Clinical and genetic heterogeneity in Wilson disease - A review

Abstract

Wilson disease (WD) is an inborn error of copper metabolism leading to its accumulation in liver, kidney and cornea. It is caused by a defective ATPase protein which is coded by ATP7B gene. It follows an autosomal recessive mode of inheritance with a prevalence of 1 in 30,000. WD shows varied clinical heterogeneity making clinical diagnosis a difficult task. The corneal Kayser-Fleischer (KF) ring is an important diagnostic criterion as it is invariably present in 95% of the WD cases. In this review, we discussed the varied clinical manifestations of WD which makes diagnosis a challenging process. Though genetic testing is a reliable technique to confirm clinical diagnosis, genotype-phenotype correlations are yet to be established. This could be attributed to the consanguinity and ethnic variation observed in the Indian population, suggesting genetic heterogeneity leading to clinical heterogeneity making diagnosis difficult. Further, genetic studies are warranted to establish genotype-phenotype correlations which can pave way for early diagnosis and treatment. Genetic testing will help in identifying pre-symptomatic siblings and other family members of the patient who should be advised for regular follow-up. A combination of clinical and genetic studies should be considered for proper understanding of disease manifestation and for making an early clinical diagnosis of WD. Keywords: Wilson disease; copper metabolism; genetic testing; ATP7B gene; KF ring

Analysis of Wilson disease mutations in copper binding domain of ATP7B gene

“…Analysis of clinical records of forty cases revealed that Kayser-Fleischer (KF) ring was present in corneas of 75% of cases at the time of diagnosis ( Table 2 ). According to Rangaraju et al, 2015 KF ring is detected in corneas of 95% of WD cases [ 15 ] which is not consistent with our data. Possible explanations for this difference can be nonappearance of detectable KF ring in cases with hepatic manifestation and early staging of disease in children as 7/10 cases without KF ring had only hepatic symptoms whereas 8/10 cases were ≤ 15 years of age ( Table 2 ) [ 19 , 20 ] Clinical details of cases showed that all forty cases had high urinary copper concentration and low serum ceruloplasmin levels.…”

“…Clinical presentation of Wilson disease (WD) is very heterogeneous with predominant reports of hepatic, neurologic, and ophthalmic involvement along with multiple other abnormalities ranging from hemolytic anemia, thrombocytopenia, renal and gynecological problems as well as bone and muscle issues [ 15 ]. Disease may remain undetected initially and in most of the cases it is diagnosed after substantial damage to liver making liver transplantation the only treatment option [ 15 ]. Genetic diagnosis provides early disease detection which may help to reduce disease associated morbidity and high mortality especially in high-risk consanguineous populations such as our Pakistani population.…”

“…as bone and muscle issues [15]. Disease may remain undetected initially and in most of the cases it is diagnosed after substantial damage to liver making liver transplantation the only treatment option [15].…”

“…as bone and muscle issues [15]. Disease may remain undetected initially and in most of the cases it is diagnosed after substantial damage to liver making liver transplantation the only treatment option [15]. Genetic diagnosis provides early disease detection which may help to reduce disease associated morbidity and high mortality especially in high-risk consanguineous…”