Abstract
Background: Diagnosis of rare Wilson disease (WD) in pediatric patients is difficult, in particular when hepatic manifestation is absent. Genetic analysis of ATP7B represents the single major determinant of the diagnostic scoring system in WD children having mild symptoms.Objectives: To assess the impact of molecularly expressed ATP7B gene products in order to assist diagnosis of Wilson disease in pediatric patients having a novel mutation and subtle neuropsychiatric disease.Methods: The medical history, clinical presentation, biochemical parameters, and the genetic analysis of ATP7B were determined. Due to ambiguous clinical and biochemical findings and identification of a novel compound ATP7B mutation with unknown disease-causing status, a molecular analysis of the ATP7B gene products in a previously well characterized cell model was performed.Results: The ATP7B variants were transgenically expressed and the respective gene function molecularly characterized. Despite normal mRNA expression, low ATP7B protein expression of the mutants p.L168P and p.S1423N was observed (34.3 ± 8% and 66.0 ± 8%, respectively). Copper exposure did not result in decreased viability of transgenic cells as compared to wild type. Intracellular copper accumulation was reduced (≤47.9 ± 8%) and intracellular protein trafficking was impaired.Conclusion: Our report suggests that functional characterization of novel ATP7B mutants can assist diagnosis; however mild functional impairments of ATP7B variants may hamper the value of such approaches.
Highlights
Wilson disease (WD; MIM#277900) is a rare, autosomal recessive, monogenetic disorder with a frequency of approximately 1:30,000 [1]
ATP7B is predominately expressed in hepatocytes where it has two main functions: it is responsible for transfer of copper to apoceruloplasmin, which is secreted into the blood for copper supply to other organs, and—in case of excess copper—excretion from the body into the bile [9]
In this work we describe a case report of a child with a novel compound ATP7B mutation and relatively mild symptoms, where we have used a previously well characterized cell model to classify the functions of ATP7B for improved diagnosis of WD [23]
Summary
Wilson disease (WD; MIM#277900) is a rare, autosomal recessive, monogenetic disorder with a frequency of approximately 1:30,000 [1]. The disease manifests at various times throughout life with children representing a major portion of patients. Disease is diagnosed between 5 and 18 years, some children below 5 years and elderly (> 60 years) can show first symptoms [5, 6]. WD results from mutations in the ATP7B gene. Clinical presentation with pure neurological symptoms in childhood, e.g., tremor or movement disorder, is rare, and most children show hepatic disease due to copper overload of the liver [10]. Therapy has to be taken lifelong and may result in side effects in a portion of the patients. Diagnosis of rare Wilson disease (WD) in pediatric patients is difficult, in particular when hepatic manifestation is absent. Genetic analysis of ATP7B represents the single major determinant of the diagnostic scoring system in WD children having mild symptoms
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