Phenotypic and Genetic Characterization of a Cohort of Pediatric Wilson Disease Patients

Abstract

BackgroundIn Egypt, Wilson disease seems to be under diagnosed and clinical data on large cohorts are limited. The aim of this study is to highlight the clinical, laboratory and genetic characteristics of this disease in our pediatric population as well as to report our experience with both treatment options and outcome.MethodsThe study included 77 patients from 50 unrelated families (62 were followed up for a mean period of 58.9 ± 6.4 months and 27 were asymptomatic siblings). Data were collected retrospectively by record analysis and patient interviews. Diagnosis was confirmed by sequencing of the ATP7B gene in 64 patientsResultsOur patients had unique characteristics compared to other populations. They had a younger age of onset (median: 10 years), higher prevalence of Kayser-Fleischer rings (97.6% in the symptomatic patients), low ceruloplasmin (93.5%), high rate of parental consanguinity (78.9%) as well as a more severe course. 71.42% of those on long term D-penicillamine improved or were stable during the follow up with severe side effects occurring in only 11.5%. Preemptive treatment with zinc monotherapy was an effective non-toxic alternative to D-penicillamine. Homozygous mutations were found in 85.7%, yet limited by the large number of mutations detected, it was difficult to find genotype-phenotype correlations. Missense mutations were the most common while protein-truncating mutations resulted in a more severe course with higher incidence of acute liver failure and neurological symptoms.ConclusionsEgyptian children with Wilson disease present with early Kayser-Fleischer rings and early onset of liver and neurological disease. The mutational spectrum identified differs from that observed in other countries. The high rate of homozygous mutations (reflecting the high rate of consanguinity) may potentially offer further insights on genotype-phenotype correlation

Factors that predict mortality in children with Wilson disease associated acute liver failure and comparison of Wilson disease specific prognostic indices

“…These features attest to the importance of divergence or variability in the clinical profile in different population groups implying the role of ethnic and geographic factors. The higher proportion of males with WD and ALF concurs with those reported from the King's College group and other studies . The greater frequency of girls appears to be restricted to a post pubertal age group and cannot be extrapolated to prepubertal children.…”

“…Wilson disease, is an autosomal recessive disease involving the ATP 7B gene whose reduced or nonfunction results in accumulation of hepatic copper culminating in liver injury . A rare disease with a prevalence of approximately one in 30 000 US population, it affects the young from all racial backgrounds and is more common in countries where consanguineous marriages are prevalent . Primarily a disease of childhood and adolescence, it has been reported in the elderly .…”

“…[1][2][3] A rare disease with a prevalence of approximately one in 30 000 US population, it affects the young from all racial backgrounds 1 and is more common in countries where consanguineous marriages are prevalent. 4 Primarily a disease of childhood and adolescence, it has been reported in the elderly. 5 However, the life-threatening presentation of acute liver failure (ALF) occurs largely in children and young adults.…”

Mutation Analysis of the ATP7B Gene in Seven Chinese Families with Wilson’s Disease

“…effect of the same mutation in different Han Chinese pedigrees with WD, which may account for the high allele frequencies of mutations p.Arg778Leu, p.Pro992Leu, and p. Ala1295Val in Asia, rather than mutation hotspots [22]. Previous studies on Japanese and Egyptian children with WD showed that genotypes for truncation of ATP7B were established to be associated with an early onset and fulminant or acute liver failure [31][32][33][34]. Consistently, the onset age of our patients (combined with our previous data) with protein-truncating mutations ranges from 2 to 20 years old (mean onset age: 12.3 ± 5.9 years old), while that of our patients with missense mutations ranges from 6 to 41 years old (mean onset age: 19.9 ± 10.9 years old) [22].…”

Spasmodic Muscle Cramps and Weakness as Presenting Symptoms in Wilson Disease

“…Despite identification of the sole mutated gene, ATP7B, and increased understanding of Wilson disease ATPase function in hepatocytes, associations between genetic mutation and clinical phenotype remain incompletely understood. [1][2][3] Liver dysfunction in WD ranges from mild aminotransferase elevation to fulminant hepatic failure. Extrahepatic findings, with or without apparent liver injury, including neuropsychiatric, endocrine, hematologic, and renal abnormalities, result in a complex clinical spectrum that may lead to delayed or inaccurate diagnoses.…”