Crigler-Najjar syndrome type I (CN-I) is a rare and severe autosomal recessive disorder of bilirubin metabolism. It is characterized by congenital familial nonhemolytic jaundice associated with high level of unconjugated bilirubin resulting from deficiency of uridine diphosphate glucuronosyltransferase (UDPG-T) activity in the liver. The high serum level of unconjugated bilirubin results in kernicterus and neurological sequelae, which can ultimately lead to severe disability or death. Crigler-Najjar syndrome type I can be diagnosed by analysing the clinical presentation, excluding other persistent unconjugated hyperbilirubinemia conditions in infancy, and non-responsiveness to phenobarbitone therapy. The only effective treatment for CN-I patients is orthotopic liver transplantation.
Crigler-Najjar syndrome type I is associated with mutations in UGT1A1 gene.
Koshy et al. (2004) described mutations in two unrelated Bedouin children suffering from Crigler-Najjar syndrome (C-N1). The subjects represented a 1 year old and a five year old females born to non-consanguineous parents, both experienced 1070A-G, Q357R mutation in exon 3 and were found to be homozygous for (TA)7 in the promoter box. The parents were tested and were found to be heterozygote for the 1070A-G, Q357R mutation in exon 3 and heterozygote for (TA)6/7 in the promoter box. Other mutations were also found in Tunisian and Moroccan patients. Based on these findings, Koshy et al. (2004) suggested that Q357R is a rare variant of C-N1 in the Arab population and that founding parents may have possessed the (TA)7 mutation [See also: Tunisia > Petit et al., 2008].
Nazer et al. (1990) reported two children, born to first-cousin Saudi parents, with the 'fetal face syndrome.' Both of the children also had the Crigler-Najjar syndrome, as did two previously born sibs who did not have the fetal face syndrome. Both died at age 4 months. The parents lost two previous children at age 2 months with progressive jaundice but without fetal facial characteristics. Later, Nazer et al. (1998) reviewed 12 patients (8 males and 4 females) who were diagnosed with Crigler-Najjar syndrome between 1986 and 1994. Jaundice was detected in the first few days of life in all but one, in whom detection was delayed for two weeks and resulted in kernicterus. Exchange transfusions were necessary in six cases. Consanguinity was present in 11 patients, eight of whom were the offspring of first cousins. None of the patients responded to phenobarbital therapy alone, which reflected the severity of their disease. Six patients required only phototherapy while the remaining six patients required a combination of phenobarbital and phototherapy. Percutaneous liver biopsy, performed in 10 patients, showed minimal and focal cholestasis in eight, while the remaining two had a normal histological picture. Almost complete absence of the activity of UDPGT in the liver was reported in seven cases. Kernicterus developed in five cases.
Al Shurafa et al. (2002) studied six children suffering from Crigler-Najjar syndrome type 1 (CNS-1) and described the first three living-related liver transplants (LRLT) for this syndrome in Saudi Arabia and the Middle East. Two of the transplanted children developed acute hepatocellular rejection, which was successfully treated with methylprednisolone pulse therapy. One patient had a biliary leak at the cut surface of the graft which was surgically repaired. Post-operative bilirubin levels returned to normal in all three transplanted children and no further phototherapy was required. One patient, who was not transplanted but received phototherapy, developed severe neurological damage, her sister is still awaiting transplantation. At the time of the study, a 14-year-old child with a bilirubin level of 420 micromol/L was undergoing phototherapy whilst awaiting orthotopic liver transplantation because of the lack of a suitable living-related donor. Six siblings of the six children in the studied series were reported dead by the families. It was found that CNS-1 is rather common in Saudi Arabia and can be treated at an early age with LRLT before the progression to kernicterus and neurological deficiency.
Labrune et al. (1994) confirmed the heterogeneity and the founder effect of Crigler-Najjar syndrome type 1 (CN-1) in the Middle East and North Africa through reporting two patients in Tunisia with the Q357R mutation of the B-UGT1 gene.
Tabarki et al. (2002) reported a 2-year-old female with Crigler-Najjar syndrome type I who presented severe cerebellar symptoms revealing bilirubin encephalopathy. The patient improved slowly with the duration of phototherapy. Tabarki et al. (2002) suggested that cerebellar symptoms can be the initial manifestation of kernicterus in children with Crigler-Najjar syndrome type I.
In 2002, Francoual et al. (2002a) studied six patients with Crigler-Najjar syndrome type I who originated from different parts of Tunisia and were not related to each other. In each patient the diagnosis of the disorder was clinically and biochemically suspected, then confirmed by enzymatic assay. The patients were found to carry an A>G transition converting codon 357 from CAA (gln) to CGA (arg) (Q357R). Furthermore, the six patients were homozygous for a TA insertion within the promoter of the UGT1A1 gene, thus resulting in TA7/TA7 homozygosity. All 12 parents were heterozygous for the Q357R mutation and the TA7 allele. These results indicated that Crigler-Najjar syndrome type I in Tunisia may be associated with a founder effect related to the Q357R mutation within the UGT1 gene. In the same year, Francoual et al. (2002b) reported DNA-based prenatal diagnosis of CN-I in two Tunisian families in whom CN-I patients were diagnosed; thus avoiding the need for enzymatic assay on liver tissue, which requires performing a liver needle biopsy. In both cases, SSCP analysis of fetal DNA showed that the fetus was heterozygous for the Q357R mutation. In both families, the pregnancies were continued.
Petit et al. (2008) investigated 21 Tunisian and 2 Kuwaiti Crigler-Najjar type 1 syndrome (CN-1) subjects and 28 healthy unrelated Tunisian controls for genetic markers on both centromeric and telomeric sides of c.1070A-G mutation in UGT1A1 gene. The investigation revealed the possibility that this mutation emerged in Bedouin nomad groups and then spread in Tunisia approximately eight centuries ago after the migration of populations from the Levant to Maghreb.