GENETIC SIDE OF WILSON'S DISEASE

WILSON’S HEPATO - LENTICULAR DEGENERTION.


  • CODE IN ICD-10 : E83.01

  • CODE IN OMIM : 277900

Frequency Of Disease In Different Populations And Ethnic Groups.

Wilson disease is found worldwide, with an estimated prevalence of 1 case per 30,000 live births in most populations , although data from population screening by molecular sequencing in the United Kingdom suggest a potentially higher prevalence, perhaps as frequent as 1 case in 7021.


SEX & AGE CHARACTERISTICS

  • Wilson's disease is a rare inherited disorder that causes copper to accumulate in your liver, brain and other vital organs. Most people with Wilson's disease are diagnosed between the ages of 5 and 35, but it can affect younger and older people, as well.

  • Wilson disease is a rare disorder that affects males and females in equal numbers. The disease is found in all races and ethnic groups. Although estimates vary, it is believed that Wilson's disease occurs in approximately one in 30,000 to 40,000 people worldwide.

TYPES OF INHERITANCE

  • Wilson disease is inherited in an autosomal recessive manner. This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell.

  • The parents of an affected person usually each carry one mutated copy of the gene and are referred to a carriers. Carriers typically do not show signs or symptoms of the condition.

  • When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

GENES & THEIR LOCALISATION

  • Wilson disease is caused by changes (mutations) in the ATP7B gene. This gene encodes a protein that plays an important role in the transport of copper from the liver to the rest of the body. It also helps remove excess copper from the body.

  • Mutations in the ATP7B gene prevent this protein from working properly, which can lead to an accumulation of copper in the body. Because high levels of copper are toxic, this buildup can damage tissues and organs and cause the many signs and symptoms of Wilson disease.

ETIOLOGY

  • Wilson's disease is caused by a mutation in the Wilson disease protein (ATP7B) gene. This protein transports excess copper into bile, where it is excreted in waste products. The condition is autosomal recessive; for a person to be affected, they must inherit a mutated copy of the gene from both parents.

PATHOGENESIS

  • Wilson disease is an autosomal-recessive disorder originating from a genetic defect in the copper-transporting ATPase ATP7B that is required for biliary copper secretion and loading of ceruloplasmin with copper.

  • Impaired ATP7B function in Wilson disease results in excessive accumulation of copper in liver, brain, and other tissues. Toxic copper deposits may induce oxidative stress, modify expression of genes, directly inhibit proteins, and impair mitochondrial function, leading to hepatic, neuropsychiatric, renal, musculoskeletal, and other symptoms.

  • Hepatocyte dysfunction initially manifests as steatosis and later may progress to other hepatic phenotypes such as acute liver failure, hepatitis, and fibrosis. In the brain, copper accumulates in astrocytes, leading to impairment of the blood-brain barrier and consequent damage to neurons and oligodendrocytes.

  • Basal ganglia and brainstem are the brain regions with highest susceptibility to copper toxicity and their lesions lead to various combinations of movement and psychiatric disorders.


CLINICAL CHARACTERISTICS

  • Kayser-Fleischer rings are seen in at least 98% of patients with neurological Wilson disease who have not received chelation therapy.

  • Frequent early symptoms include difficulty speaking, excessive salivation, ataxia, mask like faces, clumsiness with the hands, and personality changes.

DIAGNOSIS

  • Wilson's disease may be suspected on the basis of any of the symptoms mentioned above, or when a close relative has been found to have Wilson's.

  • Most have slightly abnormal liver function tests such as a raised aspartate transaminase, alanine transaminase and bilirubin level. If the liver damage is significant, albumin may be decreased due to an inability of damaged liver cells to produce this protein; likewise, the prothrombin time (a test of coagulation) may be prolonged as the liver is unable to produce proteins known as clotting factors.

  • Alkaline phosphatase levels are relatively low in those with Wilson's-related acute liver failure. If there are neurological symptoms, magnetic resonance imaging (MRI) of the brain is usually performed; this shows hyperintensities in the part of the brain called the basal ganglia in the T2 setting. MRI may also demonstrate the characteristic "face of the giant panda” pattern.

  • #There is no totally reliable test for Wilson's disease, but levels of ceruloplasmin and copper in the blood, as well of the amount of copper excreted in urine during a 24-hour period, are together used to form an impression of the amount of copper in the body. The gold standard—or most ideal test—is a liver biopsy.

CERULOPLASMIN

  • Levels of ceruloplasmin are abnormally low (<0.2 g/L) in 80–95% of cases. It can, however, be present at normal levels in people with ongoing inflammation as it is an acute phase protein.

  • Low ceruloplasmin is also found in Menkesdisease and aceruloplasminemia, which are related to, but much rarer than Wilson's disease.

  • The combination of neurological symptoms, Kayser–Fleischer rings and a low ceruloplasmin level is considered sufficient for the diagnosis of Wilson's disease. In many cases, however, further tests are needed.

SERUM AND URINE COPPER

Serum copper is low, which may seem paradoxical given that Wilson's disease is a disease of copper excess. However, 95% of plasma copper is carried by ceruloplasmin which is often low in Wilson's disease.

Urine copper is elevated in Wilson's disease and is collected for 24 hours in a bottle with a copper-free liner. Levels above 100 μg/24h (1.6 μmol/24h) confirm Wilson's disease, and levels above 40 μg/24h (0.6 μmol/24h) are strongly indicative.High urine copper levels are not unique to Wilson's disease; they are sometimes observed in autoimmune hepatitis and in cholestasis (any disease obstructing the flow of bile from the liver to the small bowel).

In children, the penicillamine test may be used. A 500 mg oral dose of penicillamine is administered, and urine collected for 24 hours. If this contains more than 1600 μg (25 μmol), it is a reliable indicator of Wilson's disease.This test has not been validated in adults.


LIVER BIOPSY

Once other investigations have indicated Wilson's disease, the ideal test is the removal of a small amount of liver tissue through a liver biopsy. This is assessed microscopically for the degree of steatosis and cirrhosis, and histochemistry and quantification of copper are used to measure the severity of the copper accumulation. A level of 250 μg of copper per gram of dried liver tissue confirms Wilson's disease.

Occasionally, lower levels of copper are found; in that case, the combination of the biopsy findings with all other tests could still lead to a formal diagnosis of Wilson's.

In the earlier stages of the disease, the biopsy typically shows steatosis (deposition of fatty material), increased glycogen in the nucleus, and areas of necrosis (cell death). In more advanced disease, the changes observed are quite similar to those seen in autoimmune hepatitis, such as infiltration by inflammatory cells, piecemeal necrosis and fibrosis (scar tissue).

In advanced disease, finally, cirrhosis is the main finding. In acute liver failure, degeneration of the liver cells and collapse of the liver tissue architecture is seen, typically on a background of cirrhotic changes. Histochemical methods for detecting copper are inconsistent and unreliable, and taken alone are regarded as insufficient to establish a diagnosis.


GENETIC TESTING

Mutation analysis of the ATP7B gene, as well as other genes linked to copper accumulation in the liver, may be performed. Once a mutation is confirmed, it is possible to screen family members for the disease as part of clinical genetics family counseling.

Regional distributions of genes associated with Wilson's disease are important to follow, as this can help clinicians design appropriate screening strategies. Since mutations of the WD gene vary between populations, research and genetic testing done in countries like the USA or United Kingdom can pose problems as they tend to have more mixed populations.


TREATMENT

Diet Therapy

In general, a diet low in copper-containing foods is recommended with the avoidance of mushrooms, nuts, chocolate, dried fruit, liver, sesame seeds and sesame oil, and shellfish.

Medication

In general, a diet low in copper-containing foods is recommended with the avoidance of mushrooms, nuts, chocolate, dried fruit, liver, sesame seeds and sesame oil, and shellfish.


Once all results have returned to normal, zinc (usually in the form of a zinc acetate prescription called Galzin) may be used instead of chelators to maintain stable copper levels in the body. Zinc stimulates metallothionein, a protein in gut cells that binds copper and prevents their absorption and transport to the liver. Zinc therapy is continued unless symptoms recur or if the urinary excretion of copper increases.

In rare cases where none of the oral treatments are effective, especially in severe neurological disease, dimercaprol (British anti-Lewisite) is occasionally necessary. This treatment is injected intramuscularly (into a muscle) every few weeks and has unpleasant side effects such as pain.

People who are asymptomatic (for instance, those diagnosed through family screening or only as a result of abnormal test results) are generally treated, as the copper accumulation may cause long-term damage in the future. It is unclear whether these people are best treated with penicillamine or zinc acetate.


Physical and occupational therapies

Physiotherapy and occupational therapy are beneficial for patients with the neurologic form of the disease. The copper chelating treatment may take up to six months to start working, and these therapies can assist in coping with ataxia, dystonia, and tremors, as well as preventing the development of contractures that can result from dystonia.


#Transplantation

Liver transplantation is an effective cure for Wilson's disease but is used only in particular scenarios because of the risks and complications associated with the procedure. It is used mainly in people with fulminant liver failure who fail to respond to medical treatment or in those with advanced chronic liver disease. Liver transplantation is avoided in severe neuropsychiatric illness, in which its benefit has not been demonstrated.


PROGNOSIS

Left untreated, Wilson's disease tends to become progressively worse and is eventually fatal. With early detection and treatment, most of those affected can live relatively normal lives. Liver and neurologic damage that occurs prior to treatment may improve, but it is often permanent.


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