Crigler-Najjar syndrome

Crigler-Najjar syndrome (CNS) is a rare inherited disorder of bilirubin metabolism caused by a deficiency or complete absence of the hepatic enzyme uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1), which is responsible for conjugating bilirubin in the liver so it can be excreted in bile. The condition results in severe unconjugated (indirect) hyperbilirubinemia, which can lead to bilirubin accumulation in the brain (kernicterus) and cause permanent neurological damage if untreated. The syndrome is classified into two types: Type I (also called Crigler-Najjar syndrome type 1) is the more severe form, characterized by a complete absence of UGT1A1 enzyme activity, presenting in the neonatal period with dangerously high levels of unconjugated bilirubin and intense jaundice. Type II (also known as Arias syndrome) is a milder form with partial enzyme deficiency, where bilirubin levels are elevated but generally lower than in Type I, and patients may respond to phenobarbital therapy, which can induce residual enzyme activity. The primary body system affected is the hepatobiliary system, but the most serious consequences involve the central nervous system due to bilirubin neurotoxicity. Key clinical features include severe neonatal jaundice, yellow discoloration of the skin and sclera, and risk of bilirubin encephalopathy (kernicterus), which can manifest as hearing loss, abnormal muscle tone, intellectual disability, and in severe cases, death. In Type I, phototherapy (exposure to blue-spectrum light for 10–16 hours daily) is the mainstay of treatment to reduce bilirubin levels by converting it to water-soluble photoisomers that can be excreted without conjugation. Liver transplantation remains the only definitive cure for Type I Crigler-Najjar syndrome, as it provides functional UGT1A1 enzyme. Experimental gene therapy approaches are under investigation. For Type II, phenobarbital can effectively lower bilirubin levels by enhancing residual enzyme activity, and the prognosis is generally more favorable. Plasmapheresis or albumin infusions may be used in acute crises to rapidly lower bilirubin levels.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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