OVERVIEW: What every practitioner needs to know

The presenting clinical features of Wilson disease have historically been divided into three groups: hepatic, neurologic, and psychiatric. The neurologic manifestations of neurologic Wilson disease include variable combinations of dysarthria, dystonia, tremor, parkinsonism, ataxia, and choreoathetosis. The hepatic presentation can be divided into four main presentations: acute hepatitis, chronic active hepatitis, cirrhosis, and acute fulminant hepatic failure.

The diagnosis of Wilson disease requires a high degree of clinical suspicion, but can be confirmed with simple evaluations. Because Wilson disease is treatable, but disabling or lethal if missed, it should be considered in the differential diagnosis more than its frequency might suggest. Although relative efficacy has not been demonstrated by rigorous clinical trials, use of zinc alone or in combination with trientine, depending on the clinical situation, is appropriate.

Are you sure your patient has Wilson Disease? What are the typical findings for this disease?

The clinical manifestations of Wilson disease can be divided into hepatic, neurologic, and psychiatric presentations. These occur in roughly equal proportions.

Continue Reading

Clinical manifestations first occur between early childhood and the fifth or sixth decade of life with a mean age at onset of neurologic symptoms from 15-21 years of age. Those with a primarily hepatic presentation appear to have an earlier age at presentation, with a mean age of onset of 11-15 years of age.

The clinical manifestations of neurologic Wilson disease include variable combinations of dysarthria, dystonia, tremor, parkinsonism, ataxia, and choreoathetosis. Dysarthria, dystonia, tremor, and less frequently parkinsonism can be present in isolation at disease onset. As the disease progresses, it is typical for complex combinations of neurologic symptoms and signs to coexist in a single patient, with a single or small subset of features predominating.

Dysarthria, present in approximately 58% of patients at diagnosis, is most frequently of the mixed type with varying spastic, ataxic, hypokinetic, and dystonic components. Dystonia, present in approximately 42% of patients at diagnosis, can be focal, segmental, multifocal, or generalized and ranges in severity from mild to debilitating. A common focal dystonic manifestation of Wilson disease is a dystonic facial expression characterized by a forced, often exaggerated, smile known as risus sardonicus.

Wilsonian tremor has been reported to be present in 22%-55% of cases and can occur at rest, upon assumption of a posture, or with action. Early in Wilson disease the tremor can be identical to the tremor of essential tremor, with the distal upper extremities most frequently involved, with less common involvement of the head and legs. As the disease progresses, Wilsonian tremor usually takes on characteristics atypical of essential tremor. A posture-induced wing beating tremor is a less frequently observed, lower frequency, higher amplitude proximal upper extremity tremor elicited by holding the arms extended laterally or with the arms held in front with flexed elbows and palms facing downward. In an individual patient, tremor can demonstrate multiple position- and task-dependent characteristics.

Bradykinesia, imbalance, and cogwheel rigidity are the most common parkinsonian features. An isolated unilateral rest tremor is atypical in Wilson’s disease. When rest tremor is present it is usually accompanied by postural and kinetic tremor that is often more severe than the rest tremor.

When present in Wilson disease, chorea is more common in young-onset disease (16 years of age and younger), where it has been reported in 20% of cases. Chorea can have many causes and is not usually present in isolation in neurologic Wilson disease.

During the course of the disease, additional neurologic features include myoclonus, seizures, ataxia, pyramidal signs, drooling, and eye movement abnormalities.

The hepatic presentation can be divided into four main presentations: acute hepatitis, chronic active hepatitis, cirrhosis, and acute fulminant hepatic failure. Other hepatic presentations include clinical pictures indistinguishable from alcoholic liver disease, and autoimmune hepatitis. Patients who present with hepatic failure may have mild failure with jaundice, low blood albumin, and edema, but not be in an acute, rapidly deteriorating, fulminant liver failure. Other patients may present with acute fulminant hepatic failure with Coombs negative hemolytic anemia, coagulopathy, renal failure, and encephalopathy.

The occurrence of hemolysis in hepatic disease should always trigger a search for Wilson disease because it is by far the most likely diagnosis. In one series, approximately 11% of cases presented with hemolysis, which can be a single event, low-grade condition, or chronic illness. Other hepatic presentations include asymptomatic hepatomegaly, isolated splenomegaly, persistently elevated transaminase, or fatty liver.

At diagnosis, the most common psychiatric symptoms have been reported to be personality change, incongruous behavior, irritability, and depression. During the course of disease, in addition to persistence of the presenting psychiatric symptoms, other features can develop and include impulsivity, dysinhibition, irritability, reckless behavior, anxiety, substance abuse, catatonia, emotionality, and mania. Patients with neurologic or psychiatric presentations frequently have subclinical liver disease with mild-to-moderate cirrhosis.

Copper deposits in the limbic region of the cornea known Kayser-Fleischer (KF) rings are seen in nearly 100% of patients with neurologic Wilson disease. In hepatic and presymptomatic Wilson disease, KF rings are present in approximately 50% of cases (Figure 1).

Figure 1.

Kayser-Fleischer (KF) Rings

What other disease/condition shares some of these symptoms?

Wilson disease in children can mimic other neurological conditions that involve a movement disorder, such as focal dystonias, tremor, or choreiform disorders. It should also be considered (and screened for) in children with new dysarthria or speech regression, new motor coordination difficulty, cognitive/academic or behavioral decline.

In children with classic tic disorders and Tourette syndrome, Wilson disease is not usually suspected unless the child has atypical features, a progressive course, or a failure of treatment. Because Wilson disease is treatable, it should be considered as a possible diagnosis in every young person with a movement disorder or unexplained neurological symptoms.

New onset psychiatric conditions such as depression and anxiety, attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), oppositional defiant disorder (ODD) or pediatric autoimmune neuropsychiatric disorder after strep (PANDAS) should also lead the clinician to screen for Wilson disease.

Primary neurologic disorders that can mimic Wilson disease include essential tremor, young onset Parkinson’s disease, focal and generalized dystonias. Rare juvenile (genetic) extrapyramidal disorders, including childhood Huntington’s disease, Hallervorden-Spatz disease (PKAN: pantothenate kinase-associated neurodegeneration), idiopathic torsion dystonia, dopa-responsive dystonia, chorea-acanthocytosis, and benign familial chorea, can mimic Wilson disease.

Since chorea is a more common neurological presentation in childhood Wilson disease, Sydenham’s chorea and other conditions that result in chorea (systemic lupus erythematosus (SLE), drug abuse, affective disorder or schizophrenia, CNS vasculitis, encephalitis, pregnancy, Niemann-Pick type C), should invoke testing to rule out Wilson disease. Diagnostic consideration for other causes of primarily choreic and ataxic diseases should be undertaken as well.

In children with unexplained neurodegenerative disorders, such as suspected but unconfirmed mitochondrial disorders, screening for Wilson disease may be a strong consideration. Brain MR imaging with bilaterally symmetric basal ganglia signal changes should alert the clinician to test for possible Wilson disease. The presence of Kayser-Fleischer rings and the co-existence of liver disease or hemolytic anemia can provide important clues to the possibility of Wilson disease.

What caused this disease to develop at this time?

It is not known why the disease manifestations of Wilson disease develop when they do. Copper load (from food sources or water), individual genetic mutation, modifying genes, and other environmental influences likely all play a role in the timing of disease onset. Although Wilson disease symptoms are typically gradual in their onset of presentation, a sudden worsening can often prompt diagnostic evaluation. Delay in the diagnosis of Wilson disease has been shown to alter the neurological recovery and prognosis significantly.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The most common screening method for Wilson disease is a blood ceruloplasmin determination. Although the ceruloplasmin value is not adequate for definitively diagnosing Wilson disease, it can provide supportive information. The ceruloplasmin value is usually low in Wilson disease, but in approximately 10% of patients it may be normal or near normal. About 10% of heterozygous carriers without clinical manifestations will also demonstrate low ceruloplasmin values.

The most useful screening procedure for Wilson disease is a 24-hour urine copper test. In symptomatic Wilson disease, the 24-hour urine copper is always elevated to a value greater than 100 µg per 24 hours (normal is 50 μg or less). The 24-hour urine sample must be collected in a container free of trace elements. A laboratory that is capable of measuring copper in low concentrations is required to do the assay. If these difficulties can be overcome, this test is a reliable screening test for Wilson disease.

Another common screening procedure is a slit-lamp examination for KF rings. Visual inspection (direct ophthalmoscope) is not adequate. KF rings are invariably present in the psychiatric and neurologic presentations of Wilson disease; however, they are present in only about 50% of patients who present with liver disease. In a patient with classic symptoms of neurologic Wilson disease, positive KF rings, and an elevated urine copper, the diagnosis can be made with certainty.

If any question remains, the gold standard for diagnosis of Wilson disease is a measure of the quantitative copper content in a percutaneous liver biopsy. The hepatic copper value in untreated Wilson disease is above 200 µg/g dry weight of hepatic tissue with the normal being 50 µg/g or less. Carriers of the Wilson disease gene may have mild elevations of hepatic copper, but never to 200 µg/g.

It is important not to rely on the stain for copper, for if the copper is still diffusely cytoplasmic, the copper stain may be negative in the face of very great elevations of hepatic copper. Radiocopper studies have been suggested for the diagnosis of Wilson disease, but their usefulness is questionable.

The gene for Wilson disease has been cloned. The gene is an amino acid copper transporting transmembrane ATPase (ATP7B), and is inherited as an autosomal recessive trait. The identification of the causative gene led to hope for the development of a genetic diagnostic test. This approach, however, is not practical because more than 300 different gene mutations that cause Wilson disease have been identified. If a specific mutation is identified in a proband, however, then a search for this DNA mutation in relatives can provide crucial information; particularly for the identification of asymptomatic relatives and heterozygous carriers. It also provides the opportunity for preventive therapy and genetic counseling.

Would imaging studies be helpful? If so, which ones?

Central nervous system imaging can be very helpful in the diagnosis of Wilson disease.

MRI scans generally demonstrate abnormalities in patients with neurologic or psychiatric symptoms, but are often normal in presymptomatic or early symptomatic patients or patients with only liver disease.

In patients with neurologic Wilson disease, the most common findings are bilaterally symmetric areas of high T2 signal in the basal ganglia (lentiform and caudate nuclei), but signal changes in the thalamus, brain stem, and cortical white matter are also seen. High signal T1-images, like those seen in portal-systemic encephalopathy, may also be observed.

In children with bilaterally symmetric basal ganglia signal changes seen on MR imaging, screening for Wilson disease is strongly recommended.

It is important to keep in mind that normal MRI findings can be seen in early onset or mildly symptomatic Wilson disease.

Confirming the diagnosis

Most experts recommend a Wilson screening algorithm with a serum ceruloplasmin level and a 24-hour urine copper test, followed by ophthalmologic KF ring determination or liver biopsy confirmation. A careful neurological examination and a brain MRI is strongly recommended as well.

Because the diagnosis and subsequent treatment of Wilson disease is often delayed by about 1 year on average, a screening algorithm is essential to the diagnostic recognition of this treatable neurodegenerative genetic disorder.

The most current and comprehensive guideline and summary of the diagnosis and treatment of Wilson disease can be found in the American Association for the Study of Liver Disease (AASLD) paper “Diagnosis and Treatment of Wilson disease: An Update” by Eva Roberts and Michael Schilsky. (Please refer to the references at the end of this article.) This paper presents algorithms for the approach to the diagnosis of neurologic and hepatic Wilson disease.

If you are able to confirm that the patient has Wilson disease, what treatment should be initiated?

The comparative efficacy and safety of the available treatments for Wilson disease have not been established by double blinded randomized placebo-controlled trials. Treatment can be divided into presymptomatic, initial, and maintenance therapy.

Treatment outcomes are better in patients with a short diagnostic delay; delay in diagnosis increases the likelihood of a poor response to treatment.

Free copper is toxic, whereas bound copper is not. The aim of treatment is to reduce the amount of toxic free copper. Available pharmacologic agents include penicillamine, trientine, and zinc acetate. Tetrathiomolybdate (TM) has been used in treating Wilson disease, but it is not FDA approved and thus not readily available.

Because of concern for neurologic worsening in patients treated with penicillamine, use of other agents have been recommended for the initial treatment of Wilson disease. Dosing in children is 7-10 mg/kg/day rounded off to the nearest 250 mg in 2 to 3 divided doses. It has been suggested that starting with lower doses for a few weeks may lessen side effects. Because its absorption is inhibited by food, penicillamine should be administered one hour prior or two hours after meals. If penicillamine is used, supplemental pyridoxine (25-50 mg) by mouth should be administered. Treatment should be monitored by measuring 24-hour urine copper excretion. Immediately after initiating penicillamine, urine copper values may exceed 1000 µg/day (normal 20 -50 μg/day). On maintenance therapy, 24-hour urine copper values of 200 – 500 µg can be expected.

Trientine, like penicillamine, is a chelator that induces urinary excretion of copper and can cause neurologic worsening in approximately 25% of cases. For children, 7-10 mg/kg/day rounded off to the nearest 250 mg divided in 2 to 3 doses can be administered. Trientine should also be given one hour prior to or two hours after meals. Upon initial treatment with trientine, 24-hour urinary copper excretion may be 1000-3000 μg. After a few weeks, the urinary copper decreases to 500-1000 μg/day, and after approximately one year of therapy should decrease to 200-500 μg/day. Nonceruloplasmin bound copper, free copper, is a useful measure for monitoring the efficacy of trientine and can be calculated by the formula: (Total serum copper in µg/ml) X100-(ceruloplasmin in mg/dl x 3) = free copper (Normal range is 5 – 15µg/dl).

Zinc acetate therapy has been used successfully in presymptomatic patients as initial treatment, in isolation as maintenance therapy, and as maintenance therapy following an initial course of decoppering. The decoppering effect of zinc is slow, requiring 4-8 months of treatment to reduce copper to non-toxic levels. In symptomatic individuals, the natural course of disease continues during this period and can lead to permanent worsening.

An advantage of zinc is its lack of serious significant side effects and safety in long-term use. Zinc therapy has been demonstrated to be safe in children. In this study, children under the age of 6 received 25 mg two times a day, children ages 7-16 years or until reaching a body weight of 125 pounds received 25 mg three times a day, and children weighing more than 125 pounds received 50 mg three times a day. It is important to separate the zinc from food by at least an hour.

Because zinc therapy does not induce urinary excretion of copper, as do trientine or penicillamine, urine copper is an accurate reflection of body copper stores. Following a year of zinc therapy, a 24-hour copper level of approximately 125 μg is a reflection of good copper control. Compliance with zinc can be assessed by monitoring 24-hour urine zinc excretion, which should be above 2 mg.

For maintenance therapy, zinc is favored over penicillamine or trientine, because while all three drugs are effective, zinc has a superior side effect profile and does not appear to cause neurologic worsening.

Taking into account efficacy and side effect profiles, a reasonable approach in the symptomatic patient is to initiate therapy with a combination of a copper chelating agent with zinc acetate therapy. Because the risks of neurologic worsening are less, and the side effect profile better with trientine, as compared with penicillamine, trientine is a better choice as a chelating agent.

In the minimally symptomatic or asymptomatic patient, zinc acetate therapy alone may be a safe treatment strategy. In patients who are minimally symptomatic, in whom zinc is used, close clinical follow-up of symptoms is required. If worsening occurs in the first 4-8 months of treatment, addition of trientine can be considered.

In patients with acute liver failure, orthotopic liver transplantation can be lifesaving. Liver transplant is not a recommended therapy for neurologic Wilson disease.

For the initial treatment of patients presenting with neurologic or psychiatric disease, the use of tetrathiomolybdate (TM) followed by zinc maintenance therapy has been suggested as providing a good balance of efficacy and side effects, but TM is not FDA approved. Given with food, TM binds food copper and endogenously secreted copper, thus preventing copper absorption. Given between meals, TM is absorbed into the blood and forms a complex with free copper and albumin. The result is a rapid removal of tissue copper, which is then bound in the serum by TM, reducing potential copper toxicity, and results in significantly less neurologic worsening compared with penicillamine or trientine. TM administered at 20 mg three times a day with meals and 20 mg three times a day between meals, given for 8 weeks along with zinc 50 mg twice daily, followed by zinc maintenance therapy, has demonstrated efficacy and safety.

What are the adverse effects associated with each treatment option?

Complications of penicillamine include neurologic worsening, rash, immune complex nephropathy, systemic lupus erythematosus, thrombocytopenia, and leucocytopenia. Toxicity secondary to penicillamine also occurs in 20%-70% of cases, frequently leading to discontinuation. An acute hypersensitivity reaction occurs in about 25% of cases, which may respond to corticosteroid therapy or withdrawal of the drug and readministration in very low doses.

Trientine can cause neurologic worsening in approximately 25% of cases. Pancytopenia has been infrequently reported, and there are also reports of hemorrhagic gastritis, loss of taste, and rash.

In patients treated with zinc, approximately 10% experience gastric discomfort or nausea upon initiation of zinc therapy. The use of zinc acetate compared to zinc sulfate reduces gastric discomfort. Generally, gastric symptoms subside within days to weeks.

What are the possible outcomes of Wilson disease?

The clinical outcomes of pediatric Wilson disease are highly variable, ranging from reversible symptoms with near-normal outcomes to severe disability or death. It is imperative to keep in mind that prognosis is highly dependent on a timely diagnosis and initiation of decoppering treatment.

Prior to the treatment era, the average survival for neurologic Wilson disease was 2-5 years, but Wilson disease can progress slowly over more than 25 years.

Long-term outcome studies in pediatric Wilson disease are available, but not fully complete at this time. A review of 57 pediatric cases (mean age at diagnosis, 9 years) has been published. Studies on liver transplantation in children with hepatic Wilson disease indicate a higher one-year and five-year survival rate (90% and 89%), compared with adults (88% and 86%). These studies also indicate that patients with neurological symptoms were older at the onset of symptoms than patients with hepatic symptoms (20 years versus 15 years). Studies have also shown that patients with predominantly neurological or psychiatric symptoms of Wilson disease often have a longer time delay from onset of symptoms to diagnosis and treatment (44 months versus 14 months for hepatic symptoms), resulting in a poorer long-term prognosis and worse outcome.

After initiating treatment, 76% of Wilson patients overall had a stable or improved course of the disease. A case report has been published of atypical childhood Wilson disease in a 9-year-old girl treated with tetrathiomolybdate anticopper therapy followed by zinc maintenance with a favorable outcome. The overall experience to date with Wilson treatment (chelation) investigations demonstrates the benefit of therapy in normalizing life expectancy.

Compliance with life-long zinc maintenance therapy is critical to long-term survival and prognosis with good outcome in Wilson disease. Documented cases of zinc non-compliance have led to neurological and hepatic relapses with poor outcome and death.

What causes this disease and how frequent is it?

Mutations in the ATP7B gene cause Wilson disease. The best estimate for the disease frequency in most populations is approximately 4 per million, which would lead to a carrier frequency of 1 in 100.

How do these pathogens/genes/exposures cause the disease?

Humans, including Wilson disease patients, take in about 1.0 mg of copper per day in their diet, but have a requirement for only about 0.75 mg. Thus, the extra 0.25 mg must be eliminated. The normal mechanism for elimination of excess copper is excretion in the bile for loss in the stool. Dietary copper is absorbed in the stomach and duodenum and transported via the portal vein to the liver, the main organ controlling copper regulation. Copper is absorbed into hepatocytes by copper transporter 1, then ATOX1 (a copper specific chaperone protein) transports copper to ATP7B (the Wilson disease gene).

The normal function of ATP7B appears to be incorporation of copper into ceruloplasmin and secretion of copper into bile. As a result of the mutation in the ATP7B gene, the liver is not capable of excreting excess copper into the bile, and a positive copper balance, averaging about 0.25 mg/d, is established. Copper accumulates over time, first in the liver and then in other parts of the body, such as the brain. The damage from excessive copper appears to be oxidant in nature.

Other clinical manifestations that might help with diagnosis and management

Other clinical manifestations include abnormalities of renal tubular function, including Fanconi syndrome. Renal stones and gallstones are not uncommon. Patients may have osteoporosis or osteomalacia, or they may have joint disorders such as arthritis or arthralgias. Female patients frequently have oligomenorrhea or amenorrhea. Abnormalities of the heart include interstitial fibrosis and myocarditis. Electrocardiographic abnormalities and orthostatic hypertension are not uncommon. Pancreatic disease, parathyroidism, and skin abnormalities may be present.

What complications might you expect from the disease or treatment of the disease?

Complications of penicillamine include neurologic worsening, rash, immune complex nephropathy, systemic lupus erythematosus, thrombocytopenia, and leucocytopenia. An acute hypersensitivity reaction occurs in about 25% of cases, which may respond to corticosteroid therapy or withdrawal of the drug and readministration in very low doses.

Trientine can cause neurologic worsening in approximately 25% of cases. Pancytopenia has been infrequently reported, and there are also reports of hemorrhagic gastritis, loss of taste, and rash.

In patients treated with zinc, approximately 10% experience gastric discomfort or nausea upon initiation of zinc therapy. The use of zinc acetate compared with zinc sulfate reduces gastric discomfort. Generally, gastric symptoms subside within days to weeks.

Are additional laboratory studies available; even some that are not widely available?

The laboratory studies useful in diagnosing Wilson disease are discussed above.

How can Wilson disease be prevented?

Identification and treatment of patients with presymptomatic Wilson disease can prevent development of symptoms.

Aggressive screening measures in populations at risk are critical. Siblings of patients diagnosed with Wilson disease have a 25% risk of carrying causative mutations. Because the risk of Wilson disease is significantly elevated in nieces, nephews (1/600), and cousins (1/800), compared with the general population, these relatives can be screened for ceruloplasmin and 24-hour urine copper levels. All full siblings, nieces, and nephews should be screened for 24-hour urine copper levels.

A 24-hour urine copper greater than 100 μg in presymptomatic siblings is diagnostic of Wilson disease. A value of less than 50 μg in an adult patient essentially excludes the diagnosis.

An intermediate level is compatible either with the carrier state or the presymptomatic state. The liver copper level in such a patient is diagnostic, and a biopsy should be undertaken to clarify the diagnosis.

The risk of a child of a Wilson disease patient developing the disease is approximately 1:200. One approach is to have children of Wilson disease patients screened at ages 5 and 15 years of age with a 24-hour urine copper test.

One important societal health measure under consideration for Wilson disease involves newborn screening. The difficulty lies in what biochemical marker to use for disease identification, as well as the method of detection. Levels of serum copper or ceruloplasmin can be determined and standardized in the newborn population, although false positive and false negative determinations may pose a technical dilemma. Newborn ceruloplasmin levels are considerably lower than in adults, and the timing of determination in blood spots may be a factor (e.g., they may not stabilize until 3 months of age). Follow-up confirmatory diagnostic testing would be required in samples identified. This would serve to provide early identification of presymptomatic Wilson disease cases and allow for important studies on prospective preventative treatment.

What is the evidence?

Ala, A, Walker, AP, Ashkan, K. “Wilson's disease”. Lancet. vol. 369. 2007. pp. 397-408. (This manuscript contains a succinct summary of Wilson disease.)

Brewer, GJ, Ashari, F, Lorincz, MT, Carlson, M. “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. vol. 63. 2006. pp. 521-7. (This manuscript describes a double blinded trial for the treatment of Wilson disease.)

Arnon, R, Annunziato, R, Schilsky, M. “Liver transplantation for children with Wilson disease: comparison of outcomes between children and adults”. Clin Transplant. vol. 25. 2011. pp. E52-E60.

Brewer, GJ, Terry, CA, Aisen, AM, Hill, GM. “Worsening of neurologic syndrome in patients with Wilson's disease with initial penicillamine therapy”. Arch Neurol. vol. 44. 1987. pp. 490-3. (This paper describes neurologic worsening following the use of penicillamine.)

Brewer, GJ. “Wilson's disease: a clinician's guide to recognition, diagnosis, and management”. 2001. (This reference contains a comprehensive discussion on the history, diagnosis, and treatment of Wilson disease.)

Bull, PC, Thomas, GR, Rommens, JM. “The Wilson disease gene is a putative copper transporting P-type AYPase similar to the Menkes gene”. Nat Genet. vol. 5. 1993. pp. 327-37. (This manuscript describes the cloning of the Wilson disease gene.)

Carlson, MD, Al-Matten, M, Brewer, GJ. “Atpical childhood Wilson's disease”. Pediatr Neurol. vol. 30. 2004. pp. 57-50.

Gahl, WA. “Newborn screening for Wilson disease: Does liquid chromatography-tandem mass spectrometry provide the solution”. Clin Chem. vol. 54. 2008. pp. 1941-2.

Hoogrenraad, TU. “Paradigm shift in treatment of Wilson's disease: zinc therapy now treatment of choice”. Brain Dev. vol. 28. 2006. pp. 141-6. (This manuscript provides an overview of the use of zinc therapy in Wilson disease.)

Lorincz, MT. “Geriatric chorea”. Clin Geriatr Med. vol. 22. 2006. pp. 879-97. (This manuscript is a comprehensive review of chorea.)

Lorincz, MT. “Neurologic Wilson disease”. Ann N Y Acad Sci. vol. 1184. 2010. pp. 173-87. (This manuscript is a comprehensive review of neurologic Wilson disease.)

Marcellini, M, Di Ciommo, V, Callea, F. “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. vol. 145. 2005. pp. 139-43. (This paper describes the treatment of pediatric Wilson disease with zinc.)

Manolaki, N, Nikolopoulou, G, Daikos, GL. “Wilson disease in children: analysis of 57 cases”. J Pediatr Gastroenterol Nutr. vol. 48. 2009. pp. 72-7.

Riley, CA. “Wilson's disease”. Pediatr Rev. vol. 5. 1984. pp. 217-22.

Roberts, EA, Schilsky, ML. “Diagnosis and treatment of Wilson disease: an update”. Hepatology. vol. 47. 2008. pp. 2089-111. (This is an excellent review of Wilson disease from the American Association for the Study of Liver Diseases. It contains algorithms and recommendations for the approach to the diagnosis and treatment of Wilson disease.)

Tanzi, RE, Petrukhin, K, Chernov, I. “The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene”. Nat Genet. vol. 5. 1993. pp. 344-50. (This manuscript describes the cloning of the Wilson disease gene.)

Tryambak, S, Sumanta, L, Radheshyam, P. “Clinicl profile, prognostic indictors and outcome of Wilson's disease in children: a hospital based study”. Trop Gastroenterol. vol. 30. 2009. pp. 163-6.

Walshe, JM, Yealland, M. “Wilson's disease: the problem of delayed diagnosis”. J Neurol Neurosurg Psychiatry. vol. 55. 1992. pp. 692-6.

Yamaguchi, Y, Heiny, Me, Gitlin, JD. “Isolation and characterization of a human liver cDNA as a candidate gene for Wilson disease”. Biochem Biophys Res Commun. vol. 197. 1993. pp. 271-7. (This manuscript describes the cloning of the Wilson disease gene.)

Ongoing controversies regarding etiology, diagnosis, treatment

Neurologic deterioration following penicillamine treatment of neurologic Wilson disease is common. In a retrospective study, Brewer and colleagues identified the risk of neurologic worsening as approximately 50%, and that 50% of those who deteriorated never recovered to their pre-penicillamine baseline (Brewer et al., 1987). Walsh and colleagues described initial worsening in 22% of cases, with a third of those remaining severely disabled.

It has been suggested that mobilization of large hepatic copper stores raises blood free copper levels, leading to increased toxic copper exposure to the brain, and subsequent neurologic worsening.