ceruloplasmin level, mg/dL 7.0 1.6 3.5 Serum zinc level, µg/dL Not available 147 43 Urine 24-h level, µg/specimen Copper Not available 6 8 Zinc Not available 2060 376 Nerve conduction Mild sensorimotor Moderate sensorimotor Mild sensory neuropathy axonal neuropathy axonal neuropathy Spine MRI showed an abnormal T2 signal Yes Yes No Possible cause of copper deficiency Gastrectomy Idiopathic, possible Possible role of iron absorption defect Mode of supplementation Oral Oral IV for 5 d and subsequent oral copper Response to supplementation Not available No improvement, Slight clinical improvement, continued progression normal copper level in 3 mo Abbreviations: IV, intravenous; MRI, magnetic resonance imaging. SI conversion factors: To convert copper to micromoles per liter, multiply by 0.157; to convert vitamin B12 to picomoles per liter, multiply by 0.738; and to convert zinc to micromoles per liter, multiply by 0.153. *In all 3 patients, the onset of disease was subacute and there was impaired central conduction on somatosensory evoked potentials. †Normal levels of the analytes were as follows: hemoglobin, 13.5 to 17.5 g/dL in men and 12.0 to 15.5 g/dL in women; methylmalonic acid, less than 0.40 µmol/L; serum ceruloplasmin, 22.9 to 43.1 mg/dL; serum copper, 75 to 145 µg/dL; serum zinc, 66 to 110 µg/dL; urinary copper, 15 to 60 µg per specimen; urinary zinc, 300 to 600 µg per specimen; and vitamin B12, 200 to 650 pg/mL. brae C2 to C7 (Figure 1A and B) and in the lower tho- lower limbs. She had a spastic-ataxic gait and a positive racic cord (Figure 1C). One year later, based on our ex- Romberg sign. perience with patients 2 and 3, we requested a test of Normal test results were noted for the hematologic serum copper and ceruloplasmin levels; these levels were group, electrolytes, creatinine, thyroid-stimulating hor- reduced to 18 µg/dL (2.8 µmol/L) (normal level, 75-145 mone, antinuclear antibody, lactate, creatine phospho- µg/dL [11.8-22.8 µmol/L]) and 7.0 mg/dL (normal level, kinase, vitamins B12 and E, homocysteine, methylmalo- 22.9-43.1 mg/dL), respectively. Oral copper supplemen- nic acid, folate, ferritin, and anti–gliadin antibody levels; tation, 2 mg/d, was recently begun. immunoelectrophoresis; and cerebrospinal fluid analy- sis. Molecular analysis results for the fragile X mutation PATIENT 2 and the spinocerebellar ataxia panel were negative. Her arylsulfatase level and very-long-chain fatty acid profile A 49-year-old woman was examined for an 18-month his- were normal. The results of serological studies for Lyme tory of gait difficulty and lower limb stiffness. At the on- disease, syphilis, the human immunodeficiency virus, and set of her illness, she had foot and distal hand paresthe- the human T-lymphotropic virus 1 were negative. A mod- sias that progressed to involve the hands and lower limbs. erately severe axonal sensorimotor neuropathy was noted Coordination difficulty with her hands was particularly on nerve conduction studies. There was evidence of slow- evident if she did not look at what she was doing. She ing in the central and peripheral somatosensory path- had stopped driving because she was unsure where her ways on the evoked potential studies. The results of a su- feet were in relation to the accelerator and brake. A short ral nerve biopsy showed an increased rate of axonal course of intravenous corticosteroids was of no benefit. degeneration with empty nerve strands and a moderate Three months before the onset of her neurological symp- collection of perivascular epineural inflammatory cells. toms, she had a hemoglobin level of 9.2 g/dL. Her vita- Spine MRI performed soon after illness onset showed min B12 level and mean corpuscular volume were nor- a hyperintense T2 signal in the paramedian dorsal mal, and the anemia responded to iron supplementation. cervical cord extending from vertebrae C2 to C6 The results of her physical examination were re- (Figure 2A-C). Serum ceruloplasmin and copper lev- markable for mild weakness of the hand muscles, hyper- els were markedly reduced to 1.6 mg/dL and 11 µg/dL reflexia, ankle clonus, and extensor plantar responses. (1.7 µmol/L), respectively, and her serum zinc level was Pinprick and touch sensation were reduced in the feet. elevated to 147 µg/dL (22.5 µmol/L) (normal level, 66- Joint position sense at the toes was severely impaired, and 110 µg/dL [10.1-16.8 µmol/L]) (Table). Urine 24-hour there was graded decreased perception of vibration in the copper excretion was reduced to 6 µg (normal level, 15-60 (REPRINTED) ARCH NEUROL / VOL 61, MAY 2004 WWW.ARCHNEUROL.COM 763 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 A B C Figure 1. Patient 1. Sagittal (A) and axial (B) T2-weighted cervical spine magnetic resonance images (MRIs) show the increased signal (arrow) in the dorsal aspect of the cord from vertebrae C2 to C7. A sagittal T2-weighted thoracic spine MRI shows the increased signal (arrow) in the lower thoracic cord (C). A B C Figure 2. Patient 2. Sagittal (A) and axial (B and C) T2-weighted cervical spine magnetic resonance images show the posteriorly located hyperintense cervical cord signal (arrow) extending from vertebrae C2 (B) to C6 (C). µg), and 24-hour urine zinc excretion was elevated to 2060 and subsequent vitamin B12 level determinations were nor- µg (normal level, 300-600 µg). Oral copper therapy, 2 mal. Her gait deterioration continued. mg/d, for 3 months failed to increase her serum copper The results of a neurological examination revealed levels, and her upper limb symptoms worsened. mild distal lower limb weakness, generalized hyperre- flexia except for depressed ankle jerks, absent vibratory PATIENT 3 sense to the level of the anterior superior iliac spine, de- creased proprioception at the ankles and toes, an ataxic A 46-year-old woman presented with a 6-month history gait, and a positive Romberg sign.
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