Wolman disease

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Wolman disease

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.

Genetic profile

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.

Prenatal diagnosis

Couples who have had one child with Wolman disease may be offered prenatal testing in future pregnancies. Prenatal testing is accomplished by measuring acid lipase activity either in cells from a chorionic villus sampling (CVS) at about 10–12 weeks of pregnancy or in amniotic fluid cells obtained by amniocentesis between the sixteenth and eighteenth weeks of pregnancy. Alternatively, if specific gene mutations have been identified in parents because they have already had a affected child, fetal DNA from chorionic villus cells or amniotic fluid cells can be studied to look for these same mutations in the fetus. Carrier couples who are considering prenatal diagnosis should discuss the risks and benefits of this type of testing with a geneticist or genetic counselor.

Treatment and management

There is no specific treatment for Wolman disease. There have been attempts to treat the milder CESD with low-fat diets and cholesterol-lowering drugs, and there has been at least one report of a liver transplant in a patient with CESD. Replacement of the missing enzyme has not been reported.

Prognosis

Infants diagnosed with Wolman disease usually die by six months of age.

Resources

BOOKS

Assmann, G., and U. Seedorf. In The Metabolic & Molecular Bases of Inherited Disease. Edited by C.R. Scriver, et al. New York: McGraw-Hill, 2001.

PERIODICALS

Anderson, R. A., et al. "Lysosomal Acid Lipase Mutations That Determine Phenotype in Wolman and Cholesterol Ester Storage Disease." Molecular and Genetic Metabolism 68, no. 3 (Nov 1999): 333–45.

Krivit, W., et al. "Wolman Disease Successfully Treated by Bone Marrow Transplantation." Bone Marrow Transplant 26, no. 5 (Sept 2000): 567–70.

Lohse, P., et al. "Molecular Defects Underlying Wolman Disease Appear To Be More Heterogeneous Than Those Resulting in Cholesteryl Ester Storage Disease." Journal of Lipid Research 40, no. 2 (Feb 1999): 221–8.

ORGANIZATIONS

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.