Wilson disease (ATP7B gene): copper, the liver and family testing

Copper is a trace metal that the body needs in tiny amounts and normally gets rid of in excess through bile. Patient explains that in Wilson disease this does not work, so copper builds up, mainly in the liver, the brain, the cornea at the front of the eye and the kidneys. When the liver cells can no longer store it, copper spills into the bloodstream and is deposited elsewhere, particularly the brain. The older name, hepatolenticular degeneration, refers to the liver and a part of the brain called the lenticular nucleus.

The NHS Genomics Education Programme says people typically present before the age of 40, with liver problems in younger people and neurological features in older ones, and that children can present with behavioural changes. Liver features range from abnormal blood tests to acute liver failure. Neurological features include tremor, speech and swallowing difficulty, dystonia and parkinsonism, and psychiatric features include depression, anxiety, irritability and sometimes psychosis. Kayser-Fleischer rings, brownish copper deposits at the edge of the cornea, may be seen on slit-lamp examination.

Patient adds that although the genetic fault is present at birth, copper takes years to accumulate, so symptoms typically start between about 6 and 20, most commonly in the teenage years, with some people not developing symptoms until middle age.

The ATP7B protein is a copper pump in liver cells. It enables copper to be excreted into bile and loaded onto caeruloplasmin, a copper-carrying protein in the blood. The NHS Genomics Education Programme says over 800 variants have been linked to disease, with different common variants in different populations, and that this diversity contributes to the range of presentations and severity.

Because of this, genetic testing is one of several diagnostic tools rather than the only one. The programme lists very low blood caeruloplasmin (below 0.1 g/L) as highly suggestive, raised copper in a 24-hour urine collection, Kayser-Fleischer rings, brain MRI and ATP7B gene sequencing as tests that support the diagnosis, with a scoring system used under specialist guidance. Patient notes that caeruloplasmin is low in nearly all people with Wilson disease, but that Kayser-Fleischer rings are not present in all cases.

Wilson disease is autosomal recessive: a person needs two altered copies of ATP7B, one from each parent. Patient explains that carriers have one normal gene, which is enough to handle copper, so they do not have the disorder but can pass the gene on. When two carriers have a child, there is a 1 in 4 chance of Wilson disease, a 2 in 4 chance of a carrier child and a 1 in 4 chance of neither.

Estimates of how common carriers are differ between sources. The NHS Genomics Education Programme gives a carrier frequency of 1 in 65 to 1 in 70, whereas Patient says about 1 in 100. Both agree that the disease itself is rare.

Siblings matter. Patient says that if Wilson disease is confirmed, siblings should be checked, and brothers and sisters of an affected person have a 1 in 4 chance of also having the condition. The NHS Genomics Education Programme says siblings should be offered screening and that it is common practice to screen the children of affected individuals. It cautions that normal biochemical tests in an at-risk person do not reliably separate someone who will develop symptoms (two altered copies) from a carrier or non-carrier, which is why genetic testing helps in families.

The NHS Genomics Education Programme says Wilson disease should be considered in children and adults with liver disease, in people aged 5 to 50 with a progressive movement disorder, and in people with unexplained haemolytic anaemia that is Coombs-negative. Diagnosis is made by specialist interpretation of the tests in the right clinical context. Patient adds that a liver biopsy can show the copper and any scarring, and that an optician or eye specialist may see Kayser-Fleischer rings.

Patient says it is essential to treat Wilson disease because untreated it can be fatal, that the earlier treatment starts the better the chance of preventing permanent liver or brain damage, and that there is no cure but treatment reduces complications. The NHS Genomics Education Programme says the mainstay is lifelong copper chelation therapy, with D-penicillamine first-line in England and trientine used if penicillamine is not tolerated, and that zinc salts should not be used first-line in symptomatic disease.

The programme adds that neurological symptoms can worsen at the start of chelation, so the dose is started low and carefully increased; that acute liver failure is a medical emergency needing urgent referral to a liver transplant centre; and that longer-term care includes monitoring urinary copper, screening for complications such as liver cancer in people with cirrhosis, and multidisciplinary treatment of neurological and psychiatric symptoms. There are currently no approved gene therapies for Wilson disease.