Some science behind the scenes

Wilsons disease

Wilson's disease also called Wilson disease or hepatolenticular degeneration is an autosomal recessive genetic disorder in which copper accumulates in tissues; this manifests as neurological or psychiatric symptoms and liver disease. It is treated with medication that reduces copper absorption or removes the excess copper from the body, but occasionally a liver transplant is required.

The condition is due to mutations in the Wilson disease protein (ATP7B) gene. Mutations can be detected in 90%. Most (60%) are homozygous for ATP7B mutations (two abnormal copies), and 30% have only one abnormal copy. Ten percent have no detectable mutation.

A single abnormal copy of the gene is present in 1 in 100 people, who do not develop any symptoms (they are carriers). If a child inherits the gene from both parents, the child may develop Wilson's disease. Symptoms usually appear between the ages of 6 and 20 years, but cases in much older people have been described. Wilson's disease occurs in 1 to 4 per 100,000 people.

 It is named after Samuel Alexander Kinnier Wilson (1878–1937), the British neurologist who first described the condition in 1912.

Symptoms

The main sites of copper accumulation are the liver and the brain, and consequently liver disease and neuropsychiatric symptoms are the main features that lead to diagnosis.

People with liver problems tend to come to medical attention earlier, generally as children or teenagers, than those with neurological and psychiatric symptoms, who tend to be in their twenties or older. Some are identified only because relatives have been diagnosed with Wilson's disease; many of these, when tested, turn out to have been experiencing symptoms of the condition but have not received a diagnosis.

Liver disease - Liver disease may present itself as tiredness, increased bleeding tendency or confusion (due to hepatic encephalopathy) and portal hypertension. The latter, a condition in which the pressure in the portal vein is markedly increased, leads to esophageal varices, blood vessels in the esophagus that may bleed in a life-threatening fashion, as well as enlargement of the spleen (splenomegaly) and accumulation of fluid in the abdominal cavity (ascites). On examination, signs of chronic liver disease such as spider angiomata (small distended blood vessels, usually on the chest) may be observed. Chronic active hepatitis has caused cirrhosis of the liver in most by the time they develop symptoms. While most people with cirrhosis have an increased risk of hepatocellular carcinoma (liver cancer), this risk is relatively very low in Wilson's disease.

About 5% of all people are diagnosed only when they develop fulminant acute liver failure, often in the context of a hemolytic anemia (anemia due to the destruction of red blood cells). This leads to abnormalities in protein production (identified by deranged coagulation) and metabolism by the liver. The deranged protein metabolism leads to the accumulation of waste products such as ammonia in the bloodstream. When these irritate the brain, the person develops hepatic encephalopathy (confusion, coma, seizures and finally life-threatening swelling of the brain).

Neuropsychiatric symptoms - About half the people with Wilson's disease have neurological or psychiatric symptoms. Most initially have mild cognitive deterioration and clumsiness, as well as changes in behavior. Specific neurological symptoms usually then follow, often in the form of parkinsonism (cogwheel rigidity, bradykinesia or slowed movements and a lack of balance are the most common parkinsonian features) with or without a typical hand tremor, masked facial expressions, slurred speech, ataxia (lack of coordination) or dystonia (twisting and repetitive movements of part of the body). Seizures and migraine appear to be more common in Wilson's disease. A characteristic tremor described as "wing-beating tremor" is encountered in many people with Wilson's; this is absent at rest but can be provoked by extending the arms.

Cognition can also be affected in Wilson's disease. This comes in two, not mutually exclusive, categories: frontal lobe disorder (may present as impulsivity, impaired judgement, promiscuity, apathy and executive dysfunction with poor planning and decision making) and subcortical dementia (may present as slow thinking, memory loss and executive dysfunction, without signs of aphasia, apraxia or agnosia). It is suggested that these cognitive involvements are related and closely linked to psychiatric manifestations of the disease.

Psychiatric problems due to Wilson's disease may include behavioral changes, depression, anxiety and psychosis. Psychiatric symptoms are commonly seen in conjunction with neurological symptoms and are rarely manifested on their own. These symptoms are often poorly defined and can sometimes be attributed to other causes. Because of this, diagnosis of Wilson's disease is rarely made when only psychiatric symptoms are present.

Other organ systems - Medical conditions have been linked with copper accumulation in Wilson's disease:

  • Eyes: Kayser–Fleischer rings (KF rings), a pathognomonic sign, may be visible in the cornea of the eyes, either directly or on slit lamp examination as deposits of copper in a ring around the cornea. They are due to copper deposition in Descemet's membrane. They do not occur in all people with Wilson's disease. Wilson's disease is also associated with sunflower cataracts exhibited by brown or green pigmentation of the anterior and posterior lens capsule. Neither cause significant visual loss. KF rings occur in approximately 66% of diagnosed cases (more often in those with neurological symptoms rather than with liver problems).
  • Kidneys: renal tubular acidosis (Type 2), a disorder of bicarbonate handling by the proximal tubules leads to nephrocalcinosis (calcium accumulation in the kidneys), a weakening of bones (due to calcium and phosphate loss), and occasionally aminoaciduria (loss of essential amino acids needed for protein synthesis).
  • Heart: cardiomyopathy (weakness of the heart muscle) is a rare but recognized problem in Wilson's disease; it may lead to heart failure (fluid accumulation due to decreased pump function) and cardiac arrhythmias (episodes of irregular and/or abnormally fast or slow heart beat).
  • Hormones: hypoparathyroidism (failure of the parathyroid glands leading to low calcium levels), infertility, and habitual abortion.

Cause

The Wilson's disease gene (ATP7B) has been mapped to chromosome 13 (13q14.3) and is expressed primarily in the liver, kidney, and placenta. The gene codes for a P-type (cation transport enzyme) ATPase that transports copper into bile and incorporates it into ceruloplasmin.

Mutations can be detected in 90%. Most (60%) are homozygous for ATP7B mutations (two abnormal copies), and 30% have only one abnormal copy. Ten percent have no detectable mutation.

Although 300 mutations of ATP7B have been described, in most populations the cases of Wilson's disease are due to a small number of mutations specific for that population. For instance, in Western populations the H1069Q mutation (replacement of a histidine by a glutamine at position 1069 in the protein) is present in 37–63% of cases, while in China this mutation is very uncommon and R778L (arginine to leucine at 778) is found more often. Relatively little is known about the relative impact of various mutations, although the H1069Q mutation seems to predict later onset and predominantly neurological problems, according to some studies.

A normal variation in the PRNP gene can modify the course of the disease by delaying the age of onset and affecting the type of symptoms that develop. This gene produces prion protein, which is active in the brain and other tissues and also appears to be involved in transporting copper. A role for the ApoE gene was initially suspected but could not be confirmed.

The condition is inherited in an autosomal recessive pattern. In order to inherit it, both of the parents of an individual must carry an affected gene. Most have no family history of the condition. People with only one abnormal gene are called carriers (heterozygotes) and may have mild, but medically insignificant, abnormalities of copper metabolism.

Wilson's disease is the most common of a group of hereditary diseases that cause copper overload in the liver. All can cause cirrhosis at a young age. The other members of the group are Indian childhood cirrhosis (ICC), endemic Tyrolean infantile cirrhosis and idiopathic copper toxicosis. These are not related to ATP7B mutations: for example, ICC has been linked to mutations in the KRT8 and the KRT18 gene.

Pathophysiology

Copper is needed by the body for a number of functions, predominantly as a cofactor for a number of enzymes such as ceruloplasmin, cytochrome c oxidase, dopamine β-hydroxylase, superoxide dismutase and tyrosinase.

Copper enters the body through the digestive tract. A transporter protein on the cells of the small bowel, copper membrane transporter 1 (CMT1; SLC31A1), carries copper inside the cells, where some is bound to metallothionein and part is carried by ATOX1 to an organelle known as the trans-Golgi network. Here, in response to rising concentrations of copper, an enzyme called ATP7A releases copper into the portal vein to the liver. Liver cells also carry the CMT1 protein, and metallothionein and ATOX1 bind it inside the cell, but here it is ATP7B that links copper to ceruloplasmin and releases it into the bloodstream, as well as removing excess copper by secreting it into bile. Both functions of ATP7B are impaired in Wilson's disease. Copper accumulates in the liver tissue; ceruloplasmin is still secreted, but in a form that lacks copper (termed apoceruloplasmin) and is rapidly degraded in the bloodstream.

When the amount of copper in the liver overwhelms the proteins that normally bind it, it causes oxidative damage through a process known as Fenton chemistry; this damage eventually leads to chronic active hepatitis, fibrosis (deposition of connective tissue) and cirrhosis. The liver also releases copper into the bloodstream that is not bound to ceruloplasmin. This free copper precipitates throughout the body but particularly in the kidneys, eyes and brain. In the brain, most copper is deposited in the basal ganglia, particularly in the putamen and globus pallidus (together called the lenticular nucleus); these areas normally participate in the coordination of movement as well as playing a significant role in neurocognitive processes such as the processing of stimuli and mood regulation. Damage to these areas, again by Fenton chemistry, produces the neuropsychiatric symptoms seen in Wilson's disease.

It is not clear why Wilson's disease causes hemolysis, but various lines of evidence suggest that a high level of free (non-ceruloplasmin bound) copper has a direct effect on either oxidation of hemoglobin, inhibition of energy-supplying enzymes in the red blood cell, or direct damage to the cell membrane.

Although the cause of the various manifestations is a mutation in the gene, this is not in fact the actual cause, as we need to know what caused the mutation.

As the problem here is a generic one for all inherited diseases caused by mutation it is discussed in the section Inherited illness, please follow the link.

References

  • Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML (2007). "Wilson's disease". Lancet 369 (9559): 397–408. doi:10.1016/S0140-6736(07)60196-2. PMID 17276780.
  • Kinnier Wilson SA (1912). "Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver" (PDF). Brain 34 (1): 295–507. doi:10.1093/brain/34.4.295.
  • Merle U, Schaefer M, Ferenci P, Stremmel W (2007). "Clinical presentation, diagnosis and long‐term outcome of Wilson's disease: a cohort study". Gut 56 (1): 115–20. doi:10.1136/gut.2005.087262. PMC 1856673. PMID 16709660.
  • Lorincz MT (2010). "Neurologic Wilson's disease". Annals of the New York Academy of Sciences 1184: 173–87. doi:10.1111/j.1749-6632.2009.05109.x. PMID 20146697.
  • Grubenbecher S, Stüve O, Hefter H, Korth C (2006). "Prion protein gene codon 129 modulates clinical course of neurological Wilson disease". Neuroreport 17 (5): 549–52. doi:10.1097/01.wnr.0000209006.48105.90. PMID 16543824.
  • Ferenci, Peter (2006-06-22). "Regional distribution of mutations of the ATP7B gene in patients with Wilson disease: impact on genetic testing". Human Genetics 120 (2): 151–159. doi:10.1007/s00439-006-0202-5. ISSN 0340-6717.
  • Brewer GJ, Askari FK (2005). "Wilson's disease: clinical management and therapy". Journal of Hepatology 42 (Suppl 1): 13–21. doi:10.1016/j.jhep.2004.11.013. PMID 15777568.
  • Robertson WM (February 2000). "Wilson's disease". Arch. Neurol. 57 (2): 276–7. doi:10.1001/archneur.57.2.276. PMID 10681092.
  • Brewer GJ (January 2000). "Recognition, diagnosis, and management of Wilson's disease". Proc. Soc. Exp. Biol. Med. 223 (1): 39–46. doi:10.1046/j.1525-1373.2000.22305.x. PMID 10632959.

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