Wilson’s disease is a rare condition characterised by abnormal copper deposition.
Wilson’s is an inherited, multi-system, progressive disorder of copper metabolism. Named after British neurologist Dr Samuel Alexander Kinnier Wilson, it has an estimated incidence between 1 in 30,000 and 1 in 100,000.
It often presents with liver involvement or neuropsychiatric symptoms, but it can present in a number of other ways including haemolysis. Though it can develop at any age, it most commonly occurs between the ages of 5 and 35.
Wilson’s disease is an autosomal recessive disorder.
It is caused by mutations to the ATP7B gene on chromosome 13. About 500 different mutations causing Wilson's disease have been identified in this gene. ATP7B encodes a copper-transporting P-type ATPase that is found in hepatocytes (in the trans-Golgi network). The majority of these mutations are missense (single base pair change) that lead to loss-of-function. This means complete disruption of the normal copper-transporting protein function and the accumulation of copper in affected tissues.
As an autosomal recessive disorder, an offspring must receive an affected gene from both their mother and their father. When two carriers of a recessive allele have a child, there is a 25% chance of developing the condition, 50% chance of being a carrier (unaffected carrier) and a 25% chance of being entirely unaffected (non-carrier).
There are a multitude of mutations of the ATP7B gene that can lead to Wilson's disease. As such it is common for an affected patient to have inherited two different mutations, one from their mother and one from their father - these are referred to as compound heterozygotes. A compound heterozygote describes the inheritance of two different recessive alleles for the same gene, one on each chromosome (as opposed to homozygous if they had inherited the same mutation from each parent).
Wilson's disease most commonly presents due to hepatic or neurological involvement.
The diagnosis of Wilson’s disease relies on both clinical and biochemical findings.
Identification of at-risk relatives can prevent significant morbidity and mortality.
Genetic counselling should be offered with clear explanations about the condition and the mechanism of inheritance.
Treatment aims to reduce levels of copper and prevent further end-organ damage.
D-Penicillamine: the mainstay of Wilson’s management. It chelates copper and promotes its urinary excretion. It, unfortunately, has numerous side effects, many severe, which prohibits around one-third of patients from using it. Neurological symptoms can worsen at the start of treatment.
Trientine: also a chelation agent, trientine promotes urinary excretion of copper. It may be used as initial therapy or for those who do not tolerate D-penicillamine.
Transplant may be required in patients presenting with acute liver failure or decompensated cirrhosis.
Orthotopic liver transplantation (removal of the patients liver which is replaced by a donor liver) results in normal hepatic handling of copper. Live, related (obligate heterozygote) transplantation offers excellent results.
Prior to conception copper levels should be optimised. Haplotype analysis of their partner should be offered.
Treatment should continue in pregnancy but must be optimised and managed by a specialist. There is limited information on the safety of breast feeding whilst on chelation agents.
Wilson's is a progressive disease, early recognition and treatment is essential.
Untreated Wilson’s disease is fatal. The majority of patients die due to liver complications, though a minority will die from neurological complications.
Prognosis is dependent, in part, on time of diagnosis, with those diagnosed and treated early having better long-term outcomes. Specialist treatment and adherence to therapy is key to improving survival.
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