Lysosomal Acid Lipase Deficiency
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|Lysosomal acid lipase deficiency|
|Classification and external resources|
Lysosomal acid lipase deficiency (or LAL deficiency) happens when the body does not produce enough active lysosomal acid lipase (LAL or LIPA) enzyme. This enzyme plays an important role in breaking down fatty material (cholesteryl esters and triglycerides) in the body. Infants, children and adults that suffer from LAL Deficiency experience a range of serious health problems. The lack of the LAL enzyme can lead to a build-up of fatty material in a number of body organs including the liver, spleen, gut, in the wall of blood vessels and other important organs.
Very low levels of the LAL enzyme lead to early onset LAL Deficiency, sometimes called Wolman disease after the physician who first described it. Early onset LAL Deficiency typically affects infants in the first year of life. The accumulation of fat in the walls of the gut in early onset disease leads to serious digestive problems including malabsorption, a condition in which the gut fails to absorb nutrients and calories from food. 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, other complications develop including increasing liver dysfunction or liver failure. Very few infants with Wolman disease survive beyond the first year of life.
Late onset LAL Deficiency is sometimes called Cholesteryl ester storage disease (CESD) and can affect children and adults. The deficiency of the LAL enzyme leads to a build-up of fat in the liver, spleen and other parts of the body. The build-up of fat in the liver and spleen can cause many problems including:
- Swelling of the liver (‘fatty’ liver or hepatomegaly)
- Abnormal liver tests (high AST or ALT)
- Scarring of the liver (liver fibrosis or cirrhosis)
- Swelling of the spleen (splenomegaly)
Infants, children and adults are at risk for significant health problems and premature death from complications due to LAL Deficiency.
Lysosomes are found in the body’s cells and play an important role in digesting nutrients and other materials. Lysosomal Storage Disorders (LSDs) are inherited conditions in which one or more of the enzymes in lysosomes is missing or not functioning effectively. When this happens, materials that would normally be broken down by the lysosome accumulate and this disturbs normal cell function.
Inheritance and diagnosis
LAL Deficiency is an inherited condition. The gene that is responsible for telling the body how to make the LAL enzymes is not normal, and the LAL enzyme either does not work properly or is not made at all.
Every person has two copies of the LAL gene. One copy is inherited from the father and one from the mother. LAL Deficiency occurs when a person has defects in both copies of the LAL gene. Each parent of a patient with LAL deficiency carries one 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.
As is the cases for many rare diseases, making a diagnosis of LAL Deficiency is highly dependent on a physician's awareness of the disease. LAL Deficiency is so rare that many physicians have not had any previous experience with this condition. The diagnosis of LAL Deficiency by your physician begins with an examination, interview, history and preliminary lab tests. The physician makes observations about the symptoms and other risk factors to identify a suspected diagnosis.
Abnormalities that a person may have, and would make the doctor think of late onset LAL Deficiency (Cholesteryl Ester Storage Disease) include:
- A high cholesterol and high triglyceride level
- A high 'bad' cholesterol (Low-density lipoprotein, or LDL)
- A very low (<10mgdl) 'good' cholesterol (HDL)
- Unexplained hepatomegaly (liver enlargement)
- Elevated liver enzymes (a marker of liver damage)
- Unexplained fat or lipid material in the liver
- Unexplained chronic liver disease that may be getting worse over time
Abnormalities that a child may have and that would make a doctor think of early onset LAL Deficiency (Wolman Disease) include:
- Feeding difficulties with frequent vomiting
- Diarrhea (loose frequent stools)
- Swelling of the abdomen (abdominal distention)
- Enlargement of the liver and spleen (hepatosplenomegaly)
- Failure to gain weight or sometimes weight loss
Once the physician thinks about the possibility of LAL Deficiency as a cause of the medical problems, he or she may order a confirmatory test such as an enzyme assay that measures the level and activity of the enzyme or a genetic sequencing analysis.
While there are no currently approved treatments for LAL Deficiency, sebelipase alfa is an investigational recombinant form of the human LAL enzyme being developed by Synageva BioPharma as an enzyme replacement therapy for LAL D. It has been granted orphan designation by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Japanese Ministry of Health, Labour and Welfare. Additionally, sebelipase alfa received Fast Track designation by the U.S. FDA, and Breakthrough Therapy designation by the U.S. FDA for LAL D presenting in infants.
However, to date, for early onset LAL Deficiency (Wolman Disease), no treatments have been shown in clinical trials to stop or reverse the abnormalities in these patients. Beyond enzyme replacement, a variety of supportive therapies are used to try to reduce specific complications. These interventions do not, however, change the poor outlook. In the absence of other treatments, bone marrow transplantation is being used on an experimental basis but has a very high mortality rate.
No treatments have been proven to stop or reverse the liver abnormalities in children and adults with late onset LAL Deficiency (CESD). The high blood lipid levels are treated with a combination of low-fat diet and lipid-lowering medications such as statins, fibrates, cholestyramine and ezetimibe. Although these treatments can lower the blood lipid levels, there is no evidence that they improve the underlying disease including the severe liver manifestations.
- National Organization for Rare Disorders (NORD)
- Hide & Seek Foundation For Lysosomal Disease Research
- LAL Solace (Support Organization for LAL Deficiency - Advocacy, Care and Expertise)
- Article - LYSOSOMAL ACID LIPASE/NIH.gov
- Article - LYSOSOMAL ACID LIPASE DEFICIENCY/NIH.gov
- Peter J. Meikle; John J. Hopwood; Alan E. Clague; et al. "Prevalence of Lysosomal Storage Disorders." JAMA, 1999; 281(3): 249-254
- W.C. Marshall; B.G. Ockenden, A.S. Fosbrooke, and J.N. Cumings. "Wolman's Disease. A Rare Lipidosis with Adrenal Calcification." Arch. Dis. Childh., 1969; 44, 331.
- Allen C. Crocker, Gordon F. Vawter, Edward B.D. Neuhauser and Andre Rosowsky. "Wolman's Disease: Three New Patients with a Recently Described Lipidosis." Pediatrics, 1965; 35; 627-640
- Sandro Muntoni, Heiko Wiebusch, Marianne Jansen-Rust, Stephan Rust, Udo Seedorf, et al.; "Prevalence of Cholesteryl Ester Storage Disease." Journal of the American Heart Association, Arterioscler. Thromb. Vasc. Biol., 2007; 27; 1866-1868