Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Crigler-Najjar Syndrome [E80.5]

OMIM numbers: 218800, 606785, 191740 (UGT1A1)

Dr. rer. nat. Christoph Marschall, Dipl.-Biol. Christine Schack,
Dipl.-Biol. Christina Sofeso

Scientific Background

Crigler-Najjar syndrome is a very rare autosomal recessive metabolic disorder of the liver which is charcterized by a nonhemolytic unconjugated hyperbilirubinemia. The incidence is approx. 1 in 1,000,000 newborns. It has been classified into two types — the severe type I with a complete deficiency of bilirubin-UDP-glucuronosyltransferase (UGT1A1) and the partial deficient type II with residual UGT1A1 activity. In the severe type I, patients show bilirubin concentrations of 20–45 mg/dl in blood serum. Initial management of affected newborns entails phototherapy and later on plasmapheresis. Liver transplantation is often indicated. Neurological complications owing to neurotoxicity of unconjugated bilirubin occur frequently. In the less severe type II, patients show bilirubin concentrations of 6–20 mg/dl. Induction therapy with phenobarbital may lower these by 60–70%.

Both types are caused by mutations in the UGT1A1 gene. In the Crigler-Najjar type I, mutations are often detected which lead to termination of translation and therefore to the complete loss of function of the affected alleles. Whereas in the type II, at least one allele bears a mild mutation which only causes a substitution of one amino acid. This results in a remaining UDP-glucuronosyltrasferase activity of approx. 10%. The common (TA)7 polymorphism in the UGT1A1 promoter region and its lowered gene expression in combination with a further mutation can lead to Crigler-Najjar syndrome type II as well. If the (TA)7 polymorphism is located on an allele with a mild mutation, a severe type I can result in combination with an additional severe mutation on the second allele. Consequently, if Crigler-Najjar syndrome is suspected the promoter region should always be analyzed as well (see Meulengracht-Gilbert syndrome).