Wilson's Disease in Children: A Position Paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition.

BACKGROUND: Clinical presentations of Wilson's disease (WD) in childhood ranges from asymptomatic liver disease to cirrhosis or acute liver failure, whereas neurological and psychiatric symptoms are rare. The basic diagnostic approach includes serum ceruloplasmin and 24-hour urinary copper excretion. Final diagnosis of WD can be established using a diagnostic scoring system based on symptoms, biochemical tests assessing copper metabolism, and molecular analysis of mutations in the ATP7B gene. Pharmacological treatment is life-long and aims at removal of copper excess by chelating agents as D-penicillamine, trientine, or inhibition of intestinal copper absorption with zinc salts. Acute liver failure often requires liver transplantation. This publication aims to provide recommendations for diagnosis, treatment, and follow-up of WD in children. METHODS: Questions addressing the diagnosis, treatment, and follow-up of WD in children were formulated by a core group of ESPGHAN members. A systematic literature search on WD using MEDLINE, EMBASE, Cochrane Database from 1990 to 2016 was performed focusing on prospective and retrospective studies in children. Quality of evidence was assessed according to the GRADE system. Expert opinion supported recommendations where the evidence was regarded as weak. The ESPGHAN core group and ESPGHAN Hepatology Committee members voted on each recommendation, using the nominal voting technique.

A genetic study of Wilson's disease in the United Kingdom.

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.

Correspondence between healthcare professionals: an evaluation of a medical student workshop on the importance of the discharge letter.

WHAT IS ALREADY KNOWN IN THIS AREA • Letters from hospital specialists to a patient's GP promote informational continuity of care. There are no benchmarks for the quality of letters from specialists to GPs. Medical student are seldom taught how to correspond with professional colleagues. WHAT THIS WORK ADDS • The majority of students recognise the value of sharing comprehensive information across the interface between primary care and secondary care. Almost one in five students retains the view that discharge summaries do not affect care provided by a GP. Some students believe it is defensible to be rude about patients in discharge letters. SUGGESTIONS FOR FUTURE RESEARCH • Those students who hold questionable views must be identified and offered a tailored educational experience if they are to adopt helpful attitudes.

Search for rare liver diseases: the case of glycosylation defects mimicking Wilson Disease.

Pediatric hepatology appears to be a very specific field of paediatrics which deals mainly with rare diseases although clinical features can be commonly found - like increased activity of transaminases. Some of these rare diseases like Wilson disease are commonly looked for and recently Wilsonian like phenotypes have been described which additionally presented with abnormal glycosylation of the plasma protein transferrin. In a subgroup of those patients with specific additional clinical symptoms (cleft uvula, low blood sugar, rhabdomyolysis and dilated cardiomyopathy) phosphoglucomutase 1 deficiency was identified. We recommend screening for abnormal glycosylation of the plasma protein transferrin in children with unexplained liver injury.

Glycogen storage disease type IX: High variability in clinical phenotype.

Glycogen storage disease type IX (GSD type IX) results from a deficiency of hepatic phosphorylase kinase activity. The phosphorylase kinase holoenzyme is made up of four copies of each of four subunits (alpha, beta, gamma and delta). The liver isoforms of the alpha-, beta- and gamma-subunits are encoded by PHKA2, PHKB and PHKG2, respectively. Mutation within these genes has been shown to result in GSD type IX. The diagnosis of GSD type IX is complicated by the spectrum of clinical symptoms, variation in tissue specificity and severity, and its inheritance, either X-linked or autosomal recessive. We investigated 15 patients from 12 families with suspected GSD type IX. Accurate diagnosis had been hampered by enzymology not being diagnostic in five cases. Clinical symptoms included combinations of hypoglycaemia, hepatosplenomegaly, short stature, hepatopathy, weakness, fatigue and motor delay. Biochemical findings included elevated lactate, urate and lipids. We characterised causative mutations in the PHKA2 gene in ten patients from eight families, in PHKG2 in two unrelated patients and in the PHKB gene in three patients from two families. Seven novel mutations were identified in PHKA2 (p.I337X, p.P498L, p.P869R, p.Y116_T120dup, p.R1070del, p.R916W and p.M113I), two in PHKG2 (p.L144P and p.H48QfsX5) and two in PHKB (p.Y419X and c.2336+965A>C). There was a severe phenotype in patients with PHKG2 mutations, a mild phenotype with patients PHKB mutations and a broad spectrum associated with PHKA2 mutations. Molecular analysis allows accurate diagnosis where enzymology is uninformative and identifies the pattern of inheritance permitting counselling and family studies.

Re-evaluation of the penicillamine challenge test in the diagnosis of Wilson's disease in children.

BACKGROUNDS/AIMS: A urinary copper (Cu) >25 micromol/24 h following penicillamine had a reported specificity of 98.2% and sensitivity of 88.2% in diagnosing Wilson's disease (WD). We have re-evaluated this test. Ninety-eight subjects were studied at presentation. METHODS: Thirty-eight (19 girls, 19 boys; median age 10.3 years; range 5-16 years) had an ultimate diagnosis of WD. Sixty (24 girls, 36 boys; median age 10.1, range 2.3-15 years) had other liver disorders. Urinary Cu was estimated for 24h before (basal Cu) and for 24h whilst giving penicillamine 500 mg orally 12 hourly x 2 (post-penicillamine Cu). RESULTS: Both basal Cu and post-penicillamine Cu differed significantly between WD patients and controls (basal Cu: median 6.5 micromol/24 h, range 0.9-109 micromol/24 h, versus median: 0.8 micromol/24 h, range 0.1-19.5, p<0.0001; post-penicillamine Cu: median 36.9 micromol/24 h, range 1.98-219 micromol/24 h, versus median 12.35 micromol/24 h, range 0.5-49.8 micromol/24 h, p<0.0001). A post-penicillamine Cu >25 micromol/24 h was observed in 29/38 patients with WD and in 4/60 controls. 25/38 WD patients were symptomatic. Twenty-three of these and 6/13 asymptomatic siblings had a positive test. The test had a sensitivity of 76% (95% confidence interval [CI], 59.8-88.6%) and a specificity of 93% (95% CI, 83.8-98.2%). Sensitivity was better in symptomatic patients (92%, [95% CI; 74-99%]) than asymptomatic (46%, [95% CI; 19.2-74.9%]). CONCLUSIONS: This test is valuable in the diagnosis of WD with active liver disease, but is unreliable to exclude the diagnosis in asymptomatic siblings.

Diagnosis and phenotypic classification of Wilson disease.

Wilson disease is an inherited autosomal recessive disorder of hepatic copper metabolism leading to copper accumulation in hepatocytes and in extrahepatic organs such as the brain and the cornea. Originally Wilson disease was described as a neurodegerative disorder associated with cirrhosis of the liver. Later, Wilson disease was observed in children and adolescents presenting with acute or chronic liver disease without any neurologic symptoms. While diagnosis of neurologic Wilson disease is straightforward, it may be quite difficult in non-neurologic cases. Up to now, no single diagnostic test can exclude or confirm Wilson disease with 100% certainty. In 1993, the gene responsible for Wilson disease was cloned and localized on chromosome 13q14.3 (MIM277900) (1, 2). The Wilson disease gene ATP7B encodes a P-type ATPase. More than 200 disease causing mutations of this gene have been described so far (3). Most of these mutations occur in single families, only a few are more frequent (like H1069Q, 3400delC and 2299insC in Caucasian (4-6) or R778L in Japanese (7), Chinese and Korean patients). Studies of phenotype-genotype relations are hampered by the lack of standard diagnostic criteria and phenotypic classifications. To overcome this problem, a working party discussed these problems in depth at the 8th International Meeting on Wilson disease and Menkes disease in Leipzig/Germany (April 16-18, 2001). After the meeting, a preliminary draft of a consensus report was mailed to all active participants and their comments were incorporated in the final text.

Haemochromatosis-associated HFE genotypes in English blood donors: age-related frequency and biochemical expression.

BACKGROUND/AIMS: There are limited data on the frequency and biochemical expression of the haemochromatosis-associated mutations C282Y and H63D in healthy people. METHODS: We genotyped (bi-directional PCR amplification of specific alleles method) and performed serum iron studies in randomly selected English male blood donors (<4 previous units donated) in four age bands <30, 30-40, 40-50 and >50 years. RESULTS: In 6261 subjects, frequency of C282Y homozygosity (+/+) was 0.3%, C282Y/H63D compound heterozygosity (+/-) 2.0%, and H63D and C282Y heterozygosity +/-, 21.7 and 10.4%, respectively. Genotype distribution was within Hardy-Weinberg equilibrium in each age band. C282Y +/- frequency fell from 11.7% in subjects <30 years to 8.2% in subjects >50 (Chi2 7.19; P<0.005). No such trend was seen for C282Y +/+. In C282Y +/+ subjects, median serum ferritin was 247 (range 60-2449) microg/l and exceeded >500 microg/l in only two of 18 subjects. Compared to wild/wild (-/-) subjects, C282Y and H63D +/- subjects had slightly higher serum iron and lower unsaturated iron binding concentrations, similar overall serum ferritin values but higher serum ferritin values in subjects who had previously donated blood. CONCLUSIONS: C282Y +/+ shows limited biochemical expression and no trend towards age-related attrition. C282Y and H63D +/- may protect against iron deficiency.