Lysosomal acid lipase deficiency

Other Names: LAL deficiency; LIPA deficiency

Lysosomal acid lipase deficiency is an inherited condition characterized by problems with the breakdown and use of fats and cholesterol in the body (lipid metabolism). In affected individuals, harmful amounts of fats (lipids) accumulate in cells and tissues throughout the body, which typically causes liver disease. There are two forms of the condition. The most severe and rarest form begins in infancy. The less severe form can begin from childhood to late adulthood.

Wolman disease: The early-onset and most severe form of the disease where lipids accumulate throughout the body, mostly in the liver, within the first weeks of life. Symptoms include an enlarged liver and spleen (hepatosplenomegaly), poor weight gain, a yellowish color of the skin and the whites of the eyes (jaundice), vomiting, diarrhea, fatty stool (steatorrhea), and poor absorption of nutrients from food (malabsorption), as well as calcium deposits in adrenal glands, anemia, liver disease (cirrhosis), and developmental delay. Infants with this form of lysosomal acid lipase deficiency develop failure in multiple organs, and severe malnutrition.

Cholesteryl ester storage disease: Less severe and starting later in life. Symptoms may include hepatosplenomegaly, liver disease (cirrhosis), and malabsorption with diarrhea, vomiting, and steatorrhea.

Cause

Mutations in the LIPA gene cause lysosomal acid lipase deficiency. The LIPA gene provides instructions for producing an enzyme called lysosomal acid lipase. This enzyme is found in cell compartments called lysosomes, which digest and recycle materials the cell no longer needs. The lysosomal acid lipase enzyme breaks down lipids such as cholesteryl esters and triglycerides. The lipids produced through these processes, cholesterol and fatty acids, are used by the body or transported to the liver for removal. Mutations in the LIPA gene lead to a shortage (deficiency) of functional lysosomal acid lipase. Decreased lysosomal acid lipase activity results in the accumulation of cholesteryl esters, triglycerides, and other lipids within lysosomes, causing fat buildup in multiple tissues. The body's inability to produce cholesterol from the breakdown of these lipids leads to an increase in alternative methods of cholesterol production and higher-than-normal levels of cholesterol in the blood. The excess lipids are transported to the liver for removal. Because many of them are not broken down properly, they cannot be removed from the body; instead they accumulate in the liver, resulting in liver disease. The progressive accumulation of lipids in tissues results in organ dysfunction and the signs and symptoms of lysosomal acid lipase deficiency.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Symptoms

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

• Abdominal distention(Abdominal bloating)
• Abdominal pain(Pain in stomach)
• Adrenal calcification
• Elevated alkaline phosphatase(Greatly elevated alkaline phosphatase)
• Elevated hepatic transaminase(High liver enzymes)
• Fatal liver failure in infancy
• Hepatic fibrosis
• Hepatosplenomegaly(Enlarged liver and spleen)
• Hypercholesterolemia(Elevated serum cholesterol)
• Hypertriglyceridemia(Increased plasma triglycerides)
• Jaundice(Yellow skin)
• Microvesicular hepatic steatosis
• Steatorrhea(Fat in feces)
• Vacuolated lymphocytes

Diagnosis

Blood tests may show anaemia and their lipid profiles are generally similar to people with more common familial hypercholesterolemia, including elevated total cholesterol, elevated low-density lipoprotein cholesterol, decreased high-density lipoprotein cholesterol and elevated serum transaminases.

Liver biopsy findings will generally show a bright yellow-orange color, enlarged, lipid-laden hepatocytes and Kupffer cells, microvesicular and macrovesicular steatosis, fibrosis, and cirrhosis.The only definitive tests are genetic, which may be conducted in any number of ways.

Screening

Because LAL deficiency is inherited, each sibling of an affected individual has a 25% chance of having pathological mutations in LAL genes from both their mother and their father, a 50% chance of having a pathological mutation in only one gene, and a 25% chance of having no pathological mutations. Genetic testing for family members and genetic prenatal diagnosis of pregnancies for women who are at increased risk are possible if family members carrying pathological mutations have been identified.

Treatment

LAL deficiency can be treated with sebelipase alfa is a recombinant form of LAL that was approved in 2015 in the US and EU. It is administered once a week via intraveneous infusion in people with rapidly progressing disease in the first six months of life. In people with less aggressive disease, it is given every other week. Statins were used in people with LAL-D prior to the approval of sebelipase alfa; they helped control cholesterol but did not appear to slow liver damage; liver transplantation was necessary in most patients. The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Sebelipase alfa (Brand name: Kanuma) Indicated for the treatment of patients with a diagnosis of lysosomal acid Lipase (LAL) deficiency.

Prognosis

Infants with LAL deficiencies typically show signs of disease in the first weeks of life and if untreated, die within 6–12 months due to multi-organ failure. Older children or adults with LAL-D may remain undiagnosed or be misdiagnosed until they die early from a heart attack or stroke or die suddenly of liver failure. The first enzyme replacement therapy was approved in 2015. In those clinical trials nine infants were followed for one year; 6 of them lived beyond one year. Older children and adults were followed for 36 weeks.

Epidemiology

Depending on ethnicity and geography, prevalence has been estimated to be between 1 in 40,000 and 1 in 300,000; based on these estimates the disease may be underdiagnosed. Jewish infants of Iraqi or Iranian origin appear to be most at risk based on a study of a community in Los Angeles in which there was a prevalence of 1 in 4200.

NIH genetic and rare disease info

• NIH info on Lysosomal acid lipase deficiency

Lysosomal acid lipase deficiency is a rare disease.

Lysosomal acid lipase deficiency Resources
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