Table 1.
Summary of case reports analyzing copper deficiency in patients with Wilson’s disease.
| Reference | Patient | Details of WD | Symptoms and Signs of CD | CD Treatment | Outcome |
|---|---|---|---|---|---|
| Ueda et al., 2022 [24] | 57-year-old man with neurological WD diagnosed aged 20 | Initially on DPA 1000 mg/day and ZA 80 mg/day; ZA increased to 150 mg/day due to neurological progression (dysphagia with gastrostomy) Cu metabolism at CD diagnosis: Cp: 5.5 mg/dL Serum Cu: 11 µg/dL Urinary Cu excretion: 74 µg/24 h |
Moderate distal weakness, hypotonia, absent tendon reflexes, sensory ataxia and severe sensory disturbances in all 4 limbs (numbness and paresthesia) Severe sensory motor polyneuropathy (EDX) Myelopathy in cervical MRI in posterior cord Anemia (Hgb 6.9 g/dL) |
ZA and DPA cessation for 9 months, with increased Cu intake to 1.67 mg/day DPA introduced thereafter |
Partial recovery after 3 months Dysesthesias reduced; about 40% improvement in gait MRI changes in spinal cord persisted Anemia stopped progressing (Hgb 9.3 g/dL after 3 weeks and 10.8 g/dL after 3 months) Cu metabolism: N/A |
| Wu et al., 2020 [20] | 18-year-old woman with neurological WD diagnosed aged 17 | Initial 1 year on DPA and TN but stopped due to ADR(skin rash after DPA, abdominal pain after TN). ZS initiated at 150 mg/day, increased to 225 mg/day Cu metabolism at CD diagnosis: Cp and serum Cu: N/A Urinary Cu excretion: “low” |
Distal weakness of both legs, sensory disturbances of legs, falls Axonal sensory neuropathy (EDX) and abnormal SSEPs Myelopathy in thoracic MRI in posterior cord Hematology N/A |
ZS cessation with Cu supplementation 10 mg/day for 6 months | Complete recovery after 6 months Complete resolution of neuropathy and myelopathy (no follow-up MRI provided) Cu metabolism: N/A |
| Cai et al., 2019 [23] | 12-year-old female with presymptomatic WD diagnosed aged 7 (abnormal LFTs that normalized during WD treatment) | ZG (150 mg elemental zinc), increased to 240 mg at age 8 due to initially increased LFT Cu metabolism at CD diagnosis: Cp: N/A Serum Cu: 12.7 µg/dL Urinary Cu excretion: 30 µg/24 h |
Abnormal gait (no details) Brain MRI normal, spine MRI rejected by patient Anemia (Hgb 4.0 g/dL; RBC 1.37 M/µL), leukopenia (WBC 1.5 K/µL) and neutropenia (0.08 K/µL) |
Temporary ZG cessation, blood transfusion | Complete recovery Gait disturbance subsided Hgb started to increase after 1 week, with normalization after 8 months (Hgb 11.7 g/dL, RBC 5.28 M/µL) Cu metabolism: N/A |
| Mohamed et al., 2018 [22] | 26-year-old woman with neurological WD diagnosed aged 13 | ZS 200 mg/day of elemental zinc, increased to 240 mg due to initially increased LFT Cu metabolism at CD diagnosis: Cp: 2 mg/dL Serum Cu: <0.1 µmol/L Urinary Cu excretion: N/A |
Bone marrow biopsy: moderate dyserythropoiesis with defects in maturation Spine MRI and SSEPs not undertaken Anemia (as above), leukopenia (WBC 1.2 K/µL) and neutropenia (0.2 K/µL) |
Temporary ZS cessation and supplementation Cu gluconate 2 mg/day After 8 months, ZS at 50% dose planned |
Complete recovery Hgb normalization after 4 months (Hgb 12.2 g/dL, neutrophil 2.5 K/µL) Serum Cu 1 µmol/L at 8 months |
| Dzieżyc et al., 2014 [19] | 37-year-old asymptomatic woman diagnosed aged 21 (family screening) | 16 years on ZS 180 mg/day Cu metabolism at CD diagnosis: Cp: 0.92 mg/dL Serum Cu: <5 µg/dL Urinary Cu excretion: 11 µg/24 h |
Paresthesias in fingers and toes for 3 months, weakness in lower limbs during fast walking Posterior column of the cervical cord (C2-Th1) myelopathy in spine MRI Myelopathy (few low-amplitude short-duration motor unit [EDX]) Leukopenia (WBC 2.9 K/µL) |
ZS cessation for 9 months, DPA introduced later | CD symptoms disappeared after 6 months EDZ normalization; SSEPs abnormalities remained in dorsal column Improved WBC (6.0 K/µL) Cp: 5 mg/dL Serum Cu: 20 µg/dL Urinary Cu excretion: 12.5 µg/24 h |
| 46-year-old man with hepatic WD diagnosed aged 41 (compensated liver failure) | 5 years on ZS (180 mg/day) Cu metabolism at CD diagnosis: Cp: 0.5 mg/dL Serum Cu: <5 µg/dL Urinary Cu excretion: 6 µg/24 h |
Upper respiratory tract infections Leukopenia (WBC 1.86 K/µL) Neutropenia (neutrophils 0.89 × 109/L) |
Decreased ZS dose to 135 mg/day and further treat WD with decreased dose of ZS (with close follow-up) | Complete recovery after 12 months Improved hematology (WBC 3.3 K/µL; neutrophils 2.0 × 109/L) Cp: 1.18 mg/dL Serum Cu: 5 µg/dL Urinary Cu excretion: 10.5 µg/24 h |
|
| 18-year-old woman with presymptomatic WD diagnosed aged 12 (family screening) | 6 years on ZS (180 mg/day) Cu metabolism at CD diagnosis: Cp: 0.9 mg/dL Serum Cu: 7 µg/dL Urinary Cu excretion: 12 µg/24 h |
Anemia (RBC 3.2 M/µL) Leukopenia (WBC 2.3 K/µL) Neutropenia (neutrophils 0.17 × 109/L) SSEPs: impaired conduction in spinal dorsal column (refused MRI) |
Cessation of ZS for 2 months initially (later for longer 1-year period) | Complete recovery after 1 year Improved hematology (WBC 7.3 K/µL; neutrophils: 5.1 × 109/L) Cp: 17 mg/dL Serum Cu: 44 µg/dL Urinary Cu excretion: 10 µg/24 h |
|
| Rau et al., 2014 [21] | 16-year-old male diagnosed aged 14 (form not provided) | 1 year on DPA then switched to ZS (dose not described) due to anemia and neutropenia Cu metabolism at CD diagnosis: Cp: <2 mg/dL Serum Cu: 31 µg/dL Urinary Cu excretion: 32 µg/24 h |
Anemia (Hgb 5.8 g/dL; RBC 1.9 M/µL) Leukopenia (WBC 1.4 × 109) Neutropenia (0.46 × 109/L) SSEPs, EDX, MRI of spine not undertaken |
Cessation of ZS for 1 year, Cu supplementation 2.5 mg/day for a few months, DPA introduced later slowly | Complete recovery after 8 weeks: Improved hematology (Hgb 13.6 g/dL, RBC 5.3 M/µL, WBC 6.3 K/µL, neutrophils 3.23 × 109/L Serum Cu: 63 µg/dL Cp and urinary Cu excretion: N/A |
| Kaleagasi et al., 2013 [28] | 29-year-old patient (details not described) | Treatment with DPA and ZA (dose not known) Cu metabolism at CD diagnosis: Serum Cu: 0.3 µg/dL Cp and urinary Cu excretion: N/A |
Recurrent seizures, complex partial seizures and secondary generalized seizures Hematology, SSEPs and MRI of head and spine not undertaken |
ZA and DPA stopped and low Cu diet introduced | Complete recovery Seizures frequency decreased Serum Cu: 16 µg/dL Cp and urinary Cu excretion: N/A |
| Teodoro et al., 2013 [18] | 36-year-old man with neurological WD diagnosed aged 20 | 16 years on ZS 150 mg/day and TN 500 mg/day (few years on DPA 600 mg/day instead of TN due to lack of TN complicated by nephrotic syndrome, then TN and ZS 330 mg/day) Cu metabolism at CD diagnosis: Cp: 3 mg/dL Serum Cu: 13.3 µg/dL Urinary Cu excretion: 41 µg/24 h |
Numbness of both hands and feet and gait worsening with falls Posterior dorsal cord myelopathy (in spine MRI) Mixed sensory/motor peripheral neuropathy (EDX) Hematology and SSEPs not undertaken |
TN and ZS were substituted by ZA 100 mg/day, which was progressively reduced and stopped due to persistent CD After 1 year ZA 150 mg/day reintroduced |
Partial improvement at 1 year Improvement in gait without support, improvement in electrophysiological assessment of neuropathy Myelopathy decreased in MRI Cp and serum Cu: N/A Urinary Cu excretion: 97 µg/24 h |
| Lozano Herrero et al., 2012 [17] | 56-year-old woman with hepatic WD diagnosed aged 18 | 28 years with DPA 750 mg/day, last 10 years on ZA 503 mg (150 mg elemental zinc) Cu metabolism at CD diagnosis: Cp: undetectable Serum Cu: 3 µg/dL Urinary Cu excretion: undetectable |
Slowly progressive unstable gait with paresthesia of hands and feet Myelopathy in cervical cord C2-C7 in MRI EDX normal, abnormal SSEPs Anemia (Hgb 11.3 g/dL) Neutropenia (neutrophils 0.7 × 109/L) |
ZA cessation and Cu supplementation (later ZA slowly introduced at low dose) | Minimal improvement during first few months Cp: 12.3 mg/dL Serum Cu: 36 µg/dL Urinary Cu excretion: 46 µg/24 h |
| Cortese et al., 2011 [15] | 51-year-old woman with neurological WD diagnosed aged 19 | 32 years of treatment, initially on DPA, then switched to ZS 600 mg/day (elemental zinc unknown) due to hyperintense reaction polyadenopathy Cu metabolism at CD diagnosis: Cp: N/A Serum Cu: 5 µg/dL Urinary Cu excretion: 20 µg/24 h |
Distal limb paresthesia, sensory loss, and gait disturbances Sensory motor peripheral polyneuropathy (EDX) SSEPs and MRI of spinal cord normal Anemia (Hgb 6.5 g/dL) Neutropenia (neutrophils 0.25 × 109/L) |
ZS reduction to 600 mg/day initially and substituted by ZA 150 mg/day (not data according to elemental zinc) and blood transfusions | Improvement in cytopenia and anemia without effect on neuropathy Cp: N/A Serum Cu: 64 µg/dL Urinary Cu excretion: 42 µg/24 h |
| Da Silva-Junior et al., 2011 [16] | 44-year-old woman with neurological WD diagnosed aged 29 (complete resolution of neurological symptoms in 1 year) | 15 years of treatment, initially on DPA but stopped due to ADR, then on ZA 450 mg/day (elemental zinc not known) Cu metabolism at CD diagnosis: Cp: 8 mg/dL Serum Cu: 3 µg/dL Urinary Cu excretion: 7.4 µg/24 h |
Progressive numbness of feet, then also arms Peripheral sensory neuropathy Spinal cord myelopathy C1-C6 Leukopenia (WBC 2.7 × 109/L) |
ZA cessation | Symptoms stabilized (partial improvement) 4 months later Serum Cu: 37 µg/dL CP and urinary Cu excretion: N/A |
| Benbir et al., 2010 [14] | 21-year-old man with neurological WD diagnosed aged 16 | 5 years on DPA 1200 mg/day and ZA 100 mg/day (180 mg/day) Cu metabolism at CD diagnosis: Cp: N/A Serum Cu: 2.2 µg/dL Urinary Cu excretion: 165 µg/24 h |
Status epilepticus with partial seizures Epileptiform activity on EEG Lack of hematology results |
Cessation of DPA and ZA, high Cu diet (discharged home on ZA only) Anti-convulsant treatment (levetiracetam and diazepam) |
Complete seizures did not re-occur Serum Cu: 13.7 µg/dL CP and urinary Cu excretion: N/A |
| Horvath et al., 2010 [13] | 41-year-old man diagnosed with neurological WD aged 25 | On DPA but stopped after 6 months due to ADR, then on ZS (200 mg elemental zinc) for 14 years; increased to 245 mg for 1 year due to fatigue and agitation (CD symptoms) Cu metabolism at CD diagnosis: Cp: 2 g/dL Serum Cu: 0.1 µmol/L Urinary Cu excretion: 0.4 µmol/24 h |
Gait disturbances, fatigue Anemia (Hgb 7.8 g/dL) Leukopenia (WBC 2.1 × 109/L) Neutropenia (neutrophils 0.26 × 109/L) Axonal sensory peripheral polyneuropathy with distal amyotrophy (EDX) Abnormal SSEPs MRI of spine normal |
Cessation of ZS | Complete resolution of hematological changes in 10 months Polyneuropathy persisted at 1 year follow-up Cp: 0.02 g/L Serum Cu: 0.27 µmol/L Urinary Cu excretion: 0.35 µmol/24 h |
| Foubert-Samier et al., 2009 [12] | 43-year-old man diagnosed with neurological WD aged 15 | 18 years on TN up to 900 mg/day and ZA 400 mg/day (elemental zinc not known) Cu metabolism at CD diagnosis: Cp: <1 mg/dL Serum Cu: 0.5 µmol/L Urinary Cu excretion: 1.7 µmol/24 h |
Distal limb weakness Sensory motor peripheral axonal neuropathy (EDX) Anemia (Hgb 10.6 g/dL) Neutropenia (neutrophils 0.95 × 109/L) |
Cessation of ZA, and decreased TN dose (300 mg/day) then increased to 900 mg/day | Anemia and neutropenia disappeared Neuropathy persisted at 2-year follow-up Cu metabolism: N/A |
| Narayan et al., 2006 [11] | 13-year-old male with neurological WD diagnosed aged 9 | 4 years on DPA 750 mg/day and ZS 280 mg/day (elemental zinc not known) Cu metabolism at CD diagnosis: Cp: 2.34 mg/dL Serum Cu: 16 µg/dL Urinary Cu excretion: N/A |
Sensory disturbances in legs (decreased vibratory on joints) Anemia (no results provided) Demyelination in brain CT (white matter tracts) |
Not provided | Not provided |
| Karunajeewa et al., 1998 [29] | 44-year-old man with neurological WD diagnosed aged 21 | Initially on DPA 1000 mg/day, reduced to 500 mg/day due to leukopenia after 6 months. Then on TN for 2 years, switched to DPA with ZS for 11 years. Switched to TH 200 mg/day and ZS 440 mg/day (elemental zinc not known) Cu metabolism at CD diagnosis: Cp: 2 mg/dL Serum Cu: 2 µmol/L Urinary Cu excretion: 0.1 µmol/24 h |
Anemia (Hgb 50 g/dL) Leukopenia (WBC 1 K/µL) Neutropenia (0.36 × 109/L) Bone marrow biopsy showed marked hypoplasia |
ZS and TH cessation for 9 months, filgrastim commenced, neutropenia disappeared, then reintroduction of TH 50 mg/day after 8 months | After 4 weeks: improved hematology (Hgb 11.6 g/dL; WBC 4.4 K/µL) Bone marrow biopsy showed mild hypocellularity and left shifted granulopoiesis Cu metabolism: N/A |
| Karunajeewa et al., 1998 [29] | 34-year-old woman with hepatic WD diagnosed aged 17 | On DPA 2000 mg/day initially. After splenectomy, increased to 2500 mg/day for 8 years due to excessive Cu liver deposition; switched to TH 200 mg/day Cu metabolism: N/A |
Anemia (Hgb 7.1 g/dL) Neutropenia (neutrophils 0.35 × 109/L) Low Cu levels in liver biopsy: 46 µg/g |
TH cessation for 4 weeks, reintroduced at lower dose of 50 mg/day | After 4 weeks: improved hematology (Hgb 11.5 g/dL, neutrophils 4.9 × 109/L) Cu metabolism: N/A |
| Van Den Hamer & Hoogenrad 1989 [10] | 56-year-old patient diagnosed aged 25 | 31 years of treatment, initially on DPA then switched to ZS 1200 mg/day (elemental zinc not known). CD occurred 2 years after switch Cu metabolism at CD diagnosis: Serum Cu: 0.05 µg/mL Cp and urinary Cu excretion: N/A |
Anemia with neutropenia | Parenteral Cu supplementation | Complete recovery Normalization of hematology in a few days Cu metabolism: N/A |
ADR = adverse drug reaction; CD = copper deficiency; Cp = ceruloplasmin; Cu = copper; DPA = d-penicillamine; EDX = electrodiagnostic testing, including nerve conduction studies and needle electromyography; EEG = electroencephalogram; Hgb = serum hemoglobin; LFT = liver function test; MRI = magnetic resonance imaging; N/A = not available; RBC = red blood cells; SSEPs = somatosensory evoked potentials; TN = trientine; TH = tetrathiomolybdate; WBC = white blood cells; WD = Wilson’s disease; ZA = zinc acetate; ZG = zinc gluconate; ZS = zinc sulphate.