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Diseases

Crigler-Najjar Syndrome

Crigler-Najjar syndrome (CNS), is a rare genetic disorder of the liver affecting less than 1 in 1 million newborns worldwide. CNS is named after two physicians John Crigler and Victor Najjar, who first described the condition in 1952. The characteristic feature of CNS is a high level of bilirubin in the blood (hyperbilirubinemia).

Under normal circumstances, bilirubin is produced during the normal process of breaking down of red blood cells. Since it is a toxic substance, bilirubin undergoes a chemical reaction in the liver where an enzyme, called uridine diphosphate glucuronosyltransferase (UGT), converts the toxic form of bilirubin into a soluble form (a process known as “bilirubin conjugation”) that can be eliminated from the body through the bile and into the intestines to be excreted out of the body. 

In CNS, two types of defects of the UGT enzyme can occur:

  • When the enzyme is either completely inactive (CNS type I) is the more severe form
  • When the enzyme is severely reduced (CNS type II); less severe

In both types, bilirubin is not broken down properly and cannot be excreted into the bile

Both types of CNS are caused by a genetic defect in the UGT1A1 gene that is responsible for the UGT enzyme in the liver. The affected new born must inherit the damaged UGT1A1 gene from both the mother and the father.

  • If only one parent passes down the gene, the new born will be affected with a less severe condition known as Gilbert’s Syndrome.

    Symptoms

    The symptoms of the severe form, CNS type I, generally become apparent shortly after birth and cause death in early childhood; since CNS type 2 is less severe symptoms only appear in adulthood

    • High levels of unconjugated bilirubin accumulate leading to yellow coloring of the skin and whites of the eyes (jaundice)
    • Sometimes the bilirubin can cross into the brain and result in a severe form of brain damage called kernicterus (bilirubin encephalopathy), a potentially life-threatening neurological condition. Kernicterus usually develops early during infancy, but in some cases, in infants with CNS type 1 may not develop kernicterus until later in childhood or in early adulthood. Kernicterus is rare in CNS type II. Symptoms for kernicterus include:
    • Lack of energy (lethargy)
    • Vomiting
    • Fever
    • Unsatisfactory feedings
    • High pitched cry
    • Mild to severe muscle spasms, including spasms in which the head and heels are bent or arched backward and the body bows forward (opisthotonus)
    • Uncontrolled involuntary muscle movements (spasticity)
    • The milder symptoms that persist beyond 3 weeks include:
    • Clumsiness and involuntary movements
    • Difficulty with fine motor skills
    • Hearing defect

    Diagnosis

    Infants with severe jaundice within days of birth must be tested for CNS

    Family history and gene testing to identify mutations in the UGT1A1 gene can confirm the diagnosis

    Investigations reveal:

    • High level of unconjugated bilirubin in the blood
    • Absent conjugated bilirubin in the bile

    Treatment

    CNS type I is mainly managed by:

    • Phototherapy, a type of treatment by which blue LED light from an apparatus is provided for 10-12 hours/day to the infant. The light has the ability to break down the unconjugated bilirubin, which can then be excreted into the bile and intestines for elimination. The infant’s skin can get thickened since many such sessions are needed.
    • Liver transplantation can provide the enzyme so that the new liver begins to function normally and conjugated bilirubin is able to be excreted from the body. Liver transplant can prevent the dangerous symptoms of kernicterus.

    It should be noted that liver transplant can save the life of an infant with CNS, but they still carry the genetic abnormality and can still pass it to their children.

    CNS type II patients

    • May require phototherapy during episodes of severe hyperbilirubinemia, most are well controlled on daily treatment with phenobarbital
    • With proper treatment, patients with CNS type II have a relatively normal life