eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases
Wilson Disease
Updated: Nov 9, 2009
Introduction
Background
Wilson disease (WD) is an inherited copper metabolism dysfunction disease characterized by cirrhosis and CNS findings. Although it is extremely rare in clinical practice, Wilson disease is important because it is fatal if not recognized and treated. Some have speculated that Wilson disease goes undiagnosed in one half of patients with the disease. Often, the diagnosis is not made until adulthood despite manifestations of the disease in childhood.
An American neurologist, Samuel Alexander Kinnier Wilson, first described Wilson disease in 1912.1 Wilson characterized the disease as a degenerative CNS disorder associated with cirrhosis.
CT scan in a 15-year-old adolescent boy who presented with CNS findings consistent with Wilson disease. CT scan reveals hypodense regions in the basal ganglia (caudate nucleus, putamen, globus pallidus). Differential diagnoses based on this image alone included leukodystrophy, vasculitis, and, less likely, infection. Ventricular enlargement and posterior fossa atrophy may also be seen on brain CT scans in a patient with Wilson disease. The extent of involvement as depicted on CT scans does not provide prognostic information.
Pathophysiology
Wilson disease is an autosomal recessive disorder. A gene for Wilson disease has been linked to the long arm of chromosome 13. The defective protein is a p-type adenosine triphosphatase (ATPase) responsible for copper transport. Research suggests that the disease also involves a defect in the copper-binding protein ceruloplasmin at the messenger RNA (mRNA) level. Organ dysfunction in patients with Wilson disease results from inadequate biliary excretion of copper and subsequent copper deposition, most notably in the liver and CNS.
Stuehler et al reported that basepair changes in the MURR1 gene were associated with an earlier presentation of Wilson disease.2 MURR1 had previously been established to cause canine copper toxicosis in Bedlington terriers.
Frequency
United States
The carrier frequency is 1 per 90 individuals. The prevalence of Wilson disease is 1 per 30,000 individuals.
International
The inbred populations of Sardinia and several Japanese islands have a higher incidence and prevalence of Wilson disease.
Mortality/Morbidity
Untreated Wilson disease is uniformly fatal. Death results from hepatic, renal, or hematologic complications, generally at age 30 years. Patients younger than 20 years typically present with hepatic manifestations. The initial findings in adults are primarily neurologic or psychiatric in nature. Stapelbroek et al reported that the H1069Q mutation is associated with a late and neurologic presentation.3
Race
Wilson disease is found in every ethnic and geographic population.
Sex
Males and females are affected in equal numbers.
Age
Children younger than 5 years rarely present with symptoms of Wilson disease; however, Wilson disease has been detected in children as young as 3 years and in adults older than 50 years.
Clinical
History
- Wilson disease may manifest as a clinical illness that resembles acute hepatitis (malaise, anorexia, nausea, jaundice).
- Patients may report CNS signs and symptoms, such as drooling, speech changes, incoordination, tremor, difficulty with fine motor tasks, and gait difficulties.
- Psychiatric manifestations include compulsive behavior, aggression, depression, impulsive behavior, and phobias.
- The patient or parent often reports deterioration in school or job performance. Intellect is unchanged.
Physical
- GI tract: Hepatic insufficiency and cirrhosis may slowly develop and may result in signs of fulminant hepatic failure, including the following:
- Ascites and prominent abdominal veins
- Spider nevi
- Palmar erythema
- Digital clubbing
- Hematemesis
- Jaundice
- CNS
- CNS pathology in patients with Wilson disease results from copper deposition in the basal ganglia. The resulting signs include drooling, dysphagia, dystonia, incoordination, difficulty with fine motor tasks, masklike facies, and gait disturbance.
- Kayser-Fleischer rings consist of copper granules in the stromal layer of the eye. Color changes are visible only in the Descemet membrane and are typically described as a golden brown, brownish green, bronze, or tannish green color seen in the limbic area of the eye. No visual impairments are associated with the color changes, which may be detected with the naked eye, although slit-lamp examination is mandatory for confirmation. If neurologic symptoms of Wilson disease are present, Kayser-Fleischer rings are always found. The rings may also be seen when only hepatic manifestations of Wilson disease are present, but this scenario is less common. The rings fade and disappear with appropriate therapy.
- Renal system
- The product of the Wilson disease gene is expressed in renal tissue, but whether the renal symptoms are primary or secondary to release of copper from the liver is unknown. Renal complications tend to be functional changes unrelated to identifiable histologic findings.
- Rarely, patients with Wilson disease develop renal stones and associated symptoms. Renal stones are precipitated by hypercalciuria and poor urine acidification. Therapy with copper-chelating agents can improve renal function.
- Musculoskeletal system: Skeletal abnormalities in patients with Wilson disease widely vary and include osteoporosis, osteomalacia, rickets, spontaneous fractures, and polyarthritis.
- Heart: Cardiac manifestations, such as rhythm abnormalities and increased autonomic tone, have been described in patients with Wilson disease. Autopsy findings have included hypertrophy, small vessel disease, and focal inflammation.
- Hematologic signs: Patients with Wilson disease exhibit signs of anemia, presumably due to oxidative injury of the cell membrane caused by excess copper.
- Skin: Skin pigmentation and a bluish discoloration at the base of the fingernails (azure lunulae) have been described in patients with Wilson disease.
Causes
- Wilson disease is an autosomal recessive disease.
- Individuals with Wilson disease are homozygous for a copper metabolism gene located on chromosome 13.
- Family history is a definite risk factor.
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References
Wilson SA. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver. Brain. 1912;34:295.
Stuehler B, Reichert J, Stremmel W, Schaefer M. Analysis of the human homologue of the canine copper toxicosis gene MURR1 in Wilson disease patients. J Mol Med. Sep 2004;82(9):629-34. [Medline].
Stapelbroek JM, Bollen CW, van Amstel JK, et al. The H1069Q mutation in ATP7B is associated with late and neurologic presentation in Wilson disease: results of a meta-analysis. J Hepatol. Nov 2004;41(5):758-63. [Medline].
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Wilson's Disease Association. Available at http://www.wilsonsdisease.org/.
Further Reading
Keywords
Wilson disease, hepatolenticular degeneration, WD, Wilson's disease, ceruloplasmin, copper accumulation, copper metabolism dysfunction, CNS disorder, cirrhosis, liver disease, hepatic disease, Kayser-Fleischer rings, neurologic disorder, copper deposition
