Ventricular arrhythmia-induced syncope as the initial presentation of Wilson disease in a 4-year-old child: a rare case report.

To test the efficacy and toxicity of a new drug, ammonium tetrathiomolybdate, in the initial treatment of a relatively large series of patients presenting with neurologic signs and symptoms caused by Wilson's disease. The key aspect of efficacy was to preserve the neurologic function present at the onset of therapy. An open study of 17 patients treated for 8 weeks each. Neurologic function was evaluated by frequent quantitative neurologic and speech examinations. Several copper-related variables were studied to evaluate the effect of the drug on copper, and a large number of biochemical and clinical variables were studied to evaluate potential toxicity. Patients were then followed up at yearly intervals, with follow-up periods of 1 to 5 years reported. A university hospital referral setting Patients were generally treated for 8 weeks with tetrathiomolybdate, followed by zinc maintenance therapy. Neurologic function was evaluated by quantitative neurologic and speech examinations. None of the patients suffered a loss of neurologic function. Copper status and potential further toxic effects were generally well controlled quickly. No toxic effects resulted from administration of tetrathiomolybdate. During the ensuing period of follow-up of 1 to 5 years, neurologic recovery in most patients was good to excellent. Tetrathiomolybdate appears to be an excellent form of initial treatment in patients with Wilson's disease presenting with neurologic signs and symptoms. In contrast to penicillamine therapy, initial treatment with tetrathiomolybdate does not result in further, often irreversible neurologic deterioration.

Wilson's disease: clinical management and therapy

EASL Clinical Practice Guidelines: Wilson’s disease

A novel nomogram based on routine clinical indicators for screening for Wilson's disease

Brainstem auditory evoked potentials in Wilson's disease

Wilson's disease is a rare disorder of copper transport in hepatic cells, and may present as cholestatic liver disease; pancreatitis and cholangitis are rarely associated with Wilsons's disease. Moreover, cases of Wilson's disease presenting as pigmented gallstone pancreatitis have not been reported in the literature. In the present report, we describe a case of a 37-year-old man who was admitted with jaundice and abdominal pain. The patient was diagnosed with acute pancreatitis, cholangitis, and obstructive jaundice caused by pigmented gallstones that were detected during retrograde cholangiopancreatography. However, because of his long-term jaundice and the presence of pigmented gallstones, the patient underwent further evaluation for Wilson's disease, which was subsequently confirmed. This patient's unique presentation exemplifies the overlap in the clinical and laboratory parameters of Wilson's disease and cholestasis, and the difficulties associated with their differentiation. It suggests that Wilson's disease should be considered in patients with pancreatitis, cholangitis, and severe protracted jaundice caused by pigmented gallstones.

Objectives: To summarize the clinical phenotypes and the variation spectrum of ATP7B gene in Chinese children with Wilson's disease (WD) and to investigate their significance for early diagnosis. Methods: Retrospective analysis was performed on the clinical data of 316 children diagnosed as WD in Guangzhou Women and Children's Medical Center during the period from January 2010 to June 2021. The general situations, clinical manifestations, lab test results, imaging examinations, and ATP7B gene variant characteristics were collected. The patients were divided into asymptomatic WD group and symptomatic WD group based on the presence or absence of clinical symptoms at the time that WD diagnosis was made. The χ2 test, t test or Mann-Whitney U test were used to compare the differences between groups. Results: Among the 316 children with WD, 199 were males and 117 were females, with the age of 5.4 (4.0, 7.6) years at diagnosis; 261 cases (82.6%) were asymptomatic with the age of 4.9 (3.9, 6.4) years; whereas 55 cases (17.4%) were symptomatic with the age of 9.6 (7.3, 12.0) years. The main symptoms invloved liver, kidney, nervous system, or skin damage. Of all the patients, 95.9% (303/316) had abnormal liver function at diagnosis; 98.1% (310/316) had the serum ceruloplasmin lever lower than 200 mg/L; 97.7% (302/309) had 24-hour urine copper content exceeding 40 μg; only 7.4% (23/310) had positive corneal K-F rings, 8.2% (23/281) had abnormal MRI signals in the lenticular nucleus, and all of them had symptoms of damage in liver, kidney or nervous system. Compared with the group of symptomatic WD, asymptomatic group had higher levels of serum alanine aminotransferase and lower levels ceruloplasmin and 24-hour urine copper [(208±137) vs. (72±78) U/L, (55±47) vs. (69±48) mg/L, 103 (72, 153) vs. 492 (230, 1 432) μg; t=9.98, -1.98, Z=-4.89, all P<0.001]. Among the 314 patients completing genetic sequencing, a total of 107 mutations in ATP7B gene were detected, of which 10 are novel variants, and 3 cases (1.0%) had large heterozygous deletion (exons 10 to exon 11) in ATP7B gene. The percentage of missense mutation in asymptomatic WD children was significantly higher than that in symptomatic WD (81.5% (422/518) vs. 69.1% (76/110), χ²=8.47, P<0.05). WD patients carrying homozygous variant of c.2 333G>T had significantly low levels of ceruloplasmin than those not carrying this variant ((23±5) vs. (61±48) mg/L, t=-2.34, P<0.001). Conclusions: The elevation of serum ALT is an important clue for early diagnosis of WD in children, while serum ceruloplasmin and 24-hour urine copper content are specific markers for early diagnosis of WD. In order to confirm the diagnosis of WD, it is necessary to combine the Sanger sequencing with multiplex ligation-dependent probe amplification or other testing technologies.

Diagnosis of Wilson's Disease Presenting as Fulminant Hepatic Failure

Metallothionein immunohistochemistry has high sensitivity and specificity for detection of Wilson disease

Wilson disease (WD) is one of the most common inborn errors of metabolism characterized by degenerative changes in the brain, liver and kidney dysfunction, and Kayser-Fleischer rings due to toxic accumulation of copper. We investigated a Korean family with WD occurred in two consecutive generations. The proband, a 14-yr-old girl, was noticed to have abnormal liver function on a routine health examination at school and was diagnosed of having WD by further laboratory tests and liver biopsy. Molecular genetic analysis of ATP7B gene demonstrated that she was homozygous for Ala-874Val mutation, one of the three common mutations in Korean patients with WD. Further study for her family members revealed that the proband's father, a paternal uncle, and the youngest sister were compound heterozygous for Ala874Val and Asn1270Ser mutations of the ATP7B gene. In addition, the proband's mother and a younger sister were heterozygous carriers of Ala874Val mutation. Therefore, WD occurred in two consecutive generations due to a WD father and a heterozygous mother. Actually, abnormal results on liver function tests were found in the proband's father and a paternal uncle a few years ago but a diagnosis of WD has not been made. Therefore, although WD has been thought to be uncommon in Korea, it should be considered in a differential diagnosis of patients exhibiting abnormal liver function with unknown cause.

Wilson's disease is an inherited disorder of copper metabolism. Resultant kidney damage can induce metabolic bone disease, and in children the radiographic manifestations are indistinguishable from those of classical rickets. The patient who is the subject of this review was originally diagnosed as having vitamin D-resistant rickets. He had been well until the age of eight years, when pain and weakness of both knees developed in association with fever. Radiographs of knees and wrists (Fig. 1) taken at another hospital disclosed rachitic changes. Anemia, hypophosphatemia, and hypocalciuria were found. A diagnosis of vitamin D-resistant rickets was made. Treatment with vitamin D at a dose of 100,000 units daily induced symptomatic and radiographic evidence of remission (Fig. 2), but vitamin D intoxication supervened and the drug was discontinued at age ten. Initial evaluation at The New York Hospital in 1966, when the patient was eleven years old, showed return of rachitic changes on radiographs of the wrists and knees, a normal intravenous pyelogram, a serum calcium of 10.1 mg per 100 cc, and serum phosphorus of 2.2 mg per 100 cc. Vitamin D therapy was resumed with a dose of 20,000 units daily. Repeat films showed osteochondritis dissecans at the knees, rachitic changes, and a healing fracture of the distal radius (Fig. 3). In January 1967 a slit-lamp examination of the cornea, requested to evaluate the possible presence of calcium deposition, instead disclosed Kayser-Fleischer rings. Serum copper and ceruloplasmin were found to be low. A detailed neurological examination revealed slight tremor of tongue, moderate hyperreflexia, and mild terminal tremor. The liver and spleen were both slightly enlarged. A liver biopsy showed no fibrosis, but hepatic cell nuclei were seen to be enlarged and filled with glycogen. This latter finding is characteristic of first stage Wilson's disease. Members of the patient's immediate family were found to have low serum ceruloplasmin and copper levels. A sister has hepatomegaly, Kayser-Fleischer rings, and abnormal liver function studies The patient, at the age of twelve years, is currently receiving penicillamine 125 mg four times daily with pyridoxine 25 mg daily. This review is intended to draw attention to the radiologic manifestations of copper-induced nephropathy suffered by patients with Wilson's disease during a period of growth, when rickets may develop. This syndrome should be considered in the differential diagnosis of rickets, especially in the older child. It is hoped that children with Wilson's disease, who might otherwise be considered to have Fanconi's syndrome or vitamin D-resistant rickets, may be recognized early in the course of their disease. Under present modes of medical management, using D-penicillamine and low-copper diet, these patients can be spared an inexorably fatal disease, hopefully before significant morbidity has occurred.

Wilson's disease, first described by Samuel Wilson in 1912, is an autosomal recessive metabolic disorder resulting from mutations in the ATP7B gene. The disease develops as a consequence of copper accumulating in affected tissues. There is no gold standard for the diagnosis of Wilson's disease, which is often delayed due to the non-specific clinical features and the need for a combination of clinical and laboratory tests for diagnosis. This delay may in turn affect clinical outcome and has implications for other family members in terms of diagnosis. The Leipzig criteria were established to help standardise diagnosis and management. However, it should be emphasised that these criteria date from 2003, and many of these have not been formally evaluated; this review examines the evidence behind biochemical testing for Wilson's disease. To determine the diagnostic accuracy of three biochemical tests at specified cut-off levels for Wilson's disease. The index tests covered by this Cochrane Review are caeruloplasmin, 24-hour urinary copper and hepatic copper content. These tests were evaluated in those with suspected Wilson's disease and appropriate controls (either healthy or those with chronic liver disease other than Wilson's). In the absence of a gold standard for diagnosing Wilson's disease, we have used the Leipzig criteria as a clinical reference standard. To investigate whether index tests should be performed in all individuals who have been recommended for testing for Wilson's disease, or whether these tests should be limited to subgroups of individuals. We identified studies by extensive searching of, e.g. the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, the Web of Science and clinical trial registries (29 May 2019). Date of the most recent search of the Cochrane Cystic Fibrosis and Genetic Disorders Inborn Errors of Metabolism Register: 29 May 2019. We included prospective and retrospective cohort studies that assessed the diagnostic accuracy of an index test using the Leipzig criteria as a clinical reference standard for the diagnosis of Wilson's disease. Two review authors independently reviewed and extracted data and assessed the methodological quality of each included study using the QUADAS-2 tool. We had planned to undertake meta-analyses of the sensitivity, specificity at relevant cut-offs for each of the biochemical tests for Wilson's, however, due to differences in the methods used for each biochemical index test, it was not possible to combine the results in meta-analyses and hence these are described narratively. Eight studies, involving 5699 participants (which included 1009 diagnosed with Wilson's disease) were eligible for inclusion in the review. Three studies involved children only, one adults only and the four remaining studies involved both children and adults. Two evaluated participants with hepatic signs and six with a combination of hepatic and neurological signs and symptoms of Wilson's disease, as well as pre-symptomatic individuals. The studies were of variable methodological quality; with high risk if bias for participant selection and the reference standard used being of greatest methodological concern. Key differences between studies include differences in assay methodology, different cut-off values for diagnostic thresholds, different age and ethnicity groups. Concerns around study design imply that diagnostic accuracy figures may not transfer to populations outside of the relevant study. caeruloplasmin Five studies evaluated various thresholds of caeruloplasmin (4281 participants, of which 541 had WD). For caeruloplasmin a cut-off of 0.2 g/L as in the Leipzig criteria achieved a sensitivity of 77.1% to 99%, with variable specificity of 55.9% to 82.8%. Using the cut-off of 0.1 g/L of the Leipzig criteria seemed to lower the sensitivity overall, 65% to 78.9%, while increasing the specificity to 96.6% to 100%. hepatic copper Four studies evaluated various thresholds of hepatic copper (1150 participants, of which 367 had WD). The hepatic copper cut-off of 4 μmol/g used in the Leipzig criteria achieved a sensitivity of 65.7% to 94.4%, with a variable specificity of 52.2% to 98.6%. 24-hour urinary copper Three studies evaluated various thresholds of 24-hour urinary copper (268 participants, of which 101 had WD). For 24-hour urinary copper, a cut-off of 0.64 to 1.6 μmol/24 hours used in the Leipzig criteria achieved a variable sensitivity of 50.0% to 80.0%, with a specificity of 75.6% to 98.3%. The cut-offs used for caeruloplasmin, 24-hour urinary copper and hepatic copper for diagnosing Wilson's disease are method-dependent and require validation in the population in which such index tests are going to be used. Binary cut-offs and use of single-test strategies to rule Wilson's disease in or out is not supported by the evidence in this review. There is insufficient evidence to inform testing in specific subgroups, defined by age, ethnicity or clinical subgroups.

Background Wilson's disease, first described by Samuel Wilson in 1912, is an autosomal recessive metabolic disorder resulting from mutations in the ATP7B gene. The disease develops as a consequence of copper accumulating in affected tissues. There is no gold standard for the diagnosis of Wilson's disease, which is often delayed due to the non-specific clinical features and the need for a combination of clinical and laboratory tests for diagnosis. This delay may in turn affect clinical outcome and has implications for other family members in terms of diagnosis. The Leipzig criteria were established to help standardise diagnosis and management. However, it should be emphasised that these criteria date from 2003, and many of these have not been formally evaluated; this review examines the evidence behind biochemical testing for Wilson's disease. Objectives To determine the diagnostic accuracy of three biochemical tests at specified cut-off levels for Wilson's disease. The index tests covered by this Cochrane Review are caeruloplasmin, 24-hour urinary copper and hepatic copper content. These tests were evaluated in those with suspected Wilson's disease and appropriate controls (either healthy or those with chronic liver disease other than Wilson's). In the absence of a gold standard for diagnosing Wilson's disease, we have used the Leipzig criteria as a clinical reference standard. To investigate whether index tests should be performed in all individuals who have been recommended for testing for Wilson's disease, or whether these tests should be limited to subgroups of individuals. Search methods We identified studies by extensive searching of, e.g. the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, the Web of Science and clinical trial registries (29 May 2019). Date of the most recent search of the Cochrane Cystic Fibrosis and Genetic Disorders Inborn Errors of Metabolism Register: 29 May 2019. Selection criteria We included prospective and retrospective cohort studies that assessed the diagnostic accuracy of an index test using the Leipzig criteria as a clinical reference standard for the diagnosis of Wilson's disease. Data collection and analysis Two review authors independently reviewed and extracted data and assessed the methodological quality of each included study using the QUADAS-2 tool. We had planned to undertake meta-analyses of the sensitivity, specificity at relevant cut-offs for each of the biochemical tests for Wilson's, however, due to differences in the methods used for each biochemical index test, it was not possible to combine the results in meta-analyses and hence these are described narratively. Main results Eight studies, involving 5699 participants (which included 1009 diagnosed with Wilson's disease) were eligible for inclusion in the review. Three studies involved children only, one adults only and the four remaining studies involved both children and adults. Two evaluated participants with hepatic signs and six with a combination of hepatic and neurological signs and symptoms of Wilson's disease, as well as pre-symptomatic individuals. The studies were of variable methodological quality; with high risk if bias for participant selection and the reference standard used being of greatest methodological concern. Key differences between studies include differences in assay methodology, different cut-off values for diagnostic thresholds, different age and ethnicity groups. Concerns around study design imply that diagnostic accuracy figures may not transfer to populations outside of the relevant study. Index test caeruloplasmin Five studies evaluated various thresholds of caeruloplasmin (4281 participants, of which 541 had WD). For caeruloplasmin a cut-off of 0.2 g/L as in the Leipzig criteria achieved a sensitivity of 77.1% to 99%, with variable specificity of 55.9% to 82.8%. Using the cut-off of 0.1 g/L of the Leipzig criteria seemed to lower the sensitivity overall, 65% to 78.9%, while increasing the specificity to 96.6% to 100%. Index test hepatic copper Four studies evaluated various thresholds of hepatic copper (1150 participants, of which 367 had WD). The hepatic copper cut-off of 4 μmol/g used in the Leipzig criteria achieved a sensitivity of 65.7% to 94.4%, with a variable specificity of 52.2% to 98.6%. Index test 24-hour urinary copper Three studies evaluated various thresholds of 24-hour urinary copper (268 participants, of which 101 had WD). For 24-hour urinary copper, a cut-off of 0.64 to 1.6 μmol/24 hours used in the Leipzig criteria achieved a variable sensitivity of 50.0% to 80.0%, with a specificity of 75.6% to 98.3%. Authors' conclusions The cut-offs used for caeruloplasmin, 24-hour urinary copper and hepatic copper for diagnosing Wilson's disease are method-dependent and require validation in the population in which such index tests are going to be used. Binary cut-offs and use of single-test strategies to rule Wilson's disease in or out is not supported by the evidence in this review. There is insufficient evidence to inform testing in specific subgroups, defined by age, ethnicity or clinical subgroups.

When Wilson's disease presents as fulminant hepatic failure, it may be extremely difficult to differentiate from other causes of hepatic insufficiency. A recently described diagnostic biochemical profile (elevated serum and urine copper levels, mild transaminase elevation, very high bilirubin levels, and low hemoglobin with intravascular hemolysis) was employed to diagnose this form of Wilson's disease prior to death in a young woman without Kayer-Fleischer rings and with a normal serum ceruloplasmin level. Since hepatic transplantation now offers a possible cure for this previously uniformly fatal form of Wilson's disease, it should be considered the treatment of choice for this disease entity. Combined with the availability of hepatic transplantation, this patient's temporary improvement and unusually long survival of four months further emphasizes the importance of this diagnostic profile in recognizing Wilson's disease quickly and accurately when it presents as fulminant hepatic failure.

Wilson disease (WD) represents a monogenic disease resulting in copper accumulation within tissues. Incidence is estimated to be approximately 1:30 000. Symptoms include acute and chronic liver disease, hemolysis, and neurodegenerative and psychiatric symptoms (1). The first symptom may be acute liver failure. Death or liver transplantation in WD is common. The European Liver Transplant Registry recorded 706 liver transplantations for WD from 1 January 1988 to 31 December 2005, underlining the relevance of this disease burden. Because symptoms and disease course are variable, diagnosis can be difficult. Effective treatment for WD such as copper chelating drugs and zinc is available, which usually prevents disease progression. Therefore, a simple, rapid and diagnostic test is required for WD, ideally to identify patients before symptoms appear. First symptoms have been reported in patients as young as 2 years of age (2)(3). Thus screening tests for WD at least at the age of 2 years would be appropriate. Penetrance of disease is expected …