Wilson Disease in Children
Introduction to Wilson Disease in Children
Wilson disease (WD) is a rare autosomal recessive disorder of copper metabolism that affects approximately 1 in 30,000 individuals worldwide. It is characterized by excessive accumulation of copper in various organs, primarily the liver and brain. In children, WD can present with a wide range of symptoms and is an important consideration in the differential diagnosis of liver disease and neurological disorders.
Key points:
- Caused by mutations in the ATP7B gene on chromosome 13
- Results in impaired biliary excretion of copper and reduced incorporation of copper into ceruloplasmin
- Typically presents in children and young adults, but can manifest at any age
- Early diagnosis and treatment are crucial for preventing irreversible organ damage
Pathophysiology of Wilson Disease
The pathophysiology of Wilson disease involves:
- Genetic Basis: Mutations in the ATP7B gene lead to dysfunction of the copper-transporting P-type ATPase.
- Copper Accumulation: Impaired biliary excretion of copper and reduced incorporation into ceruloplasmin result in copper accumulation in hepatocytes.
- Oxidative Damage: Excess free copper causes oxidative stress and cellular damage in affected organs.
- Organ Involvement: Primary organs affected include:
- Liver: Hepatitis, cirrhosis, and acute liver failure
- Brain: Basal ganglia, cerebellum, and cortex leading to neurological and psychiatric symptoms
- Eyes: Kayser-Fleischer rings and sunflower cataracts
- Kidneys: Renal tubular dysfunction
Clinical Presentation in Children
Wilson disease in children can present with a variety of symptoms, often categorized by the primary organ system involved:
1. Hepatic Presentation (40-50% of pediatric cases)
- Asymptomatic elevation of liver enzymes
- Chronic hepatitis
- Cirrhosis
- Acute liver failure (rare but can be the initial presentation)
2. Neurological Presentation (35-40% of pediatric cases)
- Movement disorders: Tremor, dystonia, chorea
- Dysarthria
- Dysphagia
- Ataxia
- Seizures (less common)
3. Psychiatric Presentation (10-20% of pediatric cases)
- Depression
- Anxiety
- Behavioral changes
- Cognitive decline
4. Other Presentations
- Kayser-Fleischer rings (may be absent in children with purely hepatic disease)
- Hemolytic anemia
- Renal abnormalities: Fanconi syndrome, nephrolithiasis
- Skeletal abnormalities: Osteoporosis, arthropathy
- Cardiomyopathy and arrhythmias (rare)
Diagnosis of Wilson Disease in Children
Diagnosis of Wilson disease in children requires a combination of clinical, biochemical, and genetic testing:
1. Serum and Urine Tests
- Serum ceruloplasmin: Typically low (<20 mg/dL)
- Serum copper: Often low due to decreased ceruloplasmin
- 24-hour urinary copper excretion: Elevated (>100 μg/24h in children; >40 μg/24h in asymptomatic siblings)
- Liver function tests: May show elevated transaminases, bilirubin, and alkaline phosphatase
2. Ophthalmologic Examination
- Slit-lamp examination for Kayser-Fleischer rings
3. Imaging Studies
- Brain MRI: May show T2 hyperintensities in basal ganglia, thalamus, and brainstem
- Abdominal ultrasound or CT: To assess liver structure and signs of portal hypertension
4. Liver Biopsy
- Hepatic copper concentration: >250 μg/g dry weight is diagnostic
- Histology: May show steatosis, inflammation, fibrosis, or cirrhosis
5. Genetic Testing
- ATP7B gene mutation analysis: Confirms diagnosis and allows for family screening
6. Scoring Systems
- Leipzig score: Combines clinical, biochemical, and genetic data for diagnostic accuracy
Treatment of Wilson Disease in Children
Treatment of Wilson disease in children is lifelong and aims to reduce copper accumulation and prevent organ damage:
1. Copper Chelation Therapy
- D-penicillamine: First-line treatment
- Initial dose: 20 mg/kg/day in 2-3 divided doses
- Maintenance dose: 10-20 mg/kg/day
- Side effects: Hypersensitivity reactions, nephrotoxicity, bone marrow suppression
- Trientine: Alternative for those intolerant to D-penicillamine
- Dose: 20-30 mg/kg/day in 2-3 divided doses
- Better tolerated than D-penicillamine
2. Zinc Therapy
- Mechanism: Interferes with intestinal absorption of copper
- Dose: 25-50 mg elemental zinc 2-3 times daily
- Used as maintenance therapy or in asymptomatic patients
3. Dietary Modifications
- Avoid copper-rich foods (shellfish, nuts, chocolate, mushrooms)
- Use of distilled or demineralized water
4. Liver Transplantation
- Indicated for acute liver failure or decompensated cirrhosis
- Curative for the hepatic manifestations of WD
5. Symptomatic Treatment
- Management of neurological symptoms: Anticholinergics, baclofen, gabapentin
- Psychiatric care: Antidepressants, antipsychotics as needed
6. Monitoring
- Regular assessment of liver function, copper levels, and neurological status
- Annual ophthalmologic examination
Prognosis and Follow-up
The prognosis for children with Wilson disease has significantly improved with early diagnosis and treatment:
1. Prognosis
- Excellent if diagnosed and treated before the onset of significant liver or neurological damage
- Variable in symptomatic patients, depending on the extent of organ involvement at diagnosis
- Poor in untreated cases or those presenting with fulminant hepatic failure
2. Long-term Follow-up
- Lifelong adherence to treatment is essential
- Regular monitoring of liver function tests, serum copper, and urinary copper excretion
- Annual neurological and psychiatric evaluation
- Periodic assessment of treatment efficacy and side effects
3. Complications
- Liver cirrhosis and its complications (portal hypertension, hepatocellular carcinoma)
- Persistent neurological deficits
- Treatment-related side effects
4. Family Screening
- Genetic counseling for family members
- Screening of siblings and other first-degree relatives
5. Transition to Adult Care
- Planned transition from pediatric to adult healthcare services
- Ongoing education about the disease and importance of treatment adherence
Wilson Disease in Children
- Question: What is the underlying genetic defect in Wilson disease? Answer: Mutations in the ATP7B gene, which encodes a copper-transporting ATPase
- Question: What is the pattern of inheritance for Wilson disease? Answer: Autosomal recessive inheritance
- Question: What is the primary pathophysiological consequence of ATP7B gene mutations? Answer: Impaired biliary excretion of copper and decreased incorporation of copper into ceruloplasmin
- Question: At what age do symptoms of Wilson disease typically first appear in children? Answer: Symptoms usually appear between ages 5 and 35, with liver disease often presenting in childhood or adolescence
- Question: What are the main organs affected by copper accumulation in Wilson disease? Answer: Liver and brain are the primary organs affected, but copper can accumulate in other tissues as well
- Question: What is the classic ophthalmological finding in Wilson disease? Answer: Kayser-Fleischer rings, which are copper deposits in the cornea
- Question: What percentage of children with Wilson disease present with liver disease as the initial manifestation? Answer: Approximately 40-50% of children with Wilson disease present with liver disease initially
- Question: What are the common neurological symptoms of Wilson disease in children? Answer: Tremor, dysarthria, dystonia, and coordination problems
- Question: What is the most sensitive and specific biochemical test for diagnosing Wilson disease? Answer: 24-hour urinary copper excretion
- Question: What is the typical ceruloplasmin level in children with Wilson disease? Answer: Ceruloplasmin levels are usually low (<20 mg/dL) in Wilson disease
- Question: How is the hepatic copper concentration measured in suspected Wilson disease? Answer: Liver biopsy with quantitative copper measurement
- Question: What is the diagnostic threshold for hepatic copper concentration in Wilson disease? Answer: >250 μg/g dry weight of liver tissue
- Question: What imaging modality is most useful for evaluating brain involvement in Wilson disease? Answer: Magnetic Resonance Imaging (MRI) of the brain
- Question: What are the characteristic MRI findings in the brain of children with Wilson disease? Answer: T2 hyperintensities in the basal ganglia, thalamus, and brainstem
- Question: What is the primary goal of treatment in Wilson disease? Answer: To reduce copper accumulation and prevent or reverse organ damage
- Question: What is the first-line medication for treating Wilson disease in children? Answer: D-penicillamine or trientine (copper chelators)
- Question: What is the role of zinc in the treatment of Wilson disease? Answer: Zinc salts can be used as maintenance therapy or in asymptomatic patients to reduce copper absorption
- Question: How long should chelation therapy be continued in children with Wilson disease? Answer: Lifelong therapy is required to prevent copper reaccumulation
- Question: What dietary modifications are recommended for children with Wilson disease? Answer: Avoidance of copper-rich foods such as shellfish, nuts, chocolate, and organ meats
- Question: What is the recommended frequency of monitoring liver function tests in children on treatment for Wilson disease? Answer: Every 3-6 months, or more frequently during initial therapy or dose adjustments
- Question: What is the role of liver transplantation in Wilson disease? Answer: Liver transplantation is indicated for fulminant hepatic failure or end-stage liver disease unresponsive to medical treatment
- Question: How does pregnancy affect women with Wilson disease? Answer: Pregnancy is generally safe with proper treatment, but medication adjustments may be necessary
- Question: What is the recommended approach for screening siblings of a child diagnosed with Wilson disease? Answer: All siblings should undergo clinical evaluation, serum ceruloplasmin measurement, and genetic testing
- Question: What is the long-term prognosis for children with Wilson disease who receive early treatment? Answer: With early diagnosis and proper treatment, most children can expect a normal lifespan and quality of life
- Question: What is the role of genetic testing in diagnosing Wilson disease? Answer: Genetic testing can confirm the diagnosis and is particularly useful in family screening
- Question: How does Wilson disease affect growth and development in children? Answer: Untreated Wilson disease can lead to growth retardation and delayed puberty
- Question: What is the significance of low serum uric acid levels in Wilson disease? Answer: Low serum uric acid levels are common in Wilson disease due to increased urinary excretion of uric acid
- Question: What is the Leipzig score and how is it used in Wilson disease? Answer: The Leipzig score is a diagnostic scoring system that combines clinical, biochemical, and genetic findings to assess the likelihood of Wilson disease
- Question: What is the role of molecular genetic testing in Wilson disease diagnosis? Answer: Molecular genetic testing can confirm the diagnosis by identifying mutations in the ATP7B gene, especially in uncertain cases
- Question: How does Wilson disease affect cognitive function in children? Answer: Cognitive impairment, including reduced attention span and executive function, can occur in children with Wilson disease, especially if neurological symptoms are present
- Question: What is the recommended approach for monitoring copper balance during treatment? Answer: 24-hour urinary copper excretion and non-ceruloplasmin bound copper (NCC) levels are used to monitor copper balance
- Question: What are the potential side effects of D-penicillamine treatment in children? Answer: Side effects may include rash, fever, proteinuria, bone marrow suppression, and elastosis perforans serpiginosa
- Question: How does Wilson disease affect fertility and reproductive health? Answer: Untreated Wilson disease can cause infertility and menstrual irregularities, but these often improve with proper treatment
- Question: What is the role of antioxidants in the management of Wilson disease? Answer: Antioxidants like vitamin E may be beneficial as adjunctive therapy to reduce oxidative stress caused by copper toxicity
