Molecular pathology of Crigler-Najjar type I and II and Gilbert's syndromes

Background and Objective. Crigler-Najjar syndromes type I and II and Gilber t's syndrome are familial unconjugated hyperbilirubinemias caused by geneti c lesions involving a single complex locus encoding for bilirubin-UDP-glucu ronosyltransferase which is involved in the detoxification of bilirubin by conjugation with glucuronic acid. Over the last few years a number of diffe rent mutations affecting this gene have been characterized. The aim of this work is to review the molecular pathology of Crigler-Najjar and Gilbert's syndromes, to discuss its impact on the clinical and genetic classification of these conditions, and on the diagnostic evaluation of clinical pictures associated with unconjugated hyperbilirubinemia. Evidence and Information Sources, The authors of the present review are inv olved in the clinical management of patients with familial unconjugated hyp erbilirubinemia as well as in the characterization of its molecular bases, Evidence from journal articles covered by the Science Citation Index(R) and Medline(R) has been reviewed and collated with personal data and experienc e. State of the Art and Perspectives, It has been known for many years that mi ld to severe deficiency of bilirubin UDP-glucuronosyltransferase in the liv er is the cause of two types of familial unconjugated hyperbilirubinemia, C rigler-Najjar syndromes I and II, and Gilbert's syndrome. Since the charact erization of the gene encoding for bilirubin UDP-glucuronosyltransferase, a number of mutations affecting the expression of this gene have been identi fied. These mutations can be classified into three groups: mutations which result in a reduced production of a normal enzyme; mutations which give ris e to the synthesis of a structurally abnormal and dysfunctional enzyme; mut ations which completely abolish the expression of the affected allele, The combination of mutations affecting the coding region of the gene and of pro moter mutations which reduce the expression of the gene accounts for the wi de clinical spectrum of familial unconjugated hyperbilirubinemias, ranging from the clinically negligible Gilbert's syndrome to the severe and often f atal Crigler-Najjar type I syndrome. A better understanding of the genetics of these conditions and the availability of molecular diagnosis will impro ve the diagnostic efficiency and afford better informed genetic counseling, not only for Crigler-Najjar and Gilbert's syndromes, but also for several acquired conditions characterized by unconjugated hyperbilirubinemia, (C)19 99, Ferrata Storti Foundation.