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Lysosomal acid lipase (LAL), encoded by the LIPA gene (HGNC:6617), hydrolyzes cholesteryl esters and triglycerides in lysosomes. Biallelic loss‐of‐function variants in LIPA underlie Wolman disease (MONDO:0019148), a rapidly progressive autosomal recessive disorder characterized by absent LAL activity and infantile‐onset multi‐organ failure. Patients present within the first months of life with failure to thrive, chronic diarrhea, adrenal calcifications, and massive hepatosplenomegaly.
Genetic evidence for LIPA–Wolman disease is robust and consistent with autosomal recessive inheritance. Over 50 independent infantile‐onset cases have been reported, including homozygosity for canonical splice‐site and nonsense variants, and compound heterozygosity across at least 15 unrelated families ([PMID:8864960], [PMID:8617513]). Segregation of biallelic null alleles with disease in multiple pedigrees confirms complete penetrance in homozygotes.
The LIPA variant spectrum in Wolman disease comprises nonsense (e.g., c.892C>T (p.Gln298Ter)), frameshift, and donor‐site mutations that abolish enzyme activity. The recurrent splice‐donor mutation c.894+1G>A (+1 donor) leads to complete exon 8 skipping and inactive protein ([PMID:8617513]). The c.892C>T (p.Gln298Ter) truncation has been identified homozygously in African kindreds, yielding no residual LAL activity and a uniformly lethal infantile phenotype ([PMID:8864960]). Founder mutations such as c.966+2T>G account for 75% of Wolman alleles in certain populations ([PMID:28220406]).
Functional assays across multiple studies demonstrate that null LIPA alleles produce inactive protein. Expression of mutant cDNAs in insect and mammalian cells shows complete loss of cholesteryl ester hydrolysis for splice (+1 donor) and nonsense variants ([PMID:8617513], [PMID:7499245]). Site‐directed mutagenesis of key catalytic residues further confirms that absence of a functional active‐site serine or complete exon loss is the mechanism of pathogenicity.
Clinically, infants with Wolman disease present with profound malabsorption, adrenal calcifications, severe hepatosplenomegaly, and rapid progression to liver and adrenal failure. Enzyme activity assays in fibroblasts or leukocytes reveal undetectable LAL levels. Early initiation of sebelipase alfa enzyme‐replacement therapy has improved survival beyond infancy in recent cohorts ([PMID:34906190]).
The association between LIPA and Wolman disease meets ClinGen criteria for a Definitive gene–disease relationship, based on >50 probands, multi‐family segregation, and concordant functional data. Genetic evidence is Strong (biallelic null variants in >30 unrelated cases) and experimental evidence is Moderate (in vitro assays demonstrating abolished enzyme activity). Early molecular diagnosis facilitates prompt enzyme‐replacement therapy, substantially altering the historically fatal course of Wolman disease.
Key Take-home: Biallelic loss‐of‐function variants in LIPA cause infantile‐onset Wolman disease; early genetic testing is critical to identify candidates for lifesaving enzyme replacement.
Gene–Disease AssociationDefinitive
Genetic EvidenceStrongAutosomal recessive inheritance; >30 pathogenic variants across ≥15 unrelated families Functional EvidenceModerateIn vitro expression assays show abolished LAL activity for null alleles and splice defects |