Wilson disease with an initial manifestation of polyneuropathy. Kim, E. Identification of three novel mutations and a high frequency of the argto-leu mutation in Korean patients with Wilson disease. Kooy, R. Physical localisation of the chromosomal marker D13S31 places the Wilson disease locus at the junction of bands q Kuan, P.
Cardiac Wilson's disease. Chest , Kuo, Y. Developmental expression of the mouse mottled and toxic milk genes suggests distinct functions for the Menkes and Wilson disease copper transporters.
Kuruvilla, A. Lang, C. Fatal deterioration of Wilson's disease after institution of oral zinc therapy. Lang, P. Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide. Nature Med. Levi, A. Presymptomatic Wilson's disease. Note: Originally Volume II. LeWitt, P. Penicillamine as a controversial treatment for Wilson's disease.
Editorial Mov. Li, Y. Spontaneous hepatic copper accumulation in Long-Evans Cinnamon rats with hereditary hepatitis: a model of Wilson's disease. Lingam, S. Neurological abnormalities in Wilson's disease are reversible. Neuropediatrics , Litin, R. Hypercalciuria in hepatolenticular degeneration Wilson's disease. Loudianos, G. Molecular characterization of Wilson disease in the Sardinian population--evidence of a founder effect. Further delineation of the molecular pathology of Wilson disease in the Mediterranean population.
Mak, C. Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: identification of 17 novel mutations and its genetic heterogeneity.
Note: Erratum: J. Margarit, E. Mutation analysis of Wilson disease in the Spanish population--identification of a prevalent substitution and eight novel mutations in the ATP7B gene.
Marsden, C. Kinnier Wilson McAlpine, P. Personal Communication. Menerey, K. The arthropathy of Wilson's disease: clinical and pathologic features.
Okada, T. Olivarez, L. Estimate of the frequency of Wilson's disease in the US Caucasian population: a mutation analysis approach. Owen, C. Inherited copper toxicosis in Bedlington terriers: Wilson's disease hepatolenticular degeneration. Park, H. Letter Clin. Park, S. Passwell, J.
Heterogeneity of Wilson's disease in Israel. Petrukhin, K. Mapping, cloning and genetic characterization of the region containing the Wilson disease gene. Polson, R. Reversal of severe neurological manifestations of Wilson's disease following orthotopic liver transplantation. Ross, M. Late-onset Wilson's disease with neurological involvement in the absence of Kayser-Fleischer rings.
Saito, T. Evaluation of segregation ratio in Wilson's disease. An expected decrease in incidence of Wilson's disease due to decrease in consanguinity. Sasaki, N. The gene responsible for LEC hepatitis, located on rat chromosome 16, is the homolog to the human Wilson disease gene.
Scheffer, H. Identification of crossovers in Wilson disease families as reference points for a genetic localization of the gene. Shokeir, M. Cytochrome oxidase deficiency in Wilson's disease: a suggested ceruloplasmin function. Investigations on the nature of ceruloplasmin deficiency in the newborn. Slovis, T. The varied manifestations of Wilson's disease. Sokol, R. Orthotopic liver transplantation for acute fulminant Wilson disease.
Starosta-Rubinstein, S. Clinical assessment of 31 patients with Wilson's disease: correlations with structural changes on magnetic resonance imaging. Sternlieb, I. Chronic hepatitis as a first manifestation of Wilson's disease. Strickland, G. Wilson's disease in the United Kingdom and Taiwan. General characteristics of cases and prognosis. A genetic analysis of 88 cases. Takeshita, Y. Two families with Wilson disease in which siblings showed different phenotypes. Tanzi, R.
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Note: Erratum:. Wilson disease in Iceland: a clinical and genetic study. Haplotypes and mutations in Wilson disease. Genetic mapping of the copper toxicosis locus in Bedlington terriers to dog chromosome 10, in a region syntenic to human chromosome region 2pp Cranial MR in Wilson disease: abnormal white matter in extrapyramidal and pyramidal tracts. Wallace, D. ATP7B variant penetrance explains differences between genetic and clinical prevalence estimates for Wilson disease. Walshe, J.
Wilson's Disease: Some Current Concepts. Oxford: Blackwell pub. Penicillamine, a new oral therapy for Wilson's disease. Wilson's disease: yesterday, today, and tomorrow.
Treatment of Wilson's disease: the historical background. Penicillamine: the treatment of first choice for patients with Wilson's disease.
Wang, L. Mutation analysis of 73 southern Chinese Wilson's disease patients: identification of 10 novel mutations and its clinical correlation. Whelton, M. Azure lunules in argyria: corneal changes resembling Kayser-Fleischer rings. Wiebers, D. Renal stones in Wilson's disease.
Wilson, J. Memories of my father. Wilson, S. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver. Brain , Wu, J. Wu, Z. Molecular diagnosis and prophylactic therapy for presymptomatic Chinese patients with Wilson disease.
Yuzbasiyan-Gurkan, V. Linkage of the Wilson disease gene to chromosome 13 in North-American pedigrees. Linkage studies of the esterase D and retinoblastoma genes to canine copper toxicosis: a model for Wilson disease. Genomics , A number sign is used with this entry because Wilson disease WND is caused by homozygous or compound heterozygous mutation in the ATP7B gene on chromosome 13q NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine.
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Clinical Trials. Gene Reviews. MedlinePlus Genetics. MGI Mouse Phenotype. Chabik et al. However, there are also case reports of siblings and homozygous twins presenting discordant clinical presentations or different post liver transplant outcomes 49 - A Japanese study in 11 families including 23 sibilings diagnosed with WD described that 5 families had identical phenotypes and 6 families different phenotypes Interestingly, there is evidence of geographical clustering within regions with smaller or isolated communities with various levels of consanguinity and presenting phenotype homogeneity.
Two large families in small mountain community in the region of Rucar in Romania were studied given the high prevalence of WD cases Of note, there was a significant phenotypic concordance between all WD patients presenting neurological and psychiatric phenotype. Patients presented mostly dysarthria and dysphagia as initial symptoms and had similar age of onset 17—20 years old.
The authors concluded that their findings demonstrate the influence of both genetic and environmental factors on the phenotype More than 70 members of a single Lebanese family were investigated for the c. AlaThr mutations. The clinical diagnosis of WD was confirmed in 9 subjects The cinsC mutation was associated hepatic and the AlaThr was associated with neurological phenotype.
A study on 4 generations of an Italian family, showed a possible association between the homozygotic mutation TR and the hepatic phenotype Different evidence comes from Gran Canaria, where the LeuPro mutation was highly prevalent, affecting 18 out of 24 patients with WD, including 12 homozygous patients, 4 compound heterozygous, and 2 with only one identified mutation However, the phenotype was variable and included prevalently neurological manifestations but also hepatic involvement with no obvious association between the genotype and phenotype.
Therefore, despite the methodological challenges, the evidence points to the presence of additional factors, other than gene mutations, affecting the clinical presentation. A modifier gene has been defined as a gene that alters the expression of a gene at another locus or the phenotypic expression of another gene It is plausible to hypothesize the presence of modifier genes influencing the varied WD phenotype.
Several genes have been proposed as possible candidates for this role. Kluska et al. The study identified two new possible variants in esterase D ESD and INO80 genes being associated with increased and reduced risk of neurological presentation, respectively. ESD , encoding for a polymorphic red cell enzyme, was previously linked to WD INO80 has important transcription regulation functions through chromatin remodeling action Other studies have previously associated APOE variants with WD 59 , in one case with delayed neurological symptoms However, other studies could not confirm the association 61 , These proteins have central regulating function in epigenetic mechanisms, including the readout of DNA methylation MBD6 interacts with the human deubiquitinase complex and reported to be a target of Oct4 in stem cells derived from adipose tissue Conversely, the analysis could not confirm any association between WD phenotypes and other previously proposed modifier genes allelic variants Even though the study results may have been affected by the relatively small population or by the analysis methodologies, the results question the validity and clinical significance of previous findings on candidate modifier genes.
A candidate modifier gene with mechanistic relevance is the patatin-like phospholipase domain-containing 3 gene PNPLA3. PNPLA3 rs polymorphism has been associated with increased risk of nonalcoholic fatty liver disease development 65 and with hepatic steatosis in hepatitis B 66 and C The protein presents various functions in lipids metabolism as it can both synthetize intracellular triglycerides and also has hydrolyzing activity against triglycerides 68 , Therefore, mutations affecting its function could favor steatosis.
MTHFR encodes 5,methylenetetrahydrofolate reductase, an enzyme in methionine metabolism that affect homocysteine levels. This is interesting as it provides evidence that aberrant homocysteine and methionine metabolism may interact with copper accumulation in the pathogenesis of WD and provides a possible explanation for the variable expressivity of this monogenetic disease.
Epigenetics can explain long-lived effects from in utero and early life environments on human disease susceptibility and resilience. Epigenetic information is layered on top of the DNA sequence through covalent modifications to nucleotides or nucleosomes 85 , The first layer of epigenetic information is DNA methylation.
DNA methylation patterns are dynamically erased and reestablished each generation during the formation of the gametes, which occurs in utero in mammals Woimant F, Trocello J-M. Disorders of heavy metals. Handb Clin Neurol Elsevier. Article Google Scholar. Genetically confirmed Wilson disease in a 9-month old boy with elevations of aminotransferases. World J Hepatol. Scheinberg IH. J Rheumatol Suppl.
Hoogenraad T. Amsterdam-Rotterdam: interned Medical Publishers; Google Scholar. A genetic study of Wilson's disease in the United Kingdom. J Hum Genet. Characteristics and prevalence of Wilson's disease: a observational population-based study in France. Clin Res Hepatol Gastroenterol. Mutation analysis in patients of Mediterranean descent with Wilson disease: identification of 19 novel mutations.
J Med Genet. Genet Test. Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. Hum Mutat. Clinical and molecular characterization of Wilson's disease in China: identification of 14 novel mutations. BMC Med Genet. Twenty-four novel mutations in Wilson disease patients of predominantly European ancestry. Twenty-four novel mutations in Wilson disease patients of predominantly Italian origin.
Frameshift and nonsense mutations in the gene for ATPase7B are associated with severe impairment of copper metabolism and with an early clinical manifestation of Wilson's disease.
Clin Genet. World J Pediatr. Indian J Gastroenterol. Mutation analysis of Wilson disease in the Spanish population - identification of a prevalent substitution and eight novel mutations in the ATP7B gene.
J Trace Elem Med Biol. Relative exchangeable copper: a new highly sensitive and highly specific biomarker for Wilson's disease diagnosis. Clin Chim Acta ; — Relative exchangeable copper: a promising tool for family screening in Wilson disease.
Mov Disord ;— Genet Med. Download references. These studies indicate that genotype-phenotype correlations in WD are ethnic-specific. This mutation can lead to complete loss of ATP binding affinity, presenting with severe symptoms.
In a previous report,[ 22 ] a male WD patient homozygous for EK developed fulminant hepatic failure. Furthermore, the thermal stability and intracellular localization of the EA mutation are just slightly different as compared to wild-type. In patients with GS and MV mutations in the M-domain, copper metabolism is defected, but the level of ceruloplasmin is mostly normal.
Modifiers are a group of genes that aggravate or relieve the phenotypes of other virulence genes. Apolipoprotein E ApoE gene, located in 19q For example, Litwin et al. Prion-related protein has been shown to bind copper in vitro and is likely to participate in the regulation of copper homeostasis in the human body. If the M allele is replaced by V allele, the onset of WD symptoms will advance about 5 years, but the phenotype of the symptoms would not alter.
To our knowledge, there have been few studies reporting that these genes are associated with specific WD phenotypes. Wilson's disease has complex clinical phenotypes, including a wide range in age of onset, diverse clinical presentations, and greatly different metabolic disorders.
On one hand, over mutations of ATP7B gene have been identified. These mutations exert widely varying effects on the ATP7B protein structure for example, loss of ATP7B integrity, misfolding, impaired interaction between proteins and function phosphorylation, abnormal copper-transportation, decreased ATP binding affinity, and abnormal intracellular transport.
The majority of studies on genotype-phenotype correlations in WD have been inconclusive. Potential reasons for this include difficulties in determining the age of onset and the clinical phenotype. Another reason is that the prevalence of WD is relatively low in the Western countries. Rare genotypes in WD can be predicted only by the bioinformatics technique or heterogeneous protein detection, establishing genotype-phenotype correlations in WD is, therefore, difficult from a statistical perspective.
In addition, the clinical presentations of WD cannot be simply attributed to specific genotypes; rather they are a manifestation of dynamic complex factors at the subcellular level. Nevertheless, establishment of genotype-phenotype correlations benefits clinical classification of WD, scientific clinical collaboration, and molecular mechanism research. WD gene detection methods include direct gene sequencing and haplotyping. Since the exons of WD gene disperse over a 4.
Haplotyping acquires genetic information according to the molecular markers inside the target gene or in the lateral wing of the target gene. In general, microsatellite or single-nucleotide polymorphisms in the ATP7B lateral wing are used for haplotyping.
There is no need to determine the type of mutations in haplotyping. Haplotyping is suitable for screening the relatives of patients with diagnosed WD. False positive results can occur if haplotyping is used for low probability gene recombination. Recently, novel sequencing technique enables sequencing of all exons even the whole genome. Therefore, gene diagnosis of WD in the future will be more efficient and comprehensive. Wilson's disease is conventionally diagnosed according to its clinical symptoms and biochemical indices.
In most affected patients, WD manifests as liver dysfunction or decreased ceruloplasmin level with unknown reasons. At this time, diagnosis is made mainly based on gene detection. Antenatal diagnosis of WD has not been recommended as routine in obstetrical care. However, ATP7B gene has obvious heterogeneity.
For example, mutations of untranslated region, including the promoter region, are also reported. Thus, a negative result of gene detection does not exclude a diagnosis of WD.
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