Disorder of copper metabolism
-Rare genetic disease
Metabolic disease with cataract
-Rare eye disease
-Rare genetic disease
Metabolic disease with corneal opacity
-Rare eye disease
-Rare genetic disease
Metabolic liver disease
-Rare genetic disease
-Rare hepatic disease
Metal transport or utilization disorder with epilepsy
-Rare neurologic disease
Nephropathy secondary to a storage or other metabolic disease
-Rare genetic disease
-Rare renal disease
Neurometabolic disease
-Rare genetic disease
-Rare neurologic disease
Rare disorder with dystonia and other neurologic or systemic manifestation
-Rare neurologic disease
Rare genetic tremor disorder
-Rare genetic disease
Rare hereditary metabolic disease with peripheral neuropathy
-Rare genetic disease
-Rare neurologic disease
Rare neurologic disease with psychiatric involvement
-Rare neurologic disease
Rare tremor disorder
-Rare neurologic disease
Supranuclear oculomotor palsy
-Rare eye disease
-Rare genetic disease
Comment:
Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism which leads to copper overload in different tissues of the body. The disorder of metabolism in patients with WD develops as a result of mutations in the adenosine triphosphatase 7B gene (ATP7B) located on the long arm of the 13th chromosome. More than 500 mutations of the ATP7B gene have been reported. Copper leads to tissue damage by accumulating in many organs including mainly the liver and brain as a result of lack of production of the proteins responsible of excretion of copper into the bile ducts in relation with these mutations. The incidence of WD is considered to be about 1/300000. Although the diagnosis of WD is made in the first decade of life in children, the neurological symptoms of WD are mostly observed in the second decade. Although WD is most frequently manifested with hepatic and neurological features related with chronic accumulation of copper, it has a wide clinical spectrum (PMID:27103860).
It is now known that it is not the accumulation of copper itself what is deleterious to the organism, but rather free copper in the blood, which determines copper intoxication, as opposed to ceruloplasmin-bound copper (PMID:26692151).
Patients with Wilson's disease have the autosomal recessive form of distal RTA (PMID:25120295).
Short-term treatment of rats with Methanobactin (MB) efficiently reversed mitochondrial impairment and liver damage in the acute stages of liver copper accumulation compared with that seen in untreated ATP7B-deficient rats. This beneficial effect was associated with depletion of copper from hepatocyte mitochondria. Moreover, MB treatment prevented hepatocyte death, subsequent liver failure, and death in the rodent model. These results suggest that MB has potential as a therapeutic agent for the treatment of acute WD (PMID:27322060).
Wilson disease is an autosomal recessive disorder characterized by dramatic build-up of intracellular hepatic copper with subsequent hepatic and neurologic abnormalities.
De Bie et al. (2007) provided a detailed review of the molecular pathogenesis of Wilson ... Wilson disease is an autosomal recessive disorder characterized by dramatic build-up of intracellular hepatic copper with subsequent hepatic and neurologic abnormalities. De Bie et al. (2007) provided a detailed review of the molecular pathogenesis of Wilson disease.
Chowrimootoo et al. (1998) investigated the neonatal diagnosis of Wilson disease by measuring ceruloplasmin isoforms in neonatal cord blood samples and venous blood from both healthy adults and patients with Wilson disease. Total ceruloplasmin levels were reduced in ... Chowrimootoo et al. (1998) investigated the neonatal diagnosis of Wilson disease by measuring ceruloplasmin isoforms in neonatal cord blood samples and venous blood from both healthy adults and patients with Wilson disease. Total ceruloplasmin levels were reduced in all neonatal specimens. The plasma isoform, however, was significantly reduced or absent only in patients with Wilson disease, whereas the biliary isoform was reduced both in healthy neonates and patients with Wilson disease. The authors commented that measurement of ceruloplasmin isoforms in cord blood or dried blood spots may permit neonatal diagnosis of this condition, before substantial tissue damage has occurred. Gow et al. (2000) reported their detailed experience of 30 patients with a diagnosis of Wilson disease seen in 2 Australian centers between 1971 and 1998. Twenty-two patients presented with chronic disease; age at diagnosis ranged from 7 to 58 years. Only 14 of these patients (64%) had Kayser-Fleischer rings; 5 of these had low serum ceruloplasmin concentrations and normal urinary copper excretion, 2 had normal ceruloplasmin levels and high urinary copper excretion, and 7 had the classic combination of low serum ceruloplasmin and high urinary copper. Eight patients presented with fulminant hepatic failure, with age at diagnosis ranging from 11 to 54 years; only 6 of these had Kayser-Fleischer rings, 7 had low serum ceruloplasmin, and 4 of them had raised urinary copper excretion. The others were anuric. Examination of the livers of these 8 patients, either at autopsy or posttransplantation, showed cirrhosis and elevated copper content. Gow et al. (2000) commented that the diagnosis of Wilson disease depended on the evaluation of clinical and laboratory evidence of abnormal copper metabolism, but that no single feature was reliable in isolation. Further, the authors suggested that Wilson disease should be considered in any patient at any age presenting with unusual liver or neurologic abnormalities. Firneisz et al. (2001) described postmortem (postcremation) diagnosis of Wilson disease on the basis of skin cells left on the deceased's electric shaver. Foye (2001) and Kuruvilla (2001) took these authors to task, noting that the man's DNA added no new information since the same mutation was identified in the man's father and 2 children. Foye (2001) commented that with the growing array of available tests, 'we must always remember in each individual case to stop first and ask not just whether a particular test could be done, but whether it should be done.' Kuruvilla (2001) noted that the man had movement disorder for at least 10 years before his death and presented to his physician with parkinsonian symptoms and florid manifestations of cirrhosis. Because Kayser-Fleischer ring is present in 100% of patients with CNS manifestations of Wilson disease, neuroophthalmologic slit-lamp assessment is mandatory and cost effective in all patients suspected of having this disease. Ferenci (2006) reviewed the geographic distribution of mutations in the ATP7B gene in Wilson disease patients to improve genetic diagnosis of Wilson disease. The most common mutation in patients from Europe is H1069Q (606882.0006). A unique 15-bp deletion in the 5-prime region (606882.0010) is frequent in Sardinia. M645R (606882.0020) is common in Spain, and R778L (606882.0009) is often found in patients from eastern Asia. Ferenci (2006) also presented a clinical algorithm for the diagnosis of Wilson disease. - Prenatal Diagnosis Cossu et al. (1992) demonstrated how one can use flanking markers to do prenatal diagnosis by the linkage principle in this disorder. The probability of the fetus being affected was estimated to be only 0.007 in the example given.
In Wilson disease, the basal ganglia and liver undergo changes that express themselves in neurologic manifestations and signs of cirrhosis, respectively. A disturbance in copper metabolism is somehow involved in the mechanism. Low ceruloplasmin (117700) is found in ... In Wilson disease, the basal ganglia and liver undergo changes that express themselves in neurologic manifestations and signs of cirrhosis, respectively. A disturbance in copper metabolism is somehow involved in the mechanism. Low ceruloplasmin (117700) is found in the serum. Shokeir and Shreffler (1969) advanced the hypothesis that ceruloplasmin functions in enzymatic transfer of copper to copper-containing enzymes such as cytochrome oxidase. Supporting the hypothesis was the finding of markedly reduced levels of activity of cytochrome oxidase in Wilson disease and moderate reductions in heterozygotes. The Kayser-Fleischer ring is a deep copper-colored ring at the periphery of the cornea which is frequently found in Wilson disease and is thought to represent copper deposits. Bearn and McKusick (1958) and Whelton and Pope (1968) described azure lunulae of the fingernails in patients with Wilson disease. These are presumably of the same significance as the Kayser-Fleischer ring and possibly arise by the same mechanism. Hypercalciuria and nephrocalcinosis are not uncommon in patients with Wilson disease. Hypercalciuria associated with this disorder was first reported by Litin et al. (1959). Wiebers et al. (1979) observed renal stones in 7 of 54 patients with Wilson disease. Penicillamine therapy was accompanied by a decrease in urinary calcium excretion to normal values in 3 patients, but hypercalciuria persisted in 3. Azizi et al. (1989) described hypercalciuria and nephrolithiasis as presenting signs in Wilson disease and postulated tubular defect in calcium reabsorption. Hoppe et al. (1993) described a 17-year-old male with a 6-year history of hypercalciuria, nephrocalcinosis, and nephrolithiasis, in whom Wilson disease was finally diagnosed. Bearn (1960) suggested that Jewish WND patients from Eastern Europe are different from other groups of patients in that the age at onset is later, the disease is generally milder, and the serum copper and serum ceruloplasmin levels are 'particularly liable to be of normal concentration.' Bonne-Tamir et al. (1990) provided a full analysis of Wilson disease in Israel. From a study of 28 Canadian families, Cox et al. (1972) suggested that there are at least 3 forms of Wilson disease. In a rare 'atypical form,' the heterozygotes show about 50% of the normal level of ceruloplasmin. This gene may have been of German-Mennonite derivation. In the 2 typical forms heterozygotes have normal ceruloplasmin levels, although they can be identified by decreased reappearance of radioactive copper into serum and ceruloplasmin. The authors referred to the 2 'typical forms' as the Slavic and the juvenile type. The Slavic type has a late age of onset and is predominantly a neurologic disease. The juvenile type, which occurs in Western Europeans and several other ethnic groups, has onset before age 16 years and is frequently a hepatic disease. Czaja et al. (1987) demonstrated reduced ceruloplasmin gene transcription in 4 patients with Wilson disease (44% of controls). Low levels of ceruloplasmin are a normal finding in the newborn (Shokeir, 1971). In Israel, Passwell et al. (1977) observed that Arab patients show an earlier age of onset and more severe course than Jewish patients. Within families of both ethnic groups, age of onset and type of disease show a close correlation. Thus, the authors concluded that the interethnic differences may reflect different mutations. Fitzgerald et al. (1975) described a 57-year-old man with liver disease that they concluded represented Wilson disease. Ross et al. (1985) described a patient who was found to have hepatosplenomegaly at age 51, developed hand tremor at 52, and was having difficulty with hand dexterity at 55. The diagnosis of Wilson disease was made at age 58 on the basis of urinary, serum, and hepatic copper studies and liver histology, and despite the absence of Kayser-Fleischer rings. Wilson disease is not generally considered in patients over 30 years of age who present with liver disease and without neurologic signs. Danks et al. (1990) reported 4 such cases: 2 men, aged 43 and 48, and 2 women, aged 44 and 58. The 58-year-old woman had been ill for only 1 week and died in 36 hours of acute hepatorenal failure. Her sister had died of cirrhosis and liver failure at age 28. Alcohol intake was minimal or completely avoided in all. None of the known hepatitis viruses could be identified and no autoantibodies were detected. Kuan (1987) demonstrated manifestations of myocardial involvement in Wilson disease. The occurrence of chondrocalcinosis and osteoarthritis in Wilson disease may be due to copper accumulation similar to the arthropathy of hemochromatosis (HFE; 235200) (Menerey et al., 1988). Starosta-Rubinstein et al. (1987) correlated clinical manifestations with the findings of magnetic resonance imaging (MRI) of the brain. Van Wassenaer-van Hall et al. (1995) also used cranial MRI to study WND patients. Although the most striking findings on their MRI scan were abnormalities of the basal ganglia in generalized cerebral atrophy, they also noted subtle white matter abnormalities in some WND patients, particularly at the dentatorubrothalamic, pontocerebellar, and corticospinal tracts. From Slovenia, Ferlan-Marolt and Stepec (1999) reported a 24-year-old woman with fulminant Wilsonian hepatitis accompanied by hemolytic anemia and leading to death in a few weeks. Kayser-Fleischer rings were said to have been absent, and there were no neurologic abnormalities until the development of the flapping tremor of hepatic failure in the last days of life. Gu et al. (2000) studied mitochondrial function and aconitase activity in Wilson disease liver tissue and compared the results with those in a series of healthy controls and patients without Wilson disease. There was evidence of severe mitochondrial dysfunction in the livers of patients with Wilson disease. Enzyme activities were decreased as follows: complex I by 62%, complex II+III by 52%, complex IV by 33%, and aconitase by 71%. These defects did not seem to be secondary to penicillamine use, cholestasis, or poor hepatocellular synthetic function. Gu et al. (2000) stated that the pattern of enzyme defects suggests that free radical formation and oxidative damage, probably mediated via mitochondrial copper accumulation, are important in Wilson disease pathogenesis, and that their results provide a rationale for a study of the use of antioxidants in Wilson disease. Both Wilson disease and hemochromatosis (235200), characterized by excess hepatic deposition of iron and copper, respectively, produce oxidative stress and increase the risk of liver cancer. Because the frequency of p53 mutated alleles (191170) in nontumorous human tissue may be a biomarker of oxyradical damage and identify individuals at increased cancer risk, Hussain et al. (2000) determined the frequency of p53 mutated alleles in nontumorous liver tissue from WND and hemochromatosis patients. When compared with the liver samples from normal controls, higher frequencies of G:C to T:A transversions at codon 249, and C:G to A:T transversions and C:G to T:A transitions at codon 250 were found in liver tissue from WND cases, and a higher frequency of G:C to T:A transversions at codon 249 was also found in liver tissue from hemochromatosis cases. Sixty percent of WND and 28% of hemochromatosis cases also showed a higher expression of inducible nitric oxide synthase in the liver, which suggested nitric oxide as a source of increased oxidative stress. The results were consistent with the hypothesis that the generation of oxygen/nitrogen species and unsaturated aldehydes from iron and copper overload in hemochromatosis and WND causes mutation in the p53 tumor suppressor gene. Hedera et al. (2002) reported a 13-year-old male with Wilson disease who exhibited leukoencephalopathy early in the disease course. MRI showed increased signal intensities in the basal ganglia and throughout the subcortical white matter in the frontal lobes, which later extended to the parietal and occipital lobes. Takeshita et al. (2002) investigated 2 families with Wilson disease in which sibs showed different clinical phenotypes and different ages at onset. In the first family, the second and fourth male children demonstrated onset of the neurologic type of Wilson disease at 16 and 28 years of age, respectively, and the first female child developed the hepatic type at 38 years of age. In family 2, the second male child showed neurologic symptoms at 32 years of age and was diagnosed as having the hepatoneurologic type of Wilson disease; the 35-year-old first female child was found to have the hepatic type in familial screening. In both families, affected individuals were compound heterozygotes for mutations in the ATP7B gene. In the first family, the mutations were R778L (606882.0009) and R919G (606882.0014). In the second family, the mutations were 2511delA (606882.0015) and A874V (606882.0016). Hlubocka et al. (2002) studied 42 patients with Wilson disease (19 men and 23 women, mean age 34 +/- 10 years) and 42 age- and sex-matched healthy volunteers. All subjects underwent complete echocardiographic examination; 24-hour Holter monitoring was performed in 23 Wilson disease patients. In comparison with healthy subjects, patients with Wilson disease had increased thickness of the interventricular septum and left ventricular (LV) posterior wall. While the 2 groups did not differ in LV mass index, relative LV wall thickness was significantly increased in the Wilson disease patients compared to control subjects. Concentric LV remodeling was present in 9 patients (21%) and LV hypertrophy in 1 patient. Diastolic filling and the frequency of valvular abnormalities were comparable in both groups. Twenty-four-hour Holter monitoring detected ECG abnormalities in 10 patients (42%), the most frequent findings being runs of supraventricular tachycardias and frequent supraventricular ectopic beats. Jung et al. (2005) reported a 17-year-old Korean man with Wilson disease who presented with polyneuropathy at least 6 months before developing more typical symptoms. Initial symptoms included intermittent paresthesia and weakness in both hands and feet with normal sensory examination. Nerve conduction studies and sural nerve biopsy were consistent with a mixed demyelinating and axonal neuropathy. Treatment with penicillamine, zinc sulfate, and vitamin B6 resulted in clinical improvement.
Gromadzka et al. (2005) studied 142 Polish patients with Wilson disease and identified 26 mutations in the ATP7B gene: 11 truncating, 14 missense, and 1 splice site mutation. Patients with 1 or 2 truncating mutations on their alleles ... Gromadzka et al. (2005) studied 142 Polish patients with Wilson disease and identified 26 mutations in the ATP7B gene: 11 truncating, 14 missense, and 1 splice site mutation. Patients with 1 or 2 truncating mutations on their alleles had lower serum copper and ceruloplasmin levels and were younger when the first symptoms of the disease appeared compared with individuals with 2 missense mutations, and the effect of truncating mutations on phenotype was dose-dependent. Gromadzka et al. (2005) found no association between type of ATP7B mutation and mode of initial disease presentation (neurologic, hepatic, or mixed).
Bull et al. (1993) identified 2 patients with Wilson disease who were homozygous for a 7-bp deletion within the coding region of the ATP7B gene (606882.0001). Tanzi et al. (1993) identified 4 mutations in the ATP7B gene in ... Bull et al. (1993) identified 2 patients with Wilson disease who were homozygous for a 7-bp deletion within the coding region of the ATP7B gene (606882.0001). Tanzi et al. (1993) identified 4 mutations in the ATP7B gene in unrelated persons with Wilson disease: 2 missense mutations (606882.0002-606882.0003) and 2 frameshift mutations resulting in a truncated gene product (606882.0004-606882.0005). The mutations were found among 50 unrelated families derived predominantly from the United States, 18 unrelated families from Russia, and 5 presumably unrelated families from Sicily. Clearly, Bull et al. (1993) and Tanzi et al. (1993) had independently isolated the same gene which was convincingly the one mutant in Wilson disease. Thomas et al. (1995) reviewed the mutations found in the ATP7B gene. Their findings suggest a wide span in the age of onset of Wilson disease, perhaps wider than previously considered typical. Mutations that completely disrupt the gene can produce liver disease in early childhood at a time when Wilson disease may not be considered in the differential diagnosis. Petrukhin et al. (1993) identified YACs spanning the Wilson disease region and derived cosmid contigs therefrom. Thirteen microsatellite markers were generated from cosmids and used for study of genetic equilibrium (linkage disequilibrium; LD). Strong LD was detected between these markers and the WND locus in 28 families from rural Russia, 43 families from Sardinia, and 67 families of predominantly North American and European descent. From their haplotype and mutation analyses, Petrukhin et al. (1993) predicted that approximately half of all Wilson disease mutations will be rare in the American and Russian populations. Given the difficulties of searching for mutations in a gene spanning more than 80 kb of genomic DNA, haplotype data are important as a guide to mutation detection. Thomas et al. (1995) did haplotyping of the Wilson disease gene region in 58 families. These haplotypes, combining 3 markers (D13S314, D13S316, and D13S301), were usually specific for each different mutation. The haplotype data suggested that as many as 20 mutations might still be unidentified; a total of 25 disease-causing mutations had been identified at that time.
Whereas the worldwide prevalence of Wilson disease 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, a higher prevalence seems to ... Whereas the worldwide prevalence of Wilson disease 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, a higher prevalence seems to exist in Sardinia, where approximately 10-12 new cases per year are identified. Figus et al. (1995) analyzed mutations and defined the chromosomal haplotype in 127 patients of Mediterranean descent affected by Wilson disease: 39 Sardinians, 49 Italians, 33 Turks, and 6 Albanians. There were 5 common haplotypes in Sardinians, 3 in Italians, and 2 in Turks, which accounted for 85%, 32%, and 30% of the Wilson disease chromosomes, respectively. They identified 16 novel mutations: 8 frameshifts, 7 missense mutations, and 1 splicing defect. In addition, they detected 5 previously described mutations, e.g., his1070-to-gln (606882.0006), which accounted for 13% of the mutations in WND chromosomes in non-Sardinian Mediterranean populations. In the Sardinian population, one haplotype accounts for 55% of WD chromosomes (Figus et al., 1995). Loudianos et al. (1999) characterized the putative promoter and 5-prime untranslated region of the WD gene and carried out mutation analysis in this region in Sardinian WD patients with the most common haplotype. They detected a single mutation resulting from a 15-nucleotide deletion (606882.0010) in all chromosomes with this common haplotype. With the addition of this mutation, the molecular defect has been found in 92% of the WD chromosomes in Sardinians. Loudianos et al. (1998) performed a mutation screen on the WND gene in 59 patients of Mediterranean origin: 26 Continental Italians, 22 Sardinians, 9 Turkish, and 2 Albanians. They found 31 novel and 3 known mutations. Most of the patients were compound heterozygotes. Because there are so many causative mutations, the preclinical and prenatal diagnosis of Wilson disease should be carried out by a combination of mutation and linkage analysis. Kim et al. (1998) identified 3 novel mutations in the ATP7B gene in Korean patients with Wilson disease. One of these, arg778 to leu (606882.0009), was found in 6 of 8 unrelated patients, giving an allele frequency of 37.5%. Ha-Hao et al. (1998) performed mutation analysis in 33 German and 10 Cuban unrelated Wilson disease patients. The common his1069-to-gln (606882.0006) mutation accounted for 42% of all WND chromosomes in the German series and haplotype C was found to be highly predictive for this mutation. Six previously undescribed WND gene mutations were identified. In 15 German WND index patients and 3 sibs, both WND mutations could be determined and a genotype-phenotype correlation was attempted. Patients homozygous for the his1069-to-gln mutation showed almost a complete range of clinical presentations; thus, in this study, the his1069-to-gln mutation was not associated with a late neurologic presentation. Okada et al. (2000) analyzed the ATP7B gene in 41 unrelated Japanese Wilson disease families, including 47 patients. They identified 21 mutations, 9 of which were novel. Garcia-Villarreal et al. (2000) identified a founder mutation in the ATP7B gene (L708P; 606882.0023) in 18 individuals with Wilson disease from the Canary Islands of Spain. Twelve patients were homozygous for the mutation. Homozygous patients tended to have a neurologic presentation at an average age of 16 years. The L708P mutation was estimated to have arisen in Gran Canaria over 56 generations ago, in pre-Hispanic times. Garcia-Villarreal et al. (2000) estimated a prevalence for Wilson disease of 1 in 2,600 individuals in the Canary Islands. Olivarez et al. (2001) undertook to estimate the frequency of Wilson disease in the U.S. Caucasian population. They used data from 4 studies to determine that approximately one-third of Wilson disease mutations in U.S. Caucasian Wilson disease patients are his1069-to-gln (606882.0006). They then determined the frequency of this mutation in random DNA samples from 2,601 U.S. Caucasian newborns to be 0.285%. Multiplying by 3 gave an estimated Wilson disease heterozygote frequency of 0.855% and an allele frequency of 0.428%, or 0.00428. These data gave a Wilson disease frequency of about 1 in 55,000 births. The 95% confidence interval was rather broad, ranging from about 1 in 18,000 to 1 in 700,000 births. Margarit et al. (2005) analyzed 40 unrelated Spanish patients with Wilson disease and identified 21 different mutations in the ATP7B gene in 35 (87%) patients. The M645R (606882.0020) mutation was particularly prevalent and found in 22 patients (55%), who were all compound heterozygotes for mutation in the ATP7B gene. In 6 patients in whom M645R was combined with a nonsense mutation, there was early onset of the disease, occurring between 5 and 14 years of age. Gupta et al. (2005) analyzed Indian patients with Wilson disease from 62 unrelated families and their first-degree relatives and identified a total of 9 mutations, 5 novel, in the ATP7B gene. The authors noted that homozygotes for different mutations that would be expected to produce similar defective proteins showed significant disparity in terms of organ involvement and severity of disease; in 1 family, 2 sibs with the same pair of mutant chromosomes had remarkably different phenotypes. Gupta et al. (2005) suggested that there may be as yet unidentified modifying loci that account for the observed phenotypic heterogeneity among patients with Wilson disease. In 120 unrelated Korean patients with Wilson disease, Park et al. (2007) identified 28 different mutations, including 6 novel mutations, in the ATP7B gene. R778L (606882.0009) was the most common mutation, occurring in 39.2% of mutant alleles. Mak et al. (2008) sequenced the ATP7B gene in 65 unrelated Han Chinese patients with Wilson disease and identified 126 disease alleles in 129 chromosomes (97.6% detection rate); the most prevalent mutation, R778L, was found in 22 chromosomes. The authors screened 660 healthy Hong Kong Han Chinese for R778L and a 2310C-G SNP in perfect linkage disequilibrium with R778L, and identified 3 carriers of both; neither variant was found in the remaining 657 individuals. Mak et al. (2008) calculated the prevalence of Wilson disease to be 1 in 5,400 in Hong Kong Han Chinese, and the East Asian-specific R778L mutation was estimated to have arisen 5,500 years earlier from a single ancestor. In the Korean population, Park et al. (2009) found that the combined carrier frequency of 3 common ATP7B mutations, R778L, A874V (606882.0016), and N1270S (606882.0017), was 1 in 50 (2%). Extrapolating from this figure, the authors estimated that the carrier frequency of Wilson disease is about 1 in 27 in the Korean population, suggesting that the disorder is more common than in U.S. Caucasian populations. Wang et al. (2011) identified 38 different pathogenic ATP7B mutations in 69 (69.86%) of 73 Chinese patients with Wilson disease. The most common mutation was R778L, which accounted for 23.29% mutant alleles, and the second most common mutation was I1148T (606882.0025), which accounted for 9.59% of mutant alleles.
Diagnosis of Wilson disease cannot be made by a single test alone and a combination of tests is always needed as outlined in detail in the AASLD guidelines [Roberts & Schilsky 2008]. ...
DiagnosisDiagnosis of Wilson disease cannot be made by a single test alone and a combination of tests is always needed as outlined in detail in the AASLD guidelines [Roberts & Schilsky 2008]. The diagnostic algorithm of the more recent EASL Clinical Practice Guidelines [European Association for Study of Liver 2012] is based on a diagnostic index (“Leipzig” score) proposed by an expert panel [Ferenci et al 2003]. This score includes clinical, biochemical, and molecular features, but has not been validated in large patient series. The diagnosis of Wilson disease is suspected in individuals from age three to 60 years (commonly 6-45 years) [Ferenci et al 2007], with varying combinations of hepatic, neurologic, and psychiatric disturbances. The diagnosis of Wilson disease is established by the presence of typical biochemical findings in combination with Kayser-Fleisher rings in the cornea. These copper deposits in the periphery of the cornea are observed in approximately 50%-60% of individuals with liver disease and about 90% of individuals with either neurologic findings or psychiatric disturbance. They are observed most reliably by slit lamp examination.The biochemical diagnosis of Wilson disease in a symptomatic individual relies on a combination of the following findings: Low serum ceruloplasmin concentration In children, interpretation of test results requires age correction or age-specific reference ranges. Note: Healthy newborns have low serum ceruloplasmin concentrations. The concentrations increase during the first six months of life and by two to three years of age peak at a concentration that may exceed the healthy adult reference range. In adults with Wilson disease, serum ceruloplasmin concentration is often below the normal range and typically very low. Note: A normal serum ceruloplasmin concentration is found in at least 5% of individuals with Wilson disease with neurologic symptoms and up to 40% of individuals with hepatic symptoms [Steindl et al 1997]. Serum ceruloplasmin concentration is, therefore, not a reliable screening test for Wilson disease.Serum concentration of copper and of non-ceruloplasmin-bound copper Most individuals with Wilson disease have a subnormal serum copper concentration that is proportional to the serum ceruloplasmin concentration. NOTE: Serum copper is low in healthy newborns. The concentrations increase during the first six months of life and by age two to three years peak at a concentration that may exceed the healthy adult reference range. The combination of low ceruloplasmin serum concentration and a normal or high serum copper concentration may suggest excess non-ceruloplasmin-bound copper in the serum. Such high non-ceruloplasmin-bound serum copper concentrations often present as a result of copper overload; however, it is not reliable for diagnosis because of its high dependency on the accuracy of both the serum ceruloplasmin concentration and the serum copper concentration. The serum concentration of non-ceruloplasmin-bound copper (in µg/L) is most reliably estimated by subtracting the amount of copper associated with ceruloplasmin, determined by the enzymatic assay (ceruloplasmin in mg/L x 3.15) from the total serum copper concentration. Normal serum concentration of non-ceruloplasmin-bound copper is approximately 50-100 µ/L. In individuals with Wilson disease, the serum concentration of non-ceruloplasmin-bound copper is usually higher than 200 µ/L. Note: Enzymatic methods for quantification of ceruloplasmin measure holoceruloplasmin (i.e., with copper incorporated) and are therefore preferred, particularly for calculation of the free copper concentration [Walshe 2003a, Macintyre et al 2004].High urinary copper. Measurement of copper in three 24-hour urine collections, free from contamination by external sources of copper, is advised. The testing laboratory should be consulted regarding its trace-element urine collection protocol prior to initiating urine specimen collection. Basal urinary copper excretion (without the use of chelating agent) is almost invariably elevated above 0.6 µmol/24 hours in the symptomatic individual. A provocative test of urinary copper excretion following oral administration of penicillamine has been validated only in pediatric cohorts, but has proven useful in many cases [Martins da Costa et al 1992], although levels in affected individuals can overlap with those of heterozygotes. Increased hepatic copper concentration. Hepatic copper concentration in Wilson disease is usually greater than 250 µg/g dry weight (normal: <55 µg/g dry weight [Nuttall et al 2003]); however, such levels may be seen in other chronic liver disorders and in cholestatic conditions as well. Note: (1) In later stages of Wilson disease, copper is distributed unevenly in the liver and measurement of hepatic copper concentration is less reliable. (2) Some individuals have only a moderately elevated hepatic copper concentration — 100 to 250 µg/g dry weight, which overlaps with values occasionally found in heterozygotes. Thus, hepatic copper concentration in this range does not exclude the diagnosis of Wilson disease.Molecular Genetic TestingATP7B, encoding a copper-transporting P-type ATPase, is the only gene in which mutations are known to cause Wilson disease (Table 1). Identification of two disease-causing mutations establishes the diagnosis of Wilson disease. Table 1. Summary of Molecular Genetic Testing Used in Wilson DiseaseView in own windowGene Symbol 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3Test AvailabilityATP7ATargeted mutation analysisVariable 4, 5100% for the targeted mutationsClinicalSequence analysis of select exons 6Sequence variants 7See footnote 8Sequence analysisSequence variants 798%Deletion/duplication analysis 9Exonic or whole-gene deletionsRare 101. See Table A. Genes and Databases for chromosome locus and protein name.2. See Molecular Genetics for information on allelic variants.3. The ability of the test method used to detect a mutation that is present in the indicated gene4. Panels to detect a limited number of mutations appear to be feasible in selected populations, such as those in Sardinia [Lovicu et al 2003] and eastern Germany [Huster et al 2004]. Mutations vary by laboratory and ethnicity of population.5. p.His1069Gln [Tanzi et al 1993] is the only mutation found relatively frequently in populations of European origin. It accounts for 35%-45% of Wilson disease alleles in a mixed European population and a greater percent in eastern Europe [Caca et al 2001]. The frequency of this mutation may be somewhat lower in probands with childhood onset and in probands presenting with liver disease. p.Arg778Leu [Thomas et al 1995] is the only relatively common mutation in Asian populations, accounting for approximately 57% of Wilson disease alleles in the Asian population younger than age 18 years. A single mutation, 15-bp deletion, has been identified in the 1-kb promoter, non-coding region and is common in Sardinia [Loudianos et al 1999]. Promoter mutations have not been described in other populations and are presumed to be rare [Cullen et al 2003].6. Exons vary by laboratory. 7. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.8. The mutation detection rate varies depending on the regions analyzed and the ethnicity of the individual. Mutations in exons 8, 14, and 18 account for approximately 60% of alleles in the British population [Curtis et al 1999]. Mutations in exons 8 and 12 account for approximately 57% of alleles in the Chinese population [Wu et al 2001]. 9. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.10. Large deletions and duplications, encompassing one or more exons, are rare. Exonic and multi-exonic deletions have been reported [e.g., Moller et al 2005, Tatsumi et al 2011].Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: (1) Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. (2) Heterozygotes may have low serum ceruloplasmin concentrations, borderline normal urinary copper, elevated urinary copper on provocative testing with penicillamine, and/or moderate elevation of hepatic copper (100-250 mg/g dry weight), which make these tests unreliable in clarifying carrier status. Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family. As index patients may present with compound heterozygous ATP7B mutations the predictive testing is most reliable in sibs only. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.
Wilson disease can manifest as hepatic, neurologic, hematologic, or psychiatric disturbances, or a combination of these, in individuals ranging in age from three years to over 60 years. Phenotypic expression varies even within families. The phenotypic spectrum has further expanded through molecular genetic testing, which has confirmed the diagnosis in individuals with atypical clinical and biochemical findings [Dening & Berrios 1989, Walshe 1989, Steindl et al 1997, Cox & Roberts 2006, Ala et al 2007]....
Natural HistoryWilson disease can manifest as hepatic, neurologic, hematologic, or psychiatric disturbances, or a combination of these, in individuals ranging in age from three years to over 60 years. Phenotypic expression varies even within families. The phenotypic spectrum has further expanded through molecular genetic testing, which has confirmed the diagnosis in individuals with atypical clinical and biochemical findings [Dening & Berrios 1989, Walshe 1989, Steindl et al 1997, Cox & Roberts 2006, Ala et al 2007].Table 2 outlines the typical clinical findings of Wilson disease. Of note, the "classic triad" of liver disease, movement disorder, and Kayser-Fleischer ring is uncommon. Table 2. Clinical Findings in Individuals with Wilson Disease by Presenting FindingView in own windowPresenting Finding % of IndividualsTypical Age of Presentation (Range) Liver DiseaseNeurologic DiseasePsychiatric DisturbanceKayser-Fleischer RingsLiver disease~40% 6-45 (3-70) + +/– +/– ~50% Neurologic disease ~40% Mid-teen - mid-adult (6-50) –/mild + +/–~90% Psychiatric disturbance~20% Adolescent - young adult –/mild +/– + ~90% Hemolitic anemiaFew %Adolescent - young adult+ – – + Bruha et al [2011], Weiss et al [2011], Hofer et al [2012], Weiss et al [2013]Liver disease. Wilson disease manifests as liver disease more commonly in children and younger adults, typically between the ages of six and 45 years; however, severe liver disease can be the initial finding in preschool-aged children [Wilson et al 2000] and in older adults. The clinical manifestations vary and can include the following findings: Recurrent jaundice, possibly caused by hemolysis Simple, acute, self-limited hepatitis-like illness with fatigue, anorexia, abdominal pain Autoimmune hepatitis, often manifest acutely with fatigue, malaise, arthropathy, and rashes. This form of liver disease responds well to chelation therapy even if cirrhosis is present (see Management). Fulminant hepatic failure with severe coagulopathy, encephalopathy, acute Coombs-negative intravascular hemolysis, and often rapidly progressive renal failure. Serum activity of aminotransferases is only moderately increased, and serum concentration of alkaline phosphatase is normal or extremely low. These individuals do not respond to chelation treatment and require urgent liver transplantation (see Management). Chronic liver disease with portal hypertension, hepatosplenomegaly, ascites, low serum albumin concentration, and coagulopathy Fatty liver of mild to moderate degree with abnormal liver function Hemolytic anemia, with either acute or chronic hemolysis, a reflection of a high serum concentration of non-ceruloplasmin-bound copper, which leads to destruction of erythrocytes. Liver disease is likely to be present in such individuals, as are Kayser-Fleischer rings. Recurrent hemolysis predisposes to cholelithiasis, even in children. Neurologic disease. Neurologic involvement follows two general patterns: movement disorders or rigid dystonia. Movement disorders tend to occur earlier and include tremors, poor coordination, loss of fine-motor control, micrographia (abnormally small, cramped handwriting), chorea, and/or choreoathetosis. Spastic dystonia disorders manifest as mask-like facies, rigidity, and gait disturbance [Svetel et al 2001]. Pseudobulbar involvement such as dysarthria, drooling, and difficulty swallowing is more common in older individuals, but also occurs in children and adolescents. In contrast to the neurologic findings in individuals with a frank neurologic presentation, the neurologic findings in individuals with a hepatic presentation may be subtle. Mood disturbance (mainly depression; occasionally poor impulse control), changes in school performance, and/or difficulty with fine motor skills (especially handwriting) or gross motor skills may be observed. Psychiatric manifestations. The psychiatric manifestations are variable. Depression is common. Neurotic behavior includes phobias, compulsive behaviors, aggression, or antisocial behavior. Older individuals may have subtle psychopathology such as progressive disorganization of personality with anxiety and affective changes such as labile mood and disinhibition. Intellectual deterioration may also occur with poor memory, difficulty in abstract thinking, and shortened attention span. Pure psychotic disorders are uncommon. Kayser-Fleischer rings. These result from copper deposition in Descemet's membrane of the cornea, and reflect a high degree of copper storage in the body. They are reduced or disappear with effective decoppering treatment. Other findings Renal involvement. Low-molecular weight proteinuria, microscopic hematuria, and Fanconi syndrome Arthritis. Involvement of large joints from synovial copper accumulation Reduced bone mineral density with a prevalence of osteoporosis in ~10% of affected individualsPancreatitis, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis of skeletal muscle, and various endocrine disorders Sunflower cataracts. Observed occasionally on slit lamp examination Hepatocellular carcinoma rarely develops in Wilson disease: the estimated incidence is below 1% [Devarbhavi et al 2012]. However, abdominal malignancies have been reported in treated individuals [Walshe et al 2003]. Fertility and pregnancy. Most individuals with Wilson disease are fertile. Successful pregnancies of women with Wilson disease who received treatment have been reported [Brewer et al 2000, Tarnacka et al 2000, Furman et al 2001]. Prior to diagnosis and treatment, affected women may experience infertility or recurrent miscarriage.
Mutations that completely prevent function of the gene may tend to produce a more severe phenotype than certain types of missense mutation [Cox 1996, Deguti et al 2004, Liu et al 2004, Panagiotakaki et al 2004]. ...
Genotype-Phenotype CorrelationsMutations that completely prevent function of the gene may tend to produce a more severe phenotype than certain types of missense mutation [Cox 1996, Deguti et al 2004, Liu et al 2004, Panagiotakaki et al 2004]. Several studies have found a mean age of onset of 20 to 22 years in individuals homozygous for the common p.His1069Gln mutation [Stapelbroek et al 2004], although earlier onset also occurs.However, disease severity and clinical features are also influenced by other modifying factors, as suggested by marked differences between sibs in some families. Thus, it has been proposed that the clinical phenotype of Wilson disease is modified by mutations in other genes including MTHFR (encoding methylenetrahydrofolate reductase) [Gromadzka et al 2011], COMMD1 [Weiss et al 2006], ATOX1 [Simon et al 2008], XIAP [Weiss et al 2010]. Although some minor associations have been reported, to date none of these genes is clinically relevant or has a significant diagnostic or predictive value.
Other liver diseases presenting with abnormal liver biochemistries with or without hepatomegaly that need to be considered include the following:...
Differential DiagnosisOther liver diseases presenting with abnormal liver biochemistries with or without hepatomegaly that need to be considered include the following:Chronic viral hepatitis Autoimmune hepatitis Non-alcoholic steatohepatitis (NASH)* Primary sclerosing cholangitis Drug hepatotoxicity HFE-associated hereditary hemochromatosis Alpha-1-antitrypsin deficiency Alcoholic liver disease Primary biliary cirrhosis *Note: Wilson disease must be specifically excluded in individuals thought to have NASH or the opportunity for life-saving treatment will be missed. Other liver diseases presenting as fulminant hepatic failure that need to be considered are acute viral hepatitis of any etiology and severe drug toxicity. Kayser-Fleischer rings are not specific for Wilson disease and may in extremely rare cases be seen in copper accumulation associated with cholestatic liver diseases or autoimmune hepatitis. Subnormal serum concentration of ceruloplasmin is not per se specific for Wilson disease, as ceruloplasmin synthesis can be reduced with acute liver failure or decompensated cirrhosis of any etiology. Decreased serum concentrations of ceruloplasmin are observed in protein-losing enteropathy, nephrotic syndrome, and malnutrition, but also in some heterozygotes for Wilson disease. Serum concentration of ceruloplasmin is physiologically low in neonates. Almost complete absence of ceruloplasmin is found in hereditary aceruloplasminemia, which results in iron storage [Miyajima et al 1987, Yoshida et al 1995]. Elevated liver copper content greater than 250 µg/g dry weight may be seen in other chronic liver disorders as well. As copper is secreted exclusively via the bile, hepatic copper concentration is not reliable in conditions associated with chronic cholestasis or impaired biliary excretion. Familial/environmental copper storage diseases not related to Wilson disease have been identified but are rare; the most common of these is Indian childhood cirrhosis. Other neurologic disorders that need to be considered:Benign familial or essential tremors Parkinson disease and its differential diagnoses, including: Huntington disease Dentatorubro-pallidoluysian atrophy (DRPLA) Juvenile Parkinson disease, including Parkin type of juvenile parkinsonism Inherited forms of dystonia, including: Early-onset primary dystonia (DYT1) Dopa-responsive dystonia (DRD). See also Dystonia Overview. Neurodegenerative diseases Drug effects or toxicity Hyperthyroidism Central nervous system neoplasia Hereditary ataxias Niemann-Pick disease type C (associated with liver disease) Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs in an individual diagnosed with Wilson disease, the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Wilson disease, the following evaluations are recommended:Evaluation of severity of the liver disease by biochemical testing and imaging of the liverUpper GI endoscopy to exclude or confirm esophageal varicesDetailed clinical neurologic assessment. A validated neurologic rating scale is available [Czlonkowska et al 2007].Brain MRI to assess for structural alteration Assessment of kidney function Medical genetics consultationTreatment of ManifestationsThe goal of therapy is to institute treatment with chelating agents as soon as possible in individuals with symptomatic Wilson disease. See extensive review by the American Association for the Study of Liver Diseases [Roberts & Schilsky 2008 (full text)] and EASL Clinical Practice Guidelines: Wilson's disease [European Association for Study of Liver 2012 (full text)]. Treatment is life-long, including during pregnancy. If one treatment modality is discontinued, an alternative modality must be substituted. Discontinuation of all treatment leads to hepatic and neurologic decompensation, which is usually refractory to further medical intervention. Copper chelating agents that increase urinary excretion of copper are the first-line treatment for persons with symptomatic Wilson disease. Note: Routine institution of chelation therapy before age three years has not been adequately assessed and may have adverse effects on growth. Penicillamine (chelator). Used since the 1950s as first-line therapy for Wilson disease [Durand et al 2001, Walshe 2003b], penicillamine is given as D-penicillamine tablets by mouth two or three times daily. Pyridoxine must be given along with penicillamine. Twenty-four-hour urine copper excretion is used to confirm chelation and increased excretion of copper. Urinary copper values should be five to ten times normal; if the values are lower, non-compliance may be an issue, or body copper stores may have been adequately depleted. Complete blood count and urinalysis must be monitored regularly during penicillamine therapy. Serious side effects can occur in up to 30% of individuals, and include: severe thrombocytopenia, leukopenia, aplastic anemia, proteinuria, nephrotic syndrome, polyserositis, Goodpasture syndrome, and severe skin reactions. An early allergic reaction with fever, rash, and proteinuria may occur. Evidence of any such side effects may require discontinuation of penicillamine and substitution of an alternate treatment. If such alternate therapies are unavailable, D- penicillamine induced adverse events might be manageable by co-administration of steroids.Penicillamine inhibits collagen cross-linking and has some immunosuppressant properties. After decades of treatment, individuals may have abnormal skin and connective tissue collagen, and possible chronic depletion of copper and possibly other trace metals.Penicillamine should NOT be used simultaneously with zinc, pending adequate clinical assessment of this treatment strategy.Trientine (chelator), also known as triethylene tetramine dihydrochloride (2,2,2-tetramine) or trien, is the usual second-line treatment for individuals who cannot tolerate penicillamine. It is gaining acceptance as a first-line drug because of good efficiency and better tolerance compared to D- penicillamine, however, it is still not generally available in all countries. Complete blood count and urinalysis must be monitored regularly in all individuals on trientine.Rare side effects are gastritis with nausea and in cases of overtreatment iron deficiency anemia has been reported.Trientine should NOT be used simultaneously with zinc pending adequate assessment of this combination. Current reports suggest that the combination of trientine and zinc, temporally dispersed throughout the day such that each drug is administered 5-6 hours apart from the other, may be effective in severely decompensated hepatic Wilson disease [Santos Silva et al 1996, Askari et al 2003].Zinc (metallothionein inducer). High-dose oral zinc interferes with absorption of copper from the gastrointestinal tract presumably by inducing enterocyte metallothionein, which preferentially binds copper from the intestinal contents and is lost in the feces as enterocytes are shed in normal turnover. Zinc therapy is most effective after initial decoppering with a chelating agent [Brewer 2001, Brewer et al 2001]. In selected cases, it can be used as an initial treatment [Milanino et al 1992, Linn et al 2009]. Zinc is taken as tablets by mouth at least twice (usually 3 times) daily, before meals. The dose is based on the elemental zinc in the tablet. Twenty-four-hour urine copper excretion is used to monitor total body copper stores, which should decrease. Increase of urinary copper excretion under zinc therapy might indicate insufficient treatment efficacy [Weiss et al 2011]. The computed estimate of non-ceruloplasmin-bound copper may be used to titrate the zinc dose. Serum or urinary zinc concentration can be measured to monitor compliance in individuals taking zinc. Note: (1) Gastritis, a common side effect, can be reduced with the use of zinc acetate or zinc gluconate; (2) zinc should NOT be used simultaneously with any chelator, pending further clinical investigation. Antioxidants. Serum and hepatic vitamin E concentrations are reported to be low in individuals with Wilson disease [Sokol et al 1994, Ogihara et al 1995], likely because of excessive consumption to counteract free radicals produced by excess copper. Antioxidants, such as vitamin E, may be used along with a chelator or zinc in protecting tissues from damage. Restriction of foods very high in copper (liver, brain, chocolate, mushrooms, shellfish, and nuts) seems prudent, especially at the beginning of treatment. It is recommended that individuals with special dietary needs (e.g., vegetarians) consult with a trained dietitian. Orthotopic liver transplantation (OLT) is reserved for individuals who fail to respond to medical therapy or cannot tolerate it because of serious adverse side effects [Schilsky et al 1994, Emre et al 2001, Sutcliffe et al 2003]. It remains controversial whether orthotopic liver transplantation should be a primary treatment for individuals with Wilson disease who have severe neurologic disease [Medici et al 2005]. Prevention of Primary ManifestationsMedical therapy is recommended for asymptomatic patients to prevent development of symptoms (see Treatment of Manifestations).Prevention of Secondary ComplicationsMonitoring of patients under therapy should include routine assessments of treatment efficacy by biochemical testing and clinical evaluation:Insufficient therapy, underdosage or malcompliance could lead to reaccumulation of copper and development of new symptomsAdverse events related to medical treatment (especially under D- penicillamine treatment) should be evaluated.Excessive long-term treatment could result in copper deficiency, leading to immobilization of iron, as observed in aceruloplasminemia, and to neurologic symptoms of copper deficiency [Horvath et al 2010, da Silva-Júnior et al 2011]. SurveillanceAccording to current guidelines (AASLD [Roberts & Schilsky 2008] and EASL Clinical Practice Guidelines [European Association for Study of Liver 2012]), routine monitoring should include the following examinationsAt least twice annually: serum copper and ceruloplasmin, liver biochemistries, international normalized ratio (INR), complete blood count (CBC), urinalysis, and physical examination Note: Patients receiving chelation therapy require a complete blood count and urinalysis regularly, no matter how long they have been on treatment At least once annually: 24-hour urinary excretion of copper Note: Measurements are recommended more frequently if there are questions on compliance or if dosage of medications is adjusted. Agents/Circumstances to Avoid Foods very high in copper (liver, brain, chocolate, mushrooms, shellfish, and nuts) should be avoided, especially at the beginning of treatment. Evaluation of Relatives at RiskThe goal is to identify those sibs of a proband who have Wilson disease preferably before symptoms occur so that the therapies described under Treatment of Manifestations can be initiated as soon as possible. Affected sibs can be by molecular genetic testing if both disease-causing mutations in the proband are known). If the disease-causing mutations in an affected family member are not known, biochemical assessment of parameters of copper metabolism (serum copper, urinary copper, ceruloplasmin) and liver function tests as well as ultrasound imaging of the liver and slit lamp examination for the presence of Kayser-Fleischer rings can be conducted.Note: Because presymptomatic individuals generally have a low serum concentration of ceruloplasmin and mildly increased basal 24-hour urinary copper excretion, biochemical testing can be used; however, sometimes asymptomatic affected individuals cannot be distinguished from heterozygotes. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management Treatment must be continued during pregnancy because of the risk of fulminant hepatic failure. Penicillamine has been used in many pregnancies with no adverse outcomes, but embryopathy may occur, possibly in about 5% of births. Such adverse outcomes may depend on dose, which should be kept as low as possible. The dose of penicillamine should be maintained at the lowest effective dose with the plan to reduce by approximately 30% in the third trimester if the mother has been well chelated prior to pregnancy. A possible over-chelated (copper deficiency) status prior to pregnancy or genetic characteristics of the mother can contribute to fetal abnormalities [Pinter et al 2004]. Trientine has been used successfully during pregnancy, but the total number of reported cases is small. Zinc has been used effectively during pregnancy. Therapies Under InvestigationAmmonium tetrathiomolybdate (chelator) interferes with copper absorption from the intestine and binds plasma copper with high affinity. It may be useful for treatment of severe neurologic Wilson disease because, unlike penicillamine, it appears not to be associated with early neurologic deterioration [Brewer et al 2003]. The safety and efficacy of this drug for treatment of Wilson disease are not established; serious side effects such as bone marrow depression (leukopenia) and hepatitis are problematic. Treatment duration with ammonium tetrathiomolybdate should be limited to only a few months, as copper depletion can occur. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.Curcumin. Experimental in vitro studies suggest partially restored protein expression of some ATP7B mutants by curcumin [van den Berghe et al 2009]. This could enable novel treatment strategies in Wilson disease by directly enhancing the protein expression of mutant ATP7B with residual copper export activity. Furthermore, curcumin is an ideal antioxidant and an effective scavenger of reactive oxygen species and can act as a copper-chelating agent. However, clinical data in patients with Wilson disease are not yet available.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Wilson Disease: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDATP7B13q14.3Copper-transporting ATPase 2Wilson Disease Mutation Database ATP7B @ LOVDATP7BData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Wilson Disease (View All in OMIM) View in own window 277900WILSON DISEASE 606882ATPase, Cu(2+)-TRANSPORTING, BETA POLYPEPTIDE; ATP7BNormal allelic variants. More than 40 normal allelic variants have been reported in several ethnic groups. In some studies, normal variants may have been inaccurately reported as disease-causing mutations. Pathologic allelic variants. More than 500 mutations have been identified (see Wilson Disease Mutation Database [Kenney & Cox 2007].ATP7B mutations in have been identified in different racial groups. The most common mutation in populations of European origin is an amino acid substitution in a highly conserved motif close to the ATP-binding region (p.His1069Gln) [Tanzi et al 1993]. This mutation occurs at a frequency of 26-70% in various populations and is associated with neurologic or hepatic disease and a mean onset age of about 20 years [Houwen et al 1995, Thomas et al 1995, Maier-Dobersberger et al 1997, Shah et al 1997]. The most common mutation in the Asian population is an amino acid substitution in exon 8, p.Arg778Leu [Thomas et al 1995], found at a high frequency in all Chinese [Gu et al 2003] and ethnically related populations studied. Mutations in the promoter region are rare [Cullen et al 2003], except in Sardinia where a deletion in the promoter predominates [Loudianos et al 1999]. Table 3. Pathologic ATP7B Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.2333G>Tp.Arg778LeuNM_000053.3 NP_000044.2c.3207C>Ap.His1069GlnSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). Normal gene product. The product of ATP7B is copper-transporting ATPase 2, an intracellular transmembrane copper transporter that is key in incorporating copper into ceruloplasmin and in moving copper out of the hepatocyte into bile. The protein is a P-type ATPase, characterized by cation channel and phosphorylation domains containing a highly conserved Asp-Lys-Thr-Gly-Thr (DKTGT) motif, in which the aspartate residue forms a phosphorylated intermediate during the transport cycle. The six copper-binding domains are similar to those found in yeast and bacteria. Eight hydrophobic regions span the cell membrane. Protein structure has been modeled based on a similar calcium transporting ATPase, SERVA1 [Fatemi & Sarkar 2002, Morgan et al 2004]. The gene is expressed mainly in liver and kidney. ATP7B has 57% identity to ATP7A, the gene defective in Menkes disease [Bull et al 1993, Tanzi et al 1993].Abnormal gene product. Tissue damage occurs after excessive copper accumulation resulting from lack of copper transport from the liver. Even when no transporter function is present, accumulation of copper occurs over several years.