Lysosomal acid lipase deficiency (ORPHA:275761)
A rare, progressive metabolic liver disease due to marked to complete lysosomal acid lipase deficiency and characterized by dyslipidemia and massive lipid accumulation leading to hepatomegaly and liver dysfunction, splenomegaly, accelerated atherosclerosis.
Epidemiology
Based on allele frequency, worldwide birth prevalence is estimated at 1/177,000; however, birth prevalence is lower in populations with Finnish, Ashkenazi Jewish, and South or East Asian ancestry.
Clinical description
Presentation is along a clinical continuum with variable rates of progression and severity. The early-onset, rapidly progressive form, Wolman disease, presents in the neonatal or infantile period with non-specific symptoms of massive hepatosplenomegaly, liver failure, diarrhea/steatorrhea and vomiting, resulting in malabsorption, and cachexia. Adrenal calcifications occur in approximately half of infants. The later onset form, cholesteryl ester storage disease (CESD), presents between childhood and adulthood with a more variable clinical course that ranges from insidious to symptomatic. Progressive lysosomal lipid accumulation leads to the characteristic liver pathology and dysfunction (including hepatomegaly, liver fibrosis and/or cirrhosis, and elevated serum transaminases), dyslipidemia (elevated serum LDL-cholesterol and triglycerides, with normal to low HDL-cholesterol concentrations), premature atherosclerosis, splenomegaly and, eventually, end-stage liver failure. Secondary complications are variable and may include portal hypertension, ascites, cachexia, esophageal varices, gastrointestinal bleeding, coronary artery disease, aneurysm, stroke, anemia and thrombocytopenia. Approximately one-third of children experience severe gastrointestinal symptoms, including frequent diarrhoea, vomiting, abdominal pain, malabsorption and steatorrhoea.
Etiology
The disease is due to mutations in the gene LIPA (10q23.2-q23.3) encoding the enzyme lysosomal acid lipase (LAL). LAL hydrolyzes cholesteryl esters and triglycerides, and thus LAL deficiency results in gradual accumulation of these lipids in the liver, spleen, and other organs. The variable phenotype is due to the amount of residual LAL activity, less than 1% for Wolman disease and between 1-12% for CESD.
Diagnostic methods
The disease is suspected on clinical presentation of hepatomegaly, elevated transaminases, total cholesterol, low-density lipoprotein, and triglycerides, and low high-density lipoprotein. Liver biopsy shows microvesicular steatosis and/or fibrosis or cirrhosis. Immunostaining for lysosomal fat accumulation may facilitate diagnosis. Confirmation is by assessment of LAL activity on dry blood spot testing or in leukocytes and/or presence of a LIPA gene mutation.
Differential diagnosis
Differential diagnosis includes familial hypercholesterolemia, non-alcoholic fatty liver disease, cryptogenic cirrhosis, and combined hyperlipidemia, as well as other lysosomal storage disorders.
Antenatal diagnosis
Prenatal molecular genetic testing is possible in affected families.
Genetic counseling
The pattern of inheritance is autosomal recessive and genetic counseling is recommended. The sibling recurrence risk is 25%.
Management and treatment
Supportive measures include statins and cholestyramine to cholesterol, and liver transplant for end-stage liver failure. Patients should follow a diet low in cholesterol and triglycerides, and nutritional status should be monitored. Magnetic resonance imaging to assess liver and spleen volumes may be useful. Enzyme replacement therapy (ERT) with the enzyme sebelipase alfa (authorized in Europe and the US) is available; however, the long-term clinical efficacy is yet to be determined. In infants with severe disease, ERT improves 1-year survival rates. In patients with later-onset disease, ERT reduces alanine aminotransferase levels and liver fat content, and improves the lipid parameters. Anemia and thrombocytopenia should be treated with standard approaches.
Prognosis
In Wolman disease, patients rarely survive beyond infancy. In CESD, the prognosis and life expectancy is variable depending on the severity of the disease and timely diagnosis. The long-term prognosis with ERT is, as yet, unknown.

                            Last update: 
                            April 2020


                            - Expert reviewer(s): 
                            Dr Barbara BURTON