|Synonyms||Hepatic ductular hypoplasia|
|Alagille syndrome is inherited in an autosomal dominant manner|
Alagille syndrome, Alagille-Watson syndrome or ALGS, is an autosomal dominant genetic disorder that affects the liver, heart, kidney, and other systems of the body. Problems associated with the disorder generally become evident in infancy or early childhood. The disorder is inherited in an autosomal dominant pattern, and the estimated prevalence of Alagille syndrome is 1 in every 100,000 live births.
The severity of the disorder can vary within the same family, with symptoms ranging from so mild as to go unnoticed to severe heart and/or liver disease requiring transplantation. It is difficult to predict a given patient's prognosis, but there are a few known indicators of earlier death.
Signs and symptoms arising from liver damage in Alagille syndrome may include a yellowish tinge in the skin and the whites of the eyes (jaundice), itching (pruritus), pale stools (acholia), an enlarged liver (hepatomegaly), an enlarged spleen (splenomegaly) and deposits of cholesterol in the skin (xanthomas). A liver biopsy may indicate too few bile ducts (bile duct paucity) or, in some cases, the complete absence of bile ducts (biliary atresia). Bile duct paucity results in the reduced absorption of fat and vitamins (A, D, E and K), which may lead to rickets or a failure to thrive in children. Around 15% of patients will experience liver cirrhosis in the course of their disease. Hepatocellular cancer has been reported in a number of cases.
Other signs of Alagille syndrome include congenital heart problems varying from heart murmurs (from pulmonary artery stenosis) to significant structural abnormalities, such as Tetralogy of Fallot. Pulmonary stenosis is common amongst Alagille patients and other defects ; overriding aorta; ventricular septal defect; and right ventricular hypertrophy. Untreated Tetralogy of Fallot mortality rates range from 70 percent by age 10 to 95 percent by age 40. However, complete surgical repair can significantly improve both longevity and quality of life in Alagille's patients. Patients may also present with ventricular septal defects, atrial septal defects, patent ductus arteriosus and coarctation of the aorta.
Other presentations of Alagille's syndrome include an unusual butterfly shape of one or more of the bones of the spinal column (visible on an x-ray), certain eye defects (such as posterior embryotoxon and pigmentary retinopathy), and narrowed pulmonary arteries that can contribute to increased pressure on the right heart valves. Many people with Alagille syndrome have similar facial features, including a broad, prominent forehead, deep-set eyes, and a small pointed chin. The kidneys and central nervous system may also be affected.
ALGS is caused by loss of function mutations in either JAG1 or NOTCH2. This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. Other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family.
JAG1 encodes a ligand critical to the notch gene–signaling cascade that is important in fetal development. Because notch signaling has been found to regulate formation of three-dimensional intrahepatic biliary architecture in murine models, its defect cause bile ducts to be narrow, malformed, and reduced in number (bile duct paucity). As a result, bile builds up in the liver and causes scarring that prevents the liver from working properly to eliminate wastes from the bloodstream.
The notch gene-signaling cascade is also important for cell-cell communication, which involves gene regulation mechanisms that control multiple cell differentiation processes during embryonic and adult life, and is specially important for:
- Atrioventricular (AV) canal development
- Ventricular development
- Ventricular outflow tract development
- Pancreatic development
- Intestinal development
- Bone development
- Respiratory system development
- Neuron cell differentiation
- Neurite development
- Adult brain function
Alagille syndrome can be determined by a special kind of newborn screening wherein DNA samples are analyzed for markers in the JAG1 section. The DNA sequence patterns of a child will be analyzed for probabilistic deletions and therefore takes weeks to complete. After detection, the child should be treated with vitamins and necessary diet to develop the liver function postnatally.
Early treatment is possible once the disease is detected. Once the classical symptoms appear, the best way to eliminate the dangers of Alagille syndrome is a full liver transplant. Most of the short-term treatments available are aimed at improving the functioning of the heart and reducing the effects of impaired liver, kidney, and spleen function.
Several medications are used to improve bile flow, including ursodiol (Actigall).These medications differ in their rates of success. Certain drugs may be used to reduce itching (pruritus): hydroxyzine (Atarax), cholestyramine, rifampicin, phenobarbital, and naltrexone. Similar to the medications which improve bile flow, the anti-itching drugs vary in their success rate.
Many patients with Alagille syndrome will also benefit from a high dose of a multivitamin such as ADEK (continuing high levels of vitamins A, D, E, and K), as the reduced bile flow makes it difficult to absorb and utilize these vitamins.
Surgery is sometimes needed to repair heart defects associated with Alagille syndrome. Also, because the pulmonary arteries are often narrow in patients with Alagille syndrome, a catheterization process similar to angioplasty may be used to widen the arteries to reduce pressure on the right side of the heart. In moderate to severe cases, stents may be placed in the arteries to increase their diameter. Transplantation of the liver has been a successful alternative to medication in severe cases.
Partial biliary diversion has been used to significantly reduce pruritus, jaundice, and xanthomas caused by poor bile flow in patients with bile duct paucity. A portion of the bile produced by the liver is directed through a surgically created stoma into a plastic pouch on the patient's lower right abdomen. The pouch is periodically drained as it fills with bile.
Patients with biliary atresia may require a Kasai procedure to improve bile drainage; however, later liver transplantation is still often necessary.
- synd/729 at Who Named It?
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This article incorporates public domain text from The U.S. National Library of Medicine