Overview of alagille syndrome
Alagille syndrome is a rare inherited disorder. It affects the liver, heart, eyes, bones, kidneys, and nervous system. The disorder is congenital, although it may not manifest later in life and is similar to other types of liver disease found in infants and young children.
However, a group of abnormal symptoms affecting other organs distinguishes Alagille syndrome from other childhood liver and biliary diseases. Alagille syndrome patients often have a distinctive facial appearance. Patients may have lower-than-normal bile ducts in the liver. A small number of patients (about 15 per cent) develop severe liver disease and require a liver transplant.
Signs and symptoms of alagille syndrome
Symptoms don’t go away until a heart or liver transplant is needed.
Symptoms may include:
- Alagille-Watson syndrome
- Arteriohepatic dysplasia
- Cholestasis with peripheral pulmonary stenosis
- Syndromic bile duct paucity
Other symptoms that may appear later:
- Jaundice that doesn’t go away.
- Development problems and continued growth in childhood.
- Enlarged liver (feels larger and firmer than normal).
- Hard, white nodules (called santons) that develop on the skin due to cholesterol and fat deposits. Nodules often appear in young children with scars from recurring injuries, such as the knee and elbow.
- Urine is very dark yellow or brown in colour (high levels of bilirubin in the bloodstream lead to the kidneys).
- Persistent itching.
Alagille syndrome is caused by mutations in one of two genes – the JAG1 gene or the NOTCH2 gene. Mutations of the JAG1 gene have been identified in more than 88 per cent of cases. Mutations in the NOTCH2 gene account for less than 1 per cent of cases. These mutations are inherited in an autosomal dominant pattern. In some cases, the mutations occur randomly due to a spontaneous genetic change (i.e., new mutation).
Dominant genetic disorders occur when only a single copy of a gene with a mutation is necessary for the appearance of the disorder. The gene with the mutation can be inherited from either parent or can be the result of a new mutation in the affected individual. If carried by a parent, the risk of passing the gene with the mutation from the affected parent to offspring is 50 per cent for each pregnancy. The risk is the same for males and females.
When Alagille syndrome is first described, a person must be diagnosed with at least three of the five main criteria for bile duct defect:
- Heart murmur (due to narrowing of the blood vessel connecting the heart to the lungs).
- Bone defects
- Kidney problems or kidney failure
- Problems with the eye – an extra thickening of a line, known as the Schwalbe’s line, on the surface of the eye.
- Vertebral abnormalities
- Eye abnormalities
With the successful identification of Jagd1 as the gene that causes Alagille syndrome, the diagnostic criteria have been revised. In recent years, it has been proven that the diagnosis of Alzheimer’s syndrome can be made in a person with a Jagged 1 mutation who does not have clinical criteria. For example, a less severely affected family member may not meet the clinical criteria for AGS, but a person with an irregular mutation similar to a severely affected family member is considered to have AGS.
In the CHOP research laboratory, it is now possible to detect a mutation in more than 90% of individuals by AGS clinical standards. A minority (<1%) of Alzheimer’s syndrome patients have a mutation in another gene called Notch 2. Currently, mutation testing for this gene is only done for research purposes.
Alagille syndrome treatment
There is no cure for Alagille syndrome. It prevents management problems of the disorder, increases the flow of bile from the liver, maintains normal growth and development, and reduces blood cholesterol levels.
Drugs In medicine are used to increase the flow of bile and relieve severe itching caused by the formation of bile in the blood and skin. Similar medications can be used to treat high cholesterol levels that cause rough, white nodules to develop on the skin of patients with Alzheimer’s syndrome.
- High triglyceride infant formula. Infant formula, a type of fat that is digested despite reducing bile flow, helps with fat absorption in babies.
- High-calorie diet. Alagille syndrome patients have a hard time absorbing the calories they eat. To prevent malnutrition and stunting, a high calorie and high protein diet may be recommended. A feeding tube can be used that provides large amounts of nutrients overnight.
- Liver transplant. A small percentage of patients develop cirrhosis (severe liver damage). Liver transplantation is the only option for these patients.
- Liver transplantation may be the last resort for patients with severe itching, portal hypertension (excessive scarring of the liver), and severe growth failure that does not respond to medication. Liver transplantation has been used successfully in these cases.