Wolman disease Health Article

Definition

Wolman disease is a rare inherited defect in the body's metabolism of fats (lipids).

Description

Wolman disease, also known as lysosomal acid lipase disease, is a lethal genetic disorder caused by the lack of the enzyme lysosomal acid lipase. Lysosomal acid lipase is a cellular enzyme widespread throughout the body. It is important in the breakdown of certain body lipids called triglycerides and cholesteryl esters. Individuals without active enzyme accumulate abnormally large amounts of these lipids in their cells. This build-up interferes with the normal metabolic functions of the cells and leads to severe neurological and physical symptoms and early death. A milder disease, cholesteryl ester storage disease (CESD), is caused by mutations in the same gene, but affected individuals may not show symptoms until adulthood.

Inheritance pattern

Wolman disease is an autosomal recessive disorder affecting both males and females. In individuals with this disorder, both copies of the gene that codes for lysosomal acid lipase are abnormal. Both parents of an affected child have one abnormal copy of the gene, but usually do not show symptoms because they also have one normal copy. The normal copy provides approximately 50% of the usual enzyme activity, a level adequate for the body's needs. Individuals with one abnormal copy of the gene and 50% enzyme activity are said to be carriers or heterozygotes. Because both parents of a child with Wolman disease are carriers, they have a 25% risk in each subsequent pregnancy of having another child who is affected with the same disorder.

Gene location

The gene for acid lipase is located on the long arm of chromosome 10 at 10q23.2-q23.3. A number of different types of mutations in this gene, all resulting in a lack of enzyme function, have been identified in patients diagnosed with Wolman disease. These include deletions of small portions of the gene, as well as changes in specific nucleotides, the building blocks of the gene. The different mutations may explain why symptoms vary from one individual to another. However, the presence of variability in symptoms even among siblings who have inherited the same mutations from their parents, suggests there may be other, as yet unknown, genetic or environmental factors that affect the severity of the disease. Milder forms, such as the related disorder CESD, appear to be associated with gene mutations that result in only partial loss of enzyme function.

Demographics

In the general population, Wolman disease is exceedingly rare, with approximately 50 or fewer well-described cases to date (2000). CESD is thought to be more common. Individuals with Wolman disease have been reported in various parts of the world including Western Europe, North America, Iraq, Iran, Israel, China, and Japan.

Signs and symptoms

Symptoms of Wolman disease appear in the first few weeks of life. Forceful vomiting and distention of the abdomen usually alert parents to a problem. Other general symptoms in the early stages of this disease are watery diarrhea or fat in the stools, fever, and a yellow tint to the skin (jaundice). Medical examination reveals massive enlargement of the liver and spleen (hepatosplenomegaly) due to a build-up of fats that cannot be broken down. Other common findings are severe anemia, calcium deposits in the adrenal glands, and a general decline in mental development.

Diagnosis

Diagnosis can be difficult because there are no general laboratory tests that point specifically to Wolman disease. Infants with hepatosplenomegaly and evidence of malnutrition should have a careful neurological examination and x rays of the abdomen to check for calcium deposits in the adrenal glands. If Wolman disease is suspected on the basis of these tests, acid lipase activity can be measured in the laboratory using white blood cells or skin cells. An absence of acid lipase activity confirms the diagnosis.

Carrier testing

Individuals suspected of being a carrier of Wolman disease can be confirmed by measuring acid lipase activity in their white blood cells. Carriers will typically demonstrate 50% of normal enzyme activity.

Mutation detection

Specific DNA tests that check for changes in the normal sequence of nucleotides in the acid lipase gene can usually detect the particular gene mutation in an affected individual or carrier. This type of test is only available in a few, very specialized DNA laboratories.