Lysosomal Acid Lipase (LAL) Deficiency
Information for Patients and Families:
What is a lysosomal storage disease?
How does a person get LAL deficiency?
How is LAL deficiency diagnosed?
How is LAL deficiency treated?
Patients and Families: Click here if you would like to speak to someone at Synageva regarding LAL deficiency
What is a lysosomal storage disease?
Lysosomes are structures found in nearly every cell in the body. They contain over 50 enzymes that help digest and recycle nutrients and other materials. Lysosomal storage diseases (LSDs) are inherited conditions in which one or more of the enzymes are either missing or do not function effectively. As a result, the lysosomes are not able to perform their natural function and a variety of materials inappropriately accumulate in cells.
LAL deficiency is a single disease that can result in a range of significant health problems and can present from infancy through adulthood. It is a lysosomal storage disease (LSD) caused by a deficiency or reduced activity of the enzyme, lysosomal acid lipase. This results in the inability of the lysosome to breakdown cholesteryl esters and triglycerides. It leads to a massive build-up of these molecules in tissues throughout the body, and a marked disturbance in the bodies’ ability to regulate cholesterol and lipid metabolism.
As with many of the other LSDs, the severity of LAL disease is thought to be generally related to the amount of remaining LAL enzyme activity the affected individual has (although this is not an exact correlation, since there are likely other factors involved). Individuals with extremely low levels of LAL enzyme activity present in infancy – this is sometimes called Wolman disease, after the physician who first described it. When LAL deficiency presents in infancy, it has a rapidly progressive and fatal disease course during which infants develop severe malabsorption, steatorrhea (fatty stool) and profound weight loss, failure to thrive, portal hypertension (high blood pressure in the liver), calcium deposits in the adrenal glands, and liver failure. These individuals usually die in the first year of life from complications of the disease.
Individuals who still have low to moderate LAL enzyme activity present early in childhood or as adults (this is sometimes called cholesteryl ester storage disease or CESD) with a significant enlargement of the liver, early death of liver cells associated with abnormal liver function tests, liver fibrosis (scarring) that can progress to liver failure, increased lipids in the blood, and aggressive, early onset atherosclerosis (hardening of the arteries). This presentation is more variable meaning that some patients may have somewhat less severe disease while many others suffer significant ill health and die prematurely from complications of the disease.
How does a person get LAL deficiency?
LAL deficiency is an inherited condition that affects both men and women. Inherited conditions develop because of an abnormality in the genes in a person’s body. Genes are responsible for telling the body how to make certain proteins. If the gene is abnormal, the protein is either not made, or is made in a way that it does not work properly.
We all inherit 2 copies of each gene – one copy from our mother and the other from our father. In LAL deficiency, a person must inherit two copies of the abnormal gene in order to have the disease. This means that the parents of a person with LAL deficiency each have one copy of the abnormal gene for LAL. Having one copy of the abnormal gene means that the parents typically don’t have the disease symptoms, but they do “carry” the abnormal gene in their DNA (this is called asymptomatic carriers). When both parents are asymptomatic carriers, there is a 25% chance with each pregnancy that their child will have LAL deficiency.
How is LAL deficiency diagnosed?
The diagnosis of LAL deficiency begins with physician examination and interview, history and differential diagnosis and is confirmed using a test called an enzyme assay that measures the activity of the enzyme. The diagnosis can be made if the assay measures a low level of activity of the enzyme in any cell in the body that has a nucleus. This is usually done by taking a blood sample and testing white blood cells, or by taking a skin biopsy and testing fibroblast cells.
Once the diagnosis is made, further tests can be done to understand the exact genetic mutation. This information may be useful for prenatal testing with future pregnancies, and for testing of other family members that may have the disease or be carriers.
How is LAL deficiency treated?
There are currently no specific treatments proven to slow the progression of LAL deficiency. For infants who have the most aggressive disease (sometimes called Wolman disease), treatment is mostly supportive in terms of providing nutrition through a naso-gastric tube or directly through the veins. In some situations medications can be provided to help with function of the adrenal glands. Bone marrow transplant is experimental and has been attempted with varying degrees of success.
For adults, lipid lowering therapy can help reduce cholesterol but has not been shown to improve the underlying disease or the severe liver manifestations.