Crigler-Najjar syndrome: therapeutic options and consequences of mutations in the UGT1A1 complex

Crigler-Najjar syndrome (CN), a rare inherited disorder characterized by failure of bilirubin glucuronidation, can lead to severe disability and death from kernicterus. Gilbert syndrome is a more common, benign familial unconjugated hyperbilirubinemia. The underlying problem in both conditions is impaired bilirubin conjugation and elimination due to a mutation in uridine 5'-diphosphate glucuronyltransferase. The mainstay of current management of CN is phototherapy, followed by liver transplantation. Here, we review other therapies, including hepatocyte transplantation, that have been successfully used to lessen the phenotype, although long-term engraftment of cells remains elusive. Gene therapy holds hope for the future whereby the patient's hepatocytes are transduced with the wild-type gene. Outstanding issues include safety of the gene vector and establishing immunotolerance to both vector and the new protein. The significant advances in understanding the relevance of mutations in UGT not only in glucuronidation of bilirubin, but other drugs and substances, are also reviewed.