Challenges in the diagnosis of Wilson disease

Abstract

The understanding and management of Wilson disease (WD) have dramatically improved since the first description of the disease by K. Wilson more than a century ago. However, the persistent long delay between the first symptoms and diagnosis emphasizes challenges in diagnosing earlier this copper overload disorder. As a treatable disease, WD should be detected early in the course of the disease by any health professionals at any care level, but the rare prevalence of the disease explains the lack of awareness of referring physicians. The most important challenge is to train physicians to recognize atypical or rare symptoms of WD that will lead to discuss the diagnosis more systematically. Atypia can come from the age of onset, the liver [non-alcoholic steatohepatitis (NASH) presentation], the central or peripheral nervous system (neuropathy, epilepsy, sleep disorders…) or may be due to lesions of other organs (renal manifestations, osteo-articular disorders or endocrine disturbances). Isolated biological anomalies, rare radiological findings or inadequate interpretation of copper test may also lead to misdiagnosis. The second challenge is to confirm the diagnosis faster and more effectively so as not to delay the initiation of treatment, and expand family screening as the genetic prevalence is higher than previously expected. Generalization of the exchangeable copper assay and the next generation sequencing (NGS) are two promising ways to overcome this ultimate challenge. By drawing attention to the earliest and rare symptoms and to new biomarkers and diagnostic tools, we hope that this article will increase diagnostic awareness and reduce delays so that patients can start their treatment earlier in the course of the illness and thus have a better disease prognosis.

Parkinson disease

“…Treatment options include copper chelators, zinc salts or both; medical therapy must be lifelong. Introduction of therapy in WD may be associated with an initial worsening of clinical features and requires careful monitoring .…”

Comprehensive and comparative exploration of the Atp7b−/− mouse plasma proteome

“…To assess the specificity of protein abundance changes, the 8 plasma proteins were also measured in patients with another liver disease: NASH. NASH was selected as the control liver disease as it shares some major clinical and histological features with WD (steatosis, inflammation, fibrosis) 23 . The quantification results were analysed by one-way ANOVA analysis followed by a post-hoc Tukey test.…”

Histopathology of Wilson Disease

“…Classically low serum copper and low ceruloplasmin levels with high urinary copper content make a triad which is usually associated with WD diagnosis. But this triad may be absent or incomplete in 3% of genetically confirmed WD cases [7].…”

“…Later, WD was observed in children and adolescents with acute or chronic liver disease without any neurologic symptoms [5]. Now, WD is considered a multi-systemic disorder, in which hepatic, neurological and psychiatric symptoms are often associated with renal, endocrine, osteoarticular, corneal and myocardial disturbances, all related to abnormal copper metabolism ending with systemic accumulation of the copper [6,7].…”