No. In about half of the Alagille syndrome cases, the child inherits the gene mutation from a parent. The other half are what we call "new mutations," meaning the mutation occurred in the gene, either when an egg or sperm cell was being made or in one of the first cells of the developing embryo. While parents whose children are diagnosed with Alagille syndrome often recall things that happened during the pregnancy, such as falls or exposures to chemicals or medications, it's important to remember that nothing you do can cause or prevent these new mutations from occurring; they happen as a part of the natural cell division process.
A person who has Alagille syndrome as a result of a new mutation has a 50 percent chance of passing that mutation on to his or her offspring. The child who does inherit a Jagged1 mutation will have some Alagille syndrome manifestations, but there is no way to predict how severely affected he or she will be. The severity of Alagille syndrome varies widely in children with Jagged1 mutations, even among members of the same family.
The first step is to identify the mutation in the family member who is known to have Alagille syndrome. Once that individual's mutation is identified, other family members can be tested.
However, in some families, current testing techniques are unable to identify a Jagged1 mutation in the affected person, making it more difficult to predict the recurrence risk for parents or other family members. In these cases, these family members should undergo clinical studies and consultations to be assessed for subtle Alagille syndrome symptoms, including:
Unfortunately, interpreting this clinical workup can sometimes be difficult, because some of these same findings are found in people who don't have Alagille syndrome. A clinical geneticist or genetic counselor familiar with Alagille syndrome should review the results of the workup of a parent or relative to try to determine the recurrence risk for the individual.
If the parents of a child with Alagille syndrome are found not to carry the gene mutation or deletion found in their child, they have a very small chance of having another child with Alagille syndrome. Although this chance is very low, it's not zero. If a new mutation occurs in an egg or sperm cell, it's also possible it's present in several other egg or sperm cells. If one of these other cells containing the mutation or deletion is used in a fertilization, the fetus would inherit the Jagged1 mutation. When a subset of cells contains the same gene mutation or deletion like this, it's called to as gonadal mosaicism. Gonadal mosaicism is a rare event, but it does occur. The risk for parents of a child with a new mutation to have another child with the same mutation is estimated at about 1 percent.
Once a mutation or deletion is identified in a child with Alagille syndrome, parents and other family members can be tested for the gene change. If a person is found to carry the mutation or deletion, he or she has a 50 percent chance of passing it on in a pregnancy. During a pregnancy, the fetus could be tested for the mutation with standard prenatal testing (chorionic villus sampling or amniocentesis). But while prenatal testing can determine if the fetus has inherited a Jagged1 mutation or deletion, it can't predict the severity of the disorder, which might range from serious cardiac and liver disease to more benign manifestations. Other prenatal tests — such as a fetal echocardiogram designed to look for severe heart defects — may offer some further information, but they are also limited.
Doctors have noted that the severity of Alagille syndrome can vary widely from person to person. Even when they have compared affected siblings or an affected parent to his or her child, they recognized that Alagille manifestations can be very different. This became more evident once it became possible to test the family members of affected individuals for gene mutations. We have found that many people with Jagged1 mutations would not have been suspected to have Alagille syndrome. They might have one or two less-serious findings — such as posterior embryotoxon, butterfly vertebrae, innocent heart murmurs or characteristic facial features — that never needed medical attention.
Although we now know that Jagged1 is the gene that causes Alagille syndrome in most cases, we don't yet understand what makes this disorder so variable, even within families. It is possible that Jagged1's function is affected by its interactions with other genes and environmental factors.
The bile buildup in the blood causes the itching that children with Alagille syndrome experience. Your child's doctor may prescribe medications such as ursodeoxycholic acid, to increase bile flow, which will in turn relieve the itching. He or she may also recommend an antihistamine medication. Be sure to keep your child's skin moist with softening lotions (ask your doctor for a recommendation) and keep his or her fingernails trimmed.
We don't fully understand why children with Alagille syndrome experience growth failure. Possible causes include insufficient calorie intake, fat malabsorption (decreased ability to absorb fat) due to liver or pancreatic disease, congenital (present at birth) defects (such as heart disease) and the defect in the Jagged1 gene.
The severe high cholesterol in AGS leads to cholesterol depositions in the skin. In children with Alagille syndrome, spontaneous improvement in bile flow often occurs in children after 3 years of age and this leads to a reduction in lipids and xanthomas.
It is well known that high cholesterol in adults increases the risk of developing heart disease. The impact of high cholesterol in children with Alagille syndrome on their risk of heart attack later in life is not known though it has not been observed to be a problem. Families often ask about putting their children on statin drugs which are used to lower cholesterol in adults. These should be used cautiously because they can cause liver problems.
No. Most children with AGS need to consume high calorie diets to optimize growth and make up for the excess fat lost in their stools. Dietary recommendations for children with AGS will depend on several factors including stage and severity of liver disease and other organ involvements (such as kidney disease). Therefore, specific recommendations should come from your child's physician and/or dietitian. However, because fat is the most concentrated source of calories, it is difficult to consume a high calorie diet that is low in fat and it is not recommended that children with AGS restrict fat. Also a low cholesterol diet is not necessary. People get cholesterol in two ways. The body, mainly the liver, produces varying amounts of cholesterol and foods can also contain cholesterol. Because children with AGS have a problem with their liver, eliminating cholesterol from the diet will not correct the problem.
Reviewed by: Binita M. Kamath, MD
Date: January 2009