Alagille syndrome pathophysiology

Overview
Alagille syndrome is a multisystem genetic disorder that affects the liver, heart, eyes,face, skeleton, kidneys and vascular system.

Pathophysiology
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.

Approximately 30-50% of individuals have an inherited mutation and about 50-70% have a de novo mutation. The parents of a child with a de novo mutation have increased risk for recurrence because of the possibility of germline mosaicism. The offspring of an individual with Alagille syndrome have a 50% chance of having Alagille syndrome.

Mutations in the JAG1 gene cause Alagille syndrome. The JAG1 gene is involved in signaling between adjacent cells during embryonic development. This signaling influences how the cells are used to build body structures in the developing embryo. Mutations in JAG1 disrupt the signaling pathway, causing errors in development, especially of the heart, bile ducts in the liver, spinal column, and certain facial features.

NOTCH2 is also associated with Alagille syndrome.

Narrowed and malformed bile ducts in the liver produce many of the health problems associated with Alagille syndrome. Bile is produced in the liver and moves through the bile ducts into the small intestine, where it helps to digest fat. In Alagille syndrome, the bile builds up in the liver and causes scarring that prevents the liver from working properly to eliminate wastes from the bloodstream.

Children with Alagille syndrome may be at risk for pathologic fractures, which manifest at an early age and in a unique distribution favoring the lower extremity long bones.

The cerebral vasculopathy of Alagille syndrome predominantly involves the internal carotid arteries. It is more prevalent than would be suggested by the number of symptomatic individuals, appears to be progressive and shares many similarities with moyamoya. Magnetic resonance imaging with angiography is useful to detect these lesions and may have a valuable role in screening for treatable lesions such as aneurysms.