Information on the following diseases can be found in the Related Disorders section of this report:

• Zellweger Syndrome
• Cholestasis-Lymphedema Syndrome
• Byler Disease
• Alpha-1-Antitrypsin Deficiency
• .

Alagille syndrome is a rare genetic disorder characterized by slowed bile passage due to an absence of or fewer-than-normal, bile ducts in the liver. Symptoms of Alagille Syndrome can range from mild to severe. Prolonged yellow skin discoloration (jaundice) is usually present at birth. Itching usually occurs shortly after birth. In addition, the liver and spleen may become enlarged (hepatosplenomegaly). Nodules may develop in the skin due to fatty (lipid) deposits. High levels of cholesterol, phospholipids and triglyceride may also be present. Some affected individuals experience mental and/or growth retardation that may be related to abnormal function of the pancreas.

Alagille syndrome consists of some distinct physical abnormalities. The face is marked by a broad forehead; a straight nose with a bulbous tip; deep-set, widely spaced eyes; and a small pointed lower jaw. Fingers may be shorter than normal (hypoplastic). Various cardiovascular and spinal (vertebral) abnormalities may also be present, including abnormalities of heart valves and arteries, abnormally shaped "butterfly" vertebrae, compression of nerve space inside the lower spine, and absence of deep tendon reflexes.

Alagille syndrome is caused by a mutation in the gene called Jag 1 on chromosome 20. This gene encodes for a protein, jagged 1, that has a role in the communication between cells as they develop in the womb and through out the development of the human embryo. It is inherited as an autosomal dominant trait.

Human traits including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed "dominating" the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

Researchers have shown that the abnormal gene that causes Alagille syndrome is expressed in a portion of the short arm (p) of chromosome 20 (20p12). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." In order for researchers to clearly refer to the thousands of genes that may be present on one chromosome, both the long arm and short arm of each chromosome are divided into many bands that are numbered.

Alagille syndrome is a rare disorder which often affects more than one person in a family and many generations of an affected family.

Symptoms of the following disorders can be similar to those of Alagille syndrome. Comparisons may be useful for a differential diagnosis:

Zellweger syndrome is a rare hereditary disorder affecting infants. It is characterized by reduction or absence of peroxisomes (microbodies rich in certain enzymes) in the cells of the liver, kidneys and brain. Unusual problems in prenatal development, an enlarged liver, high levels of iron and copper in the blood, and vision disturbances are among the major manifestations of this disorder. (For more information on this disorder, choose "Zellweger" as your search term in the Rare Disease Database.)

Cholestasis-lymphedema syndrome (Aagene’s syndrome) is a genetic liver disorder characterized by blockage of bile and yellow discoloration of the skin (jaundice) at birth, which tends to recur throughout life. Swelling occurs in the legs due to underdevelopment of lymphatic vessels usually at around five or six years of age.

Byler disease is a genetic liver disorder, which is characterized by an early onset with loose, foul smelling stools, yellow discoloration of the skin (jaundice), an enlarged liver and spleen, and dwarfism. Symptoms are caused by an error in conjugated bile salt metabolism. This disorder is inherited as an autosomal recessive trait, which means that both parents must carry the gene in order for a child to be affected.

Alpha-1-antitrypsin deficiency is an inherited deficiency of a glycoprotein of blood serum, which may be moderate or severe. This deficiency allows proteolytic enzymes to attack various body tissues. Emphysema (a lung disease) or liver abnormalities may be caused by or associated with this deficiency. (For more information on this disorder, choose "Alpha-1- Antitrypsin" as your search term in the Rare Disease Database.)

Diagnosis
Alagille syndrome may be diagnosed based upon a liver biopsy. A genetic test is still experimental.

Treatment
Treatment of Alagille syndrome is symptomatic and supportive. Genetic counseling is recommended for affected individuals and their families.

A high calorie diet with an ample amount of protein may prevent malnutrition and growth failure. Medium-chain triglycerides formulas are used for infants. The consumption of fat should be monitored because fat tolerance varies in individuals with cholestasis.

Research at the Children’s Hospital of Philadelphia under the guidance of Dr. Andrew Mulberg suggests that fat malabsorption in children with Alagille syndrome may be related to dysfunction of the pancreas. The Children’s Hospital of Philadelphia and the Cincinnati Children’s Hospital Medical Center are actively involved in treatment and investigation regarding Alagille syndrome.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

The U.S. Food and Drug Administration (FDA) granted the drug Ursocarb orphan status in September 2004. It is the first orphan drug designated for Alagille syndrome. Digestive Care, Inc., of Bethlehem, Pennsylvania, manufactures Ursocarb.

Two clinical studies regarding Alagille syndrome are currently (2005) listed on the NIH website. Both have been completed. One study involved the investigation of magnesium sulfate in children with reduced bone density as a result of liver disease, including Alagille syndrome. The other study was sponsored by the National Human Genome Research Institute and sought to identify and possibly clone the gene (s) responsible for Alagille syndrome.

ONLINE MENDELIAN INHERITANCE IN MAN (OMIM). Victor A. McKusick, Editor; Johns Hopkins University, Last Edit Date 6/15/99, Entry Number 118450.

ARTERIOHEPATIC DYSPLASIA (ALAGILLE SYNDROME): EXTREME VARIABILITY AMONG AFFECTED FAMILY MEMBERS. S. A. Shulman et al.; Am J Med Genet (Oct 1984; 19(2)). Pp. 325-32.

POSSIBLE DEFECT IN THE BILE SECRETORY APPARATUS IN ARTERIOHEPATIC DYSPLASIA (ALAGILLE'S SYNDROME): A REVIEW WITH OBSERVATIONS ON THE ULTRASTRUCTURE OF LIVER. P. Valencia-Mayoral et al.; Hepatology (Jul- Aug 1984; 4(4)). Pp. 691-98.

EXOCRINE PANCREATIC INSUFFICIENCY IN SYNDROMIC PAUCITY OF INTERLOBULAR BILE DUCTS. S. K. F. Chong et al.; Journal of Pediatric Gastroenterology and Nutrition (1989; 9(4)). Pp. 445-49.

ALAGILLE SYNDROME IS CAUSED BY MUTATION IN HUMAN JAGGED1, WHICH ENCODES A LIGAND FOR NOTCH1. L. Li et al.; Nature Genetics (1997; 16(3)). Pp. 243-51.

MUTATIONS IN THE HUMAN JAGGED1 GENE ARE RESPONSIBLE FOR ALAGILLE SYNDROME. T. Oda et al; Nature Genetics (1997; 16(3)). Pp. 235-42.