Disease relevance of Crigler-Najjar Syndrome

• Patients with Crigler-Najjar syndrome (CN) type I inherit an autosomal recessive trait for hyperbilirubinemia, which is characterized by the total absence of bilirubin UDP-glucuronosyltransferase (transferase) activity [1].
• Since devastating kernicteric brain injury is the invariable outcome of Type I Crigler-Najjar syndrome, liver transplantation should be performed when phototherapy cannot maintain the serum bilirubin concentration at an unequivocally safe level [2].
• A genetic deficiency of bilirubin UDP-glucuronyl transferase (GT) occurs in 5 to 7% of the population (Gilbert's disease, Crigler-Najjar syndrome) and this could predispose such people to acetaminophen hepatotoxicity [3].
• OBJECTIVES: Intestinal metabolism of bilirubin is implicated in the pathogenesis of neonatal jaundice and Crigler-Najjar syndrome [4].
• Using Gunn rats, a model animal for Crigler-Najjar syndrome type I, the long-term transcriptional function of the CAG promoter (a combination of chicken beta-actin promoter and cytomegalovirus immediate-early enhancer) was evaluated in the rat liver [5].

High impact information on Crigler-Najjar Syndrome

• These findings raise the possibility that Sn-protoporphyrin may prove clinically useful in maintaining low levels of serum bilirubin in congenitally jaundiced individuals, such as patients with the Crigler-Najjar syndrome [6].
• A mutation in bilirubin uridine 5'-diphosphate-glucuronosyltransferase isoform 1 causing Crigler-Najjar syndrome type II [7].
• The present study documents a reduced biliary bilirubin secretion and suggests that the addition of the second glucuronic acid moiety to the bilirubin molecule may be defective in Crigler-Najjar syndrome (type II) [8].
• Correction of the UDP-glucuronosyltransferase gene defect in the gunn rat model of crigler-najjar syndrome type I with a chimeric oligonucleotide [9].
• Crigler-Najjar syndrome type II (CN-II) is caused by a severely reduced hepatic activity of bilirubin UDP-glucuronosyltransferase (UGT) [10].

Chemical compound and disease context of Crigler-Najjar Syndrome

• BACKGROUND/AIMS: Unconjugated bilirubin (UCB) can be neurotoxic in jaundiced neonates and in patients with Crigler-Najjar syndrome [11].
• A new type of defect in the gene for bilirubin uridine 5'-diphosphate-glucuronosyltransferase in a patient with Crigler-Najjar syndrome type I [12].
• We describe a 23-yr-old man with congenital unconjugated hyperbilirubinemia secondary to uridine diphosphate glucuronosyltransferase deficiency, and who cannot readily be classified as type I or type II Crigler-Najjar syndrome [13].
• Successful photo-and phenobarbital therapy during pregnancy in a woman with Crigler-Najjar syndrome type II [14].
• Type 2 Crigler-Najjar syndrome. Quantitation of ultrastructural data and evolution under therapy with phenytoin [15].

Biological context of Crigler-Najjar Syndrome

• Homozygous missense mutations of the gene have been generally recognized as responsible for Crigler-Najjar syndrome type II; the results obtained here, however, confirm that Gilbert syndrome may also be caused by a homozygous missense mutation of UGT1A1 [16].
• Genetic polymorphisms of bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese patients with Crigler-Najjar syndrome or Gilbert's syndrome as well as in healthy Japanese subjects [17].
• A 34-year-old woman, gravida 4, para 1, with Crigler-Najjar syndrome Type II was treated with phenobarbital administration following phototherapy during each of 2 pregnancies [18].
• Contribution of two missense mutations (G71R and Y486D) of the bilirubin UDP glycosyltransferase (UGT1A1) gene to phenotypes of Gilbert's syndrome and Crigler-Najjar syndrome type II [19].

Anatomical context of Crigler-Najjar Syndrome

• To test this hypothesis, congeneic normal rat hepatocytes were transplanted into UDP-glucuronosyltransferase (UGT1A1)-deficient jaundiced Gunn rats (a model of Crigler-Najjar syndrome type I), following HIR and adenovirus-mediated FasL gene transfer [20].
• The method was helpful in diagnosing biliary-tract obstruction in a newborn and a partial deficiency state of bilirubin conjugation (Crigler-Najjar syndrome) in a 10-year-old male [21].
• Liver microsomes from patients suffering Crigler-Najjar syndrome, who are genetically deficient in bilirubin UDP-glucuronosyltransferase, could also glucuronidate AZT to a similar extent, thus indicating that this protein was not involved in that process [22].

Gene context of Crigler-Najjar Syndrome

• Genetic lesions of bilirubin-uridine-diphosphoglucuronate glucuronosyltransferase-1 (UGT1A1) completely or partially abolish hepatic bilirubin glucuronidation, causing Crigler-Najjar syndrome type 1 or 2, respectively [23].
• Crigler-Najjar syndrome types I and II (CN1 and CN2) are usually inherited as autosomal recessive conditions and are characterized by non-hemolytic unconjugated hyperbilirubinaemia [24].
• UGT1A1 deficiency causes CN-1 (Crigler-Najjar syndrome type 1), which is characterized by potentially lethal unconjugated hyperbilirubinaemia [25].
• A novel compound heterozygous variation of the uridine-diphosphoglucuronosyl transferase 1A1 gene that causes Crigler-Najjar syndrome type II [26].
• Based on these studies and our experience with hepatocyte transplantation in a child with Crigler-Najjar syndrome, isolated hepatocyte transplantation was performed to attempt metabolic reconstitution in a male infant with severe ornithine transcarbamylase (OTC) deficiency [27].

Analytical, diagnostic and therapeutic context of Crigler-Najjar Syndrome

• Because of placental excretion of unconjugated bilirubin, type 1 Crigler-Najjar syndrome patients and Gunn rats are not jaundiced in utero, making prenatal diagnosis difficult [28].
• Removal of protein-bound and unbound unconjugated bilirubin by perfusion of plasma through an anion-exchange resin in a case of Crigler-Najjar syndrome type I [29].
• Plasmapheresis has been shown to reduce total and free bilirubin levels in acute exacerbations of Crigler-Najjar syndrome, type I (CNS-TI), but its effectiveness in long-term management has not been reported [30].

References