Wilson’s disease (WD) is a rare disease, defined as an autosomal recessive disorder characterised by release of free copper and dramatic accumulation of intracellular hepatic copper with subsequent hepatic and central nervous system abnormalities. Mutations of the ATP7B gene are responsible for the metabolic dysfunction.
Small open studies have reported spinal radiological abnormalities including scoliosis, diffuse bone demineralisation, osteochondritis and occasionally fracture. Prevalence of osteoporosis in young adult patients is debated, ranging from 10%, with normal mean Z -score values, to 43% in adults. Past history of spinal or peripheral fractures might be present in 50% of patients.
Articular disorders include arthralgias of large joints, such as knee pain, rare effusions, early onset of radiological features of osteoarthritis and associated osteochondritis of the knee joint. Radiological chondrocalcinosis, an unusual feature in young adults, has to be confirmed. Few patients may develop drug-induced lupus with arthralgias, positive anti-nuclear and anti-histone antibodies, secondary to D-penicillamine, the major copper chelator used in WD. In this orphan disease, small retrospective studies cannot allow ascertaining definite WD-related articular and bone manifestations. However, such clinical and radiological abnormalities are occasionally the first symptoms leading to diagnosis. Physicians should be aware that unexplained joint pain and effusion, or even radiological features of osteoarthritis, of the large joints in adolescents could suggest WD and lead to copper survey.
Wilson’s disease (WD) is an autosomal recessive genetic disorder in which copper accumulates in tissues, especially in the liver and in the neurologic system, and occasionally osteoarticular manifestations have been reported.
WD
Epidemiology and physiopathology
WD is a rare disease. The worldwide prevalence is estimated to be on the order of 30 per 1 million, with a gene frequency of 0.56% and a carrier frequency of 1 in 90. In France, the incidence is estimated at 1/30 000–1/100 000 new case per year and its prevalence at 1/25 000 (ORPHANET 905; MIM 277900 : ).
WD is an autosomal recessive disorder, due to a mutation in the gene ATP7B mapped to chromosome 13 (13q14.3). This gene codes for a copper-transporting ATPase ( Cu ( 2 +)- Transporting , Beta Polypeptide , ATP7B). This protein is expressed mainly in the hepatocyte, and is responsible, first for the incorporation of copper in serum ceruloplasmin (the main copper transport protein) and, second, for the elimination of excess copper in bile ( Fig. 1 ). The loss of function of this gene causes a toxic accumulation of copper in the hepatocyte and an increase of copper unbound to ceruloplasmin in the serum. It is this excess of free fraction of copper that would potentially cause extrahepatic damage and, in particular, neurological damage.
Clinical manifestations
Symptoms are polymorphic, rare before 3 years, and usually appear between the ages of 6 and 20 years, but cases in much older people have been described. Main symptoms are liver disease (acute hepatitis, chronic liver disease and cirrhosis) and neurological manifestations. People with liver problems tend to come to medical attention earlier (generally as children or teenagers) than those with neurological symptoms, who tend to be in their twenties or older.
Neurological symptoms are mainly tremor, dystonia and occasionally choreic movements, swallowing disorders, writing disorders, dysarthria or extrapyramidal syndrome. Neuropsychological disorders may precede the onset of abnormal movements. They combine irritability, obsession, loss of inhibition, memory and attentional impairment, difficulties in planning, inducing the patient’s scholarship or professional career’s failure.
The boundary between these forms revealed by cognitive-behavioural disorders and psychiatric forms is still very unclear.
Magnetic resonance imaging (MRI) of the brain shows hyper signals at T2 and fluid attenuated inversion recovery (FLAIR (Fluid attenuated inversion recovery)) sequences, in basal ganglia, dentate nuclei, thalamus, midbrain, cerebellum as well as the corpus callosum ( Fig. 2 ).
When there is a neurological involvement, there is always a liver disease associated with it.
Other possible manifestations are haematologic (haemolysis with negative Coombs) and less frequently kidney involvement (renal tubular) or heart disease (cardiomyopathy and arrhythmia). Association between acute hepatitis and haemolytic anaemia can be related to WD. Finally, we can observe in the eye a Kayser–Fleischer (KF) corneal ring ( Fig. 3 ), inconstant in the liver forms, but constant in the neurological forms. This ring corresponds to a copper deposit on the periphery of the cornea, resulting in a reddish–brown or brown–green ring, highlighted by an examination at the slit lamp. Its semiological and diagnostic value is essential.
Diagnosis
Diagnosis is based on a set of clinical, biological, radiological and sometimes histological features.
The biological test for copper must include ceruloplasmin and copper in the blood, as well for the amount of copper excreted in urine during a 24-h period ( Table 1 ).
| Health patients | Wilson’s disease | |
|---|---|---|
| Ceruloplasmin in plasma | 0.2 to 0.4 g/l | <0.1 g/l (normal in 10% of patients with Wilson’s disease) |
| Serum copper | 13 to 22 μmol/l or 0.80 to 1.40 mg/l | <10 μmol/l or <0.60 mg/l Can be normal if acute hepatitis or haemolysis |
| Urinary copper | <0.8 μmol/24 h or <0.050 mg/24 h | >1.5 μmol/24 h or 0.096 mg/24 h |
| Copper in liver | <0.9 μmol/g of dry tissue or >56 μg/g of dry tissue | >4 μmol/g of dry tissue or >250 μg/g of dry tissue |
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
