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|Classification and external resources|
Wolman disease (also known as Wolman’s disease or early onset lysosomal acid lipase deficiency is a rare genetic disorder caused by a deficiency of an enzyme known as lysosomal acid lipase (LAL or LIPA). This enzyme is necessary to break down certain lipids inside the cells. Deficiency of the LAL/LIPA enzyme causes a build-up of fat in the liver, gut and other parts of the body.
What causes Wolman disease? Every person has two copies of the LAL gene (sometimes known as the LIPA gene). One copy is inherited from the father and one from the mother. LAL Deficiency occurs when a person has defects (mutations) in both copies of the LAL gene. Each parent of a patient with LAL deficiency carries one copy of the defective LAL gene. With every pregnancy, parents with a son or daughter affected by LAL Deficiency have a 1 in 4 (25%) chance of having another affected child. A person born with defects in both LAL genes is not able to produce adequate amounts of the LAL enzyme.
Lysosomes function as recycling centers within cells breaking down unwanted materials into substances that the cells can reuse. The LAL enzyme is responsible for the breakdown of specific fats within the lysosomes. When the lysosome does not have enough LAL enzyme, it is unable to break down these fats.
How common is Wolman disease? Like many rare diseases, Wolman disease may go undiagnosed or misdiagnosed which means that there is not much information in the medical literature about how common this condition is. Wolman disease affects males and females in equal numbers. In one report, 8 cases of Wolman disease were identified out more than 4.2 million births over the 16-year period. This translates to an incidence around 1 case per 500,000 live births. For a country the size of the United States, this means there may be 8 babies with Wolman disease born each year.
Are there any specific populations that get Wolman disease more frequently than others? Because Wolman disease is autosomal recessive, it is expected to occur at higher frequencies in certain populations where marriages between genetically related individuals occur (consanguinity). A higher frequency of an abnormal LAL gene has been recently described in the Iranian-Jewish population.
A diagnosis of Wolman disease may be suspected in newborn infants based upon identification of characteristic symptoms such as abnormally enlarged liver and gastrointestinal problems.
The signs and symptoms of Wolman disease usually appear shortly after birth, typically in the first few weeks of life. Affected infants may have the following:
The accumulation of fat in the walls of the gut in Wolman disease leads to serious digestive problems including malabsorption, a condition in which the gut fails to absorb nutrients and calories from food. The malabsorption associated with Wolman disease is often accompanied by persistent and often forceful vomiting, frequent diarrhea, foul-smelling and fatty stools (steatorrhea). Because of these digestive complications, affected infants usually fail to grow and gain weight at the expected rate for their age (failure to thrive).
As the disease progresses, increasing fat accumulation in the liver leads to other complications including yellowing of the skin and whites of the eyes (jaundice), and a persistent low-grade fever.
The complications of Wolman disease progress over time, eventually leading to life-threatening problems such as extremely low levels of circulating red blood cells (severe anemia), liver dysfunction or failure, and physical wasting (cachexia). Very few infants with Wolman disease survive beyond the first year of life.
There are currently no approved treatments for Wolman disease and no treatments have been shown in clinical trials to stop or reverse the abnormalities in patients with Wolman disease.
Treatment is mainly focused on reducing specific complications and these complications may differ between patients. Treatment is often provided in specialized centers and may require input from a team of different specialists. Genetic counseling may be of benefit for affected individuals and their families. Specific interventions may include:
Some children with Wolman disease have had an experimental therapy called hematopoietic stem cell transplantation (HSCT), also known as bone marrow transplant, to try to prevent the disease from getting worse.
Researchers are currently studying enzyme replacement therapy for LSDs such as Wolman disease. Enzyme replacement therapy involves replacing a missing enzyme in individuals who are deficient or lack the particular enzyme in question. Synthetic versions of missing enzymes have been developed and used to successfully treat individuals with other LSDs including Fabry disease and Gaucher disease.
Gene therapy is also being studied as another possible approach to therapy for some LSDs. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the production of active enzyme and prevent the development and progression of the disease in question. Given the permanent transfer of the normal gene, which is able to produce active enzyme at all sites of disease, this form of therapy is theoretically most likely to lead to a "cure." However, at this time, there are many technical difficulties to resolve before gene therapy can succeed.
Synageva BioPharma Corp. of Lexington, Massachusetts, is recruiting patients to participate in a clinical trial that evaluates an enzyme replacement therapy of Lysosomal Acid Lipase (LAL) Deficiency.