Crigler–Najjar syndrome


Crigler–Najjar syndrome is a rare inherited disorder affecting the metabolism of bilirubin, a chemical formed from the breakdown of the heme in red blood cells. The disorder results in a form of nonhemolytic jaundice, which results in high levels of unconjugated bilirubin and often leads to brain damage in infants. The disorder is inherited in an autosomal recessive manner.
This syndrome is divided into types I and II, with the latter sometimes called Arias syndrome. These two types, along with Gilbert's syndrome, Dubin–Johnson syndrome, and Rotor syndrome, make up the five known hereditary defects in bilirubin metabolism. Unlike Gilbert's syndrome, only a few causes of CNS are known.

Cause

It is caused by abnormalities in the gene coding for uridine diphosphoglucuronate glucuronosyltransferase. UGT1A1 normally catalyzes the conjugation of bilirubin and glucuronic acid within hepatocytes. Conjugated bilirubin is more water soluble and is excreted in bile.

Diagnosis

Type I

This is a very rare disease, and consanguinity increases the risk of this condition. Inheritance is autosomal recessive.
Intense jaundice appears in the first days of life and persists thereafter. Type 1 is characterised by a serum bilirubin usually above 345 µmol/L .
No UDP glucuronosyltransferase 1-A1 expression can be detected in the liver tissue. Hence, there is no response to treatment with phenobarbital, which causes CYP450 enzyme induction. Most patients have a mutation in one of the common exons, and have difficulties conjugating several additional substrates. A smaller percentage of patients have mutations limited to the bilirubin-specific A1 exon; their conjugation defect is mostly restricted to bilirubin itself.
Before the availability of phototherapy, these children died of kernicterus or survived until early adulthood with clear neurological impairment. Today, therapy includes
The inheritance patterns of both Crigler–Najjar syndrome types I and II are autosomal recessive.
However, type II differs from type I in a number of different aspects:
may develop in the presence of sepsis, hypoxia, hypoglycemia, hypothyroidism, hypertrophic pyloric stenosis, galactosemia, fructosemia, etc.
Hyperbilirubinemia of the unconjugated type may be caused by:
In Crigler–Najjar syndrome and Gilbert syndrome, routine liver function tests are normal, and hepatic histology usually is normal, too. No evidence for hemolysis is seen. Drug-induced cases typically regress after discontinuation of the substance. Physiological neonatal jaundice may peak at 85–170 µmol/l and decline to normal adult concentrations within two weeks. Prematurity results in higher levels.

Treatment

Plasmapheresis and phototherapy are used for treatment. Liver transplant is curative.

Research

A San Francisco based company named Audentes Therapeutics is currently investigating the treatment of Crigler-Najjar syndrome with one of their gene replacement therapy products, AT342. Preliminary success has been found in early stages of a phase 1/2 clinical trial.
One 10-year-old girl with Crigler–Najjar syndrome type I was successfully treated by liver cell transplantation.
The homozygous Gunn rat, which lacks the enzyme uridine diphosphate glucuronyltransferase, is an animal model for the study of Crigler–Najjar syndrome. Since only one enzyme is working improperly, gene therapy for Crigler-Najjar is a theoretical option which is being investigated.

Eponym

The condition is named for John Fielding Crigler, an American pediatrician and Victor Assad Najjar, a Lebanese-American pediatrician.