Crigler-Najjar syndrome is a genetic disease from the class of fermentopathies characterized by a violation of one of the links in the process of neutralization and elimination of bilirubin – conjugation. Symptoms of this condition are jaundice of hepatic genesis and severe neurological disorders that can lead to death even in infancy. Diagnosis is carried out by means of biochemical tests and determination of the level of unconjugated bilirubin in blood plasma, as well as by molecular genetic techniques. There is no specific treatment for the disease (with the exception of liver transplantation), therapy is reduced to increasing the destruction and elimination of bilirubin from the body (hemosorption, phototherapy, plasmapheresis, barbiturates).
General information
Crigler-Najjar syndrome is a severe genetic disease characterized by a violation of the binding of bilirubin with glucuronic acid, which is a key stage of its neutralization and excretion from the body. This disease was first described in 1952 by two American pediatricians, John Crigler and Victor Najjar. Further study of the Crigler-Najjar syndrome showed that this condition has a genetic nature and an autosomal recessive nature of inheritance, in addition, it was possible to identify two clinical varieties of this pathology. The disease is quite rare, so the exact numbers of occurrence have not been determined – most researchers believe that it is at the level of 1:1,000,000. The sexual distribution of patients with Crigler-Najjar syndrome has no peculiarities, the disease affects both boys and girls with the same frequency. In the treatment of this condition, early (ideally prenatal) diagnosis is extremely important, since the prognosis of the disease and the quality of life of the patient depend very much on the timeliness of the therapy initiated.
Causes
Crigler-Najjar syndrome belongs to the class of fermentopathies (according to another classification – to the group of unconjugated hyperbilirubinemia), the cause of this disease lies in the insufficiency of uridine diphosphate glucuronidase 1, the function of which is the binding of bilirubin with two molecules of glucuronic acid. As a result of this biochemical process, bilirubin becomes able to dissolve in water, be excreted as part of bile and, most importantly, its toxicity significantly decreases. With Crigler-Najjar syndrome, this process is sharply slowed down or does not occur at all, as a result of which there is a delay in the elimination of bilirubin from the body and its accumulation.
Bilirubin has a pronounced neurotoxicity, with an increase in the concentration in the blood, this substance begins to be deposited in the tissues of the skin and mucous membranes, leading to the development of jaundice. When the concentration of bilirubin exceeds a certain threshold, the compound begins to penetrate the blood-brain barrier into the brain, leading to severe encephalopathy (especially the basal nuclei are damaged). In the absence of treatment, patients with Crigler-Najjar syndrome die from numerous neurological disorders and an increasing hepatic coma.
The reason for the low activity of uridine diphosphate glucuronidase is mutations of the UGT1A1 gene, which is located on the 2nd chromosome, is responsible for the amino acid sequence and isolation of this enzyme. In addition to the Crigler-Najjar syndrome, defects in this gene can lead to a number of other disorders of bilirubin metabolism of a hereditary nature – Gilbert syndrome, transient neonatal bilirubinemia of the family type. The mechanism of inheritance of UGT1A1 gene mutations in Crigler-Najjar syndrome is autosomal recessive. At the same time, several variants of possible damage to this gene are described, which lead to a different course of this disease.
Classification and symptoms
Currently, two main clinical forms of Crigler-Najjar syndrome are described, mainly differing in severity of manifestations and prognosis of the disease. This is due to the type of genetic defect in UGT1A1. The first type of disease (CNS-1) is caused by missense mutations leading to the appearance of an inferior enzyme having a signaling sequence of amino acids characteristic of proteins undergoing intracellular utilization. Thus, in this form, the gene defect affects coding regions (exons), which causes the development of pathology in homozygotes. Shortly after its formation, uridine diphosphate glucuronidase 1 is destroyed and bilirubin conjugation does not occur at all.
Type 1 Crigler-Najjar syndrome is characterized by a severe and rapid course – the first signs of hyperbilirubinemia in the form of jaundice are detected within a few hours after birth. Over time, neurological disorders join them – nystagmus, convulsive seizures, sometimes opisthotonus occurs. Jaundice persists throughout the child’s life, his mental development sharply lags behind that of his peers, the symptoms of the disease steadily increase even with intensive treatment. Usually, patients with type 1 die during the first year of life due to bilirubin intoxication and damage to the basal subcortical nuclei (nuclear encephalopathy).
The cause of the type 2 Crigler-Najjar syndrome is also the missense mutations of the UGT1A1 gene, however, they can occur both in the coding sequence (exons) and in the promoter – the site responsible for the expression of this gene. Most patients with CNS-2 have an exon defect on one chromosome and a promoter on the other, that is, such individuals are compound heterozygotes. The result of the violation is the production of a defective form of the enzyme uridine diphosphate glucuronidase, which is not destroyed, but has a reduced (at the level of 20-25% of the norm) functional activity. Therefore, type 2 is characterized by a less severe clinical picture and a more favorable prognosis.
In the first months and even years of life of patients, this type often manifests itself only with minor jaundice, if left untreated, neurological abnormalities may develop by adolescence. In some cases, especially with properly prescribed therapeutic measures, no disorders from the central nervous system do not occur at all. Manifestations of jaundice of varying severity in patients with type 2 Crigler-Najjar syndrome can persist throughout life and are often regarded as an indicator of complications and deterioration of the patient’s condition. With age, nystagmus sometimes appears, convulsive seizures may be registered, but the course and severity of the symptoms of the disease depend entirely on the quality of treatment and the implementation of the recommendations of specialists.
Diagnostics
Diagnosis of the Crigler-Najjar syndrome is made on the basis of data from a general examination of the child, biochemical studies of blood, bile and urine, molecular genetic analyses. The examination reveals jaundice that occurred in the first hours (with CNS-1) or months (CNS-2) of life, signs of neurological disorders (opisthotonus, nystagmus, long-term preservation of transient reflexes). In patients with type 2 , neurological disorders can be registered in adulthood, whereas only jaundice is observed in children. Also, with age, manifestations such as sensorineural deafness or choreoathetosis may join.
A biochemical blood test reveals pronounced indirect hyperbilirubinemia (up to 200-350 mmol / L), absence (with type 1) or a sharp decrease in the concentration of direct bilirubin. The conjugated fraction of this compound is absent in the bile at CNS-1 and is present in insignificant amounts at CNS-2. The phenobarbital test for Crigler-Najjar syndrome is positive only in the presence of uridine diphosphate glucuronidase, that is, with CNS-2. The study of the concentration of unconjugated bilirubin in urine shows its increase. Molecular genetic diagnosis is performed by a geneticist – he performs direct sequencing of the UGT1A1 gene sequence in order to identify mutations. If the heredity of the parents is burdened by this disease, prenatal diagnosis of pathology can be carried out. Differential diagnosis should be carried out with the usual transient jaundice of newborns and Gilbert’s syndrome.
Treatment
There is currently no specific or etiotropic treatment for Crigler-Najjar syndrome, all therapeutic measures are prescribed to accelerate the breakdown of bilirubin, its excretion from the body and the protection of the central nervous system. There are no special differences in the therapy of type 1 or type 2 of the disease (with the exception of activation of microsomal oxidation with barbiturates, which is not performed with type 1), however, with CNS-1 treatment only slightly delays the onset of death. The most radical method of treatment is currently an operation for liver allotransplantation from a relative or a genetically similar donor – uridine diphosphate glucuronidase is formed in this organ.
Type 2 is treated with moderate doses of barbiturates to activate bilirubin oxidation and increase the formation of the desired enzyme. In addition, plasmapheresis, hemosorption, replacement blood transfusion are shown – all these procedures are aimed at removing unconjugated bilirubin from the body. Phototherapy gives good results in patients – irradiation of the skin leads to partial destruction of bilirubin and the release of tissue receptors for new portions of this toxin, which reduces its concentration in the blood. Proper drinking regimen and increased fluid intake accelerates the elimination of the toxin from the body, so dehydration should be avoided. Constant monitoring of the level of this substance in the blood plasma is necessary, its amount over 300-340 mmol / l is considered especially dangerous – at such a concentration, bilirubin becomes able to penetrate the blood-brain barrier.
Prognosis and prevention
The prognosis of type 1 is exceptionally poor – due to the complete lack of activity of the enzyme uridine diphosphate glucuronidase 1, patients die during the first year of life due to complications of nuclear encephalopathy. The course of CNS-2 depends on factors such as the severity of manifestations, the timeliness of diagnosis and initiation of treatment, compliance with the recommendations of specialists, the presence or absence of concomitant diseases. In most cases, the prognosis is relatively favorable – patients with type 2 Crigler-Najjar syndrome can live to an advanced age, of the characteristic manifestations of pathology, only jaundice can bother them. Prevention of this condition is possible only within the framework of a geneticist’s consultation for parents who have a burdened heredity for this disease, as well as with the help of prenatal diagnostics.