Rare diseases treatment : an insight in Crigler-Najjar treatment

Abstract

Crigler-Najjar Syndrome is a rare disease characterized by an unconjugated hyperbilirrubinemia since birth. This disease is classified into two distinct forms: Crigler-Najjar type 1 and Crigler-Najjar type 2. The Crigler-Najjar type 1 is a rare autosomal recessive disorder with a complete deficiency of bilirubin uridine diphosphate-5'-glucuronosyltransferase type 1 enzyme (UGT1A1) activity, resulting in a total loss of bilirubin glucuronidation. This condition can be fatal due to the permanent and severe unconjugated hyperbilirrubinemia associated with kernicterus. Patients with Crigler-Najjar disease type 2 have residual UGT1A1 activity, resulting in a milder phenotype. These patients are still able to conjugate and excrete bilirubin via the bile. Bile of type 2 patients contains mono-conjugates and some bi-conjugates, although the bile of type 1 patients contains essentially no conjugated bilirubin. Patients with Crigler-Najjar type 2 can be treated with phenobarbital, which enhances the residual UGT1A1 activity and decreases plasma UCB concentrations by approximately 30%. In order to decrease plasma UCB levels, Crigler- Najjar type 1 patients rely on lifelong phototherapy, the routine treatment for unconjugated hyperbilirubinemia. However, it becomes less effective with age and eventually fails to prevent bilirubin-induced brain damage in several patients. This fact suggests the call for the development of alternative treatment strategies for severe unconjugated hyperbilirubinemia.