Diagnosis of Wilson disease in young children: molecular genetic testing and a paradigm shift from the laboratory diagnosis

Abstract

Wilson disease (WD) is an autosomal recessive disorder of copper metabolism that results in accumulation of copper primarily in the liver, brain and cornea. Mutations in the WD gene, ATP7B, cause failure of copper excretion from hepatocyte into bile and a defective synthesis of ceruloplasmin. More than 500 mutations are now recognized, scattered throughout the ATP7B gene. Since WD has protean clinical presentations, awareness of WD in clinical practice is important for the early diagnosis and prevention of accumulated copper toxicity. Molecular genetic testing is playing an increasingly important role in the diagnosis of WD in uncertain cases and family screening. Siblings should be screened for WD once an index case has been diagnosed. Discrimination of heterozygotes from asymptomatic patients is essential to avoid inappropriate lifelong therapy for heterozygotes. Genetic testing, either by haplotype analysis or by mutation analysis, is the only definite solution for differentiating heterozygote carriers from affected asymptomatic patients. Routine genetic testing, because of the multitude of documented mutations, has been thought to be impractical until recently. However, genetic testing is now being more actively applied to the diagnosis of WD, particularly in young children in whom conventional biochemical diagnosis has much limitation and only genetic testing is able to confirm WD. Because advancement of modern biochemical technology now allows more rapid, easier, and less expensive mutation detection, direct DNA sequencing could be actively considered as the primary mode of diagnostic investigation rather than a supplementary test to the conventional biochemical tests. This review will focus on the recent advancement of molecular genetics and genetic diagnosis of WD in very young children on the basis of research data of the Seoul National University Children's Hospital and recent literature.

Keywords: ATP7B; Child; Genetic diagnosis; Mutation; Wilson disease.

Fig. 1

(A) Severe cirrhotic liver in a 13 year old girl with Wilson disease who underwent the first liver transplantation in Korea in 1988 [11], (B) Micro and macro-nodular cirrhosis of the removed liver after liver transplantation at Seoul National University Children's Hospital.

Fig. 2

Three types of defects in copper dependent trafficking pathway among various types of missense mutations [15,17,18]. CTR1: copper-transporter 1, ER: endoplasmic reticulum, TGN: trans-Golgi network.

Fig. 3

The failure of Cu dependent trafficking pathway and functional defects of copper transport to apoenzyme in representative missense mutations [15,17,18]. ER: endoplasmic reticulum, TGN: trans-Golgi network.

Fig. 4

Structural abnormalities of mitochondriae in the hepatocytes from the article of Sternlieb (Hepatology 1992; 16:728-32) [33].

Fig. 5

High signal intensity in the putamen on T2 weighted magnetic resonance image (A) and reversal of the lesion after therapy in children with neurologic WD (B). From a case of Seoul National University Children's Hospital [35].

Fig. 6

Genetic diagnosis and copper metabolism associated 3 tests in 114 children with Wilson disease (WD) at Seoul National University Children's Hospital (Low ceruloplasmin+ high urine copper+Kayser-Fleischer ring).

Fig. 7

Diagnostic approach for Wilson disease (WD) in infants and preschool children - paradigm shift in the era of molecular genetics (at Seoul National University Children's Hospital).