Lysosomal acid lipase (LAL) deficiency
- 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) (1)
- is an autosomal recessive lysosomal storage disorder, caused by homozygous or compound heterozygous disease-causing variants in the LIPA gene located on chromosome 10q23.2
- depending on the genetic variant in the LIPA gene and consequently residual lysosomal acid lipase (LAL) activity
- LAL deficiency can result in the very severe, infantile-onset, and lethal form known as Wolman disease, or in the milder, late-onset phenotype, known also as cholesteryl ester storage disease (CESD) (2)
LAL serves as a non-redundant enzyme in hydrolyzing triglycerides and cholesteryl esters in lysosomes (3)
- key mechanism of LAL deficiency involves the progressive accumulation of cholesteryl esters and triglycerides in the lysosomes of hepatocytes and macrophages, thereby inducing organ damage over time
Prevalence of the Wolman disease is estimated at approximately 1/350,000, whereas the prevalence of the CESD is estimated between 1/40,000 and 1/300,000, depending on ethnicity and geographic location (2)
- 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
- NICE have stated that
- Sebelipase alfa is recommended as an option for long-term enzyme replacement therapy in Wolman disease (rapidly progressive lysosomal acid lipase deficiency [LAL deficiency]), only if people are 2 years or under when treatment starts
- hematopoietic stem cell transplantation/liver transplantation in Wolman disease
- hematopoietic stem cell transplantation seems to be a more successful treatment in Wolman disease than liver transplantation, but there are also reports about disease progression and fatal transplant-related complications (2)
- 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 (2)
- 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
- may have a normal life span depending on the severity of disease manifestations
Reference:
- Hoffman EP, Barr ML, Giovanni MA, et al. Lysosomal Acid Lipase Deficiency. 2015 Jul 30 [Updated 2016 Sep 1]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews (R)[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK305870/
- Sustar U, Groselj U, Trebusak Podkrajsek K, Mlinaric M, Kovac J, Thaler M, Drole Torkar A, Skarlovnik A, Battelino T, Hovnik T. Early Discovery of Children With Lysosomal Acid Lipase Deficiency With the Universal Familial Hypercholesterolemia Screening Program. Front Genet. 2022 Jul 12;13:936121. doi: 10.3389/fgene.2022.936121.
- Strebinger G, Müller E, Feldman A, Aigner E. Lysosomal acid lipase deficiency - early diagnosis is the key. Hepat Med. 2019 May 23;11:79-88. doi: 10.2147/HMER.S201630.
- NICE (January 2024). Sebelipase alfa for treating Wolman disease