AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Wilson disease, or hepatolenticular degeneration, is a neurodegenerative disease of copper metabolism. In 1912, Wilson first described it as a familial disorder associated with neurologic symptoms and cirrhosis. In 1956, Walshe first treated patients with the chelating agent penicillamine.

Although the animal models are not human equivalents of Wilson disease, they are helpful in studying copper metabolism and potential treatments. The Bedlington terrier has an autosomal recessive inherited disease characterized by copper toxicosis.¹ The Bedlington terrier does not develop neurologic symptoms, but its liver pathology is similar to that of Wilson disease. Canine copper toxicosis is caused by a mutation of the MURR1 gene, which is also believed to be essential for copper excretion. The MURR1 gene is downstream of the gene that causes Wilson disease.

The Long Evans Cinnamon (LEC) rat and toxic milk mouse both develop autosomal recessive inherited diseases associated with copper overload. LEC rats are reported to develop neurologic symptoms, though hemolysis and hepatitis are the usual presenting symptoms. However, the liver histologic findings in the LEC rats and toxic milk mice are substantially different from those of Wilson disease.

Tetrathiomolybdate (TM) was initially developed to treat chronic nutritional copper poisoning in sheep and is now used for Wilson disease. The Menkes disease gene (MNK) was cloned in January 1993 and identified as a P-type adenosine triphosphatase (ATPase), which led to the identification of the Wilson disease gene (WND) at the end of 1993.

Pathophysiology

Wilson disease involves loss of the ability to export copper from the liver into bile and to incorporate copper into hepatic ceruloplasmin. As a consequence, copper accumulates in the liver, brain, kidney, and cornea. The gene for Wilson disease encodes a cation-transporting P-type ATPase with 14 domains: 6 copper binding, 4 transmembrane, 1 phosphatase, 1 transduction, 1 phosphorylation, and 1 adenosine triphosphate (ATP) binding. About 24.6% of all mutations involve the ATP-binding domain.

A patient with a mutation causing a deletion of transmembrane domain 8 and entire the C-terminal cytoplasmic tail was reported to have liver disease and Kayser-Fleisher rings without neurologic symptoms. The Menkes and Wilson genes have 55% identity in amino acids. The Menkes and Wilson ATPases use common biochemical mechanisms, but their tissue-specific expression differs. The ATPase affected in Wilson disease, ATP7B, is predominantly in the liver and transports copper in the hepatocyte, allowing for the incorporation of copper into ceruloplasmin and its subsequent excretion into the bile. This is the only important pathway for copper removal.

ATP7B, also known as Wilson disease protein or WNDP, delivers copper to ferroxidase ceruloplasmin in Purkinje neurons. WNDP is active during development and adulthood but seems to be downregulated with age. About 58.2% of mutations in the Wilson disease gene are missense mutations, 27% are small deletions or insertions, 7.4% are splice-site mutations, and 7.4% are nonsense mutations. Of the point mutations in Wilson disease, 58.2% are missense mutations, 7.4% are at the splice site, 7.4% are nonsense and 27% are small insertions and/or deletions. Individuals in the same family who have the same genetic mutation in ATP7B may have different phenotypes.

Accumulation of copper in the cytoplasm of hepatocytes results in cellular necrosis and leakage of copper into the plasma. The excess copper then collects in extrahepatic tissues, including the basal ganglia and the limbus of the cornea. All copper-transporting ATPases have a histidine residue in the large cytoplasmic loop, adjacent to the ATP-binding domain. The histidine residue is essential for function, and it is the most common mutation in Wilson disease. The Wilson protein is synthesized as a single-chain polypeptide and is localized to the trans-Golgi network of cells.

ATP7B transports copper into the secretory pathway of the cell for incorporation into the cuproenzymes and excretion from the cell. An increase in the intracellular copper level causes ATP7B to move to a cytoplasmic vesicular compartment. As the copper is concentrated into vesicles for excretion from the cell, the cytosolic copper concentration decreases, and ATP7B returns to the trans-Golgi network. The movement of ATP7B appears to involve amino acid sequences in its carboxyl terminus. The copper concentration is higher in brains of people with Wilson disease than in other people or animals with diseases of copper overload.

Frequency

International

Incidence is 1 in 35,000-100,000 live births, with a gene frequency of 0.56%; the incidence in Sardinia may be higher.

Mortality/Morbidity

• After patients become symptomatic, Wilson disease is lethal if untreated.
• Patients who present with fulminant liver failure have a mortality rate as high as 70%.

Age

• The onset of liver disease is usually at the age of 8-16 years.
• Neurologic symptoms are rare before the age of 12 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Liver disease is the most common initial manifestation in children.
• Older individuals often present with neuropsychiatric symptoms.
• About 40-50% of patients present with liver disease, and 35-50%, with neurologic or psychiatric symptoms.
• KF rings are almost always present when the patient has neurologic symptoms.
• Wilson disease can be divided into 4 stages: presymptomatic, symptomatic, symptomatic but treated, and maintenance.

Physical

• Neurologic signs
• • Parkinsonian symptoms - Rigidity, bradykinesia
  • Dysarthria
  • Tremor at rest or with action
  • Dystonia mainly of the face
  • Dysdiadochokinesia
  • Poor handwriting
  • Incoordination
  • Abnormal eye movements
  • Respiratory dyskinesia which can present as an unusual cough
  • Polyneuropathy (may be initial manifestation and reversible with treatment)
• Psychiatric signs
• • Hyperkinetic behavior
  • Irritability or anger
  • Emotional lability
  • Psychosis
  • Mania
  • Difficulty concentrating
  • Abnormal behavior
  • Personality changes
  • Depression
  • Schizophrenia
• Skeletal abnormalities
• • Osteoporosis
  • Osteomalacia
  • Chondrocalcinosis
  • Osteoarthritis
  • Joint hypermobility
• Ophthalmic findings
• • KF rings are greenish yellow or brown rings seen at the limbus of the cornea. They are best seen on slitlamp examination and usually progress from just the superior pole to both the superior and inferior poles and then finally to a full circle. They may not be present in children or other individuals without neurologic symptoms.
  • Sunflower cataracts are brilliantly multicolored and visible only by slitlamp examination. They do not impair vision.
  • Other relatively uncommon findings include exotropic strabismus, optic neuritis or pallor of the optic disc, and nightblindness.
• Other physical findings
• • Azure lunulae of the fingernails
  • Arthropathy

Causes

Wilson disease is an autosomal recessive inherited condition caused by mutations or deletions of the ATP7B protein encoded by chromosome subbands 13q14.3-q 21.1. This gene encodes a 1411–amino acid protein that is a P-type ATPase. The gene is found predominantly in liver, kidney, and placenta but also in the heart, brain, lung, muscle, and pancreas. The most common genetic mutations are single–base pair changes or frame-shift mutations due to small deletions. On occasion, splicing errors are found. Genetic testing may be helpful in diagnosing the disease in a patient's asymptomatic relatives, but it has not replaced the traditional laboratory studies because of the large number (>200) of mutations that have been identified.

About 95% of serum copper is bound to ceruloplasmin. The serum ceruloplasmin level is usually low in Wilson disease, not because copper levels affect the synthesis of apoceruloplasmin but because the half-life of apoceruloplasmin decreases from 4-5 days to 4-5 hours in the absence of copper. The copper in liver cells is not excreted and is thought to cause oxyradical damage.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Drug-induced parkinsonism

Neuroleptics
Antiemetics - Metoclopramide (Reglan)
Antihypertensives - Verapamil (Calan), methyldopa (Aldomet), reserpine (Serpasil)
Flunarizine
Lovastatin (Mevacor)
Amiodarone
Cytosine arabinoside

Toxin-induced parkinsonism

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
Carbon monoxide poisoning
Cyanide poisoning
Manganese poisoning
Industrial chemical toxicity - Diquat, carbon disulfide, methanol, N-hexane, lacquer thinners

Miscellaneous conditions

Vascular parkinsonism
Structural lesions
Hydrocephalus
Metabolic parkinsonism - Hypothyroidism, hyperthyroidism, hypoparathyroidism
Posttraumatic parkinsonism - Dementia pugilistica
Hemiatrophy hemiparkinsonism
Postencephalitic parkinsonism

Differential diagnosis for pigmented corneal rings

Carotenemia arcus senilis
Chronic active hepatitis
Chronic cholestasis
Chronic jaundice
Cryptogenic cirrhosis
Intraocular foreign body with <85% copper (if >85%, severe suppurative inflammatory reaction usually present)
Multiple myeloma
Primary biliary cirrhosis
Topical copper solution treatment of the eye
Trypanosomiasis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Need for correlation: No one test is completely reliable. The diagnosis depends on a high index of suspicion and supporting laboratory abnormalities.
• Proposed diagnostic criteria: At the 8th international meeting on Wilson and Menkes disease in Leipzig, Germany in 2001, the following recommendations were made for the diagnosis of Wilson disease: Extrapyramidal symptoms, KF rings, low ceruloplasmin level, and high urinary copper excretion in patients presenting with neurologic symptoms and KF rings, low serum ceruloplasmin level, and high urinary copper excretion in patients presenting with hepatic symptoms.
• The serum copper level is low (normal, 80-160 mcg/dL).
• Low serum ceruloplasmin level of <20 mg/dL (normal, 20-60 mcg/dL)
• • The ceruloplasmin level may be normal in patients with active liver disease and in women taking oral contraceptives or during pregnancy.
  • Ceruloplasmin values may also be reduced in a number of other illnesses, including Huntington disease, multiple sclerosis, subacute sclerosing panencephalitis, Hallervorden-Spatz syndrome, and aceruloplasminemia.
• Increased urinary copper level, >100 mcg/24 hours (normal, 10-80 mcg/24 h)
• • The level may be normal in children and asymptomatic siblings.
  • A repeat collection after oral challenge with D-penicillamine 500 mg at the beginning and 12 hours later can be done.
• Renal involvement
• • Hypercalciuria and nephrocalcinosis
  • Secondary Fanconi syndrome with renal tubular acidosis and/or aminoaciduria
• Hypoparathyroidism
• Coombs-negative hemolytic anemia
• Abnormal transaminase levels

Imaging Studies

• Radiography or dual-energy x-ray absorptiometry (DEXA) scan - Osteoporosis
• CT of the head
• • Hypoattenuations in the putamen
  • Atrophy
• MRI of the brain
• • High signal in the basal ganglia, thalami, dentate nuclei, and cerebellar white matter on T2-weighted images
  • Cortical atrophy
  • Ventricular enlargement
  • Sinha et al reported reversible central pontine myelinolysis like changes in 10 patients. All had contiguous midbrain involvement with a round, bisected or trisected shape.²
• Magnetic resonance spectroscopy
• • In 1999, Kraft et al found no statistically significant differences between 12 treated patients (9 with neurologic symptoms) and 12 healthy control subjects in ratios myoinositol/creatine (MI/Cr) and choline-containing compounds/creatinine (Cho/Cr), N-acetyl-aspartate/creatine (NAA/Cr), and lactate/creatine (Glx/Cr) in the parietal gray matter and white matter, as well as the putamen. The authors thought that decreased MI/Cr and Cho/Cr ratios were correlated with hepatic encephalopathy.³
  • In 2005, Lucato et al reported findings in 36 patients compared with 37 healthy control subjects. Individuals with Wilson disease had decreased NAA/Cr ratios in the parieto-occipital white matter, frontal white matter, and basal ganglia. They also found an increased MI/Cr ratio in the basal ganglia.⁴
• Tc-99m TRODAT-1 SPECT
• • Wang et al found decreased striatal Tc-99m TRODAT-1 uptake in both symptomatic and asymptomatic patients with Wilson disease in the striatum, especially the posterior putamina.⁵
  • Wang et al also found that the striatum/cerebellum ratio had a negative correlation with the severity of neurologic symptoms.⁵
• Transcranial sonography (TCS) of the brain parenchyma can show lenticular nuclei hyperechogenicity in asymptomatic patients and can be more sensitive than brain MRI.

Other Tests

• Liver biopsy - Increased hepatic copper levels, as much as 200-3000 mcg/g dry weight (normal, 20-50 mcg/g)
• • This should be measured by mass spectroscopy or atomic absorption spectroscopy.
  • Histochemical copper staining with rhodanine is insensitive (<10%).
  • Patients with other chronic liver disease, especially those with cholestasis may also have elevated copper levels.
  • Because of sampling error, normal copper content does not rule out Wilson disease.
• Mutation analysis
• • Conformation-sensitive gel electrophoresis can be used to screen members of a family with known Wilson disease.⁶
  • Allele dropout can occur in PCR analysis with compound heterozygotes when one allele fails to amplify.^{7, 8}
  • Genotyping microarray⁹
• Echocardiography - May show cardiomyopathy
• Neuropsychological testing - Difficulties with Reitan trail test part B, which is sensitive for cognitive impairment associated with liver disease
• Cell culture - Normal or only slight copper accumulation

Procedures

• Slitlamp examination for KF rings (deep copper–colored rings at the periphery of the cornea) due to deposition of copper in the Descemet membrane.
• An experienced ophthalmologist should perform the slitlamp examination.

Histologic Findings

• Brain findings
• • Copper deposition in the basal ganglia
  • Opalski cells - Periodic acid-Schiff–positive altered glial cells
  • Cavitary degeneration
  • Gliosis
  • Neuronal loss
• Liver findings¹⁰
• • Diffuse cytoplasmic copper accumulation seen with special histochemical stains can be associated with macrosteatosis, microsteatosis, and glycogenated nuclei.
  • Periportal inflammation, mononuclear cellular infiltrates, erosion of the limiting plate, lobular necrosis, bridging fibrosis, and Mallory bodies
  • Cirrhosis with micronodular or mixed macronodular-micronodular pattern

Staging

Eisenbach et al¹¹ found that patients with acute liver failure due to Wilson disease had much lower alanine aminotransferase and aspartate aminotransferase levels than patients with acute liver failure due to other causes. Alanine aminotransferase level was less than 100 in Wilson disease but more than 1000 in patients with acute liver failure due to other causes. They also noted lower choline esterase activity and hemoglobin levels, but the urinary copper concentration was much higher in patients with acute liver failure due to Wilson disease. Acute liver failure was defined as new-onset liver disease characterized by coagulopathy [international normalized ratio (INR) ≥1.5] and any grade of hepatic encephalopathy in the absence of any prediagnosed liver disease. Of their 7 patients, 4 did survive without liver transplantation.

Petrasek et al¹² found that the Revised Wilson Disease Prognostic Index (RWPI) had a higher accuracy and lower false negative rate than the Wilson Disease Prognostic Index (WPI) or the Model for End-Stage Liver Disease (MELD) Score in predicting response to chelation therapy. All their patients with decompensated chronic Wilson disease improved with chelation therapy with penicillamine initially, although 6 of the 14 patients later required transplantation. They all had a MELD score less than 30, WPI 7 or lower, and RWPI 11 or lower.

In the Petrasek study, fulminant Wilson disease (group 1) was defined as fulminant hepatic failure at the first presentation of Wilson disease, severe coagulopathy (INR >2), and either encephalopathy or hemolytic anemia. Decompensated chronic Wilson disease (group 2) was defined as known chronic liver disease with sudden onset of jaundice with liver synthetic dysfunction with neither encephalopathy nor hemolytic anemia. Of the 21 patients with fulminant liver disease, 4 died after being listed for liver transplantation. The 17 remaining patients received transplants but 5 of those patients also died in the early posttransplant period within 29 days of the transplant.

The survival of 4 patients without liver transplantation in the Eisenbach group may be due to the slightly different criteria with INR 1.5 or greater in Eisenbach's study as compared with the INR of greater than 2 used in Petrasek's study.

Czlonkowska et al¹³ proposed a novel scale for rating the neurologic symptoms in Wilson disease. The scale consists of 3 points for consciousness, 39 points for a historical review based on the Barthel scale, and 143 points for the neurologic examination. They developed the new scale to integrate the dystonia, ataxia, and parkinsonism that are often seen in combination in patients with Wilson disease.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Medical therapy for Wilson disease is still controversial.
• • In 1999, Walshe recommended D-penicillamine as the initial therapy of choice¹⁴, and Brewer stated that D-penicillamine should not be used in Wilson disease at all¹⁵.
  • In 2005, Brewer recommended TM with zinc for 8-16 weeks and zinc or trientine if TM is not available.¹⁶
  • Although initial use of D-penicillamine can worsen neurologic symptoms, Czlonkowska et al¹⁶ did not note any difference in mortality for 164 patients treated with D-penicillamine or zinc sulphate as initial therapy.
  • Pranshanth et al recommend a start-low, go-slow approach if penicillamine is used.
  • Both D-penicillamine and zinc can reverse liver fibrosis.
  • Brewer et al reported a double-blind randomized trial of TM 20 mg tid with meals and 20 mg tid between meals vs 500 mg of trientine hydrochloride bid in 48 patients with a neurologic presentation. All patients also received zinc 50 mg tid in 2006.¹⁷
  • • Neurologic deterioration occurred in 6 of the 23 patients receiving trientine and 1 of the 25 patients receiving TM.
    • During the 3-year study, 4 of the 6 patients with initial neurologic deterioration who were receiving trientine died.
• Zinc is the recommended therapy during pregnancy because D-penicillamine and trientine are both teratogenic in animals and because D-penicillamine is teratogenic in humans.
  • Zinc therapy reduces copper accumulation in the LEC rat.
  • In 2005, Carelli reported zinc use with 10-year follow-up in children. Zinc was given to individuals younger than 6 years without an adverse effect on growth. Dosages were 25 mg of elemental zinc bid to age 6 years, 25 mg tid to age 16 years or 125 lb, and 50 mg tid after that.
• Gene therapy¹⁸: Investigational in animal models. Viral gene transfer provided transient transgene expression that did reverse clinical symptoms.

Surgical Care

Liver transplantation is indicated for patients with acute hepatic insufficiency; it also can be considered in patients whose disease does not respond to medical therapy. Whether liver transplantation is indicated in patients with neurologic or psychiatric disease without liver insufficiency is debatable; however, liver transplantation provides neurologic and psychiatric improvement.

Pal et al reported that left-sided stereotactic thalamotomy reduced severe bilateral postural kinetic tremor of the hands.¹⁹

Diet

A low copper diet, with 1 mg/d at first (0.5 mg/d for children), is recommended. Dietary copper intake can be increased to 1-1.5 mg/d after good control is established; however, average diets usually contain 1 mg/d. Foods high in copper content include shellfish, liver, mushrooms, broccoli, chocolate, and nuts.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Chelating agents

These agents were initially developed to prevent intoxication resulting from drug overdose. Dimercaptopropanol (or British anti-Lewisite [BAL]) was the first therapy used in Wilson disease. It has 2 sulfhydryl groups that form a 5-member ring with copper. BAL can cross the blood-brain barrier. It must be administered intramuscularly and is known to cause tachyphylaxis, probably secondary to induction of liver enzymes. Dimercaptopropane sulphonate (Unithiol) is an orally active derivative of BAL. The agents listed below are those most widely used today.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

Treatment of fulminant liver disease

• Plasma exchange and exchange transfusion as well as peritoneal dialysis with albumin 1-1.5 g/dL and penicillamine 200 mg/dL.
• Intravenous penicillamine or trientine can also be given.
• Almost all patients need liver transplantation (see Staging).

Prognosis

• Improvement usually begins 5-6 months after the start of therapy and continues for about 24 months. The deficits present at 24 months are likely to be permanent.
• Psychiatric symptoms can resolve, and many neurologic symptoms can improve or resolve as well. However, patients usually have cirrhosis even if liver function is normal. Patients can have complications related to cirrhosis, such as portal hypertension, varices, and hypersplenism resulting in leukopenia and thrombocytopenia.
• Merle et al²⁰ found that patients presenting with neuropsychiatric symptoms were more likely to have a longer delay to definitive diagnosis (44.4 mo vs 14.4 mo), progression of symptoms despite treatment, and a poorer outcome than patients presenting with hepatic symptoms. Treatment side effects also occurred in 74.4% of their 163 patients. Patients also presented at a younger age with hepatic symptoms (15.5 y vs 20.2 y).
• Patients who present with fulminant liver failure have a mortality rate as high as 70%.

Patient Education

For excellent patient education resources, visit eMedicine's Liver, Gallbladder, and Pancreas Center and Hepatitis Center. Also, see eMedicine's patient education article, Cirrhosis.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Special Concerns

• Noncompliance is an important problem.
• In 1 study, occasional noncompliance was reported in 25% of patients, and serious problems with regular noncompliance were found in 10% of patients though patients received free medication and care and though urinary copper values were monitored every 6 months.
• Sinha and Taly²¹ reported that 44 of 45 patients on zinc and penicillamine maintenance therapy remained stable after penicillamine was discontinued but 1 patient worsened. Mishra et al²² reported 2 cases of disease progression from presymptomatic to symptomatic disease and biochemical abnormalities despite treatment with zinc. The 2 children both responded to penicillamine.
• Narayan and Kaveer²³ reported a 13-year-old child with hypodensity of the white matter of the frontal, parietal, and temporal lobes consistent with demyelination and both generalized atrophy of the cerebral hemispheres and atrophy of the basal ganglia after 4 years of treatment with 750 mg/d penicillamine, which is equivalent to the adult maintenance dose, and 280 mg/d of zinc, which is nearly double the adult maintenance dose. 
  
  The authors noted that the serum ceruloplasmin was virtually undetectable and the serum copper (16 μg/dL) was much lower than the normal range of 80-120 μg/dL. They thought the CT changes were due to hypocupremia. The child presented at age 9 years with difficulty using hands and ambulating and with slurred speech for 6 months. He did have basal ganglia atrophy on the initial head CT. On follow-up examination, the KF ring was still present on the superior and inferior margins of both corneae and other abnormalities were apparent.
• Walshe²⁴ reported that in 67 patients seen from 1948-2000, diagnostic failure was the principal cause of death. Multiple other causes of death included poor compliance and the development of malignant disease after 10 years of follow-up.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Owen CA Jr, Ludwig J. Inherited copper toxicosis in Bedlington terriers: Wilson's disease (hepatolenticular degeneration). Am J Pathol. Mar 1982;106(3):432-4. [Medline].
2. Sinha S, Taly AB, Ravishankar S, Prashanth LK, Vasudev MK. Central pontine signal changes in Wilson's disease: distinct MRI morphology and sequential changes with de-coppering therapy. J Neuroimaging. Oct 2007;17(4):286-91. [Medline].
3. Kraft E, Trenkwalder C, Then Bergh F, Auer DP. Magnetic resonance proton spectroscopy of the brain in Wilson's disease. J Neurol. 246(8):693-9. [Medline].
4. Lucato LT, Otaduy MC, Barbosa ER, et al. Proton MR spectroscopy in Wilson disease: analysis of 36 cases. AJNR Am J Neuroradiol. May 2005;26(5):1066-71. [Medline].
5. Wang P, Hu P, Yue DC, Liang H, Xu JH. The clinical value of Tc-99m TRODAT-1 SPECT for evaluating disease severity in young patients with symptomatic and asymptomatic Wilson disease. Clin Nucl Med. Nov 2007;32(11):844-9. [Medline].
6. Sundaresan S, Eapen CE, Shaji RV, Chandy M, Kurian G, Chandy G. Screening for mutations in ATP7B gene using conformation-sensitive gel electrophoresis in a family with Wilson's disease. Med Sci Monit. Mar 2007;13(3):CS38-40. [Medline].
7. Lam CW, Mak CM. Allele dropout in PCR-based diagnosis of Wilson disease: mechanisms and solutions. Clin Chem. Mar 2006;52(3):517-20. [Medline].
8. Gupta A, Nasipuri P, Das SK, Ray K. Simple and effective strategies for detection of allele dropout in PCR-based diagnosis of Wilson disease. Clin Chem. Aug 2006;52(8):1611-2. [Medline].
9. Gojová L, Jansová E, Külm M, Pouchlá S, Kozák L. Genotyping microarray as a novel approach for the detection of ATP7B gene mutations in patients with Wilson disease. Clin Genet. May 2008;73(5):441-52. [Medline].
10. Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML. Wilson's disease. Lancet. Feb 3 2007;369(9559):397-408. [Medline].
11. Eisenbach C, Sieg O, Stremmel W, Encke J, Merle U. Diagnostic criteria for acute liver failure due to Wilson disease. World J Gastroenterol. Mar 21 2007;13(11):1711-4. [Medline].
12. Petrasek J, Jirsa M, Sperl J, Kozak L, Taimr P, Spicak J, et al. Revised King's College score for liver transplantation in adult patients with Wilson's disease. Liver Transpl. Jan 2007;13(1):55-61. [Medline].
13. Czlonkowska A, Tarnacka B, Möller JC, Leinweber B, Bandmann O, Woimant F, et al. Unified Wilson's Disease Rating Scale - a proposal for the neurological scoring of Wilson's disease patients. Neurol Neurochir Pol. Jan-Feb 2007;41(1):1-12. [Medline].
14. Walshe JM. Penicillamine: the treatment of first choice for patients with Wilson's disease. Mov Disord. Jul 1999;14(4):545-50. [Medline].
15. Brewer GJ. Penicillamine should not be used as initial therapy in Wilson's disease. Mov Disord. Jul 1999;14(4):551-4. [Medline].
16. Brewer GJ. Neurologically presenting Wilson's disease: epidemiology, pathophysiology and treatment. CNS Drugs. 2005;19(3):185-92. [Medline].
17. Brewer GJ, Askari F, Lorincz MT, Carlson M, Schilsky M, Kluin KJ, et al. Treatment of Wilson disease with ammonium tetrathiomolybdate: IV. Comparison of tetrathiomolybdate and trientine in a double-blind study of treatment of the neurologic presentation of Wilson disease. Arch Neurol. Apr 2006;63(4):521-7. [Medline].
18. Merle U, Stremmel W, Encke J. Perspectives for gene therapy of Wilson disease. Curr Gene Ther. Jun 2007;7(3):217-20. [Medline].
19. Pal PK, Sinha S, Pillai S, Taly AB, Abraham RG. Successful treatment of tremor in Wilson's disease by thalamotomy: A case report. Mov Disord. Nov 15 2007;22(15):2287-90. [Medline].
20. Merle U, Schaefer M, Ferenci P, Stremmel W. Clinical presentation, diagnosis and long-term outcome of Wilson's disease: a cohort study. Gut. Jan 2007;56(1):115-20. [Medline].
21. Sinha S, Taly AB. Withdrawal of penicillamine from zinc sulphate-penicillamine maintenance therapy in Wilson's disease: promising, safe and cheap. J Neurol Sci. Jan 15 2008;264(1-2):129-32. [Medline].
22. Mishra D, Kalra V, Seth R. Failure of prophylactic zinc in Wilson disease. Indian Pediatr. Feb 2008;45(2):151-3. [Medline].
23. Narayan SK, Kaveer N. CNS demyelination due to hypocupremia in Wilson's disease from overzealous treatment. Neurol India. Mar 2006;54(1):110-1. [Medline].
24. Walshe JM. Cause of death in Wilson disease. Mov Disord. Nov 15 2007;22(15):2216-20. [Medline].
25. Adler CH. Differential diagnosis of Parkinson's disease. Med Clin North Am. Mar 1999;83(2):349-67. [Medline].
26. Aoki T. Genetic disorders of copper transport--diagnosis and new treatment for the patients of Wilson''s disease [in Japanese]. No To Hattatsu. Mar 2005;37(2):99-109. [Medline].
27. Aoki T. Wilson's disease and Menkes disease. Pediatr Int. Aug 1999;41(4):403-4. [Medline].
28. Asfaha S, Almansori M, Qarni U, Gutfreund KS. Plasmapheresis for hemolytic crisis and impending acute liver failure in Wilson disease. J Clin Apher. 2007;22(5):295-8. [Medline].
29. Barnes N, Tsivkovskii R, Tsivkovskaia N, Lutsenko S. The copper-transporting ATPases, Menkes and Wilson disease proteins, have distinct roles in adult and developing cerebellum. J Biol Chem. Mar 11 2005;280(10):9640-5. [Medline].
30. Brewer GJ. The treatment of Wilson's disease. Adv Exp Med Biol. 1999;448:115-26. [Medline].
31. Chakraborty PP, Mandal SK, Bandyopadhyay D, Bandyopadhyay R, Chowdhury SR. Recurrent limb weakness as initial presentation of Wilson's disease. Indian J Gastroenterol. Jan-Feb 2007;26(1):36-8. [Medline].
32. Crone NE, Jinnah HA, Reich SG. Wilson's disease presenting with an unusual cough. Mov Disord. Jul 2005;20(7):891-3. [Medline].
33. Czlonkowska A, Tarnacka B, Litwin T, Gajda J, Rodo M. Wilson's disease-cause of mortality in 164 patients during 1992-2003 observation period. J Neurol. Jun 2005;252(6):698-703. [Medline].
34. Dhawan A, Ferenci P, Geubel A, et al. Genes and metals: a deadly combination. Acta Gastroenterol Belg. Jan-Mar 2005;68(1):26-32. [Medline].
35. Ferenci P. Wilson's Disease. Clin Gastroenterol Hepatol. Aug 2005;3(8):726-33. [Medline].
36. Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int. Jun 2003;23(3):139-42. [Medline].
37. Fox AN, Schilsky M. Once daily trientine for maintenance therapy of Wilson disease. Am J Gastroenterol. Feb 2008;103(2):494-5. [Medline].
38. Gonzalez BP, Nińo Fong R, Gibson CJ, Fuentealba IC, Cherian MG. Zinc supplementation decreases hepatic copper accumulation in LEC rat: a model of Wilson's disease. Biol Trace Elem Res. Summer 2005;105(1-3):117-34. [Medline].
39. Goodyer ID, Jones EE, Monaco AP, Francis MJ. Characterization of the Menkes protein copper-binding domains and their role in copper-induced protein relocalization. Hum Mol Genet. Aug 1999;8(8):1473-8. [Medline].
40. Gow PJ, Smallwood RA, Angus PW, Smith AL, Wall AJ, Sewell RB. Diagnosis of Wilson's disease: an experience over three decades. Gut. Mar 2000;46(3):415-9. [Medline].
41. Gupta A, Aikath D, Neogi R, et al. Molecular pathogenesis of Wilson disease: haplotype analysis, detection of prevalent mutations and genotype-phenotype correlation in Indian patients. Hum Genet. Oct 2005;118(1):49-57. [Medline].
42. Howell JM. Animal models of Wilson's disease. Adv Exp Med Biol. 1999;448:139-52. [Medline].
43. Hsi G, Cox DW. A comparison of the mutation spectra of Menkes disease and Wilson disease. Hum Genet. Jan 2004;114(2):165-72. [Medline].
44. Johns Hopkins University. #277900. Wilson disease. OMIM: Online Mendelian Inheritance in Man. Updated December 28, 2005. [Full Text].
45. Jung KH, Ahn TB, Jeon BS. Wilson disease with an initial manifestation of polyneuropathy. Arch Neurol. Oct 2005;62(10):1628-31. [Medline].
46. Kashani AA. Ocular manifestations of Wilson's disease in Iran. Trans Ophthalmol Soc U K. Apr 1977;97(1):18-9. [Medline].
47. Kashani AA. Wilson's disease: presymptomatic patients and Kayser-Fleischer rings. Ophthalmic Genet. Dec 1998;19(4):215-8. [Medline].
48. Kim TJ, Kim IO, Kim WS, Cheon JE, Moon SG, Kwon JW, et al. MR imaging of the brain in Wilson disease of childhood: findings before and after treatment with clinical correlation. AJNR Am J Neuroradiol. Jun-Jul 2006;27(6):1373-8. [Medline].
49. Leggio L, Addolorato G, Abenavoli L, Gasbarrini G. Wilson's disease: clinical, genetic and pharmacological findings. Int J Immunopathol Pharmacol. Jan-Mar 2005;18(1):7-14. [Medline].
50. LeWitt PA. Penicillamine as a controversial treatment for Wilson's disease. Mov Disord. Jul 1999;14(4):555-6. [Medline].
51. Marcellini M, Di Ciommo V, Callea F, Devito R, Comparcola D, Sartorelli MR, et al. Treatment of Wilson's disease with zinc from the time of diagnosis in pediatric patients: a single-hospital, 10-year follow-up study. J Lab Clin Med. Mar 2005;145(3):139-43. [Medline].
52. Marin C, Robles R, Parrilla G, Ramírez P, Bueno FS, Parrilla P. Liver transplantation in Wilson's disease: are its indications established?. Transplant Proc. Sep 2007;39(7):2300-1. [Medline].
53. Menkes JH. Menkes disease and Wilson disease: two sides of the same copper coin. Part I: Menkes disease. Eur J Paediatr Neurol. 1999;3(4):147-58. [Medline].
54. Moller LB, Ott P, Lund C, Horn N. Homozygosity for a gross partial gene deletion of the C-terminal end of ATP7B in a Wilson patient with hepatic and no neurological manifestations. Am J Med Genet A. Nov 1 2005;138(4):340-3. [Medline].
55. Oracz G, Klimczak-Slaczka D, Sokolowska-Oracz A, Socha P, Gralek M, Szaflik J, et al. [Prevalence of Kayser-Fleischer ring in patients with Wilson's disease]. Klin Oczna. 2005;107(1-3):54-6. [Medline].
56. Robles R, Parrilla P, Sicilia J, Ramírez P, Bueno FS, Rodríguez JM, et al. Indications and results of liver transplants in Wilson's disease. Transplant Proc. Sep 1999;31(6):2453-4. [Medline].
57. Sakaida I, Kawaguchi K, Kimura T, Tamura F, Okita K. D-Penicillamine improved laparoscopic and histological findings of the liver in a patient with Wilson's disease: 3-year follow-up after diagnosis of Coombs-negative hemolytic anemia of Wilson's disease. J Gastroenterol. Jun 2005;40(6):646-51. [Medline].
58. Selimoglu MA, Ertekin V, Doneray H, Yildirim M. Bone mineral density of children with Wilson disease: efficacy of penicillamine and zinc therapy. J Clin Gastroenterol. Feb 2008;42(2):194-8. [Medline].
59. Selimoglu MA, Ertekin V, Doneray H, Yildirim M. Bone mineral density of children with Wilson disease: efficacy of penicillamine and zinc therapy. J Clin Gastroenterol. Feb 2008;42(2):194-8. [Medline].
60. Shim H, Harris ZL. Genetic defects in copper metabolism. J Nutr. May 2003;133(5 Suppl 1):1527S-31S. [Medline].
61. Shimizu N, Yamaguchi Y, Aoki T. Treatment and management of Wilson's disease. Pediatr Int. Aug 1999;41(4):419-22. [Medline].
62. Suzuki M, Gitlin JD. Intracellular localization of the Menkes and Wilson's disease proteins and their role in intracellular copper transport. Pediatr Int. Aug 1999;41(4):436-42. [Medline].
63. Waggoner DJ, Bartnikas TB, Gitlin JD. The role of copper in neurodegenerative disease. Neurobiol Dis. Aug 1999;6(4):221-30. [Medline].
64. Walshe JM. Diagnostic significance of reduced serum caeruloplasmin concentration in neurological disease. Mov Disord. Dec 2005;20(12):1658-61. [Medline].
65. Walter U, Krolikowski K, Tarnacka B, et al. Sonographic detection of basal ganglia lesions in asymptomatic and symptomatic Wilson disease. Neurology. May 24 2005;64(10):1726-32. [Medline].
66. Weiner WJ, Lang AE. Movement Disorders: A Comprehensive Survey. Mount Kisco, NY: Futura;. 1989;257-91.
67. Werlin SL, Grand RJ, Perman JA, Watkins JB. Diagnostic dilemmas of Wilson's disease: diagnosis and treatment. Pediatrics. Jul 1978;62(1):47-51. [Medline].
68. Wiebers DO, Hollenhorst RW, Goldstein NP. The ophthalmologic manifestations of Wilson's disease. Mayo Clin Proc. Jul 1977;52(7):409-16. [Medline].
69. Wijmenga C, Klomp LW. Molecular regulation of copper excretion in the liver. Proc Nutr Soc. Feb 2004;63(1):31-9. [Medline].

Article Last Updated: Nov 26, 2008