Previous studies have failed to identify mutations in the Wilson's disease gene ATP7B in a significant number of clinically diagnosed cases. This has led to concerns about genetic heterogeneity for this condition but also suggested the presence of unusual mutational mechanisms. We now present our findings in 181 patients from the United Kingdom with clinically and biochemically confirmed Wilson's disease. A total of 116 different ATP7B mutations were detected, 32 of which are novel. The overall mutation detection frequency was 98%. The likelihood of mutations in genes other than ATP7B causing a Wilson's disease phenotype is therefore very low. We report the first cases with Wilson's disease due to segmental uniparental isodisomy as well as three patients with three ATP7B mutations and three families with Wilson's disease in two consecutive generations. We determined the genetic prevalence of Wilson's disease in the United Kingdom by sequencing the entire coding region and adjacent splice sites of ATP7B in 1000 control subjects. The frequency of all single nucleotide variants with in silico evidence of pathogenicity (Class 1 variant) was 0.056 or 0.040 if only those single nucleotide variants that had previously been reported as mutations in patients with Wilson's disease were included in the analysis (Class 2 variant). The frequency of heterozygote, putative or definite disease-associated ATP7B mutations was therefore considerably higher than the previously reported occurrence of 1:90 (or 0.011) for heterozygote ATP7B mutation carriers in the general population (P < 2.2 × 10(-16) for Class 1 variants or P < 5 × 10(-11) for Class 2 variants only). Subsequent exclusion of four Class 2 variants without additional in silico evidence of pathogenicity led to a further reduction of the mutation frequency to 0.024. Using this most conservative approach, the calculated frequency of individuals predicted to carry two mutant pathogenic ATP7B alleles is 1:7026 and thus still considerably higher than the typically reported prevalence of Wilson's disease of 1:30 000 (P = 0.00093). Our study provides strong evidence for monogenic inheritance of Wilson's disease. It also has major implications for ATP7B analysis in clinical practice, namely the need to consider unusual genetic mechanisms such as uniparental disomy or the possible presence of three ATP7B mutations. The marked discrepancy between the genetic prevalence and the number of clinically diagnosed cases of Wilson's disease may be due to both reduced penetrance of ATP7B mutations and failure to diagnose patients with this eminently treatable disorder.

/pdf/a-genetic-study-of-wilson-s-disease-in-the-united-kingdom-50wb1l3u89.pdf

A genetic study of Wilson’s disease in the United Kingdom

Background A serum ceruloplasmin concentration below 0.20 g/L is conventionally considered as one of the major diagnostic criteria for Wilson disease. This decision threshold has not been fully validated for its diagnostic characteristics, however. In this study, we evaluated various decision thresholds of serum ceruloplasmin concentration in the diagnosis of Wilson disease based on genotype-verified Wilson disease patients, carriers, and normal individuals. Methods Serum ceruloplasmin concentration was measured by a nephelometric method in 57 Wilson disease patients and 71 family members (49 heterozygotes and 22 wild-type homozygotes), a validation group of 25 subjects clinically suspected of Wilson disease, and 690 normal individuals. We performed ROC analysis using Analyze-it software and confirmed the genotypes by direct DNA sequencing of ATP7B. Results Serum ceruloplasmin concentrations Conclusions The diagnostic accuracy for Wilson disease using a serum ceruloplasmin concentration of 0.14 g/L as the local decision threshold was better than that using a threshold of 0.20 g/L. We suggest that laboratories providing ceruloplasmin assays determine decision thresholds based on local populations.

Diagnostic Accuracy of Serum Ceruloplasmin in Wilson Disease: Determination of Sensitivity and Specificity by ROC Curve Analysis among ATP7B-Genotyped Subjects

Wilson's disease (WD) is an autosomal recessive disease caused by a mutation of the ATP7B gene, resulting in abnormal copper metabolism. The major clinical features of WD include liver disease, neurological disorders, K-F rings, and osteoporosis. The prevalence of WD in China is higher than that in Western countries. Early diagnosis and lifelong treatment will lead to better outcomes. Drugs such as sodium dimercaptosuccinate (Na-DMPS), Zn, and Gandou Decoction can be used to treat WD. Some studies have shown that the combination of traditional Chinese medicine and Western medicine is the best approach to treating WD. In order to identify better treatments, this article describes the specific clinical symptoms of Wilson's disease, its diagnosis, and treatment options.

/pdf/epidemiology-diagnosis-and-treatment-of-wilson-s-disease-1q4j8cp60b.pdf

Epidemiology, diagnosis, and treatment of Wilson's disease.

Wilson's disease (WND) is a rare autosomal recessive disorder. Here we have evaluated 62 WND cases (58 probands) from the Chinese Han population to expand our knowledge of ATP7B mutations and to more completely characterize WND in China. The coding and promoter regions of the ATP7B gene were analyzed by direct sequencing in 62 Chinese patients (58 probands) with WND (male, n = 37; female, n = 25; age range, 2 ~ 61 years old). Neurologic manifestations were associated with older age at diagnosis (p < 0.0001) and longer diagnostic delay (p < 0.0001). Age at diagnosis was also correlated with urinary copper concentration (r = 0.58, p < 0.001). Forty different mutations, including 14 novel mutations, were identified in these patients. Common mutations included p.Arg778Leu (31.9%) and p.Pro992Leu (11.2%). Homozygous p.Arg778Leu and nonsense mutation/frameshift mutations were more often associated with primary hepatic manifestations (p = 0.0286 and p = 0.0383, respectively) and higher alanine transaminase levels at diagnosis (p = 0.0361 and p = 0.0047, respectively). Nonsense mutation/frameshift mutations were also associated with lower serum ceruloplasmin (p = 0.0065). We identified 14 novel mutations and found that the spectrum of mutations of ATP7B in China is quite distinct from that of Western countries. The mutation type plays a role in predicting clinical manifestations. Genetic testing is a valuable tool to detect WND in young children, especially in patients younger than 8 years old. Four exons (8, 12, 13, and 16) and two mutations (p.Arg778Leu, p.Pro992Leu) should be considered high priority for cost-effective testing in China.

/pdf/clinical-and-molecular-characterization-of-wilson-s-disease-5d4tz46s4b.pdf

Clinical and molecular characterization of Wilson's disease in China: identification of 14 novel mutations

This study was designed to investigate the molecular basis and the correlation between genotype and phenotype in the southern Chinese patients with Wilson's disease (WD). Genotypes of the ATP7B gene in 73 WD patients were examined by denaturing high-performance liquid chromatography (DHPLC) and DNA sequencing. A total of 38 different disease-causing mutations were identified, including 10 novel mutations: missense mutations (p.Gln707Arg, p.Cys1079Phe, p.Gly1149Glu, p.Ser855Tyr, p.Ala874Pro and p.Ser921Arg), nonsense mutation (p.Arg1228Stop), splice-site mutations (2121+3A>T and 3244-2A>G) and frameshift mutation (1875_1876insAATT). We found that a pair of siblings carried the same genotype but different clinical type, and two patients were found to have three mutations. In addition, we compared the clinical data for p.Arg778Leu homozygotes and compound heterozygotes. Our research has enriched the mutation spectrum of the ATP7B gene in the Chinese population and can serve as the basis for genetic counseling and clinical/prenatal diagnosis to prevent WD in China.

/pdf/mutation-analysis-of-73-southern-chinese-wilson-s-disease-5giivoltpr.pdf

Mutation analysis of 73 southern Chinese Wilson's disease patients: identification of 10 novel mutations and its clinical correlation.

The correct name of the eighth author should be given as Sik-To Lai, not Jak-Yiu Lai.

/pdf/mutational-analysis-of-65-wilson-disease-patients-in-hong-5bf5tvsgdc.pdf

Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: Identification of 17 novel mutations and its genetic heterogeneity (Journal of Human Genetics (2008) 53 (55-63) DOI: 10.1007/s10038-007-0218-2)

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Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: Identification of 17 novel mutations and its genetic heterogeneity (Journal of Human Genetics (2008) 53 (55-63) DOI: 10.1007/s10038-007-0218-2)