Lysosomal acid lipase deficiency

Medical quality assurance by Dr. Albrecht Nonnenmacher, MD at December 29, 2016
StartDiseasesLysosomal acid lipase deficiency

Lysosomal acid lipase deficiency, also known as LAL deficiency, occurs when the body does not produce enough of the enzyme necessary for breaking down certain fats. This can lead to the buildup of fatty substances in the liver, spleen, and blood vessels. This can result in serious digestive problems, liver failure, and other life-threatening health problems. 

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Definition & Facts

The prevalence of LAL deficiency is believed to be somewhere between 1:40,000 and 1:500,000 and can vary based on geography and ethnicity. People of Jewish-Iranian descent may be at greatest risk.

LAL deficiency actually refers to two conditions known as Wolman disease and cholesteryl ester storage disease. Wolman disease presents in infants and is named after Dr. Moshe Wolman who first described the condition in an infant of Persian Jewish origin.

Cholesteryl ester storage disease occurs when a form of cholesterol called cholesteryl esters and triglycerides are stored in blood cell­s, lymph, and lymphatic tissue. This form of the condition is seen in pediatric and adult patients.

Symptoms & Complaints

Infants born with the condition may initially appear healthy but quickly deteriorate within the first few weeks of life. Most infants with Wolman’s disease die by the age of one.

The child will typically have significant gastrointestinal symptoms, including diarrhea, fatty stools, vomiting, and abdominal distention. The liver and spleen are often enlarged (hepatomegaly, splenomegaly, respectively).

Fat buildup in the gut can interfere with the absorption of dietary nutrients, which can lead to growth failure. Children with the condition are often anemic and bruise easily. As liver function deteriorates, the child may develop jaundice, which is characterized by the yellowing of the skin and whites of the eyes (sclera), and the skin may become itchy.

Individuals with cholesteryl ester storage disease may not present with symptoms until their teens or adulthood. In addition to abdominal distention and enlarged liver and spleen, patients with cholesteryl ester storage disease may have high levels of lipids in their blood, which can lead to cardiovascular disease. Patients with cholesteryl ester storage disease often succumb to premature death from heart attacks, strokes, or liver failure.

Causes

LAL deficiency is the result of an inherited genetic disorder. It is caused by a genetic mutation in the LIPA gene that is responsible for lysosomal lipase protein. Under normal circumstances, the protein breaks down the triglycerides and cholesteryl esters found in low-density lipoprotein cholesterol into free fatty acids and free cholesterol that can be reused by the body. Because of the genetic mutation, the cholesteryl esters and triglycerides are allowed to accumulate in various organs.

The condition is autosomal recessive, which means that an affected person receives a copy of the defective gene from each parent. Parents who each have one copy of the gene have a 25 percent chance of having an affected child, a 50 percent chance of having a child who carries the gene but is not affected, and a 25 percent chance of having a child who is not affected or a genetic carrier.

Diagnosis & Tests

The clinical symptoms, rapid deterioration, and failure to thrive seen in infants with Wolman disease may lead a health care provider to suspect LAL deficiency. Late-onset LAL deficiency can be harder to diagnose since many of the symptoms mimic other health conditions. It is not uncommon for patients with late-onset LAL deficiency to go months or even years before receiving an accurate diagnosis.

A physical examination may show signs of jaundice, abdominal distention caused by an accumulation of fluid in the abdominal cavity, and yellowish fat deposits under the skin. The liver and spleen may feel enlarged when palpated.

Blood tests will typically show severe anemia and a lipid profile that includes elevated total cholesterol and low-density lipoprotein cholesterol and decreased high-density lipoprotein cholesterol. Serum transaminases may also be elevated, which is an indication of liver damage.

An ultrasound examination will typically reveal accumulations of chalky materials called calcifications in the adrenal glands. A liver biopsy will often show a wide range of abnormalities, including a bright yellow-orange color, cirrhosis, fibrosis, enlargement of certain liver cells, and significant fat accumulation within the liver tissue.

Treatment & Therapy

There is no cure and only limited treatments available for lysosomal acid lipase deficiency. Until recently, the only treatment options available for infants were focused on reducing complications. This might include changing the infant to a specialized formula that is low in fat, corticosteroids to compensate for decreased adrenal function, antibiotics for opportunistic infections, and intravenous feeding.

Hematopoietic stem cell transplants, also known as bone marrow transplants, have been attempted in some children with LAL deficiency to prevent the progression of the disease; however, this treatment is associated with severe complications and a high rate of mortality.

In older children and adults with LAL deficiency, statins may help lower serum cholesterol levels but do not normally affect the progression of liver disease. Most patients with the disorder will eventually require a liver transplant because of liver failure.

In 2015, an enzyme replacement therapy called sebelipase alfa was approved as an orphan drug for the treatment of LAL deficiency. Sebelipase alfa is a form of the lysosomal acid lipase enzyme produced in the egg whites of genetically modified chickens. The drug is administered by intravenous infusion on a weekly basis during the first 6 months of life in patients with a rapidly progressing form of LAL deficiency. In patients with a less aggressive form of the disease, the infusions are given every other week.

Prevention & Prophylaxis

Since LAL deficiency is the result of an inherited genetic mutation, there is no way to prevent the condition. Even with currently available treatments, the prognosis for patients with the condition is poor.

Genetic testing is available for those at increased risk of being a carrier of the genetic mutation because of a family history of LAL deficiency. Individuals considering genetic testing should speak with a genetic counselor to ensure that they fully understand the potential ramifications of genetic testing and what the results may mean for them and their family.