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Copper Deficiency Myelopathy (Human Swayback)

  • Neeraj Kumar
    Correspondence
    Individual reprints of this article are not available. Address correspondence to Neeraj Kumar, MD, Department of Neurology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905
    Affiliations
    Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minn
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      The hematologic manifestations of copper deficiency are well known and include anemia and neutropenia. In the past few years, the neurological manifestations of acquired copper deficiency in humans has been recognized, the most common being a myelopathy presenting with a spastic gait and prominent sensory ataxia. The known causes of acquired copper deficiency include prior gastric surgery, excessive zinc ingestion, and malabsorption; however, often the cause is unclear. Hyperzincemia may be present even in the absence of exogenous zinc ingestion. The clinical features and neuroimaging findings are similar to the subacute combined degeneration seen in patients with vitamin B12 deficiency. Copper and vitamin B12 deficiency may coexist. The neurological syndrome may be present without the hematologic manifestations. Copper supplementation resolves the anemia and neutropenia promptly and completely and may prevent the neurological deterioration. Improvement, when it occurs, is often subjective and preferentially involves sensory symptoms. This article describes patients with copper deficiency myelopathy seen at the Mayo Clinic in Rochester, Minn, and reviews the literature on neurological manifestations of acquired copper deficiency in humans.
      CNS (central nervous system), MRI (magnetic resonance imaging)
      The hematologic manifestations of acquired copper deficiency are well known and include anemia, neutropenia, and a left shift in granulocytic and erythroid maturation with vacuolated precursors and ringed sideroblasts in the bone marrow.
      • Dunlap WM
      • James III, GW
      • Hume DM
      Anemia and neutropenia caused by copper deficiency.
      • Summerfield AL
      • Steinberg FU
      • Gonazlez JG
      Morphologic findings in bone marrow precursor cells in zinc-induced copper deficiency anemia.
      • Fiske DN
      • McCoy III, HE
      • Kitchens CS
      Zinc-induced sideroblastic anemia: report of a case, review of the literature, and description of the hematologic syndrome.
      • Willis MS
      • Monaghan SA
      • Miller ML
      • et al.
      Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination.
      Only in recent years have the neurological manifestations of acquired copper deficiency in humans been recognized.
      • Prodan CI
      • Holland NR
      CNS demyelination from zinc toxicity?.
      • Schleper B
      • Stuerenburg HJ
      Copper deficiency-associated myelopathy in a 46-year-old woman.
      • Gregg XT
      • Reddy V
      • Prchal JT
      Copper deficiency masquerading as myelodysplastic syndrome.
      • Prodan CI
      • Holland NR
      • Wisdom PJ
      • Burstein SA
      • Bottomley SS
      CNS demyelination associated with copper deficiency and hyperzincemia.
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Myelopathy due to copper deficiency.
      • Hedera P
      • Fink JK
      • Bockenstedt PL
      • Brewer GJ
      Myelopolyneuropathy and pancytopenia due to copper deficiency and high zinc levels of unknown origin: further support for existence of a new zinc overload syndrome.
      • Kumar N
      • McEvoy KM
      • Ahlskog JE
      Myelopathy due to copper deficiency following gastrointestinal surgery.
      • Greenberg SA
      • Briemberg HR
      A neurological and hematological syndrome associated with zinc excess and copper deficiency.
      • Kumar N
      • Crum B
      • Petersen RC
      • Vernino SA
      • Ahlskog JE
      Copper deficiency myelopathy.
      • Kumar N
      • Low PA
      Myeloneuropathy and anemia due to copper malabsorption.
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      • Kumar N
      • Ahlskog JE
      • Gross Jr, JB
      Acquired hypocupremia after gastric surgery.
      • Prodan CI
      • Holland NR
      • Wisdom PJ
      • Bottomley SS
      Myelopathy due to copper deficiency.
      • Kumar N
      • Crum BA
      • Ahlskog JE
      Copper deficiency myelopathy [abstract]?.
      • Rowin J
      • Lewis SL
      Copper deficiency myeloneuropathy and pancytopenia secondary to overuse of zinc supplementation.
      • Kumar N
      • Ahlskog JE
      • Klein CJ
      • Port JD
      Imaging features of copper deficiency myelopathy: a study of 25 cases.
      • Kumar N
      • Elliott MA
      • Hoyer JD
      • Harper Jr, CM
      • Ahlskog JE
      • Phyliky RL
      “Myelodysplasia,” myeloneuropathy, and copper deficiency.
      • Crum BA
      • Kumar N
      Electrophysiologic findings in copper deficiency myeloneuropathy [abstract]?.
      • Bartner R
      • Will M
      • Conrad J
      • Engelhardt A
      • Schwarz-Eywill M
      Pancytopenia, arthralgia and myeloneuropathy due to copper deficiency [in German].
      The most common manifestation is that of a myelopathy presenting with a spastic gait and prominent sensory ataxia.
      • Schleper B
      • Stuerenburg HJ
      Copper deficiency-associated myelopathy in a 46-year-old woman.
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Myelopathy due to copper deficiency.
      • Hedera P
      • Fink JK
      • Bockenstedt PL
      • Brewer GJ
      Myelopolyneuropathy and pancytopenia due to copper deficiency and high zinc levels of unknown origin: further support for existence of a new zinc overload syndrome.
      • Kumar N
      • McEvoy KM
      • Ahlskog JE
      Myelopathy due to copper deficiency following gastrointestinal surgery.
      • Greenberg SA
      • Briemberg HR
      A neurological and hematological syndrome associated with zinc excess and copper deficiency.
      • Kumar N
      • Crum B
      • Petersen RC
      • Vernino SA
      • Ahlskog JE
      Copper deficiency myelopathy.
      • Kumar N
      • Low PA
      Myeloneuropathy and anemia due to copper malabsorption.
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      • Kumar N
      • Ahlskog JE
      • Gross Jr, JB
      Acquired hypocupremia after gastric surgery.
      • Prodan CI
      • Holland NR
      • Wisdom PJ
      • Bottomley SS
      Myelopathy due to copper deficiency.
      • Kumar N
      • Crum BA
      • Ahlskog JE
      Copper deficiency myelopathy [abstract]?.
      • Rowin J
      • Lewis SL
      Copper deficiency myeloneuropathy and pancytopenia secondary to overuse of zinc supplementation.
      • Kumar N
      • Ahlskog JE
      • Klein CJ
      • Port JD
      Imaging features of copper deficiency myelopathy: a study of 25 cases.
      • Kumar N
      • Elliott MA
      • Hoyer JD
      • Harper Jr, CM
      • Ahlskog JE
      • Phyliky RL
      “Myelodysplasia,” myeloneuropathy, and copper deficiency.
      • Bartner R
      • Will M
      • Conrad J
      • Engelhardt A
      • Schwarz-Eywill M
      Pancytopenia, arthralgia and myeloneuropathy due to copper deficiency [in German].
      Clinical or electro-physiological evidence of an associated peripheral neuropathy is common. Isolated peripheral neuropathy,
      • Willis MS
      • Monaghan SA
      • Miller ML
      • et al.
      Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination.
      • Gregg XT
      • Reddy V
      • Prchal JT
      Copper deficiency masquerading as myelodysplastic syndrome.
      central nervous system (CNS) demyelination,
      • Prodan CI
      • Holland NR
      CNS demyelination from zinc toxicity?.
      • Prodan CI
      • Holland NR
      • Wisdom PJ
      • Burstein SA
      • Bottomley SS
      CNS demyelination associated with copper deficiency and hyperzincemia.
      myopathy,
      • Kumar N
      • Low PA
      Myeloneuropathy and anemia due to copper malabsorption.
      and optic neuritis
      • Gregg XT
      • Reddy V
      • Prchal JT
      Copper deficiency masquerading as myelodysplastic syndrome.
      have also been described in association with copper deficiency, but these associations are less well established. Often, the cause of the copper deficiency is unclear. The most common abnormality on the spinal magnetic resonance image (MRI) is increased signal on T2-weighted images that involve the dorsal column in the cervical cord.
      • Kumar N
      • Ahlskog JE
      • Klein CJ
      • Port JD
      Imaging features of copper deficiency myelopathy: a study of 25 cases.
      Somatosensory evoked potential and nerve conduction studies suggest impaired central conduction and varying degrees of peripheral neuropathy.
      • Crum BA
      • Kumar N
      Electrophysiologic findings in copper deficiency myeloneuropathy [abstract]?.
      Response of the anemia and neutropenia to copper supplementation is prompt and complete.
      • Willis MS
      • Monaghan SA
      • Miller ML
      • et al.
      Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination.
      • Gregg XT
      • Reddy V
      • Prchal JT
      Copper deficiency masquerading as myelodysplastic syndrome.
      • Greenberg SA
      • Briemberg HR
      A neurological and hematological syndrome associated with zinc excess and copper deficiency.
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      With copper supplementation, the neurological deterioration may be prevented, and improvement is slight and often subjective.
      • Willis MS
      • Monaghan SA
      • Miller ML
      • et al.
      Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination.
      • Prodan CI
      • Holland NR
      • Wisdom PJ
      • Burstein SA
      • Bottomley SS
      CNS demyelination associated with copper deficiency and hyperzincemia.
      • Greenberg SA
      • Briemberg HR
      A neurological and hematological syndrome associated with zinc excess and copper deficiency.
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      In this article, I describe patients with copper deficiency myelopathy and review the literature on neurological manifestations of acquired copper deficiency in humans.

      PATIENTS AND METHODS

      The case records of 25 patients with copper deficiency myelopathy seen at the Mayo Clinic in Rochester, Minn, were reviewed. These 25 patients include 13 patients described earlier as a series.
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      Our experience with the 25 patients described herein has been previously published in abstract form
      • Kumar N
      • Crum BA
      • Ahlskog JE
      Copper deficiency myelopathy [abstract]?.
      • Crum BA
      • Kumar N
      Electrophysiologic findings in copper deficiency myeloneuropathy [abstract]?.
      ; details regarding the neuroimaging findings in this cohort have been previously published,
      • Kumar N
      • Ahlskog JE
      • Klein CJ
      • Port JD
      Imaging features of copper deficiency myelopathy: a study of 25 cases.
      as have the clinical details of some cases.
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Myelopathy due to copper deficiency.
      • Kumar N
      • McEvoy KM
      • Ahlskog JE
      Myelopathy due to copper deficiency following gastrointestinal surgery.
      • Kumar N
      • Crum B
      • Petersen RC
      • Vernino SA
      • Ahlskog JE
      Copper deficiency myelopathy.
      • Kumar N
      • Low PA
      Myeloneuropathy and anemia due to copper malabsorption.
      • Kumar N
      • Ahlskog JE
      • Gross Jr, JB
      Acquired hypocupremia after gastric surgery.
      • Kumar N
      • Elliott MA
      • Hoyer JD
      • Harper Jr, CM
      • Ahlskog JE
      • Phyliky RL
      “Myelodysplasia,” myeloneuropathy, and copper deficiency.
      All 25 patients were evaluated as part of routine clinical practice within the Department of Neurology. Only 2 patients (patients 13 and 14) were identified retrospectively. Of the 25 patients, 23 were evaluated within a 24-month period. Demographic information, clinical presentation, laboratory and neurophysiological findings, neuroimaging, and response to therapy were studied. Additional investigations were performed in each patient to rule out other causes of a noncompressive myelopathy. Wilson disease as a cause of low serum copper levels was excluded in all patients by 24-hour urinary copper excretion and/or slit lamp examination for Kayser-Fleischer rings.
      Available MRI studies were reviewed by a neuroradiologist. Cervical and thoracic spine MRIs were available in all patients except patient 13, in whom only a cervical spine MRI was available. Contrast imaging was performed in 14 of the 25 patients (patients 4-10, 16-19, 21, 22, and 24). A brain MRI was available in all except patients 4, 11, 20, and 25. The images were acquired using a 1.5-T strength magnet.
      Electrophysiological tests included nerve conduction studies, needle electromyography, and somatosensory and visual evoked potentials. The electrophysiological studies were performed using standard techniques for our laboratory. Nerve conduction studies were available in all patientsexcept patient 16. Somatosensory evoked potential studies were available in 20 patients (all except patients 3, 10, 14, 16, and 19). Of these 20, both tibial and median somatosensory evoked potential studies were performed in 17, tibial only in 1 (patient 11), and median only in 2 (patients 13 and 21). Eight patients had visual evoked potential studies performed (patients 6, 16, 17, 18, 19, 21, 22, and 24). In 1 patient (patient 16), it was the only electrophysiological testing done.
      In 2 patients with hypocupremic myelopathy and no evident cause of copper deficiency, colonic copper was measured to determine whether an absorptive defect similar to that seen in Menkes syndrome may have been responsible for the hypocupremia (patients 17 and 23). In 1 of these 2 patients (patient 17), mutations in the ATP7A gene were sought to determine whether a mutation similar to that seen in Menkes syndrome could have been responsible for the hypocupremia and increased colonic mucosal copper content.

      RESULTS

      Demographics and Clinical Features

      The demographics of this cohort, duration of neurological symptoms before diagnosis, and likely cause of copper deficiency are summarized in Table 1. Also shown in Table 1 and Figure 1 are serum copper and zinc levels at presentation. The duration of neurological symptoms before the diagnosis of copper deficiency myelopathy ranged from 2 months to 10 years. The age range at the time of diagnosis was 36 to 78 years (mean age, 56 years). Twenty of the 25 patients were women. The serum copper level ranged from being undetectable in 8 to 0.45 μg/mL in 1 (reference range, 0.75-1.45 μg/mL). The mean serum copper level at presentation in this cohort was 0.13 μg/mL. A high or high-normal serum zinc level was seen in 17 of the 23 patients for whom this information was available.
      TABLE 1Demographics, Symptom Duration, Serum Copper and Zinc Levels at the Time of Diagnosis, and Likely Cause of Copper Deficiency in 25 Patients With Copper Deficiency Myelopathy
      Patient No./sex/age (y)Symptom duration (y)Serum copper (μg/mL)
      Reference range, 0.75 to 1.45 μg/mL.
      Serum zinc (μg/mL)
      Reference range, 0.66 to 1.10 μg/mL.
      Possible cause of copper deficiencyReference(s)
      l/M/655.00.451.51Zinc ingestion
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Myelopathy due to copper deficiency.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      2/F/460.50.240.43Iron ingestion
      • Kumar N
      • Crum B
      • Petersen RC
      • Vernino SA
      • Ahlskog JE
      Copper deficiency myelopathy.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      3/F/7810.00.001.09Peptic ulcer surgery
      • Kumar N
      • McEvoy KM
      • Ahlskog JE
      Myelopathy due to copper deficiency following gastrointestinal surgery.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      4/M/720.750.181.36Peptic ulcer surgery
      • Kumar N
      • Crum B
      • Petersen RC
      • Vernino SA
      • Ahlskog JE
      Copper deficiency myelopathy.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      5/M/521.500.190.91Peptic ulcer surgery
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      6/F/582.00.350.77Peptic ulcer surgery
      7/F/711.00.160.96Peptic ulcer surgery
      • Kumar N
      • Ahlskog JE
      • Gross Jr, JB
      Acquired hypocupremia after gastric surgery.
      8/F/592.50.001.92Peptic ulcer surgery
      9/F/532.00.000.66Peptic ulcer surgery
      10/F/495.00.170.64Bariatric surgery
      • Kumar N
      • McEvoy KM
      • Ahlskog JE
      Myelopathy due to copper deficiency following gastrointestinal surgery.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      ll/F/640.750.110.97Bariatric surgery
      • Kumar N
      • Ahlskog JE
      • Gross Jr, JB
      Acquired hypocupremia after gastric surgery.
      12/F/363.50.001.13Bariatric surgery
      13/F/455.00.090.93Malabsorption
      • Kumar N
      • Low PA
      Myeloneuropathy and anemia due to copper malabsorption.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      14/F/550.170.051.46Malabsorption
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      15/F/551.50.240.57Malabsorption
      16/F/572.00.120.52Malabsorption
      17/F/480.750.111.47Unknown
      • Kumar N
      • Crum B
      • Petersen RC
      • Vernino SA
      • Ahlskog JE
      Copper deficiency myelopathy.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      ,
      • Kumar N
      • Ahlskog JE
      • Gross Jr, JB
      Acquired hypocupremia after gastric surgery.
      18/F/513.00.221.61Unknown
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      19/F/452.750.05Not availableUnknown
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      20/F/590.50.001.95Unknown
      • Kumar N
      • Elliott MA
      • Hoyer JD
      • Harper Jr, CM
      • Ahlskog JE
      • Phyliky RL
      “Myelodysplasia,” myeloneuropathy, and copper deficiency.
      21/M/525.00.001.60Unknown
      22/M/472.00.001.29Unknown
      23/F/700.830.310.99Unknown
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      ,
      • Kumar N
      • Ahlskog JE
      • Gross Jr, JB
      Acquired hypocupremia after gastric surgery.
      24/F/552.00.00Not availableUnknown
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      25/F/543.00.321.55Unknown
      * Reference range, 0.75 to 1.45 μg/mL.
      Reference range, 0.66 to 1.10 μg/mL.
      Figure thumbnail gr1
      FIGURE 1Serum copper and zinc levels in the cohort. Serum zinc levels were not available in patients 19 and 24. The dotted lines indicate the reference range for serum zinc, and the solid lines indicate the reference range for serum copper.
      The presenting complaint was gait difficulty, and all patients reported lower limb paresthesias. The gait difficulty was primarily due to severe sensory ataxia secondary to dorsal column dysfunction. In some patients, the gait also had a mild spastic component with associated corticospinal signs. Symptoms suggestive of an upper motor neuron bladder were present in 9 patients, a Lhermitte sign was present in 3 patients, and upper limb signs or symptoms were present in all except 2 patients (Table 2). A brisk knee jerk was seen in all except 4 patients. The ankle jerk was depressed in 15patients, and an extensor plantar response was seen in 12 patients.
      TABLE 2Clinical Features and Laboratory Findings in 25 Patients With Copper Deficiency Myelopathy
      AJ = ankle jerk; Hb = hemoglobin; KJ = knee jerk; N = normal; UL = upper limb signs or symptoms; WBC = white blood cell count; ↑ = increased; ↓ = decreased;? = equivocal; – = absent.
      Patient No.Urinary symptomsLhermitte signULKJAJPlan-tarsHistory of decreased HbHb (g/dL)
      Reference range, 13.5 to 17.5 g/dL for men and 12.0 to 15.5 g/dL for women.
      History of decreased WBCWBC (× 109/L)
      Reference range, 3.5 to 10.5 × 109/L.
      History of B12 deficiencyBl2 (ng/L)
      Reference range, 200 to 650 ng/L.
      Reference(s)
      1YesNoNoNo14.8No7.3No565
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Myelopathy due to copper deficiency.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      2YesNoYes?Yes12.6No9.5Yes404
      • Kumar N
      • Crum B
      • Petersen RC
      • Vernino SA
      • Ahlskog JE
      Copper deficiency myelopathy.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      3NoNoNoYes9.4Yes3.0Yes631
      • Kumar N
      • McEvoy KM
      • Ahlskog JE
      Myelopathy due to copper deficiency following gastrointestinal surgery.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      4NoNoYesYes12.5No4.3Yes2000
      • Kumar N
      • Crum B
      • Petersen RC
      • Vernino SA
      • Ahlskog JE
      Copper deficiency myelopathy.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      5YesNoYesNo16.0No4.5Yes307
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      6YesNoYes?Yes11.4Yes5.6Yes287
      7NoNoYesYes12.4No3.7Yes507
      • Kumar N
      • Ahlskog JE
      • Gross Jr, JB
      Acquired hypocupremia after gastric surgery.
      8NoNoYesNYes10.7Yes1.0Yes317
      9NoNoYesYes11.4No12.4No419
      10YesNoYesNo11.9No5.8Yes228
      • Kumar N
      • McEvoy KM
      • Ahlskog JE
      Myelopathy due to copper deficiency following gastrointestinal surgery.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      11NoNoYesNYes10.6No3.3No1108
      • Kumar N
      • Ahlskog JE
      • Gross Jr, JB
      Acquired hypocupremia after gastric surgery.
      12NoNoYesYes9.4Yes1.3No459
      13NoNoYesYes10.6Yes3.1No297
      • Kumar N
      • Low PA
      Myeloneuropathy and anemia due to copper malabsorption.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      14NoNoYesYes10.0Yes1.5Yes905
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      15YesYesYesNo14.2No6.8No≥2000
      16YesYesYesNo12.1No2.4No419
      17NoNoYesYes14.0No8.9No388
      • Kumar N
      • Crum B
      • Petersen RC
      • Vernino SA
      • Ahlskog JE
      Copper deficiency myelopathy.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      ,
      • Kumar N
      • Ahlskog JE
      • Gross Jr, JB
      Acquired hypocupremia after gastric surgery.
      18YesNoYesNo11.4No5.9No342
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      19NoYesYesYes7.9Yes1.8No315
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      20NoNoYesYes8.3Yes1.5No388
      • Kumar N
      • Elliott MA
      • Hoyer JD
      • Harper Jr, CM
      • Ahlskog JE
      • Phyliky RL
      “Myelodysplasia,” myeloneuropathy, and copper deficiency.
      21NoNoYes?No13.6No4.2No265
      22NoNoYesYes10.4Yes2.2No1493
      23NoNoYesNYes13.2Yes3.4No1055
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      ,
      • Kumar N
      • Ahlskog JE
      • Gross Jr, JB
      Acquired hypocupremia after gastric surgery.
      24YesNoYesNo12.3No3.7No1196
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      25NoNoYesYes10.5No4.2No371
      * AJ = ankle jerk; Hb = hemoglobin; KJ = knee jerk; N = normal; UL = upper limb signs or symptoms; WBC = white blood cell count; ↑ = increased; ↓ = decreased;? = equivocal; – = absent.
      Reference range, 13.5 to 17.5 g/dL for men and 12.0 to 15.5 g/dL for women.
      Reference range, 3.5 to 10.5 × 109/L.
      § Reference range, 200 to 650 ng/L.

      Possible Cause of Hypocupremia

      In one patient, copper deficiency was secondary to consumption of excessive amounts of zinc (patient 1) and in another possibly due to large doses of iron (patient 2). In 10 patients, the hypocupremia was attributed to a history of gastric surgery (patients 3-12), and in 4 it was due to malabsorption (patients 13-16). In the remaining 9 patients, the origin of the hypocupremia was unclear. The colonic copper level in patients 17 and 23 was increased to 39 μg/g and 57 μg/g of dry weight, respectively (reference range, 6-13 μg/g of dry weight). DNA sequence analysis of the ATP7A gene in patient 17 did not demonstrate any abnormalities.
      • Kumar N
      • Gross Jr, JB
      Mutation in the ATP7A gene may not be responsible for hypocupraemia in copper deficiency myelopathy?.
      All 22 coding exons and flanking introns were sequenced.

      Laboratory Investigations

      Anemia or leukopenia at presentation or in the past was seen in all except 5 patients (patients 1, 5, 15, 21, and 24) (Table 2). A history of vitamin B12 deficiency was present in 9 patients. Of these, 7 had a prior history of gastric surgery. All patients had a normal vitamin B12 level at presentation. The methylmalonic acid level was available in 14 patients (patients 2-7, 10, 12, 14, 16-19, and 21) and was elevated in 3 (patients 6, 10, and 21). Serum homocysteine measurements were within the reference range in the 14 patients for whom this information was available (patients 3-7, 12, 14, 16-19, 21, 23, and 24). Patients with a history of vitamin B12 deficiency showed neurological progression despite periodic vitamin B12 administration and repeatedly normal vitamin B12 levels.

      Electrophysiological Studies

      Clinical findings and nerve conduction studies suggested varying degrees of peripheral neuropathy (Table 3). An axonal peripheral neuropathy was detected in 21 of 24 patients. Eleven were mixed sensory motor, 5 were pure motor, 2 pure sensory, 2 predominantly motor, and 1 predominantly sensory. The neuropathy was mild in 10, moderately severe in 3, and severe in 8. In 3 patients, severe, bilateral, posterior interosseous neuropathies were superimposed on the generalized neuropathy. Myopathic changes were noted on the electromyogram in 4 patients (patients 6, 13, 23, and 24). Somatosensory evoked potential studies were abnormal in all 20 patients in whom these data were available, although in patient 13 the abnormality was only peripheral. Nineteen patients had neurophysiological evidence of impaired conduction in the central pathways. This correlated with the clinical presentation that suggested myelopathy. Visual evoked potentialswere abnormal in 2 of 8 patients in whom these data were available.
      TABLE 3Neurophysiological and Neuroimaging Findings in 25 Patients With Copper Deficiency Myelopathy
      On nerve conduction studies (NCS) and electromyography (EMG), mild involvement was defined as minimal NCS and EMG changes with no absent NCS responses and no signs of active denervation on EMG. Moderate involvement was defined as absent or low amplitude motor and/or sensory responses on NCS and signs of denervation by EMG. Predominantly absent NCS responses and prominent signs of denervation indicated severe peripheral involvement. MRI = magnetic resonance imaging; M(S) = predominantly motor; N = normal; NA = not available; SEP = somatosensory evoked potentials; SM = sensory motor; S(M) = predominantly sensory.
      Patient No.NCSSEPSpine MRIBrain MRIReference(s)
      1Severe, SM, axonalAbnormalIncidental disk diseaseLacunar infarcts (left thalamus, right pons, cerebellum)
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Myelopathy due to copper deficiency.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      2Mild, sensory, axonalAbnormalIncidental disk diseaseNegative
      • Kumar N
      • Crum B
      • Petersen RC
      • Vernino SA
      • Ahlskog JE
      Copper deficiency myelopathy.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      3Mild, SM, axonalNAIncidental disk disease, osteoporosis, slightly atrophie thoracolumbar cord, probable multiple patchy T2 hyper intensities from C2 to C6Minimal cerebellar atrophy, lacunes
      • Kumar N
      • McEvoy KM
      • Ahlskog JE
      Myelopathy due to copper deficiency following gastrointestinal surgery.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      4Mild, SM, axonalAbnormalIncreased T2 signal in posterior column from Cl to C7 and in mid and lower thoracic region, incidental disk diseaseNA
      • Kumar N
      • Crum B
      • Petersen RC
      • Vernino SA
      • Ahlskog JE
      Copper deficiency myelopathy.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      5Mild, SM, axonal, ulnar elbow, median wristAbnormalDiffuse posterior cord signal abnormality from cervicomedullary junction to lower thoracic level, incidental disk disease, status postlaminectomy (C4 through C6)Single focus of increased T2 signal in left frontal lobe
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      6Moderate, SM, axonal, myopathyAbnormalT2 hyperintensity in dorsal midline cervical cord from C2 to T6, patchy focal T2 hyperintensity in dorsal cord at T8, multiple nerve root sheath cysts, incidental disk diseaseMultiple periventricular and pontine T2 hyperintensities, minimal biparietal atrophy, inferior right frontal cavernoma
      7Mild, SM, axonalAbnormalAbnormal T2 signal in posterior cord from medulla to C7, patches of abnormal signal in mid and lower thoracic cord, incidental disk diseaseMultiple periventricular and pontine foci of T2 hyperintensity
      • Kumar N
      • Ahlskog JE
      • Gross Jr, JB
      Acquired hypocupremia after gastric surgery.
      8Severe, M(S), axonalAbnormalSubtle T2 signal change in posterior paramedian cord at the cervical level and T10/11 level, incidental disk disease, prominent pial vasculatureNormal
      9Old right C7 radiculopathyAbnormalCentral cord signal change at C5/6, subtle central cord signal change at C4, moderately severe multilevel cervical stenosis, incidental hemangiomasNonspecific T2 hyperintensity in right frontal and parietal lobes
      10Mild, SM, axonalNAIncidental disk diseaseNonspecific foci of increased T2 signal in frontal lobes
      • Kumar N
      • McEvoy KM
      • Ahlskog JE
      Myelopathy due to copper deficiency following gastrointestinal surgery.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      11NAbnormal (tibial only)Incidental disk diseaseNA
      • Kumar N
      • Ahlskog JE
      • Gross Jr, JB
      Acquired hypocupremia after gastric surgery.
      12Mild, sensory, axonalAbnormalIncidental disk diseaseNormal
      13Severe, SM, axonal, myopathyAbnormal (median only: peripheral)NormalNormal
      • Kumar N
      • Low PA
      Myeloneuropathy and anemia due to copper malabsorption.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      14Severe, S(M), axonalNANormalMinimal generalized atrophy
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      15NAbnormalIncidental disk diseaseNonspecific foci of T2 hyperintensity
      16NANANormalHyperintense T2 foci in subcortical white matter
      17Moderate, SM, axonalAbnormalIncreased T2 signal in paramedian dorsal cervical cord from C2 through C7, incidental disk diseaseChiari I malformation, partially empty sella
      • Kumar N
      • Crum B
      • Petersen RC
      • Vernino SA
      • Ahlskog JE
      Copper deficiency myelopathy.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      ,
      • Kumar N
      • Ahlskog JE
      • Gross Jr, JB
      Acquired hypocupremia after gastric surgery.
      18Mild, motor, axonalAbnormalThin central syrinx from T7 to T10, incidental disk diseaseSeveral punctate foci of white matter hyperintensity
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      19Severe, M(S), axonal, posterior interosseousNAIncidental disk diseaseFoci of T2 hyperintensity (right cerebellum, right temporal, left frontal)
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      20Severe, multifocal, motor, axonal, carpal tunnel, posterior interosseousAbnormalIncidental disk diseaseNA
      • Kumar N
      • Elliott MA
      • Hoyer JD
      • Harper Jr, CM
      • Ahlskog JE
      • Phyliky RL
      “Myelodysplasia,” myeloneuropathy, and copper deficiency.
      21Severe, axonal, SM posterior interosseousAbnormal (median only)Central T2 hyperintensity from T7 to T9, possible focus of T2 hyperintensity at T4, incidental disk disease, lower thoracic cord atrophyPeriventricular T2 hyperintensity, moderate biparietal atrophy, minimal cerebellar atrophy
      22Moderate, axonal. SMAbnormalPossible patchy T2 hyperintensity from C3 through C5, incidental disk diseasePunctate T2 hyperintensities (periventricular, right basal ganglia, right frontal, left parietal)
      23Mild, motor, axonal, myopathyAbnormalIncidental disk diseaseIncreased Tl signal in basal ganglia, foci of increased T2 signal in white matter
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      ,
      • Kumar N
      • Ahlskog JE
      • Gross Jr, JB
      Acquired hypocupremia after gastric surgery.
      24Mild, motor, axonal, myopathyAbnormalSubtle T2 signal change in dorsal column of spinal cord at C2 and C6, small caliber of thoracic spinal cord, incidental disk diseaseFocal and confluent areas of increased T2 signal in periventricular white matter, internal and external capsule, and corona radiata; increased T2 signal in middle cerebellar peduncles, midbrain and thalami. Small incidental right temporal meningioma
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      25Severe, motor, axonalAbnormalCompression fracture T12NA
      * On nerve conduction studies (NCS) and electromyography (EMG), mild involvement was defined as minimal NCS and EMG changes with no absent NCS responses and no signs of active denervation on EMG. Moderate involvement was defined as absent or low amplitude motor and/or sensory responses on NCS and signs of denervation by EMG. Predominantly absent NCS responses and prominent signs of denervation indicated severe peripheral involvement. MRI = magnetic resonance imaging; M(S) = predominantly motor; N = normal; NA = not available; SEP = somatosensory evoked potentials; SM = sensory motor; S(M) = predominantly sensory.

      Neuroimaging

      A signal change in the spinal cord on MRI has been the most consistent neuroimaging finding and was seen in 11 of the 25 patients in this series (patients 3-9, 17, 21, 22, and 24) (Table 3). The cervical cord was involved in 10 (patients 3-9, 17, 22, and 24), thoracic cord in 6 (patients 4-8 and 21), and both in 5 (patients 4-8). Of the 6 patients with thoracic cord involvement, the involvement was contiguous with the cervical involvement in 2 (patients 5 and 6). The involvement was most often in the paramedian dorsal cord that involved the dorsal columns (Figure 2, A and B), although in 2 patients (patients 9 and 21) the central cord was involved. It is difficult to be certain that this did not represent a small central syrinx. Slight cord atrophy of the thoracolumbar cord was seen in 3 patients (patients 3, 21, and 24). Of the 11 patients with signal change in the spinal cord, contrast was given in all except 1 (patient 3). None of these 10 had any evidence of contrast enhancement. Often the involvement was subtle and in 2 patients (patients 3 and 24) had been missed before a neuroradiologist's review. Foci of increased T2 signal on the brain MRI were seen in 15 patients (patients 1, 3, 5-7, 9, 10, 15, 16, 18, 19, 21, and 22-24), and in some (patients 1, 6, 7, 19, 22, and 24) the appearance and distribution of the lesions suggested lacunar disease. The importance of this finding is uncertain.
      Figure thumbnail gr2
      FIGURE 2Magnetic resonance images and bone marrow study. Sagittal (A) and axial (B) T2-weighted magnetic resonance images of patient 17 show increased signal in the paramedian aspect of the dorsal cervical cord (single arrow). C, Bone marrow study in patient 14 shows vacuolated myeloid precursors (single arrow). D, Iron staining in patient 20 shows a ringed sideroblast (single arrow) and iron-containing plasma cells (double arrows). A and B from Neuroradiology,
      • Kumar N
      • Ahlskog JE
      • Klein CJ
      • Port JD
      Imaging features of copper deficiency myelopathy: a study of 25 cases.
      with permission from Springer Science and Business Media.

      Response to Therapy and Follow-up

      Inadequate follow-up data were available for patients 7, 9, 12, 16, and 25. With oral or parenteral copper replacement, normal serum copper levels were achieved in 18 of the remaining 20 patients (Table 4). Hematologic manifestations when present were promptly and completely reversed. Residual neurological deficits were present in all 20. In all 20 patients except patient 5, further deterioration was prevented. A few months after diagnosis, patient 21 died after a massive stroke. Neurological improvement when present was often more subjective than objective. The cervical dorsal column signal change noted on the T2-weightedMRI in patient 17 showed nearly complete resolution with normalization of serum copper.
      TABLE 4Route of Copper Supplementation and Response to Therapy in 25 Patients With Copper Deficiency Myelopathy
      Hematologie manifestations when present showed a prompt and complete response to therapy. Neurological improvement when present was often more subjective than objective. IV = intravenous; PO = oral; ? = inadequate follow-up data.
      Patient No.Route of copper supplementationNormal copper levels achievedResidual deficitsFurther deterioration preventedReference(s)
      1POYesYesYes
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Myelopathy due to copper deficiency.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      2IV, POYesYesYes
      • Kumar N
      • Crum B
      • Petersen RC
      • Vernino SA
      • Ahlskog JE
      Copper deficiency myelopathy.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      3IV, PONoYesYes
      • Kumar N
      • McEvoy KM
      • Ahlskog JE
      Myelopathy due to copper deficiency following gastrointestinal surgery.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      4POYesYesYes
      • Kumar N
      • Crum B
      • Petersen RC
      • Vernino SA
      • Ahlskog JE
      Copper deficiency myelopathy.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      5PONoYesNo
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      6POYesYesYes
      7PO???
      • Kumar N
      • Ahlskog JE
      • Gross Jr, JB
      Acquired hypocupremia after gastric surgery.
      8IV, POYesYesYes
      9PO???
      10IV, POYesYesYes
      • Kumar N
      • McEvoy KM
      • Ahlskog JE
      Myelopathy due to copper deficiency following gastrointestinal surgery.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      11POYesYesYes
      • Kumar N
      • Ahlskog JE
      • Gross Jr, JB
      Acquired hypocupremia after gastric surgery.
      12PO???
      13POYesYesYes
      • Kumar N
      • Low PA
      Myeloneuropathy and anemia due to copper malabsorption.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      14POYesYesYes
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      15IV, POYesYesYes
      16PO???
      17IV, POYesYesYes
      • Kumar N
      • Crum B
      • Petersen RC
      • Vernino SA
      • Ahlskog JE
      Copper deficiency myelopathy.
      ,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      ,
      • Kumar N
      • Ahlskog JE
      • Gross Jr, JB
      Acquired hypocupremia after gastric surgery.
      18POYesYesYes
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      19POYesYesYes
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      20POYesYesYes
      • Kumar N
      • Elliott MA
      • Hoyer JD
      • Harper Jr, CM
      • Ahlskog JE
      • Phyliky RL
      “Myelodysplasia,” myeloneuropathy, and copper deficiency.
      21POYesYesYes
      22POYesYesYes
      23PO, IVYesYesYes
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      ,
      • Kumar N
      • Ahlskog JE
      • Gross Jr, JB
      Acquired hypocupremia after gastric surgery.
      24POYesYesYes
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      25PO???
      * Hematologie manifestations when present showed a prompt and complete response to therapy. Neurological improvement when present was often more subjective than objective. IV = intravenous; PO = oral; ? = inadequate follow-up data.

      DISCUSSION

      Neurological Manifestations in Copper-Deficient Animals

      Copper deficiency-associated myelopathy has been well described in various animal species.
      • Bennetts HW
      • Chapman FE
      Copper deficiency in sheep in western Australia: a preliminary account of the aetiology of enzootic ataxia of lambs and anaemia of ewes.
      • Barlow RM
      Further observations on swayback, I: transitional pathology.
      • Smith RM
      • Osborne-White WS
      • O'Dell BL
      Cytochromes in brain mitochondria from lambs with enzootic ataxia.
      • Tan N
      • Urich H
      Menkes' disease and swayback: a comparative study of two copper deficiency syndromes.
      • Penrith ML
      • Tustin RC
      • Thornton DJ
      • Burdett PD
      Swayback in a blesbok (Damaliscus dorcas phillipsi) and a black wildebeest (Connochaetes gnou).
      Often seen in ruminants, it has been referred to as swayback or enzootic ataxia. The typical distribution of lesions in the spinal cord is greater involvement of the cervical cord with less severe changes in the thoracic and lumbar segments.
      • Penrith ML
      • Tustin RC
      • Thornton DJ
      • Burdett PD
      Swayback in a blesbok (Damaliscus dorcas phillipsi) and a black wildebeest (Connochaetes gnou).
      Wallerian degeneration and demyelination with microcavitation of the white matter of the spinal cord and brainstem are seen.
      • Barlow RM
      Further observations on swayback, I: transitional pathology.
      Menkes syndrome is the well-known copper deficiency-related disease in humans and is due to congenital copper deficiency.
      • Menkes JH
      • Alter M
      • Steigleder GK
      • Weakley DR
      • Sung JH
      A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration.
      • Danks DM
      • Campbell PE
      • Stevens BJ
      • Mayne V
      • Cartwright E
      Menkes's kinky hair syndrome: an inherited defect in copper absorption with widespread effects.
      Comparative neuropathological studies have shown similarity between Menkes syndrome and swayback.
      • Tan N
      • Urich H
      Menkes' disease and swayback: a comparative study of two copper deficiency syndromes.
      Both are characterized by defects in mitochondrial oxidative metabolism due to a decrease in a copper metalloenzyme, cytochrome oxidase.
      • Pedespan JM
      • Jouaville LS
      • Cances C
      • et al.
      Menkes disease: study of the mitochondrial respiratory chain in three cases.
      • Alleyne T
      • Joseph J
      • Lalla A
      • Sampson V
      • Adogwa A
      Cytochrome-c oxidase isolated from the brain of swayback-diseased sheep displays unusual structure and uncharacteristic kinetics.
      Abnormalities of CNS myelination are seen in copper-deficient rats.
      • Dipaolo RV
      • Kanfer JN
      • Newberne PM
      Copper deficiency and the central nervous system: myelination in the rat: morphological and biochemical studies.
      • Zimmerman AW
      • Matthieu JM
      • Quarles RH
      • Brady RO
      • Hsu JM
      Hypomyelination in copper-deficient rats: prenatal and postnatal copper replacement.
      Zinc-induced copper deficiency has been known to cause ataxia in kittens who were exposed to zinc from the galvanized iron bar doors of their cages.
      • Hendriks WH
      • Allan FJ
      • Tartelin MF
      • Collett MG
      • Jones BR
      Suspected zinc-induced copper deficiency in growing kittens exposed to galvanised iron.
      Wallerian degeneration in the spinal cord was present at necropsy.

      Role of Copper in Maintaining the Structure and Function of the Nervous System

      Copper functions as a prosthetic group, permitting electron transfer in key enzymatic pathways. It is a component of key metalloenzymes that have a critical role in the structure and function of the nervous system. These include cytochrome-c oxidase for electron transport and oxidative phosphorylation in the mitochondrial respiratory chain, copper-zinc superoxide dismutase for antioxidant defense, tyrosinase for melanin synthesis, dopamine β-hydroxylase for catecholamine biosynthesis, lysyl oxidase for crosslinking of collagen and elastin, peptidylglycine α-amidating monooxygenase for neuropeptide and peptide hormone processing, and ceruloplasmin for brain iron homeostasis. Reduction in cytochrome oxidase activity may be the likely basis for neurological dysfunction associated with the copper deficient state.

      Causes of Copper Deficiency

      In the study patients, the most common association with copper deficiency was a remote history of gastric surgery. Copper absorption in humans most likely occurs in the stomach and proximal duodenum.
      • Mason KE
      A conspectus of research on copper metabolism and requirements of man.
      Prompt appearance of copper 64 in the blood after oral administration suggests that most copper absorption occurs from the proximal gut.
      • Sternlier I
      • Morell AG
      • Bauer CD
      • Combes B
      • De Bobes-Sternberg S
      • Schein-Berg IH
      Detection of the heterozygous carrier of the Wilson's disease gene.
      Although no data are available on the incidence or prevalence of hypocupremia after gastric surgery, copper deficiency after gastric surgery (for peptic ulcer disease or bariatric surgery) is being increasingly recognized.
      • Schleper B
      • Stuerenburg HJ
      Copper deficiency-associated myelopathy in a 46-year-old woman.
      • Gregg XT
      • Reddy V
      • Prchal JT
      Copper deficiency masquerading as myelodysplastic syndrome.
      • Kumar N
      • McEvoy KM
      • Ahlskog JE
      Myelopathy due to copper deficiency following gastrointestinal surgery.
      • Kumar N
      • Crum B
      • Petersen RC
      • Vernino SA
      • Ahlskog JE
      Copper deficiency myelopathy.
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      • Kumar N
      • Ahlskog JE
      • Gross Jr, JB
      Acquired hypocupremia after gastric surgery.
      • Kumar N
      • Crum BA
      • Ahlskog JE
      Copper deficiency myelopathy [abstract]?.
      • Bartner R
      • Will M
      • Conrad J
      • Engelhardt A
      • Schwarz-Eywill M
      Pancytopenia, arthralgia and myeloneuropathy due to copper deficiency [in German].
      • Hayton BA
      • Broome HE
      • Lilenbaum RC
      Copper deficiency-induced anemia and neutropenia secondary to intestinal malabsorption.
      Neurological complications after gastrectomy for ulcer disease or bariatric surgery have been well recognized, but frequently the cause has not been determined.
      • Banerji NK
      • Hurwitz LJ
      Nervous system manifestations after gastric surgery.
      • Hoffman PM
      • Brody JA
      Neurological disorders in patients following surgery for peptic ulcer [abstract]?.
      • Feit H
      • Glasberg M
      • Ireton C
      • Rosenberg RN
      • Thal E
      Peripheral neuropathy and starvation after gastric partitioning for morbid obesity.
      • Paulson GW
      • Martin EW
      • Mojzisik C
      • Carey LC
      Neurologic complications of gastric partitioning.
      • Abarbanel JM
      • Berginer VM
      • Osimani A
      • Solomon H
      • Charuzi I
      Neurologic complications after gastric restriction surgery for morbid obesity.
      • Thaisetthawatkul P
      • Collazo-Clavell ML
      • Sarr MG
      • Norell JE
      • Dyck PJ
      A controlled study of peripheral neuropathy after bariatric surgery.
      • Chang CG
      • Adams-Huet B
      • Provost DA
      Acute post-gastric reduction surgery (APGARS) neuropathy.
      Excessive zinc ingestion, although seen in only 1 of the study patients (patient 1), is a well-recognized cause of copper deficiency (Figure 3, A).
      • Summerfield AL
      • Steinberg FU
      • Gonazlez JG
      Morphologic findings in bone marrow precursor cells in zinc-induced copper deficiency anemia.
      • Fiske DN
      • McCoy III, HE
      • Kitchens CS
      Zinc-induced sideroblastic anemia: report of a case, review of the literature, and description of the hematologic syndrome.
      • Willis MS
      • Monaghan SA
      • Miller ML
      • et al.
      Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination.
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Myelopathy due to copper deficiency.
      • Rowin J
      • Lewis SL
      Copper deficiency myeloneuropathy and pancytopenia secondary to overuse of zinc supplementation.
      • Porter KG
      • McMaster D
      • Elmes ME
      • Love AH
      Anaemia and low serum-copper during zinc therapy?.
      • Prasad AS
      • Brewer GJ
      • Schoomaker EB
      • Rabbani P
      Hypocupremia induced by zinc therapy in adults.
      • Patterson WP
      • Winkelmann M
      • Perry MC
      Zinc-induced copper deficiency: megamineral sideroblastic anemia.
      • Hoffman II, HN
      • Phyliky RL
      • Fleming CR
      Zinc-induced copper deficiency.
      • Simon SR
      • Branda RF
      • Tindle BF
      • Burns SL
      Copper deficiency and sideroblastic anemia associated with zinc ingestion.
      • Broun ER
      • Greist A
      • Tricot G
      • Hoffman R
      Excessive zinc ingestion: a reversible cause of sideroblastic anemia and bone marrow depression.
      • Gyorffy EJ
      • Chan H
      Copper deficiency and microcytic anemia resulting from prolonged ingestion of over-the-counter zinc.
      • Bennett DR
      • Baird CJ
      • Chan KM
      • et al.
      Zinc toxicity following massive coin ingestion.
      • Hassan HA
      • Netchvolodoff C
      • Raufman JP
      Zinc-induced copper deficiency in a coin swallower.
      • Kumar A
      • Jazieh AR
      Case report of sideroblastic anemia caused by ingestion of coins.
      • Irving JA
      • Mattman A
      • Lockitch G
      • Farrell K
      • Wadsworth LD
      Element of caution: a case of reversible cytopenias associated with excessive zinc supplementation.
      In addition to the common use of zinc in the prevention or treatment of common colds and sinusitis, zinc therapy has been used for conditions such as acrodermatitis enteropathica, decubitus ulcers, sickle cell disease, celiac disease, memory impairment, and acne. Unusual sources of excess zinc have included a patient who consumed an entire tube of a denture cream that contained zinc daily for 5 years
      • Willis MS
      • Monaghan SA
      • Miller ML
      • et al.
      Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination.
      and patients swallowing coins containing zinc.
      • Broun ER
      • Greist A
      • Tricot G
      • Hoffman R
      Excessive zinc ingestion: a reversible cause of sideroblastic anemia and bone marrow depression.
      • Bennett DR
      • Baird CJ
      • Chan KM
      • et al.
      Zinc toxicity following massive coin ingestion.
      • Hassan HA
      • Netchvolodoff C
      • Raufman JP
      Zinc-induced copper deficiency in a coin swallower.
      • Kumar A
      • Jazieh AR
      Case report of sideroblastic anemia caused by ingestion of coins.
      Zinc causes an up-regulation of metallothionein production in the enterocytes.
      • Yuzbasiyan-Gurkan V
      • Grider A
      • Nostrant T
      • Cousins RJ
      • Brewer GJ
      Treatment of Wilson's disease with zinc, X: intestinal metallothionein induction.
      Metallothionein is an intracellular ligand, and copper has a higher affinity for metallothionein than zinc. Copper displaces zinc from metallothionein, binds preferentially to the metallothionein, remains in the enterocytes, and is lost in the feces as the intestinal cells are sloughed off (Figure 3, A). In patient 2, excess iron consumption may have contributed to the hypocupremia. In animals, excess iron has been associated with copper deficiency.
      • Smith CH
      • Bidlack WR
      Interrelationship of dietary ascorbic acid and iron on the tissue distribution of ascorbic acid, iron and copper in female guinea pigs.
      • Yu S
      • West CE
      • Beynen AC
      Increasing intakes of iron reduce status, absorption and biliary excretion of copper in rats.
      • Klevay LM
      Iron overload can induce mild copper deficiency.
      If the diagnosis of copper deficiency is not suspected, iron supplementation may be administered for presumed iron deficiency anemia, which may further exacerbate the copper deficiency.
      • Kumar N
      • Crum B
      • Petersen RC
      • Vernino SA
      • Ahlskog JE
      Copper deficiency myelopathy.
      • Cordano A
      • Baertl JM
      • Graham GG
      Copper deficiency in infancy.
      • Takeuchi M
      • Tada A
      • Yoshimoto S
      • Takahashi K
      Anemia and neutropenia due to copper deficiency during long-term total parenteral nutrition [in Japanese].
      The extent to which oral iron interferes with copper absorption in humans is unknown. Tetrathiomolybdate may have a role in inhibiting tumor angiogenesis, and chemotherapy regimens using tetrathiomolybdate can also result in copper deficiency.
      • Brewer GJ
      • Dick RD
      • Grover DK
      • et al.
      Treatment of metastatic cancer with tetrathiomolybdate, and anticopper, antiangiogenic agent: phase I study.
      • Lang TF
      • Glynne-Jones R
      • Blake S
      • Taylor A
      • Kay JD
      Iatrogenic copper deficiency following information and drugs obtained over the Internet.
      Figure thumbnail gr3
      FIGURE 3Copper (Cu) absorption and distribution. A, Excess dietary zinc (Zn) decreases Cu absorption by inducing metallothionein formation in mucosal cells. Metallothionein has a high affinity for Cu and binds it preferentially, and the bound Cu is lost as the cells slough into the intestinal lumen. By this mucosal block, Zn induces a negative Cu balance. Failure to mobilize absorbed Cu from intestinal cells forms the basis of Menkes syndrome (1). In Wilson disease, there is decreased incorporation of Cu into ceruloplasmin (2a) and impaired biliary excretion of Cu (2b).
      • Kumar N
      Progressive ataxia with a twist.
      B, Cu trafficking in yeast. Copper is reduced by a plasma membrane reductase and then transported across the membrane by a Cu transporter (Ctr1). Three Cu transporters or chaperones (Cox17, Lys7, and Atx1) deliver Cu to specific proteins (cytochrome-c [cyt c] oxidase, CuZn superoxide dismutase [SOD], and Fet3, respectively) in different cellular compartments. Human counterparts for Ctr1 and the 3 Cu chaperones are indicated in the figure. The human Wilson disease protein is homologous to yeast Ccc2, a P-type ATPase transmembrane Cu transporter. The multi-Cu oxidase Fet3 is homologous to human ceruloplasmin. Adapted from Clin Gastroenterol Hepatol,
      • Kumar N
      • Ahlskog JE
      • Gross Jr, JB
      Acquired hypocupremia after gastric surgery.
      with permission from the American Gastroenterology Association. alb = albumin; Cp = ceruloplasmin; M = metallothionein.
      Copper deficiency since birth is seen in Menkes syndrome.
      • Menkes JH
      • Alter M
      • Steigleder GK
      • Weakley DR
      • Sung JH
      A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration.
      In this syndrome, copper absorption from the gut is impaired,
      • Danks DM
      • Campbell PE
      • Stevens BJ
      • Mayne V
      • Cartwright E
      Menkes's kinky hair syndrome: an inherited defect in copper absorption with widespread effects.
      and high levels of copper are seen in duodenal mucosal cells.
      • Danks DM
      • Cartwright E
      • Stevens BJ
      • Townley RR
      Menkes' kinky hair disease: further definition of the defect in copper transport.
      A defect in enterocyte transport ofabsorbed copper causes copper accumulation in the intestinal mucosa and resulting hypocupremia (Figure 3, A). The genetic basis is mutations in the ATP7A gene, which encodes a P-type adenosine triphosphatase (MNK) that has multiple copper binding motifs near its amino terminus.
      • Vulpe C
      • Levinson B
      • Whitney S
      • Packman S
      • Gitschier J
      Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase [published correction appears in Nat Genet. 1993;3:273].
      • Chelly J
      • Tumer Z
      • Tonnesen T
      • et al.
      Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein.
      • Mercer JF
      • Livingston J
      • Hall B
      • et al.
      Isolation of a partial candidate gene for Menkes disease by positional cloning.
      Loss of function of this protein results in failure of copper transfer across the gastrointestinal tract, placenta, and blood-brain barrier, with resultant copper deficiency. The increased colonic copper seen in patients 17 and 23 suggests that a similar defect in copper transport may underlie idiopathic hypocupremia. Similar observations have been made in a patient with a progressive neurological disease and hypocupremia.
      • Godwin-Austen RB
      • Robinson A
      • Evans K
      • Lascelles PT
      An unusual neurological disorder of copper metabolism clinically resembling Wilson's disease but biochemically a distinct entity.
      Even though an ATP7A mutation was not identified in patient 17, changes in the promoter or other noncoding regions and large intragenic deletions could not be ruled out.
      It is known that mutations in the ATP7A gene are responsible for a wide spectrum of manifestations of Menkes syndrome.
      • Kaler SG
      Metabolic and molecular bases of Menkes disease and occipital horn syndrome.
      Emerging knowledge about copper transport
      • Valentine JS
      • Gralla EB
      Delivering copper inside yeast and human cells.
      • Mercer JF
      • Llanos RM
      Molecular and cellular aspects of copper transport in developing mammals.
      may help clarify the origin of idiopathic hypocupremia. Studies in yeast have shown that reduced copper is transported across the membrane by the high-affinity copper transporter Ctr1, and 3 different proteins transport copper to cytochrome-c oxidase, copper-zinc superoxide dismutase, and the post-Golgi compartment for insertion into a multicopper oxidase essential for high-affinity iron uptake (Figure 3, B). The copper transporter Ctr1 is the primary avenue for copper uptake in mammalian cells and provides an essential function in mammalian embryonic development.
      • Kuo YM
      • Zhou B
      • Cosco D
      • Gitschier J
      The copper transporter CTR1 provides an essential function in mammalian embryonic development.
      Copper deficiency may occur in premature infants and low-birth-weight infants.
      • al-Rashid RA
      • Spangler J
      Neonatal copper deficiency.
      • Yuen P
      • Lin HJ
      • Hutchinson JH
      Copper deficiency in a low birthweight infant.
      Because of copper's ubiquitous distribution and low daily requirement, acquired dietary copper deficiency is rare.
      • Williams DM
      Copper deficiency in humans.
      It may occur in malnourished infants,
      • Cordano A
      • Baertl JM
      • Graham GG
      Copper deficiency in infancy.
      • Lahey ME
      • Behar M
      • Viteri F
      • Scrimshaw NS
      Values for copper, iron and iron-binding capacity in the serum in kwashiorkor.
      • Brubaker C
      • Sturgeon P
      Copper deficiency in infants: a syndrome characterized by hypocupremia, iron deficiency anemia, and hypoproteinemia.
      • Graham GG
      • Cordano A
      Copper depletion and deficiency in the malnourished infant.
      patients with nephrotic syndrome,
      • Cartwright GE
      • Gubler CJ
      • Wintrobe MM
      Studies on copper metabolism, XI: copper and iron metabolism in the nephrotic syndrome.
      and those with enteropathies associated with malabsorption.
      • Kumar N
      • Low PA
      Myeloneuropathy and anemia due to copper malabsorption.
      • Gordon Jr, RS
      Exudative enteropathy: abnormal permeability of the gastrointestinal tract demonstrable with labelled polyvinylpyrrolidone.
      • Gross PA
      • Embree LJ
      • Bally P
      • Shipp JC
      • Thorn GW
      Hypoalbuminemia (with anasarca) due to hypercatabolism, serum protein exudation into the gastrointestinal tract, increased capillary permeability and hypoanabolism: the unusual occurrence of increased capillary permeability temporarily reversed by human growth hormone therapy.
      • Sternlieb I
      • Janowitz HD
      Absorption of copper in malabsorption syndromes.
      • Cordano A
      • Graham GG
      Copper deficiency complicating severe chronic intestinal malabsorption.
      Malabsorption without a history of gastric surgery was the second most commonly identified cause of hypocupremia in the cohort.
      Copper deficiency may be a complication of prolonged total parenteral nutrition,
      • Takeuchi M
      • Tada A
      • Yoshimoto S
      • Takahashi K
      Anemia and neutropenia due to copper deficiency during long-term total parenteral nutrition [in Japanese].
      • Karpel JT
      • Peden VH
      Copper deficiency in long-term parenteral nutrition.
      Nutrient deficiencies after intensive parenteral alimentation [letter].
      • Vilter RW
      • Bozian RC
      • Hess EV
      • Zellner DC
      • Petering HG
      Manifestations of copper deficiency in a patient with systemic sclerosis on intravenous hyperalimentation.
      • Heller RM
      • Kirchner SG
      • O'Neill Jr, JA
      • et al.
      Skeletal changes of copper deficiency in infants receiving prolonged total parenteral nutrition.
      • Bozzetti F
      • Inglese MG
      • Terno G
      • Pupa A
      • Sequeira C
      • Migliavacca S
      Hypocupremia in patients receiving total parenteral nutrition.
      • Wasa M
      • Satani M
      • Tanano H
      • Nezu R
      • Takagi Y
      • Okada A
      Copper deficiency with pancytopenia during total parenteral nutrition.
      particularly so when copper supplementation in total parenteral nutrition is withheld because of cholestasis.
      • Fuhrman MP
      • Herrmann V
      • Masidonski P
      • Eby C
      Pancytopenia after removal of copper from total parenteral nutrition.
      • Spiegel JE
      • Willenbucher RF
      Rapid development of severe copper deficiency in a patient with Crohn's disease receiving parenteral nutrition.
      Enteral feeding with inadequate copper has also been known to result in copper deficiency.
      • Tamura H
      • Hirose S
      • Watanabe O
      • et al.
      Anemia and neutropenia due to copper deficiency in enteral nutrition.
      • Nagano T
      • Toyoda T
      • Tanabe H
      • et al.
      Clinical features of hematological disorders caused by copper deficiency during long-term enteral nutrition.

      Associated Hyperzincemia

      An elevated serum zinc level in the absence of exogenous zinc ingestion was commonly seen in the study patients. Hyperzincemia in association with hypocupremia has also been reported by others.
      • Willis MS
      • Monaghan SA
      • Miller ML
      • et al.
      Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination.
      • Prodan CI
      • Holland NR
      • Wisdom PJ
      • Burstein SA
      • Bottomley SS
      CNS demyelination associated with copper deficiency and hyperzincemia.
      • Hedera P
      • Fink JK
      • Bockenstedt PL
      • Brewer GJ
      Myelopolyneuropathy and pancytopenia due to copper deficiency and high zinc levels of unknown origin: further support for existence of a new zinc overload syndrome.
      • Greenberg SA
      • Briemberg HR
      A neurological and hematological syndrome associated with zinc excess and copper deficiency.
      The hyperzincemia (as assessed by increased serum zinc or urinary zinc excretion) may persist or increase despite correction of the copper deficient state.
      • Prodan CI
      • Holland NR
      • Wisdom PJ
      • Burstein SA
      • Bottomley SS
      CNS demyelination associated with copper deficiency and hyperzincemia.
      • Hedera P
      • Fink JK
      • Bockenstedt PL
      • Brewer GJ
      Myelopolyneuropathy and pancytopenia due to copper deficiency and high zinc levels of unknown origin: further support for existence of a new zinc overload syndrome.
      • Greenberg SA
      • Briemberg HR
      A neurological and hematological syndrome associated with zinc excess and copper deficiency.
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      The importance of the associated hyperzincemia seen in the absence of exogenous zinc ingestion is unclear,
      • Hedera P
      • Brewer GJ
      Myeloneuropathy due to copper deficiency or zinc excess? [reply to letter]?.
      • Kumar N
      • Ahlskog JE
      Myelopolyneuropathy due to copper deficiency or zinc excess? [letter.].
      as is the importance of increased urinary zinc excretion without elevation of the plasma zinc level.
      • Kumar N
      • McEvoy KM
      • Ahlskog JE
      Myelopathy due to copper deficiency following gastrointestinal surgery.
      • Kumar N
      • Low PA
      Myeloneuropathy and anemia due to copper malabsorption.
      Copper deficiency may result from a zinc overload syndrome.
      • Hedera P
      • Fink JK
      • Bockenstedt PL
      • Brewer GJ
      Myelopolyneuropathy and pancytopenia due to copper deficiency and high zinc levels of unknown origin: further support for existence of a new zinc overload syndrome.
      A metabolic abnormality that results in increased zinc absorption or decreased intestinal excretion has been proposed. Since the syndrome of myeloneuropathy has been described with hypocupremia and normal zinc levels,
      • Schleper B
      • Stuerenburg HJ
      Copper deficiency-associated myelopathy in a 46-year-old woman.
      • Kumar N
      • McEvoy KM
      • Ahlskog JE
      Myelopathy due to copper deficiency following gastrointestinal surgery.
      • Kumar N
      • Crum B
      • Petersen RC
      • Vernino SA
      • Ahlskog JE
      Copper deficiency myelopathy.
      • Kumar N
      • Low PA
      Myeloneuropathy and anemia due to copper malabsorption.
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      • Kumar N
      • Crum BA
      • Ahlskog JE
      Copper deficiency myelopathy [abstract]?.
      it is unlikely that hyperzincemia is causative. No definite reports have been published of neurological toxicity due to hyperzincemia without hypocupremia in animals or humans. Elevated zinc levels have been described as a heritable anomaly with no clinical manifestations.
      • Smith JC
      • Zeller JA
      • Brown ED
      • Ong SC
      Elevated plasma zinc: a heritable anomaly.
      High doses of oral zinc have been administered long term in patients with Wilson disease with no development of neurological complications. The hyperzincemia seen in some patients with neurological manifestations and copper deficiency is probably a secondary feature associated with the hypocupremia.

      Associated Vitamin B12 Deficiency

      Some of the study patients had a history of vitamin B12 deficiency, most of whom had undergone gastric surgery. None of the patients had low vitamin B12 levels at the time the copper deficient state was diagnosed. The myelopathy of copper deficiency closely mimics the subacute combined degeneration of vitamin B12 deficiency.
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      Copper and vitamin B12 deficiency may coexist.
      • Willis MS
      • Monaghan SA
      • Miller ML
      • et al.
      Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination.
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      Patients may be given vitamin B12 despite normal serum vitamin B12 levels.
      • Schleper B
      • Stuerenburg HJ
      Copper deficiency-associated myelopathy in a 46-year-old woman.
      A similar spine MRI appearance can be seen in patients with vitamin B12 deficiency.
      • Katsaros VK
      • Glocker FX
      • Hemmer B
      • Schumacher M
      MRI of spinal cord and brain lesions in subacute combined degeneration.

      Clinical Features, Neurophysiology, and Neuroimaging in Copper Deficiency Myelopathy

      The clinical presentation of all the study patients was that of a gait difficulty primarily due to severe sensory ataxia. The sensory ataxia was primarily due to dorsal column dysfunction. At times, symptom onset was subacute. Clinical or electrophysiological evidence of a peripheral neuropathy was often present. Involvement of the peripheral nervous system was not the predominant reason for the sensory ataxia in any patient. The MRI and evoked potential studies provided additional evidence of posterior column dysfunction (Table 3, Figure 2, A and B). The most consistent finding on spine MRI is increased signal on T2-weighted images that involve the dorsal columns. The cervical cord is most commonly involved, and contrast enhancement is not present. Follow-up imaging was available in 1 patient (patient 17) and showed resolution of the dorsal column signal change with improvement in serum copper.
      • Kumar N
      • Ahlskog JE
      • Klein CJ
      • Port JD
      Imaging features of copper deficiency myelopathy: a study of 25 cases.
      Vitamin B12 deficiency and copper deficiency can coexist, and the ataxic myelopathy of copper deficiency can mimic the subacute combined degeneration seen with vitamin B12 deficiency.
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      Clioquinol, a copper-zinc chelating antibiotic, is the likely etiologic agent in subacute myelo-opticoneuropathy,
      • Konagaya M
      • Matsumoto A
      • Takase S
      • et al.
      Clinical analysis of longstanding subacute myelo-optico-neuropathy: sequelae of clioquinol at 32 years after its ban.
      and both copper deficiency myelopathy and myelo-opticoneuropathy are characterized by involvement of the dorsal column and corticospinal tracts. It is speculative whether copper deficiency could have been the proximate cause of myelo-opticoneuropathy.
      • Kumar N
      • Knopman DS
      SMON, clioquinol, and copper?.
      Table 5 details the salient features in some of the other described patients with neurological manifestations due to acquired copper deficiency.
      TABLE 5Clinical and Imaging Characteristics of Other Reported Patients With Neurological Manifestations Due to Acquired Copper Deficiency
      Symptom duration refers to duration of neurological symptoms before diagnosis of copper deficiency. MRI = magnetic resonance imaging,
      SourceAge (y)/sexSymptom durationNeurological manifestationsSerum copper at diagnosis (μg/dL)
      Reference range is shown parenthetically.
      Possible cause of copper deficiencySpine MRIBrain MRIAdditional observations
      Buchman et al
      • Buchman AL
      • Keen CL
      • Vinters HV
      • et al.
      Copper deficiency secondary to a copper transport defect: a new copper metabolic disturbance.
      21/M6 yAtaxia, peripheral neuropathy41 (70–155)Intestinal pseudo-obstruction and malnutritionNo informationIncreased intensity in white matter on T2-weighted brain MRINo increase in serum copper level despite parenteral copper administration
      Schleper et al
      • Schleper B
      • Stuerenburg HJ
      Copper deficiency-associated myelopathy in a 46-year-old woman.
      46/F18 moMyelopathy308 (760–1800)Gastric surgery, segmental colonic resectionHyperintense T2 signal involving the dorsomedial part of the cord from C1 to C7NormalElevated blood manganese level, normal serum zinc level
      Gregg et al
      • Gregg XT
      • Reddy V
      • Prchal JT
      Copper deficiency masquerading as myelodysplastic syndrome.
      44/FUnknownPeripheral neuropathy and optic neuritisUndetectableGastric surgeryNo informationNo informationMyelodysplastic syndrome
      Prodan et al
      • Prodan CI
      • Holland NR
      • Wisdom PJ
      • Burstein SA
      • Bottomley SS
      CNS demyelination associated with copper deficiency and hyperzincemia.
      (patient 1)
      45/F2 yBrisk reflexes, reduced vibratory sense in lower limbs, ataxic gait5 (70–155)Unknown, hyperzincemia presentNormalMultiple bilateral subcortical white matter lesions, predominantly frontal, consistent with demyelinationSplenomegaly, improved sensory symptoms with copper level normalization, further increase in serum zinc level
      Prodan et al
      • Prodan CI
      • Holland NR
      CNS demyelination from zinc toxicity?.
      • Prodan CI
      • Holland NR
      • Wisdom PJ
      • Burstein SA
      • Bottomley SS
      CNS demyelination associated with copper deficiency and hyperzincemia.
      (patient 2)
      45/M4 moSaccadic dysmetria, decreased feet vibratory and joint position sense, hyper-reflexia, truncal ataxiaUndetectableUnknown, hyperzincemia presentNo informationDemyelination involving the peri-ventricular regions, corpus callosum, and cerebellar pedunclesSignificant neuro-logical improvement with copper supplementation, persisting hyperzincemia
      Hedera et al
      • Hedera P
      • Fink JK
      • Bockenstedt PL
      • Brewer GJ
      Myelopolyneuropathy and pancytopenia due to copper deficiency and high zinc levels of unknown origin: further support for existence of a new zinc overload syndrome.
      46/M5 moMyeloneuropathy<10 (80–120)Unknown, hyperzincemia presentNormal3-mm area of increased T2 signal in the left centrum semiovaleImprovement with partial reversal of neurological signs
      Greenberg et al
      • Greenberg SA
      • Briemberg HR
      A neurological and hematological syndrome associated with zinc excess and copper deficiency.
      52/F2 yMyeloneuropathyUndetectable (>200)Unknown, hyperzincemia present (serum and urine)T2 hyper-intensity at T6-7NormalHistory of gluten-sensitive enteropathy controlled with diet
      Prodan et al
      • Prodan CI
      • Holland NR
      • Wisdom PJ
      • Bottomley SS
      Myelopathy due to copper deficiency.
      45/FUnknownMyelopathy“Markedly reduced”Unknown, no hyperzincemiaNo informationNo informationNo information
      Rowin et al
      • Rowin J
      • Lewis SL
      Copper deficiency myeloneuropathy and pancytopenia secondary to overuse of zinc supplementation.
      53/F4 moMyeloneuropathy7 (70–155)Hyperzincemia present, exogenous ingestionNormalNormalImproved gait and nerve conductions
      Willis et al
      • Willis MS
      • Monaghan SA
      • Miller ML
      • et al.
      Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination.
      47/M30 moPeripheral neuropathy8 (70–145)Hyperzincemia present, cause unknownNo informationNo informationNo neurological improvement
      Willis et al
      • Willis MS
      • Monaghan SA
      • Miller ML
      • et al.
      Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination.
      42/M8 moPeripheral neuropathy ingestionUndetectableHyperzincemia, exogenousNo informationNo informationNo neurological improvement
      Bartner et al
      • Bartner R
      • Will M
      • Conrad J
      • Engelhardt A
      • Schwarz-Eywill M
      Pancytopenia, arthralgia and myeloneuropathy due to copper deficiency [in German].
      71/F6 moAtaxic gait<100 (850–1900)Gastric surgery and possibly urinary copper loss due to glomerulo-nephritisHyperintensity dorsal part of cervical and thoracic cordNo informationNo neurological improvement
      * Symptom duration refers to duration of neurological symptoms before diagnosis of copper deficiency. MRI = magnetic resonance imaging,
      Reference range is shown parenthetically.
      Most of the noted areas of increased T2 signal on brain MRI in the study patients were nonspecific; however, the appearance and distribution of some of these lesions suggested lacunar disease. Neuropathological studies in Menkes syndrome have shown arterial tortuosity and fragmentation of the internal elastica in large arteries.
      • Danks DM
      • Campbell PE
      • Stevens BJ
      • Mayne V
      • Cartwright E
      Menkes's kinky hair syndrome: an inherited defect in copper absorption with widespread effects.
      Some of the pathological changes in the CNS in Menkes syndrome are likely due to vascular involvement. Experimental copper deficiency has been associated with aneurysmal dilation of large arteries and massive hemorrhage.
      • Everson GJ
      • Tsai HC
      • Wang TI
      Copper deficiency in the guinea pig.
      The possible role of acquired copper deficiency in cerebrovascular disease requires further study. Two described patients have had brain MRI findings that were believed to be consistent with demyelinating disease.
      • Prodan CI
      • Holland NR
      CNS demyelination from zinc toxicity?.
      • Prodan CI
      • Holland NR
      • Wisdom PJ
      • Burstein SA
      • Bottomley SS
      CNS demyelination associated with copper deficiency and hyperzincemia.
      The importance of the brain MRI findings requires further study. Neurophysiological studies show varying degrees of axonal peripheral neuropathy, at times predominantly motor. Abnormalities in somatosensory evoked potential studies indicating central conduction delay are common. Other reported electrophysiological abnormalities noted in patients with copper deficiency and neurological manifestations include prolonged visual evoked potentials
      • Prodan CI
      • Holland NR
      CNS demyelination from zinc toxicity?.
      and impaired central conduction on transcranial magnetic stimulation.
      • Schleper B
      • Stuerenburg HJ
      Copper deficiency-associated myelopathy in a 46-year-old woman.

      Associated Hematologic Manifestations

      A history of anemia or leukopenia or anemia or leukopenia at presentation was present in most of the study patients. It is being increasingly recognized that hematologic manifestations may not accompany the neurological syndrome.
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Myelopathy due to copper deficiency.
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      • Kumar N
      • Crum BA
      • Ahlskog JE
      Copper deficiency myelopathy [abstract]?.
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Myelopathy due to copper deficiency [reply to letter]?.
      The hematologic hallmark of copper deficiency is anemia and neutropenia.
      • Dunlap WM
      • James III, GW
      • Hume DM
      Anemia and neutropenia caused by copper deficiency.
      • Hoffman II, HN
      • Phyliky RL
      • Fleming CR
      Zinc-induced copper deficiency.
      • Tamura H
      • Hirose S
      • Watanabe O
      • et al.
      Anemia and neutropenia due to copper deficiency in enteral nutrition.
      • Nagano T
      • Toyoda T
      • Tanabe H
      • et al.
      Clinical features of hematological disorders caused by copper deficiency during long-term enteral nutrition.
      • Zidar BL
      • Shadduck RK
      • Zeigler Z
      • Winkelstein A
      Observations on the anemia and neutropenia of human copper deficiency.
      The anemia may be microcytic,
      • Prasad AS
      • Brewer GJ
      • Schoomaker EB
      • Rabbani P
      Hypocupremia induced by zinc therapy in adults.
      • Hoffman II, HN
      • Phyliky RL
      • Fleming CR
      Zinc-induced copper deficiency.
      • Gyorffy EJ
      • Chan H
      Copper deficiency and microcytic anemia resulting from prolonged ingestion of over-the-counter zinc.
      macrocytic,
      • Willis MS
      • Monaghan SA
      • Miller ML
      • et al.
      Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination.
      • Gregg XT
      • Reddy V
      • Prchal JT
      Copper deficiency masquerading as myelodysplastic syndrome.
      or normocytic.
      • Willis MS
      • Monaghan SA
      • Miller ML
      • et al.
      Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination.
      • Tamura H
      • Hirose S
      • Watanabe O
      • et al.
      Anemia and neutropenia due to copper deficiency in enteral nutrition.
      Thrombocytopenia and resulting pancytopenia are relatively rare.
      • Wasa M
      • Satani M
      • Tanano H
      • Nezu R
      • Takagi Y
      • Okada A
      Copper deficiency with pancytopenia during total parenteral nutrition.
      • Fuhrman MP
      • Herrmann V
      • Masidonski P
      • Eby C
      Pancytopenia after removal of copper from total parenteral nutrition.
      • Spiegel JE
      • Willenbucher RF
      Rapid development of severe copper deficiency in a patient with Crohn's disease receiving parenteral nutrition.
      A prolonged copper deficient state may be necessary for the development of thrombocytopenia.
      • Nagano T
      • Toyoda T
      • Tanabe H
      • et al.
      Clinical features of hematological disorders caused by copper deficiency during long-term enteral nutrition.
      Typical bone marrow findings include a left shift in granulocytic and erythroid maturation with cytoplasmicvacuolization in erythroid and myeloid precursors (Figure 2, C) and the presence of ringed sideroblasts (Figure 2, D).
      • Dunlap WM
      • James III, GW
      • Hume DM
      Anemia and neutropenia caused by copper deficiency.
      • Summerfield AL
      • Steinberg FU
      • Gonazlez JG
      Morphologic findings in bone marrow precursor cells in zinc-induced copper deficiency anemia.
      • Willis MS
      • Monaghan SA
      • Miller ML
      • et al.
      Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination.
      • Prodan CI
      • Holland NR
      CNS demyelination from zinc toxicity?.
      Hemosiderin-containing plasma cells (Figure 2, D) may be present.
      • Dunlap WM
      • James III, GW
      • Hume DM
      Anemia and neutropenia caused by copper deficiency.
      • Gregg XT
      • Reddy V
      • Prchal JT
      Copper deficiency masquerading as myelodysplastic syndrome.
      The bone marrow findings are not pathognomic but are highly characteristic, and reports have been published of patients in whom the diagnosis of the copper deficient state was first suggested by the bone marrow findings.
      • Willis MS
      • Monaghan SA
      • Miller ML
      • et al.
      Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination.
      Patients may be diagnosed as having sideroblastic anemia or myelodysplastic syndrome.
      • Fiske DN
      • McCoy III, HE
      • Kitchens CS
      Zinc-induced sideroblastic anemia: report of a case, review of the literature, and description of the hematologic syndrome.
      • Willis MS
      • Monaghan SA
      • Miller ML
      • et al.
      Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination.
      • Gregg XT
      • Reddy V
      • Prchal JT
      Copper deficiency masquerading as myelodysplastic syndrome.
      • Kumar N
      • Elliott MA
      • Hoyer JD
      • Harper Jr, CM
      • Ahlskog JE
      • Phyliky RL
      “Myelodysplasia,” myeloneuropathy, and copper deficiency.
      • Patterson WP
      • Winkelmann M
      • Perry MC
      Zinc-induced copper deficiency: megamineral sideroblastic anemia.
      • Simon SR
      • Branda RF
      • Tindle BF
      • Burns SL
      Copper deficiency and sideroblastic anemia associated with zinc ingestion.
      • Kumar A
      • Jazieh AR
      Case report of sideroblastic anemia caused by ingestion of coins.
      In one described patient with copper deficiency and hematologic abnormalities, a pretransplantation evaluation was considered, and treatment with blood transfusions, erythropoietin, and granulocyte colony-stimulating factors was given before copper deficiency was detected.
      • Gregg XT
      • Reddy V
      • Prchal JT
      Copper deficiency masquerading as myelodysplastic syndrome.
      Copper-containing enzymes likely play a role in cell differentiation and proliferation in the bone marrow. Impaired erythroid and myeloid maturation and reduced erythrocyte and neutrophil life spans are the likely reasons for the anemia and neutropenia.

      Treatment of Copper Deficiency

      No studies have addressed the most appropriate dose, duration, route, and form of copper supplementation. Little information is available on human copper stores. Serum copper may be inadequate for assessing total body copper stores, and activity of copper enzymes, such as erythrocyte superoxide dismutase and platelet or leukocyte cytochrome-c oxidase, may be a better indicator of metabolically active copper stores.
      • Uauy R
      • Castillo-Duran C
      • Fisberg M
      • Fernandez N
      • Valenzuela A
      Red cell superoxide dismutase activity as an index of human copper nutrition.
      • L'Abbe MR
      • Friel JK
      Copper status of very low birth weight infants during the first 12 months of infancy.
      • Milne DB
      Assessment of copper nutritional status.
      In patients with zinc-induced copper deficiency, discontinuing use of the zinc may suffice, and no additional copper supplementation may be required.
      • Willis MS
      • Monaghan SA
      • Miller ML
      • et al.
      Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination.
      • Simon SR
      • Branda RF
      • Tindle BF
      • Burns SL
      Copper deficiency and sideroblastic anemia associated with zinc ingestion.
      • Gyorffy EJ
      • Chan H
      Copper deficiency and microcytic anemia resulting from prolonged ingestion of over-the-counter zinc.
      At times, prolonged oral therapy may not result in improvement; parenteral therapy may be required, and elimination of excess zinc may be slow, and until such elimination occurs, the intestinal absorption of copper may be blocked.
      • Hoffman II, HN
      • Phyliky RL
      • Fleming CR
      Zinc-induced copper deficiency.
      Some investigators have used initial parenteral administration followed by oral administration.
      • Gregg XT
      • Reddy V
      • Prchal JT
      Copper deficiency masquerading as myelodysplastic syndrome.
      • Rowin J
      • Lewis SL
      Copper deficiency myeloneuropathy and pancytopenia secondary to overuse of zinc supplementation.
      Despite a suspected absorption defect, oral copper supplementation is generally the preferred route of supplementation. Copper supplements may not be adequately absorbed when administered through a jejunostomy tube, necessitating parenteral therapy.
      • Jayakumar S
      • Micallef-Eynaud PD
      • Lyon TD
      • Cramb R
      • Jilaihawi AN
      • Prakash D
      Acquired copper deficiency following prolonged jejunostomy feeds.
      Studies of yeast have shown that the copper transport pathways are high-affinity pathways active in conditions of low copper concentration, and increasing the concentration of copper may result in the pathways being bypassed.
      • Valentine JS
      • Gralla EB
      Delivering copper inside yeast and human cells.
      This may explain why in most of the current study patients normal serum copper levels were achieved by increasing the amount of copper ingested. Oral administration of 2 mg/d of elemental copper seems sufficient. A comparable dose of elemental copper may be given intravenously. Doses as high as 9 mg/d orally have been used.
      • Gregg XT
      • Reddy V
      • Prchal JT
      Copper deficiency masquerading as myelodysplastic syndrome.
      • Hedera P
      • Fink JK
      • Bockenstedt PL
      • Brewer GJ
      Myelopolyneuropathy and pancytopenia due to copper deficiency and high zinc levels of unknown origin: further support for existence of a new zinc overload syndrome.
      • Bartner R
      • Will M
      • Conrad J
      • Engelhardt A
      • Schwarz-Eywill M
      Pancytopenia, arthralgia and myeloneuropathy due to copper deficiency [in German].
      Commonly used copper salts include copper gluconate
      • Bartner R
      • Will M
      • Conrad J
      • Engelhardt A
      • Schwarz-Eywill M
      Pancytopenia, arthralgia and myeloneuropathy due to copper deficiency [in German].
      and copper chloride.
      • Gregg XT
      • Reddy V
      • Prchal JT
      Copper deficiency masquerading as myelodysplastic syndrome.
      The oral bioavailability of copper gluconate may be limited.
      • Pratt WB
      • Omdahl JL
      • Sorenson JR
      Lack of effects of copper gluconate supplementation.
      Currently, my colleagues and I at the Mayo Clinic give 6 mg/d of elemental copper orally for a week, 4 mg/d for the second week, and 2 mg/d thereafter. Periodic assessment of serum copper is essential to determine adequacy of replacement and the most appropriate long-term administration strategy. Because of the need for long-term replacement, parenteral therapy is not preferred and is generally not required. If required, a daily dose of 2 mg of elemental copper may be administered intravenously for 5 days periodically thereafter.
      Response of the hematologic parameters (including bone marrow findings) is prompt and often complete.
      • Fiske DN
      • McCoy III, HE
      • Kitchens CS
      Zinc-induced sideroblastic anemia: report of a case, review of the literature, and description of the hematologic syndrome.
      • Willis MS
      • Monaghan SA
      • Miller ML
      • et al.
      Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination.
      • Gregg XT
      • Reddy V
      • Prchal JT
      Copper deficiency masquerading as myelodysplastic syndrome.
      • Greenberg SA
      • Briemberg HR
      A neurological and hematological syndrome associated with zinc excess and copper deficiency.
      • Prasad AS
      • Brewer GJ
      • Schoomaker EB
      • Rabbani P
      Hypocupremia induced by zinc therapy in adults.
      • Wasa M
      • Satani M
      • Tanano H
      • Nezu R
      • Takagi Y
      • Okada A
      Copper deficiency with pancytopenia during total parenteral nutrition.
      • Tamura H
      • Hirose S
      • Watanabe O
      • et al.
      Anemia and neutropenia due to copper deficiency in enteral nutrition.
      • Zidar BL
      • Shadduck RK
      • Zeigler Z
      • Winkelstein A
      Observations on the anemia and neutropenia of human copper deficiency.
      Hematologic recovery may be accompanied by reticulocytosis.
      • Greenberg SA
      • Briemberg HR
      A neurological and hematological syndrome associated with zinc excess and copper deficiency.
      • Takeuchi M
      • Tada A
      • Yoshimoto S
      • Takahashi K
      Anemia and neutropenia due to copper deficiency during long-term total parenteral nutrition [in Japanese].
      • Tamura H
      • Hirose S
      • Watanabe O
      • et al.
      Anemia and neutropenia due to copper deficiency in enteral nutrition.
      • Zidar BL
      • Shadduck RK
      • Zeigler Z
      • Winkelstein A
      Observations on the anemia and neutropenia of human copper deficiency.
      Transient improvement with hematopoietic growth factors may occur even if copper deficiency is the cause of the hematologic manifestations.
      • Gregg XT
      • Reddy V
      • Prchal JT
      Copper deficiency masquerading as myelodysplastic syndrome.
      • Kumar N
      • Elliott MA
      • Hoyer JD
      • Harper Jr, CM
      • Ahlskog JE
      • Phyliky RL
      “Myelodysplasia,” myeloneuropathy, and copper deficiency.
      Recovery of neurological signs and symptoms seen in association with copper deficiency varies. Improvement in neurological symptoms is variable, although progression is typically halted.
      • Willis MS
      • Monaghan SA
      • Miller ML
      • et al.
      Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination.
      • Prodan CI
      • Holland NR
      • Wisdom PJ
      • Burstein SA
      • Bottomley SS
      CNS demyelination associated with copper deficiency and hyperzincemia.
      • Greenberg SA
      • Briemberg HR
      A neurological and hematological syndrome associated with zinc excess and copper deficiency.
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.
      • Kumar N
      • Crum BA
      • Ahlskog JE
      Copper deficiency myelopathy [abstract]?.
      A relapse in the copper deficient state may not be necessarily accompanied by neurological deterioration.
      • Prodan CI
      • Holland NR
      • Wisdom PJ
      • Burstein SA
      • Bottomley SS
      CNS demyelination associated with copper deficiency and hyperzincemia.
      Improvement when present is often subjective and preferentially involves sensory symptoms.
      • Schleper B
      • Stuerenburg HJ
      Copper deficiency-associated myelopathy in a 46-year-old woman.
      • Prodan CI
      • Holland NR
      • Wisdom PJ
      • Burstein SA
      • Bottomley SS
      CNS demyelination associated with copper deficiency and hyperzincemia.
      • Kumar N
      • McEvoy KM
      • Ahlskog JE
      Myelopathy due to copper deficiency following gastrointestinal surgery.
      There are some reports of definite improvement in the neurological deficits,
      • Prodan CI
      • Holland NR
      CNS demyelination from zinc toxicity?.
      • Hedera P
      • Fink JK
      • Bockenstedt PL
      • Brewer GJ
      Myelopolyneuropathy and pancytopenia due to copper deficiency and high zinc levels of unknown origin: further support for existence of a new zinc overload syndrome.
      • Rowin J
      • Lewis SL
      Copper deficiency myeloneuropathy and pancytopenia secondary to overuse of zinc supplementation.
      nerve conduction studies,
      • Rowin J
      • Lewis SL
      Copper deficiency myeloneuropathy and pancytopenia secondary to overuse of zinc supplementation.
      evoked potential studies,
      • Kumar N
      • Gross Jr, JB
      • Ahlskog JE
      Myelopathy due to copper deficiency.
      and MRI T2 cord signal change
      • Kumar N
      • Ahlskog JE
      • Klein CJ
      • Port JD
      Imaging features of copper deficiency myelopathy: a study of 25 cases.
      with normalization of serum copper.

      CONCLUSION

      I believe that myelopathy due to acquired copper deficiency in adults is an underrecognized syndrome. Estimation of serum copper levels should be a part of the work-up in patients with myelopathy or myeloneuropathy, particularly in those with a high risk of developing copper deficiency. Hematologic manifestations such as anemia or neutropenia are often but not always present. The presence of unexplained cytopenia in association with neurological manifestations should prompt clinicians to look for copper deficiency. The clinical picture resembles the subacute combined degeneration seen with vitamin B12 deficiency. The 2 conditions can coexist. Continued neurological deterioration in patients with a history of vitamin B12 deficiency-related myelopathy who have a normal vitamin B12 level while receiving vitamin B12 replacement therapy should be evaluated for copper deficiency. Exogenous zinc ingestion, prior gastric surgery, prematurity, malnutrition, parenteral alimentation, and malabsorption are the commonly recognized risk factors for the copper deficient state. Often, the cause of copper deficiency is unknown. Hyperzincemia may be present even in the absence of exogenous zinc supplementation. Somatosensory evoked potential studies may show delay in central conduction. Variable degrees of peripheral neuropathy may be seen on nerve conduction studies. Spine MRI may show a dorsal paramedian cord signal hyperintensity on T2-weighted images. The hematologic manifestations reverse promptly with copper replacement. Early recognition and prompt treatment may prevent significant neurological morbidity.
      It is unclear which patients may develop copper deficiency after gastric surgery and if routine screening and supplementation should be considered as is commonly done in these patients for vitamin B12 deficiency. Given the increasing rates of bariatric surgery, this is a particularly pertinent issue. The copper deficient state may not manifest for decades. The role of the commonly observed hyperzincemia in the absence of exogenous zinc ingestion is unclear. The association between copper deficiency and CNS demyelination, isolated peripheral neuropathy, and optic neuritis requires further study. Studies are needed to determine the best dose, route, and duration of copper therapy. Further understanding of copper transport and trafficking may provide insights into the cause of copper deficiency in those with idiopathic hypocupremia.

      ADDENDUM

      Three additional patients with copper deficiency myelopathy and prior gastric surgery were recently described.
      • Wu J
      • Ricker M
      • Muench J
      Copper deficiency as cause of unexplained hematologic and neurologic deficits in patient with prior gastrointestinal surgery.
      • Prodan CI
      • B