Wolman disorder (WD) was first described in Iranian-Jewish (IJ) children, and it is caused by a deficiency of the lysosomal acid lipase (LAL). Newborns with WD are healthy and active at birth but soon develop severe malnutrition symptoms and often die before 1 year. In particular, spleens, livers, bone marrows, intestines, adrenal glands, and lymph nodes accumulate harmful amounts of lipids. G87V mutation in LIPA is responsible for Wolman disorder. Some reports suggest that δ-tocopherol can reduce lipid accumulation in cholesterol storage disorders. Hence, we used δ-tocopherol for the virtual screening process in this study. Initially, the lead compounds were docked with native and G87V mutant LIPA. Subsequently, the ADME and toxicity parameters for screened compounds were determined to ensure the safety profiles. Finally, the molecular dynamics simulations result indicated that dl-alpha-Tocopherol-13C3, a molecule obtained from the PubChem database, is identified as a potential and stable lead molecule that could be effective against the G87V mutant form of LIPA.
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http://dx.doi.org/10.1016/bs.apcsb.2022.10.010 | DOI Listing |
Cureus
November 2024
Pediatrics, "Carol Davila" University of Medicine and Pharmacy, Bucharest, ROU.
Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive genetic disease arising from mutations in the lipase A, lysosomal acid type (LIPA) gene, characterised by the formation of cholesterol esters and triglyceride storages, primarily in the liver and spleen. By analysing the level of lysosomal acid lipase (LAL), two forms were described in the literature: Wolman disease and cholesteryl-ester storage disease (CESD). Wolman disease usually manifests with rapidly progressive symptoms within the first year of life, while CESD is a latent condition, with significant features appearing later in life.
View Article and Find Full Text PDFMol Ther
December 2024
Center for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH 43215, USA; Department of Pediatrics, The Ohio State University School of Medicine, Columbus, OH 43210, USA. Electronic address:
Lysosomal acid lipase deficiency (LAL-D) is caused by mutations in the LIPA gene, which encodes the lysosomal enzyme that hydrolyzes triglycerides and cholesteryl esters to free fatty acids and free cholesterol. The objective of this study was to develop a curative single-treatment therapy for LAL-D using adeno-associated virus (AAV). Treatment at both early (1-2 days) and late (8-week) timepoints with rscAAVrh74.
View Article and Find Full Text PDFInt J Mol Sci
October 2024
Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria.
Lysosomal acid lipase (LAL) is the only known enzyme that degrades cholesteryl esters and triglycerides at an acidic pH. In LAL deficiency (LAL-D), dysregulated expression of matrix metalloproteinase 12 (MMP-12) has been described. The overexpression of MMP-12 in myeloid lineage cells causes an immune cell dysfunction resembling that of knockout ( KO) mice.
View Article and Find Full Text PDFFetal Diagn Ther
October 2024
Division of Ultrasound in ObGyn at Lis Maternity and Women's Hospital, Tel Aviv Medical Center, Tel Aviv, Israel.
Int J Mol Sci
August 2024
Unidade de Genética, Instituto da Criança, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo (FMUSP), Sao Paulo 05403-000, SP, Brazil.
Lysosomal acid lipase deficiency (LALD) varies from a severe infantile-onset form (Wolman disease) to a late-onset form known as cholesteryl ester storage disease (CESD), both of which are autosomal recessive disorders caused by biallelic pathogenic variants. We evaluated seventy-three patients enlisted for liver transplant (LT) at Instituto da Criança (HCFMUSP-Brazil) who were subjected to LAL activity measurement and Sanger sequencing analysis, resulting in a positive LALD diagnosis for only one of these individuals. This LALD patient presented recurrent diarrhea, failure to thrive, hepatomegaly, and dyslipidemia at the age of 4 months and liver failure by the age of 13 years.
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