Crigler-Najjar Syndrome, Type I

A number sign (#) is used with this entry because Crigler-Najjar syndrome type I is caused by homozygous or compound heterozygous mutation in the UDP-glycuronosyltransferase gene (UGT1A1; 191740) on chromosome 2q37.

Mutations in the same gene cause Gilbert syndrome (143500) and Crigler-Najjar syndrome type II (606785).

Clinical Features

Crigler-Najjar syndrome was first described under the title 'congenital familial nonhemolytic jaundice with kernicterus' (Crigler and Najjar, 1952). The first patients originated from an inbred Old American kindred living in southern Maryland since the 1600s. Other rare recessives found in the same group included Morquio syndrome (253000), homocystinuria (236200), and metachromatic leukodystrophy (250100). In Crigler-Najjar syndrome, intense jaundice appears in the first days of life and persists thereafter. Some affected infants die in the first weeks or months of life with kernicterus. Others survive with little or no neurologic defect. The level of total serum bilirubin, predominantly indirect-reacting, ranges from 20 to 45 mg/dL. In Crigler-Najjar syndrome type II, total serum bilirubin ranges from 6 to 20 mg/dL, and in Gilbert syndrome, total serum bilirubin ranges from 1 to 6 mg/dL. Type I patients, as illustrated by those originally reported by Crigler and Najjar (1952), have complete absence of bilirubin UDP-glucuronosyltransferase (UDPGT). Type II patients have a partial deficiency of this enzyme, are less severely jaundiced, have pigmented bile that contains bilirubin glucuronide, and generally survive into adulthood without neurologic or intellectual impairment, although bilirubin encephalopathy may develop in later life. Response to phenobarbital only in type II is the most useful differential point. Further insight into the natural history of this disease was afforded by the observations of Blumenschein et al. (1968). A male member of the kindred originally studied by Crigler and Najjar was normal, apart from his jaundice, until age 16 when he developed neurologic disability progressing to death after 6 months. Gardner and Konigsmark (1969) described the histopathologic findings in that patient.

Rubboli et al. (1997) studied the neurophysiologic features of 5 patients, aged 4 to 20 years, suffering from Crigler-Najjar syndrome type I, with a follow-up ranging from 3 months to 4.5 years. Two patients presented with neurologic disturbances consisting mainly of mental slowing, motor impairment, and seizures. Both presented an abnormal EEG, characterized by slowing of background activity associated with paroxysmal discharges. Liver transplantation performed in 1 of these 2 patients was followed by improvement of both the neurologic picture and the EEG. In a third patient, who was clinically normal, after 2 years of follow-up, the EEG started to show paroxysmal activity during sleep or when evoked by intermittent photic stimulation. In these 3 patients, multimodal-evoked potentials were unremarkable. The remaining 2 younger subjects did not show any clinical or EEG abnormalities. The findings suggested that whereas evoked potentials are reliable techniques to monitor bilirubin neurotoxicity in newborns and infants, EEG is more sensitive in evaluating children and adolescents for neurologic damage and effectiveness of therapeutic strategies.

Review of the literature by Shevell et al. (1998) revealed distinct, often age-related, patterns of neurologic sequelae reflecting injury to basal ganglia, cerebellar, and likely hippocampal structures. The authors stated that definitive prevention of the neurologic sequelae requires that curative treatment (hepatic transplantation and in the future gene therapy) be applied before the onset of neurologic symptoms in adolescence.

Biochemical Features

Childs et al. (1959) concluded that tests using sodium salicylate show impairment of glucuronide conjugation in heterozygotes. Direct demonstration of the enzyme defect was provided by Szabo et al. (1962). The same group found reduced urinary excretion of menthol following oral loading dose in both parents, 3 grandparents and 6 sibs of a case. The values were midway between those of normal controls and the very low values observed in affected persons. Both parents had normal bilirubin tolerance tests. Bilirubin is linked to glucuronic acid by an ester bond, whereas menthol and other test substances, such as paraaminophenol, salicylamide and 4-methyl umbelliferone, have an ether bond.

Using a monoclonal antibody, van Es et al. (1990) found that UDPGT activity toward bilirubin was undetectable in all 4 patients with Crigler-Najjar syndrome type I and that activity toward phenolic compounds and 5-hydroxytryptamine was reduced in 2 and normal in 2. UDPGT activity toward steroids was normal. This and another monoclonal antibody showed heterogeneity in the 4 patients. By immunoblot studies, 1 antibody recognized 2 polypeptides (54 and 56 kD) in 1 patient and none in a second, whereas the second antibody showed no immunoreactive polypeptides in either patient. A third patient showed a normal banding pattern of 3 polypeptides and a fourth showed only the 53-kD band at decreased intensity. Robertson et al. (1991) studied liver biopsy samples from 8 patients with the Crigler-Najjar syndrome. Bilirubin UDPGT activity was not detectable in type I livers, and low levels (9-26% of controls) of monoglucuronide conjugates only were observed in type II livers.

A review of glucuronidation research in relation to the Crigler-Najjar syndrome was provided by Jansen et al. (1992).

Clinical Management

Shevell et al. (1987) demonstrated that phototherapy is useful in the first years of life in keeping levels of unconjugated hyperbilirubinemia under 15 mg/dl. Later, however, phototherapy is inadequate and orthotopic hepatic transplantation may be required. In two 17-year-old boys with type I Crigler-Najjar syndrome, Galbraith et al. (1992) found that plasma bilirubin concentrations could be decreased and the rebound hyperbilirubinemia that occurs after plasmapheresis could be blunted by treatment with the inhibitor of heme oxygenase, tin-mesoporphyrin. Phototherapy was also administered for 10 hours nightly. Prolonged treatment with the inhibitor was well tolerated and no progression of the preexisting neurologic impairment occurred during the clinical trials. Phototherapy is the preferred long-term treatment for type I Crigler-Najjar disease (Jansen et al., 1992). Children with this disease usually sleep undressed under a light canopy. Since kernicterus can develop at a later age, if serum bilirubin levels cannot be kept below 450 to 500 micromol/L, liver transplantation may be necessary.

Information from a multicenter survey on the management of patients with Crigler-Najjar syndrome type I was reported by van der Veere et al. (1996). Fifty-seven patients were included. At the time of inclusion, 21 patients (37%) had received a liver transplant. The average age of transplantation was 9.1 +/- 6.9 years (range, 1 to 23 years); the age of patients who had not been transplanted at the time of inclusion was 6.9 +/- 6.0 years (range, 0 to 23 years). Brain damage had developed in 15 patients (26%). Five patients died, and 10 were alive with some degree of mental or physical handicap. In 2 patients, aged 22 and 23 years, early signs of bilirubin encephalopathy could be reversed, in 1 by prompt medical intervention followed by liver transplantation and in the other by prompt liver transplantation. Phototherapy (12 h/d), although initially very effective, is socially inconvenient and becomes less efficient in the older age group. Liver transplantation is the only fully effective therapy. Since liver transplantation had been performed after some brain damage had occurred in 7 patients, this procedure should probably be performed at a young age, particularly in situations in which reliable administration of phototherapy cannot be guaranteed.

Fox et al. (1998) reported treatment of Crigler-Najjar syndrome type I with hepatocyte transplantation (7.5 billion cells via portal vein catheter over 15 hours) in a 10-year-old girl. Prior to transplantation, she had required 10 to 12 hours of phototherapy daily to maintain serum bilirubin levels of 24 to 27 mg/deciliter; after transplantation, 6 to 8 hours of phototherapy daily maintained serum bilirubin levels of 10.6 to 14 mg/deciliter. She was able to withstand a bacterial sinusitis without hospitalization. Engraftment and survival were completely stable to 11 months.

Inheritance

The pattern of inheritance for Crigler-Najjar syndrome type I has been shown to be autosomal recessive (Chowdhury et al., 2001). Sugar (1961) described a patient who survived to adulthood, married and had 2 children, of whom 1 was severely affected. In 2 offspring, a boy and a girl, of first-cousin Saudi parents, Nazer et al. (1990) described the concurrence of Robinow syndrome and Crigler-Najjar syndrome. Two previously born children had died at the age of 2 months with progressive jaundice but without the fetal facial characteristics of Robinow syndrome. Presumably, the 2 disorders were segregating independently of each other. The Robinow syndrome in this family was probably the recessive form (268310).

Shevell et al. (1998) reported follow-up studies of 2 patients with the same mutation of the UGT1 gene causing Criger-Najjar syndrome type I. The patients were apparently not known to be related; however, both came from consanguineous parentage of southern Italian origin. Despite radically different therapeutic interventions, the 2 patients did not differ in outcome measures.

Molecular Genetics

Gollan et al. (1975) reported 3 brothers with type II Crigler-Najjar syndrome who were severely jaundiced for over 50 years. Parenteral feeding with glucose caused hyperbilirubinemia, even when the patient was receiving phenobarbital. One of these brothers was shown by Moghrabi et al. (1993) to have a missense mutation in the UGT1 gene (191740.0005) in the same codon in which a nonsense mutation resulted in type I Crigler-Najjar syndrome (191740.0003).

Animal Model

In the homozygous Gunn rat, which lacks the enzyme uridine diphosphate glucuronyltransferase (UDPGT), Matas et al. (1976) found that sustained reduction of plasma bilirubin followed infusion into the portal vein of hepatocytes from heterozygous rats (possessing enzyme). Roy Chowdhury et al. (1987) found functionally defective forms of UDPGT in the Gunn rat.

Roy-Chowdhury et al. (1991) demonstrated deletion of a single guanosine residue in the coding region of rat UGT, causing a frameshift in both the bilirubin-specific and the 3-methylcholanthrene-inducible UDPGT. Iyanagi et al. (1989) had reported the deletion in the 3-MC-inducible UDPGT in Gunn rats, which explained the loss of the terminal 150 amino acids of this UDPGT isoform. However, the molecular mechanism for lack of bilirubin-UDPGT activity in Gunn rats had not previously been known. As explanation for the sharing of the mutation, the possibilities considered were gene conversion and, alternatively, origin of the 2 from a common transcript by the mechanism of alternative splicing. Iyanagi (1991) demonstrated that the latter possibility is in fact the case. The deletion of 1 G causes premature termination with loss of 115 amino acids from the COOH terminus of the protein.

Gene Therapy

Recombinant adenoviruses are highly efficient at transferring foreign genes in vivo. Duration of gene expression is limited, however, by the host antiviral immune response which precludes expression upon viral readministration. In the enzyme-deficient Gunn rat, a model of Crigler-Najjar syndrome, Ilan et al. (1996) tested the feasibility of prolonging gene expression by induction of central tolerance to adenoviral antigens. Tolerance was induced by intraperitoneal injection of antilymphocyte serum, followed by intrathymic inoculation of a recombinant adenovirus carrying the human UGT1A1 gene. In 'tolerized' rats, they found that the enzyme was expressed in the liver with decrease in serum bilirubin levels within 1 week and remaining low for 7 weeks. Similar findings were observed following repeat injections given on days 45 and 112. In control rats, serum bilirubin levels were reduced for only 4 weeks, and viral readministration was ineffective. In all tolerized groups, but not in controls, there was a marked inhibition of appearance of neutralizing antibodies and cytotoxic lymphocytes against the recombinant adenovirus.