Presymptomatic Wilson's Disease Research Articles

Familial screening of children with Wilson disease: Necessity of screening in previous generation and screening methods.

Wilson disease (WD) is an autosomal recessive genetic disorder associated with copper metabolism. Early diagnosis and therapy can result in good prognosis of WD. Thus, it is highly recommended to perform familial screening. In this study, we aimed to investigate the range of familial screening of children with WD and determine the appropriate screening methods.We enrolled 20 children with WD and 50 family members of each of these patients (40 parents and 10 siblings). All the subjects underwent a physical examination, Kayser–Fleischer (K-F) rings in the cornea, abdominal ultrasonography (Abdl Ur), cranial magnetic resonance imaging (MRI), serum ceruloplasmin, serum copper, 24-hour urine copper, blood alanine transaminase (ALT) and aspartate transaminase (AST), and ATP7B gene.Two new patients with presymptomatic WD (1 mother and 1 brother) in 2 families were found by screening. They had no clinical symptoms and K-F rings in corneal. Biochemical examination indicated decreased serum ceruloplasmin and serum copper in the mother and decreased serum ceruloplasmin in the brother. Gene sequencing revealed compound heterozygous mutations in them. In addition, 48 heterozygous carriers of Wilson disease (WHDzc) were found in this study. The levels of ceruloplasmin and serum copper in patients of WD were significantly less than WHDzc and 24-hour urinary copper were significantly higher than WHDzc (P = .000). The biochemical profiles of WD and WDHzc overlapped in range of 0.8 to 1.5 g/L in ceruloplasmin, above 9 μmol/L in serum copper and below 100 μg/24 h in urinary copper. Gene sequencing showed 2 pathological mutations in all patients with WD and 1 pathological mutation in all WDHzc.Not only siblings but also the previous generation of children probands with WD should be screened. Genetic testing should be conducted for the diagnosis of presymptomatic patients with WD.

Zinc monotherapy for young children with presymptomatic Wilson disease: A multicenter study in Japan.

Few studies of zinc monotherapy for presymptomatic Wilson disease have focused on young children. We therefore evaluated long-term efficacy and safety of zinc monotherapy for such children and established benchmarks for maintenance therapy. We retrospectively and prospectively examined children under 10years old with presymptomatic Wilson disease who received zinc monotherapy from time of diagnosis at 12 participating pediatric centers in Japan. Twenty-four patients met entry criteria. Aspartate aminotransferase and alanine aminotransferase decreased significantly beginning 1month after initiation of treatment and usually remained under 50U/L from 1 to 8years of treatment. Twenty four-hour urinary copper decreased significantly at 6months and usually remained under 75μg/day and between 1 and 3μg/kg/day for the remainder of the study. All patients continued to take zinc, and none became symptomatic. In patients under 6years old who received 50mg/day of zinc as an initial dose, aspartate aminotransferase and alanine aminotransferase significantly decreased at 1month after initiation of treatment, as did γ-glutamyltransferase and 24-h urinary copper at 6months. To our knowledge, this is the first multicenter study of zinc monotherapy for young children with presymptomatic Wilson disease. Such monotherapy proved highly effective and safe. Maintaining normal transaminase values (or values under 50U/L when normalization is difficult) and 24-h urinary copper excretion between 1 and 3μg/kg/day and under 75μg/day is a reasonable goal. An initial dose of 50mg/day is appropriate for patients under 6years old.

Managing pre-symptomatic Wilson disease in genetic era – More questions than answers

Managing pre-symptomatic Wilson disease in genetic era – More questions than answers

Linkage Analysis based on Four Microsatellite Markers to Screen for Unknown Mutation in Families with Wilson Disease.

Wilson disease (WD) is a rare autosomal recessive disorder of copper metabolism due to mutations in ATP7B gene on the chromosome 13. Linkage analysis using microsatellite markers is a powerful screening technique to identify mutant chromosomes especially in affected families with unknown mutations. Previous studies in southern Iran have failed to identify mutations in the ATP7B in some clinically diagnosed cases. Hence, the present study was undertaken to provide a screening method for these WD affected families. Genomic DNA was prepared from the peripheral blood of 12 WD affected families. Four short tandem repeat (STR) markers around the WD locus (D13S301, D13S296, D13S201, and D13S297) were amplified by multiplex polymerase chain reaction (PCR) and amplified DNA fragments were analyzed by polyacrylamide gel electrophoresis (PAGE). In addition, 24 samples were amplified by PCR using fluorescent labeled primer and then examined by capillary electrophoresis (CE). Finally, haplotype and genotype analysis was done for each family. According to the results of linkage analysis by STR markers, the genotypes of all the children related to the WD families were predicted. However, the genotypes of 8 persons remained unclear due to uninformative markers. This investigation indicated that 3 out of 4 selected STR markers were informative among Iranian population. Based on the results, linkage analysis by STR markers is a powerful method for detection of potential carriers and presymptomatic WD homozygotes in families with at least one previously affected child. This approach is an efficient, accurate, and cost-effective method that can be used in clinical laboratories, especially in recently developed molecular genetics centers in countries whose patients have not yet been diagnosed for WD-causing ATP7B gene mutations.

Novel mutations of the ATP7B gene in Han Chinese families with pre-symptomatic Wilson's disease.

Wilson's disease (WD) is an autosomal recessive genetic disorder of copper metabolism, caused by mutations in the ATP7B gene, resulting in copper accumulation in the liver, brain, kidney, and cornea and leading to significant disability or death if untreated. Early diagnosis and proper therapy usually predict a good prognosis, especially in pre-symptomatic WD. Genetic testing is the most accurate and effective diagnostic method for early diagnosis. The clinical and biochemical features of three unrelated Han Chinese families with pre-symptomatic WD were reported. The molecular defects in these families were investigated by polymerase chain reaction and DNA sequencing. Hundred healthy children with the same ethnic background served as controls. Bioinformatic tools (polymorphism phenotyping-2, sorting intolerant from tolerant, protein analysis through evolutionary relationships, and predictor of human deleterious single nucleotide polymorphisms) were combined and used to predict the functional effects of mutations. We identified 2 novel ATP7B mutations (p.Leu692Pro and p.Asn728Ser) and 3 known mutations (p.Met769fs, p.Arg778Leu and p.Val1216Met) in these Chinese WD families. These mutations were not observed in the 100 normal controls. The bioinformatic method showed that p.Leu692Pro and p.Asn728Ser mutations are pathogenic. Our research enriches the mutation spectrum of the ATP7B gene worldwide and provides valuable information for studying the mutation types and mode of inheritance of ATP7B in the Chinese population. Liver function analysis and genetic testing in young children with WD are necessary to shorten the time to the initiation of therapy, reduce damage to the liver and brain, and improve prognosis.

Zinc Mono-Therapy in Pre-Symptomatic Chinese Children with Wilson Disease: A Single Center, Retrospective Study

BackgroundThere is no official consensus regarding zinc therapy in pre-symptomatic children with Wilson Disease (WD); more data is needed.ObjectiveTo investigate the safety and efficacy of zinc gluconate therapy for Chinese children with pre-symptomatic WD.MethodsWe retrospectively analyzed pre-symptomatic children receiving zinc gluconate in a single Chinese center specialized in pediatric hepatology. Short-term follow-up data on safety and efficacy were presented, and effects of different zinc dosages were compared.Results30 children (21 males) aged 2.7 to 16.8 years were followed for up to 4.4 years; 26 (87%) children had abnormal ALT at baseline. Most patients (73%) received higher than the currently recommended dose of elemental zinc. Zinc gluconate significantly reduced mean ALT (p<0.0001), AST (p<0.0001), GGT (p<0.0001) levels after 1 month, and urinary copper excretion after 6 months (p<0.0054). Mean direct bilirubin levels dropped significantly at 1 month (p = 0.0175), 3 months (p = 0.0010), and 6 months (p = 0.0036). Serum zinc levels gradually increased and reached a significantly higher level after 6 months (p<0.0026), reflecting good compliance with the therapy. Complete blood count parameters did not change throughout the analysis period. 8 children experienced mild and transient gastrointestinal side effects. The higher zinc dose did not affect treatment response and was not associated with different or increased side effects when compared to conventional zinc dose.ConclusionIn our cohort, zinc gluconate therapy for Chinese children with pre-symptomatic WD was effective, and higher initial dose of elemental zinc had the same level of efficacy as the conventional dose.

Isolated persistent elevation of alanine transaminase for early diagnosis of pre-symptomatic Wilson’s disease in Chinese children

Recent studies presented a contradictory approach for the investigation of pediatric patients with an isolated increase in alanine transaminase. While classical teaching advised for a thorough investigation, recent studies suggested the yield on further investigation was low and thus not necessary. Yet the approach to the same clinical problem may need to be different due to variable disease prevalence rates among different ethnic populations. For the population with a higher prevalence rate of genetic liver diseases like Wilson's disease, an abnormal liver function may be the first presenting feature for some patients. We reviewed 10 Chinese children with Wilson's disease who were diagnosed at a presymptomatic stage because of an isolated persistent elevation of alanine transaminase. All 10 patients did not have overt symptoms of liver impairment or neurological deficit. They were picked up incidentally with an abnormal liver function test. All patients were started on treatment shortly after diagnosis, and they remained well and symptom-free on the latest follow-up. This case series illustrated that an isolated persistent elevation of alanine transaminase is an important clue to the early diagnosis of pre-symptomatic Wilson's disease. It is particularly relevant in the Asian population where the disease is more prevalent.

Zinc Monotherapy From Time of Diagnosis for Young Pediatric Patients With Presymptomatic Wilson Disease

In 4 young pediatric patients with presymptomatic Wilson disease, we found zinc monotherapy beginning at time of diagnosis to be safe and highly effective for follow-up intervals between 1 and 2 years. Such maintenance therapy with zinc can maintain urinary copper excretion between 1 and 3 μg · kg(-1) · day.

Mass screening for Wilson's disease by measuring urinary holoceruloplasmin

We conducted a mass-screening method to detect presymptomatic Wilson's disease in children by measuring urinary holoceruloplasmin. Two cases of Wilson's disease were found by testing urine samples from 48,819 children. The diagnosis was confirmed by clinical laboratory tests and the detection of a mutated ATP 7B gene. (J Pediatr 2002;140:614-6)

Acute Hepatitis After Starting Zinc Therapy in a Patient With Presymptomatic Wilson's Disease

HepatologyVolume 32, Issue 4 p. 877-877 CorrespondenceFree Access Acute hepatitis after starting zinc therapy in a patient with presymptomatic Wilson's disease Luis Castilla-Higuero M.D., Ph. D., Luis Castilla-Higuero M.D., Ph. D. Digestive Diseases Unit, Valme University Hospital, Seville, SpainSearch for more papers by this authorManuel Romero-Gomez M.D., Ph. D., Manuel Romero-Gomez M.D., Ph. D. Digestive Diseases Unit, Valme University Hospital, Seville, SpainSearch for more papers by this authorEmilio Suarez M.D., Emilio Suarez M.D. Digestive Diseases Unit, Valme University Hospital, Seville, SpainSearch for more papers by this authorManuel Castro M.D., Ph. D., Manuel Castro M.D., Ph. D. Digestive Diseases Unit, Valme University Hospital, Seville, SpainSearch for more papers by this author Luis Castilla-Higuero M.D., Ph. D., Luis Castilla-Higuero M.D., Ph. D. Digestive Diseases Unit, Valme University Hospital, Seville, SpainSearch for more papers by this authorManuel Romero-Gomez M.D., Ph. D., Manuel Romero-Gomez M.D., Ph. D. Digestive Diseases Unit, Valme University Hospital, Seville, SpainSearch for more papers by this authorEmilio Suarez M.D., Emilio Suarez M.D. Digestive Diseases Unit, Valme University Hospital, Seville, SpainSearch for more papers by this authorManuel Castro M.D., Ph. D., Manuel Castro M.D., Ph. D. Digestive Diseases Unit, Valme University Hospital, Seville, SpainSearch for more papers by this author First published: 30 December 2003 https://doi.org/10.1053/jhep.2000.17917Citations: 12AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat REFERENCES 1 Brewer GJ, Johnson VD, Dick RD, Hedera P, Fink JK, Kluin KF. Treatment of Wilson's disease with zinc. XVII: Treatment during Pregnancy. Hepatology 2000; 31: 364– 370.MEDLINE 2 Brewer GJ, Yuzbasiyan-Gurkan V. Wilson Disease. Medicine 1992; 71: 139– 164.MEDLINE 3 Brewer GJ. Practical recommendations and new therapies for Wilson's disease. Drugs 1995; 50: 240– 249.MEDLINE 4 Lang CJG, Rabas-Kolominsky P, Engelhardt A, Kbras G, Konig HJ. Fatal deterioration of Wilson's disease after institution of oral zinc therapy. Arch Neurol 1993; 50: 1007– 1008.MEDLINE 5 Walshe JM, Munro NAR. Zinc-induced deterioration in Wilson's disease aborted by treatment with penicillamine, dimercaprol, and a novel zero copper diet. Arch Neurol 1995; 52: 10– 11.MEDLINE 6 Mulder TP, Janssens AR, Verpaget HW, van Hattum Lamers CB. Metallothionein concentration in the liver of patients with Wilson's disease, primary biliary cirrhosis, and liver metastasis of colorectal cancer. J Hepatol 1992; 16: 346– 350.MEDLINE 7 Friedman LS. Zinc in the treatment of Wilson's disease: how it works. Gastroenterology 1993; 104: 1566– 1568.MEDLINE Citing Literature Volume32, Issue4October 2000Pages 877-877 ReferencesRelatedInformation

Screening for Wilson's disease in patients with liver diseases by serum ceruloplasmin

Background/Aims: A low serum ceruloplasmin level is considered a diagnostic test for Wilson's disease. To examine whether it is useful to detect presymptomatic patients with Wilson's disease, serum ceruloplasmin was determined by radial immunodiffusion (normal: 20–60 mg/dl) in all patients ( n=2867) admitted for evaluation of a liver disease in 1993 and 1994. Methods: Patients with levels lower than 20 mg/dl were further evaluated by determination of serum copper concentration, urine copper excretion and ophthalmological examination. If possible, a liver biopsy was performed and the hepatic copper content was determined by flame atomic absorption spectroscopy. Results: Seventeen patients had serum ceruloplasmin levels <20 mg/dl. One had asymptomatic Wilson's disease (no Kayser-Fleischer rings or neurological symptoms). In the other 16 patients Wilson's disease was excluded. Based on elevated hepatic copper concentration, three were considered as heterozygous carriers of the WD gene. The remaining patients had various liver diseases (acute viral hepatitis in three, chronic hepatitis in two, drug-induced liver disease in three, alcoholic induced liver disease in two) or malabsorption ( n=3). Conclusions: The positive predictive value of low serum ceruloplasmin was only 5.9%. Although helpful for identifying presymptomatic Wilson's disease, screening by determining of serum ceruloplasmin in unselected patients with clinical or laboratory evidence of liver disease in neither feasible nor cost effective.

Wilson's disease: Presymptomatic patients and Kayser-Fleischer rings

Purpose: We evaluated patients with Wilson's disease to determine (1) whether presymptomatic patients who have Kayser-Fleischer (kf) rings demonstrate a more significant alteration of copper metabolism than those who do not have kf rings, and (2) whether presymptomatic patients have smaller kf rings than symptomatic Wilson's disease patients. Methods: Thirty-two patients with presymptomatic Wilson's disease were retrospectively analyzed. Sixteen of these had received no prior anti-copper therapy and underwent testing for baseline copper metabolism (24-hour urine copper, liver copper, and plasma ceruloplasmin). Quantitative measurements of kf rings were made for the group of untreated presymptomatic patients and a control group of symptomatic Wilson's disease patients. Results: We hypothesized that the 24-hour urine copper, in particular, would correlate with the presence of a kf ring. However, no significant difference was found between any of the baseline copper variables for presymptomatic patients who had kf rings compared to those who did not. kf rings of presymptomatic patients were found to be significantly smaller than kf rings of patients with symptomatic Wilson's disease (p < 0.05). Conclusions: While this study does not show any relationship between urinary copper excretion and the presence of kf rings, it suggests that the larger kf ring size correlates with Wilson's disease severity.

Development of Neurologic Symptoms in a Patient With Asymptomatic Wilson's Disease Treated With Penicillamine

To report a case of presymptomatic Wilson's disease in a patient who became severely neurologically disabled after treatment with penicillamine and to discuss alternative initial therapy for such patients. Case report. The patient described is briefly compared with a previously studied group of 13 similar presymptomatic patients who received zinc therapy without any clinical worsening and who have had 3 to 9 years of follow-up. Referral hospital. The patient was referred to us. The patient had initially been treated with penicillamine. The main outcome of interest is permanent neurologic disability, depending on type of initial treatment. The result of initial penicillamine therapy in the patient described is permanent neurologic disability. This is believed to be due to mobilization and redistribution of hepatic copper causing higher levels of copper in key areas of the brain. We conclude that penicillamine used as initial therapy, even in patients with neurologically asymptomatic Wilson's disease, increases the risk of inducing permanent neurologic damage.

Wilson's disease: the problem of delayed diagnosis.

To discover the earliest symptoms and signs of neurological Wilson's disease we analysed the case histories of 136 patients who were seen between 1955-87: patients with hepatic or presymptomatic Wilson's disease were excluded from this series. Thirty one patients (23%) gave a history of an episode of liver damage. The onset of symptoms ranged from nine to 40 years with a median of 16.2 years. The correct diagnosis was made at presentation in only 43 patients. The mean delay before diagnosis was 12.8 months for the others. The earliest symptoms were dysarthria or difficulty with the hands, or often both. There was often an associated change in personality or deteriorating performance at school. The four common clinical pictures were Parkinsonian (61 cases), "pseudosclerotic" (33 cases), dystonic (21 cases) and choreic (15 cases): six cases were unclassified. Parkinsonian symptoms were equally common in children (under 17 years) and adults, a "pseudosclerotic" picture was much more common in adults but dystonic and choreic symptoms were seen more often in children. Experience suggests that no two patients are ever the same, even in a sibship.

Presymptomatic Wilson's disease: further questions and comments.

In ninety families with at least one proven case of Wilson's disease, seen over 32 years, all close relatives were examined and “presymptomatic” disease was diagnosed in 30.11 had one or more abnormal physical signs when examined and 7 of these had Kayser Fleischer rings. In a further 10 patients the abnormalities of copper metabolism were so pronounced as to leave no doubt as to the diagnosis. 6 patients were not seen until they had been on treatment for 2 years or more; in some, much of the evidence on which the diagnosis was based is not available. In 3 patients there were only minor histological abnormalities in the liver and no increase in urinary copper but other indices of copper metabolism pointed to a diagnosis of Wilson's disease. 2 patients had transient neurological signs after starting treatment; otherwise, all but one (who died in an accident) have remained well for up to 26 years.

The Pattern of the Whole Body Distribution of Radioactive Copper (&lt;sup&gt;67&lt;/sup&gt;Cu, &lt;sup&gt;64&lt;/sup&gt;Cu) in Wilson's Disease and Various Control Groups

Radioactive copper (64Cu, 67Cu), injected intravenously, was used to study abnormalities of copper transport in patients with Wilson's disease in the presymptomatic, symptomatic and treated phases of the disease. The findings are compared with data obtained from individuals heterozygous for the Wilson's disease gene and from a control group consisting of patients of similar age with a variety of diseases of the motor nervous system. The measurements made included plasma levels of radioactive copper, liver uptake, and whole body distribution measured both by profile scanning and whole body scintiscanning. Results from the various techniques are in good agreement. They confirm earlier findings that in presymptomatic Wilson's disease the uptake of copper by the liver is significantly greater than in controls, and rises continuously. Heterozygotes take up an intermediate position between the two groups. Disappearance of copper from plasma roughly corresponds to the sequestration of the metal by liver. Untreated, symptomatic Wilson's disease patients show much delayed uptake of copper by the liver and slow clearance from plasma. Treatment with chelating agents restores the pattern towards that seen in presymptomatic patients. A feature of the profile scan and the scintiscans in the controls is the appearance of copper in the gut at or soon after 48 hours, a feature which has not been seen in heterozygotes and presymptomatic patients. The shape of the protile scan in the heterozygotes is more akin to that seen in presymptomatic Wilson's disease than in controls and this observation increases the possibility of diagnosing the carrier state with greater precision than was previously possible.

Metabolic studies in Wilson's disease: Evaluation of efficacy of chelation therapy in respect to copper balance

Long-term copper balance studies were performed in fifteen patients with Wilson's disease, six of their parents and siblings, and one normal control subject. Patients with Wilson's disease required a daily dietary copper intake of 1.1 mg or less to attain negative copper balance whereas their family members were in balance at 1.4 mg/day. Penicillamine therapy elicited a markedly negative copper balance initially by increasing the urinary excretion of copper, but as therapy continued, both urinary and fecal copper excretion diminished. The effect of oral ehelators on fecal copper varied: DTPA was of no value; carbacrylamine resin and potassium sulfide increased the fecal copper content. Most patients with Wilson's disease could be maintained in negative copper balance with a daily dietary copper intake of 1.5 mg or less with these latter agents. The addition of these drugs offered no advantage over the use of penicillamine alone. The combination of a low copper diet and the oral chelating agent, carbacrylamine resin, should be considered for interim periods to treat presymptomatic Wilson's disease or in patients with clinical Wilson's disease whose tissue copper stores have been reduced by penicillamine therapy.

PRESYMPTOMATIC WILSON'S DISEASE

Presymptomatic Wilson's disease must be diagnosed because the severe consequences of the disease may be prevented by adequate chelation therapy. Seventeen children from five families having members with Wilson's disease have been studied to detect presymptomatic subjects. Seven had clinical Wilson's disease, five were diagnosed as presymptomatic (homozygotes), and five were believed normal or heterozygotes. Kayser-Fleischer rings must be looked for with a slit lamp. They were present in symptomatic but absent in presymptomatic patients. All presymptomatic homozygotes had low serum copper and cæruloplasmin levels, but these estimations could not distinguish them with certainty from heterozygotes. A liver-copper concentration, performed on needle-biopsy samples, over 25 mg. per 100 g. dry weight, confirmed the presymptomatic state. The liver histology may be normal or abnormal, depending on the stage of the disease. Two heterozygotes