TY - JOUR
T1 - Crigler-Najjar syndrome
T2 - Therapeutic options and consequences of mutations in the UGT1A1 complex
AU - Fitzpatrick, Emer
AU - Mtegha, Marumbo
AU - Dhawan, Anil
PY - 2008/12/1
Y1 - 2008/12/1
N2 - 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.
AB - 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.
KW - Bilirubin glucuronidation
KW - Crigler-Najjar syndrome
KW - Gene therapy
KW - Gilbert syndrome
KW - Hepatocyte transplantation
KW - Liver transplantation
KW - UGT1A1
UR - http://www.scopus.com/inward/record.url?scp=69949187937&partnerID=8YFLogxK
U2 - 10.1586/17446651.3.6.725
DO - 10.1586/17446651.3.6.725
M3 - Review article
AN - SCOPUS:69949187937
SN - 1744-6651
VL - 3
SP - 725
EP - 737
JO - Expert Review of Endocrinology and Metabolism
JF - Expert Review of Endocrinology and Metabolism
IS - 6
ER -