Wilson’s Disease in Children: Genetic Diagnosis and Long-Term Management

Introduction:

Wilson’s disease is a rare disorder that affects copper metabolism in the body. It is primarily seen in the liver and brain. It is mainly seen in children. Dr. Samuel Alexander Kinnier Wilson was the first person to introduce it. This article explores this disease, focusing on its genetic cause and long-term management.

What Is the Pathophysiology of Wilson’s Disease?

• Genetics: Wilson’s disease is an autosomal recessive genetic disorder, which means two copies of the ATP7B mutated gene on chromosome 13 are inherited, one from each parent. This gene is responsible for transporting excess copper out of the liver. When this gene is mutated, a dysfunctional protein is formed, which is involved in copper buildup within the liver. When copper is in excess in the liver, it gets released into the blood.

• Copper Metabolism: Copper is an element necessary for mitochondrial respiration. Copper foods are consumed, digested, and taken up through the intestines and transported to the liver via the portal system. ATP7A is the transporter involved. ATP7B also helps the excretion of copper into bile. The copper molecules also get incorporated into ceruloplasmin.

Mutations in the ATP7B gene lead to increased copper accumulation in the liver. Other tissues, like brain, eyes, and heart, take the copper excess. This excess leads to a condition of oxidative stress, and free radicals cause great damage to cell structures. Copper also binds with proteins involved in homeostatic regulation and accumulates in lysosomes. These lead to liver fibrosis, inflammation, and cirrhosis.

What Are the Clinical Manifestations of This Disease?

Wilson disease can affect any age group but is more common in young children. However, symptoms are commonly detected after three years of age.

• Hepatic Manifestation: Some individuals are asymptomatic and get to know their diagnosis only from testing and screening. Others may develop serious liver complications. The patient is usually asymptomatic initially, with slight enzyme elevations found on routine tests. Once the disease moves to advanced stages, there may be signs of liver issues. Commonly seen are:

1. Jaundice.

2. Hepatitis.

3. Hepatomegaly.

4. Coagulopathy.

Some patients might have a history of hepatitis. They may have a history of mild elevation of liver enzymes and high bilirubin and low alkaline phosphatase.

• Neurological Manifestation: Chronic toxicity of copper levels leads to demyelination and damage to the cerebellum, brainstem, and thalamus. These are rarely seen in children below ten years of age. When they occur, the common neurological manifestations include :

1. Coordination.

2. Reduced learning ability.

3. Mild cognitive impairment.

4. Movement disorders.

5. Personality issues.

6. Mood disorders.

7. Psychosis.

8. Dysarthria.

• Ophthalmic Manifestation:

1. Kayser-Fleischer rings (gold or brown opacity).

2. Sunflower cataract.

• Others: A sudden increase in copper levels in the bloodstream leads to hemoglobin damage and anemia. In muscles, it inhibits the sodium-potassium pump, leading to rhabdomyolysis. In the kidney, excess copper leads to tubulopathy.

How Is Wilson’s Disease Diagnosed?

Clinical evaluation is carried out, but the signs and symptoms are varied and can mimic other disorders. Therefore, a combination of laboratory and clinical testing is carried out.

• Serum Copper Determination: Total copper levels in the body are determined. A new test of exchangeable ciphers is developed to measure the unbound copper specifically. This does not include the ceruloplasmin quantity and is more reliable. Normal values are 0.62 to 1.15 micromolecules per liter. However, this test is costly and not easily available currently.

• Penicillamine Challenges Urine Copper: Urine copper tests check how much copper is excreted. The accuracy of urine tests depends on the collection method, type of container, and expertise. A penicillamine test is done by administering two doses of 500 mg penicillamine and conducting a 24-hour urine collection to check the copper levels.

• Liver Copper: A liver biopsy is advised whenever there is doubt about additional liver lesions and biochemical tests do not give conclusive results. The histological evaluation of Wilson disease is not very specific; it can present as steatosis, copper deposition, iron deposition, portal fibrosis, and inflammation may also be seen.

• Ceruloplasmin: Ceruloplasmin is a copper transport agent and a potent antioxidant. It can be assessed using enzymatic assays and immunologic methods. However, conditions such as malnutrition and inflammation can affect ceruloplasmin levels.

• Genetic Analysis: This is the most important tool to confirm Wilson's disease and to distinguish between heterozygous catties and pre-symptomatic patients. Around 900 mutations within the ATP7B gene have been identified to be involved with this disease. Further molecular analysis may be needed in some patients to study large gene defects. Genetic counseling is essential for families with this disease, and first-degree raises are to be screened. The disadvantages include they are less accessible and can take time.

• Imaging: Brain MRI is performed on patients with neurological signs. Hyperactive intensity lesions may be visualized on the basal ganglia, suggesting cerebral involvement.

How Is Wilson’s Disease Managed in the Long Term?

Long-term management mainly involves preventing copper accumulation, reducing circulation and stored levels.

• Pharmacological:

1. Penicillamine: This helps to bind copper and also helps in its excitation. It is started at a low dose and then increased gradually. Patients may present with hypersensitive reactions. Pyridoxine supplements is used along with it as it interferes with its metabolism.

2. Trientine: Chelating agent, also create an iron chelate problem.

3. Zinc: This interferes with copper uptake from the digestive system and increases excretion in stool lit. In patients with neurological manifestations, zinc should be given as a first-line drug. Side effects include gastritis.

4. Ammonia Tetrathiomolybdate: This medication is still under research

5. Liver Transplantation: In patients with severe liver damage and rapid dysfunction along with hepatic encephalopathy, liver failure occurs despite therapy. In such serious cases, liver transplantation is advised.

• Gene Therapy: Genetic correction of mutated genes is under research in humans. It involves the transplantation of healthy human hepatocytes. Technological aids to correct the targeted gene are also being used. If proven successful, this can revolutionize the treatment.

• Others: Reduced consumption of copper-enriched foods like meat, liver, nuts, and mushrooms should be done until the symptoms are relieved and blood tests for copper levels are normal.

Conclusion:

Wilson disease is a rare genetic disorder seen in children. It requires early detection and comprehensive treatment to prevent irreversible damage to organs. Advances in medical diagnosis and therapy, including genetic testing and advanced imaging, have helped to provide personalized care to affected children. Proper, timely intervention, including pharmacological chelation therapy of copper and providing good nutritional support, can significantly improve the prognosis for Wilson's disease.