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CRIGLER-NAJJAR SYNDROME

Crigler-Najjar syndrome is a rare inherited metabolic disorder caused due to a defective gene that leads to absence or impairment of enzyme activity for the metabolism of a substance known as bilirubin. Bilirubin is a yellow coloured bile component that is produced by the liver. It has to be converted from its toxic insoluble unconjugated form to a non-toxic conjugated form that binds with a protein called albumin. After binding with albumin, it becomes easily dissolvable in water and is removed from the body. Thus impaired activity of the enzyme hepatic bilirubin uridine diphosphate glucuronosyl transferase(UGT) leads to the accumulation of unconjugated bilirubin in the blood which is very toxic to the body. Mutations in UGT1A1 gene lead to reduced UGT activity.

This disease was first recognized and reported in medical literature in 1952 by two doctors, Dr. Crigler and Dr. Najjar after whom the disease is named.

Inheritance:

Crigler-Najjar syndrome is an autosomal recessive disorder. Hence a person can contract the disease only if both the parents are affected or atleast carriers of the disease. If both the parents are affected then the baby will definitely be affected. If both parents are carriers then there are is 25% chance for the baby to have the disease. If one parent is affected and the other is a carrier, then there is 50% chance for the baby to be affected by the disease.

Approximately, every 1 in a million new - borns are affected by the disease.

Types of Syndrome:

Crigler-Najjar syndrome is of 2 types:

o	Type I - It is a highly sporadic condition which is life-threatening. It occurs due to complete lack of enzyme activity that causes accumulation of perilously high levels of toxic bilirubin in the blood leading to a condition known as kernicterus. It is found in babies right after birth and often leads to death within 2 years of age if left undiagnosed and untreated. Efficacy of treatment is less. Blood bilirubin levels exceed 20-50 mg/dL of blood.

o	Type II- It is also known as Arias’ syndrome which is less uncommon and less dangerous than type I. Here, enzyme activity is present but it is impaired. Affected babies can survive into adulthood with proper treatment as they are less likely to develop kernicterus. Sometimes it is left undiagnosed until adulthood. Blood bilirubin levels stay within 6-20mg/dL of blood.

Symptoms and Causes:

o	Since bilirubin is yellow in colour, its accumulation leads to yellowish colouring of the skin, mucous membranes and eyes which is indicative of jaundice.

o	Extremely high levels of bilirubin in the blood(kernictus) can cross the blood-brain barrier, infiltrating the brain tissues and thus causing confusions and changes in thinking, involuntary writhing movements, eventual deafness or reduced intellectual ability.

o	As unconjugated bilirubin cannot be metabolized by the liver due to reduced enzyme activity, it can also lead to liver damage.

o	Affected children may also show lethargy and reduced muscle content in the body.

o	Other symptoms that may follow include absence of certain reflexes ; mild to severe muscle spasms, including spasms in which the head and heels are bent or arched backward and the body bows forward (opisthotonus).

Diagnosis:

o	Crigler-Najjar syndrome can be diagnosed even with basic tests such as the total serum bilirubin levels.

o	Presence of bilirubin glucuronides in bile is also indicative of this disorder.

o	Genomic DNA analysis is the conformation test of Crigler-Najjar syndrome which can also differentiate between type I and type II. It identifies any mutations in the gene coding for UGT enzyme.

o	It can also be diagnosed by enzyme assay tests and liver biopsy to check for the enzyme activity in the liver.

Treatment:

There are several treatments available for the treatment of Crigler-Najjar syndrome but the efficacy of the treatment varies with the type of the disorder, intensity and also the age the patient.

o	Blue-light phototherapy – It is a long-term therapy that makes use of short wavelength blue LED light to breakdown the bilirubin into more soluble compounds that can be excreted from the body. But this treatment’s efficacy decreases with age as the skin becomes thick and does not allow easy penetration of light. This therapy prevents brain damage.

o	Liver transplantation – Since liver is the site of bilirubin metabolism, liver transplantation restores the normal enzymatic activities of the liver. This is the most effective treatment.

o	Phenobarbital – administration of this drug reduces the level of bilirubin in the blood by about 30% - 70% for type II syndrome. It works by inducing the gene responsible for UGT production. However, it does not have any significant effect on type I syndrome.

o	Plasma transfusions- As bilirubin is found in the blood, removal of the plasma and replacement with fresh plasma from donor can remove all the bilirubin in that portion of the plasma.

o	Enzyme replacement therapy is under research for the treatment of Crigler-Najjar syndrome.

Related Disorders:

o	Gilbert syndrome – It is an inherited metabolic disorder characterized by a defect in the clearance of unconjugated bilirubin from the liquid portion of the blood (plasma) by the liver. Symptoms of this disorder (if any) may result from reduced activity of the liver UGT1A1 enzyme. Gilbert syndrome is caused by mutations of the same gene that causes Crigler-Najjar syndrome, but affected individuals maintain about one third of the normal activity of the UGT1A1 enzyme. Most affected individuals have no symptoms (asymptomatic) or may only exhibit mild yellowing of the skin, mucous membranes, and whites of the eyes (jaundice), which may be intermittent.

o	Rotor syndrome – It is an extremely rare inherited metabolic disorder characterized by the presence of excessive bilirubin in the blood (hyperbilirubinemia). While most of the conjugated bilirubin produced in the liver cells is excreted in bile, a small fraction goes back to the blood plasma. The conjugated bilirubin is taken up by other liver cells (re-uptake). Rotor syndrome is caused by an inherited abnormality simultaneously affecting two genes, SLCO1B1 and SLCO1B3. In most instances, affected individuals exhibit no symptoms of this disorder (asymptomatic) or have persistent jaundice. Unlike Crigler-Najjar syndrome, affected individuals have high levels of conjugated bilirubin.

o	Rh disease (isoimmunization) – It is a rare disorder in which red blood cells from the fetus are not compatible with those of the mother. In Rh disease, red blood cells from the fetus may cross the placenta and enter into the mother’s bloodstream during pregnancy. This stimulates maternal antibody formation against these foreign blood cells. These antibodies eventually reach the fetus via the placenta and cause destruction of fetal red blood cells (hemolysis), resulting in low levels of circulating red blood cells (anemia) in the fetus. In response, the fetal bone marrow releases immature red blood cells into the fetal bloodstream. The hemoglobin from the destroyed red blood cells is broken down into bilirubin thus causing elevated bilirubin levels leading to jaundice.

Reference links:

o	https://rarediseases.org/rare-diseases/crigler-najjar-syndrome/

o	https://medlineplus.gov/ency/article/001127.htm

o	https://ghr.nlm.nih.gov/condition/crigler-najjar-syndrome#statistics

o	www.epjnonlinearbiomedphys.springeropen.com

o	http://patient.info/in/doctor/crigler-najjar-syndrome

o	http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79235