SCIENTIFIC BACKGROUND

UGT1A1

SCIENTIFIC BACKGROUND

Crigler-Najjar syndrome is a very rare, autosomal recessive metabolic disorder of the liver that is characterized by non-hemolytic unconjugated hyperbilirubinemia. The prevalence is estimated at 1:1,000,000 in newborns. A differentiation is made between severe type I with complete absence of bilirubin-UDP-glucuronyltransferase (UGT1A1) activity, and partially deficient type II with residual UGT1A1 activity. In severe type I, the serum bilirubin concentration is 20-45 mg/dl. Initial treatment of neonates involves phototherapy, and later plasmapheresis; a liver transplant is often necessary. Neurological complications due to neurotoxicity of unconjugated bilirubin are common. In the milder type II, the bilirubin concentration is 6-20 mg/dl. This can be reduced by 60-70% with induction therapy using phenobarbital.

 

The molecular cause of both types are pathogenic variants in the UGT1A1 gene. In Crigler-Najjar type I, frequently detected variants lead to translation termination and thus to the complete functional loss of the affected alleles. In contrast, in type II, at least one allele carries a mild variant associated with the substitution of only one amino acid. This leaves a residual activity of UDP-glucuronyl transferase of about 10%. The common (TA)7 polymorphism in the UGT1A1 promoter region, which results in decreased expression of the gene, can also lead to Crigler-Najjar type II in combination with another pathogenic variant. A combination of the (TA)7 polymorphism localized on one allele with a mild variant and an additional severe variant on the second allele can result in severe type I. Therefore, if Crigler-Najjar syndrome is suspected, the promoter region should always be analyzed (see also Meulengracht-Gilbert syndrome).

 

References

Memon et al. 2016, Pediatr Res 79:378 / Strassburg 2010, Best Pract Res Clin Gastroenterol 24:555 / Teng et al. 2007, Clin Genet 72:321 / Servedio et al. 2005, Hum Mutat 25:325 / Kadakol et al. 2000, Hum Mutat 16:297 / Iolascon et al. 2000, J Med Genet 37:712

GENES

UGT1A1

ASSOCIATED TESTS

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