Crigler-Najjar syndrome has been classified into two types according to the degree of hyperbilirubinaemia and to the response to phenobarbital administration.
The more severe Crigler-Najjar type I (Online Mendelian Inheritance in Man #218800 ) is characterized by severe chronic non-haemolytic unconjugated hyperbilirubinaemia with high levels of serum bilirubin (between 20-50 mg/dL) due to the absence of bilirubin B-UDPGT (UGT1A1) activity.
In the milder Crigler-Najjar type II (known also as Arias syndrome) (Online Mendelian Inheritance in Man #606785 ), bilirubin UGT1A1 activity is only decreased and a consistently significant reduction of hyperbilirubinemia is obtained with phenobarbital treatment, which does not occur in Crigler-Najjar type I. The response to phenobarbital may represent induction on the residual UGT1A1 activity present in type II patients.Clinically, Crigler-Najjar type I and type II syndrome are discriminated on the basis of the following clinical criteria:
- Type I patients do not respond to phenobarbital treatment and only traces of bilirubin glucuronides can be found in their bile.
- In type II, phenobarbital treatment (3-5 mg/kg/die, single administration) lowers serum bilirubin levels by more than 30%.
- In type II bilirubin glucuronides are present in bile.
- Analysis of liver tissue reveals residual activity of UGT1A1 activity in type II and absent activity in type I.
Serum bilirubin concentration 20-50 mg/dL < 20 mg/dL Hepatic UGT1A1 activity Absent Markedly reduced Effect of phenobarbital on serum bilirubin concentration None Reduction Bile Usually pale: contains small amounts of unconjugated bilirubin Increased proportion of bilirubin monoglucoronide Prognosis Kernicterus Usually benign Mode of inheritance Autosomal recessive Most likely autosomal recessive
Several alteration in the UGT1A1 gene have been described both in Crigler-Najjar type I and Crigler-Najjar type II patients (see The Human Gene Mutation Database). As a general rule mutations in Crigler-Najjar type I patients disrupt completely UGT1A1 activity, while mutations discovered in Crigler-Najjar type II patients have a milder effect on the protein activity even if there is considerable variability in type II, making it difficult to classify some cases.
Crigler-Najjar type I is inherited as an autosomal recessive trait. Also type II is believed to be autosomal recessive even if the pattern of inheritance is not certain. For Crigler-Najjar type II, in fact, also an autosomal dominant transmission model has been proposed.
In an autosomal recessive inheritance two copies of an altered gene located on one of the autosomes (that is, not the X or Y chromosomes) must be present for an individual to be affected with the trait or condition determined by that gene.
- An affected individual (homozygote) has two parents who are unaffected but each parent carries the altered gene (heterozygote).
- The risk of two heterozygotes, or carriers, having an affected child is 25%, 1 in 4, for each child that they have; similarly, there is a 3 in 4 chance (75%) that each child will not be affected.
- Males and females are at equal risk for being affected.
- Two affected individuals (homozygotes) usually produce children all of whom are affected as well.
Autosomal dominant inheritance is marked by the primary feature that one copy of an allele is sufficient for expression of a trait; the gene located on one of the 22 autosomes (that is, not the X or Y sex chromosome) is expressed in the heterozygous state.
- Each affected person has at least one affected parent. Exceptions may occur for one of three reasons:
The affected person is the result of a new mutation.
The parent transmitting the gene did not show the trait, even though he or she carried the allele; this is known as incomplete penetrance, that is, the inconsistent phenotypic expression of a gene even though the gene is present.
The parent of the affected individual expressed the gene but in ways that were not readily recognized; this is known as variable expressivity.
Other characteristics of autosomal dominance:
- An affected person has a 50% chance of passing the trait to a child.
- Males and females are equally likely to be affected.
- Two affected people can have an unaffected child.
Crigler Najjar Type 2 - from the Journal of Formosan Medical Association.
Crigler Najjar Type II - from the Indian Journal of Pediatrics.
Molecular pathology of Crigler-Najjar type I and II and Gilbert's syndromes - from Haematologica).
Crigler-Najjar Syndrome Type 2 in a Young Adult - from J Medicine).
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