Lysosomal Acid Lipase Deficiency

Clinical characteristics: The phenotypic spectrum of lysosomal acid lipase (LAL) deficiency ranges from the infantile-onset form (Wolman disease) to later-onset forms collectively known as cholesterol ester storage disease (CESD).

Wolman disease is characterized by infantile-onset malabsorption that results in malnutrition, storage of cholesterol esters and triglycerides in hepatic macrophages that results in hepatomegaly and liver disease, and adrenal gland calcification that results in adrenal cortical insufficiency. Unless successfully treated with hematopoietic stem cell transplantation (HSCT), infants with classic Wolman disease do not survive beyond age one year.

CESD may present in childhood in a manner similar to Wolman disease or later in life with such findings as serum lipid abnormalities, hepatosplenomegaly, and/or elevated liver enzymes long before a diagnosis is made. The morbidity of late-onset CESD results from atherosclerosis (coronary artery disease, stroke), liver disease (e.g., altered liver function ± jaundice, steatosis, fibrosis, cirrhosis and related complications of esophageal varices, and/or liver failure), complications of secondary hypersplenism (i.e., anemia and/or thrombocytopenia), and/or malabsorption. Individuals with CESD may have a normal life span depending on the severity of disease manifestations.

Diagnosis/testing: Diagnosis of LAL deficiency is suspected in individuals with characteristic clinical findings such as hepatomegaly, elevated transaminases, and a typical serum lipid profile: high total serum concentrations of cholesterol, low-density lipoprotein, and triglycerides; and low serum concentration of high-density lipoprotein. The diagnosis is confirmed by identification of either biallelic pathogenic variants in LIPA or deficient LAL enzyme activity in peripheral blood leukocytes, fibroblasts, or dried blood spots.

Management: Treatment of manifestations:

1. Both Wolman disease and CESD: Enzyme replacement therapy (ERT) with sebelipase alfa was recently approved by the FDA and is administered at a dose of 1 mg/kg body weight every other week; this treatment can be life saving for those with severe Wolman syndrome and life improving with prolonged survival in those who have CESD. Consider referral to a liver specialist. Liver transplantation may be indicated when liver disease progresses to cirrhosis and liver failure.

2. Wolman disease: Consultation with a nutrition team to limit malnutrition if possible, including use of parenteral nutrition; corticosteroid and mineralocorticoid replacement in the presence of adrenal insufficiency.

3. CESD: Reduce cholesterol through the use of statins, cholestyramine, and a diet low in cholesterol and triglycerides. Aggressive reduction of additional cardiovascular risk factors and lipophilic vitamins may also be beneficial. Consult with a nutrition team for children with failure to thrive or adults with weight loss.

Prevention of primary manifestations: Successful hematopoietic stem cell transplantation can correct the metabolic defect.

Prevention of secondary complications: Use nonspecific beta-blockers in those with esophageal varices to reduce the risk of bleeding.

Surveillance: No standard guidelines for surveillance of CESD have been developed.

1. For children: Monitor growth and nutritional status; evaluate fasting lipid levels, platelet count, and liver enzymes every six months.

2. For adults: reevaluate every 6-12 months depending on disease severity. Monitor nutritional status. Evaluate fasting lipid levels, platelet count, and liver enzymes routinely. Evaluate those with severe liver disease for esophageal varices by upper endoscopy every three years. Monitor and treat those with hepatosplenomegaly thrombocytopenia to prevent bleeding complications.

3. For children and adults: monitor hepatosplenic volume and screen for hepatocellular carcinoma with serial liver and spleen imaging.

Agents/circumstances to avoid: In the presence of thrombocytopenia avoid use of nonsteroidal anti-inflammatory drugs.

Evaluation of relatives at risk: It is appropriate to evaluate the sibs of a proband in order to identify those who would benefit from early treatment and surveillance.

Genetic counseling: LAL deficiency is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing of a pregnancy at increased risk are possible if the LIPA pathogenic variants in the family have been identified.