Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)

GENE/GENE PANEL: ATP7B
Condition: Wilson Disease
GENEDISEASE PAIRS: ATP7B277900
Topic
Narrative Description of Evidence
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The prevalence of Wilson disease is usually reported as one in 30,000 in most populations. However, recent studies suggest genetic prevalence as high as one in 7,026. Prevalence may be greater in certain more isolated populations. Mismatch between clinical and genetic prevalence may be due to reduced penetrance and/or missed diagnoses.
1 2 3 4 5
Clinical Features
(Signs / symptoms)
Wilson disease results from absent or reduced function of the metal-transporting ATP7B protein, expressed mainly in hepatocytes, which leads to decreased hepatocellular excretion of copper into bile. The condition manifests as liver disease more commonly in children and younger adults; other major symptomology may include neurologic disease (e.g. movement disorders or rigid dystonia), mood disturbances, difficulty with motor skills, and psychiatric manifestations (e.g. depression, phobias, compulsive behaviors, aggression, or antisocial behavior). Kayser-Fleischer rings (deposits of copper in the cornea) are often present in patients with neurologic symptoms and may be found in those without neurologic symptoms but do not cause ocular difficulties. Clinical features of Wilson disease overlap with other liver diseases such as autoimmune liver diseases, and with neurologic symptoms characteristic of a variety of other neurologic disorders, resulting in potential for misdiagnosis. As a result, Wilson disease must be excluded in any patient with unexplained liver disease along with neurological or neuropsychiatric disorder.
1 2 3
Natural History
(Important subgroups & survival / recovery)
Decreased copper excretion results in hepatic copper accumulation and injury, release of copper into the bloodstream, and copper deposition in other organs such as brain, kidneys, and cornea. After a presymptomatic period, approximately 40% of patients present acutely with liver failure, hemolytic anemia, or both, or more chronically with liver conditions such as chronic hepatitis, portal hypertension, or cirrhosis. In other patients, liver disease remains subclinical and neuropsychiatric symptoms develop, reflecting ongoing copper deposition in other organs. Clinically evident liver disease may precede neurologic manifestations by as much as 10 years, and most patients with neurologic symptoms have some degree of liver disease. However, neurological, behavioral, and/or psychiatric signs are present in almost 50% of patients at any one time, and present before motor signs in 20% of cases. Neuropsychiatric presentation can be extremely subtle, and intermitted for many years, but may also develop very rapidly, leading within a few months to complete disability. Wilson disease is uniformly fatal without treatment, with most patients dying from liver disease and a minority from complications of progressive neurologic disease. The majority of patients present between ages 5 and 35 but the oldest patients have been diagnosed in their early 70s. Symptoms at any age are frequently nonspecific and the spectrum of disease at presentation is highly variable.
2 3 4 6
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extent of the disease and treatment needs of an individual diagnosed with Wilson disease, the following evaluations are recommended following initial diagnosis: biochemical testing and imaging of the liver, upper GI endoscopy to exclude or confirm esophageal varices, detailed clinical neurologic assessment, assessment of kidney function, medical genetics consultation. (Tier 4)
1
Treatment of presymptomatic patients can be accomplished with a chelating agent or with zinc. Treatment is lifelong and should not be discontinued (including during pregnancy). (Tier 2)
2 3
In a systematic review of 10 studies of chelation therapy in asymptomatic patients (1 randomized comparative effectiveness trial, 5 prospective and 4 retrospective cohort studies), mean age at diagnosis of Wilson disease was 10 to 11 years, age range was 1.5 to 39 years. Clinical effectiveness was defined as the ability of the interventional drug to prevent clinical symptoms related to Wilson disease over the mean evaluation periods of 57 months (range 12-186) and 81 months (range 12-144) for D-penicillamine and zinc, respectively. Both D-penicillamine (chelator) and zinc were effective in 70/70 (100%) and 66/66 (100%) of presymptomatic patients, respectively. However, given the average age of onset, the lack of untreated comparison groups, or an explanation in the review for why these followup periods were reported, it is unclear whether patients would have progressed without treatment. (Tier 1)
4
Surveillance
For routine monitoring, serum copper and ceruloplasmin, liver biochemistries and international normalized ratio, complete blood count and urinalysis (especially for those on chelation therapy), as well as physical and neurological examination should be performed regularly, at least twice annually. Patients receiving chelation therapy require a complete blood count and urinalysis regularly, no matter how long they have been on treatment. (Tier 2)
2 3
The 24-hour urinary excretion of copper while on medication should be measured yearly, or more frequently if there are questions on compliance or if dosage of medications is adjusted. The serum unbound copper may be another useful parameter for monitoring therapy. (Tier 2)
2 3
Family Management
Siblings of any patient newly diagnosed with WD should be screened for WD and offspring of patients should be tested by serum ceruloplasmin concentration after age one year unless consanguinity is present. (Tier 4)
1
Circumstances to Avoid
Patients should avoid intake of foods and water with high concentrations of copper, especially during the first year of treatment. (Tier 2)
3
Diets deficient in copper may delay the onset of the disease and control disease progression. (Tier 3)
2
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Recessive
 
Wilson disease is inherited in an autosomal recessive manner. Most patients are compound heterozygotes. Clinical disease is not known to occur in carriers.
1 3
Prevalence of Genetic Mutations
Traditionally, estimates for carrying one copy of a mutation in ATP7B have been 1 in 90 individuals. A recent UK study of newborn blood spots suggests this prevalence may be substantially higher at 1 in 18 to 25 individuals (depending on the categorization of variant pathogenicity); the corresponding number of homozygotes would be 1 in 2,500 to 7,026 individuals. (Tier 5)
5
Penetrance
OR
Relative Risk
(Include any high risk racial or ethnic subgroups)
No estimates of penetrance were found.
 
No estimates of penetrance were found.
 
 
 
No information on relative risk was found.
 
 
Expressivity
Wilson disease can manifest as hepatic, neurologic, hematologic, or psychiatric disturbances, or a combination of these, in individuals ranging in age from three years to over 60 years. Phenotypic expression is variable, even within families. (Tier 4)
1
4. What is the Nature of the Intervention?
Nature of Intervention
Interventions are noninvasive surveillance and lifelong pharmacologic treatment (all available in capsule/tablet form). D-penicillamine in particular, although extensively used, is associated with severe early (e.g. sensitivity reactions, fever, proteinuria) and late side effects (e.g. significant bone marrow toxicity, nephrotoxicity, lupus-like syndrome, dermatological toxicities, and, rarely, myasthenia gravis, polymyositis, serous retinitis) requiring the drug to be discontinued in approximately 30% of patients.
 
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Acute or chronic hepatitis with Wilson's disease presents similarly to any other acute or chronic cases of hepatitis. A delay in diagnosing Wilson's disease in patients with neuropsychiatric presentations is frequent. (Tier 3)
3
 

 
Final Consensus Scores
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Liver disease / Chelation/zinc therapy
2
3D
3A
2
10DA
Neuropsychiatric disease / Chelation/zinc therapy
2
3D
3A
2
10DA
To see the scoring key, please go to: https://clinicalgenome.org/working-groups/actionability/projects-initiatives/actionability-evidence-based-summaries/
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. Wilson disease. Gene reviews. (2013) Website: http://www.ncbi.nlm.nih.gov/books/NBK1512/
2. Roberts EA, Schilsky ML. Diagnosis and treatment of wilson disease: an update. Hepatology. (2008) 47(6):2089-111.
3. Easl clinical practice guidelines: wilson's disease. J Hepatol. (2012) 56(3):671-85.
4. Wiggelinkhuizen M, Tilanus ME, Bollen CW, Houwen RH. Systematic review: clinical efficacy of chelator agents and zinc in the initial treatment of wilson disease. Aliment Pharmacol Ther. (2009) 29(9):947-58.
5. Coffey AJ, Durkie M, Hague S, McLay K, Emmerson J, Lo C, Klaffke S, Joyce CJ, Dhawan A, Hadzic N, Mieli-Vergani G, Kirk R, Elizabeth Allen K, Nicholl D, Wong S, Griffiths W, Smithson S, Giffin N, Taha A, Connolly S, Gillett GT, Tanner S, Bonham J, Sharrack B, Palotie A, Rattray M, Dalton A, Bandmann O. A genetic study of wilson's disease in the united kingdom. Brain. (2013) 136(Pt 5):1476-87.
6. Bonnot O, Klunemann HH, Sedel F, Tordjman S, Cohen D, Walterfang M. Diagnostic and treatment implications of psychosis secondary to treatable metabolic disorders in adults: a systematic review. Orphanet J Rare Dis. (2014) 9:65.
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