Submission Details

LIPA was first reported in relation to lysosomal acid lipase deficiency, an autosomal recessive lysosomal storage disorder, in 1993 (Klima H et al., PMID: 8254026). LIPA encodes a hydrolase, lysosomal acid lipase A (LAL), involved in the degradation of lysosomal cholesterol esters and triglycerides. Deficiency of LAL results in accumulation of cholesterol esters and triglycerides predominantly in the liver, spleen, adrenals, bone marrow, lymph nodes, and in macrophages throughout the body, particularly in the intestinal villi. Therefore, deficiency of LIPA is expected to result in reduced LAL activity which causes various symptoms such as hepatosplenomegaly, dyslipidemia, and liver failure. Lysosomal acid lipase deficiency has a phenotypic continuum and can be divided into two clinical phenotypes: infantile-onset Wolman disease and later-onset cholesterol ester storage disease. The diagnosis of lysosomal acid lipase deficiency 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 (Hoffman et al., 2015, PMID: 26225414).

Seven variants (1 frameshift, 2 splice site, 2 nonsense, 2 synonymous) that have been reported in seven probands across four publications (Bychkov IO, et al., 2019, PMID: 31230978; Fasano T, et al., 2012, PMID: 22227072; Aslanidis C, et al., 1996, PMID: 8617513; Lin P, et al., 2015, PMID: 25722898) are included in this curation. Individuals with significantly decreased enzyme activity (≤5% of controls) typically have the infantile phenotype, whereas individuals with less severely reduced residual enzymatic activity (2%-11% of controls) typically have the later-onset phenotype (Fasano T, et al., 2012, PMID: 22227072). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is loss of function.

This gene-disease relationship is also supported by experimental evidence including biochemical function of the LAL enzyme, animal models systems, rescue in animal models, and rescue in humans. Individuals with LAL deficiency show accumulation of cholesterol esters and triglycerides in the liver and spleen due to reduced or undetectable levels of LAL activity (Fasano T, et al., 2012, PMID: 22227072). LAL knockout mouse models exhibit loss of enzyme activity, massive accumulation of triglycerides and cholesteryl esters in several organs, and hepatomegaly which recapitulates the phenotype in humans with LAL deficiency (Du H, et al., 1998, PMID: 9700186). Gene therapy in mice dramatically lowered hepatosplenomegaly, liver and spleen triglyceride and cholesterol levels, and serum expression of markers of liver damage. Measures of liver inflammation and fibrosis were also reduced, and decreased LAL activity was corrected (Lam P, et al., 2022, PMID: 36092360). Enzyme therapy in mice with recombinant human LAL resulted in a significant improvement in organ size and tissue histology as well as significant decreases in cholesterol esters and triglycerides, extended life spans, and diminished liver fibrosis and macrophage proliferation (Sun Y, et al., 2014, PMID: 24837159). Long-term sebelipase alfa treatment in humans has been generally well-tolerated and has provided multiple benefits for patients with LAL deficiency including improvements in liver and lipid parameters, and liver histology was mostly stable or improved from baseline with treatment (Burton BK, et al., 2022, PMID: 34774639).

In summary, LIPA is definitively associated with lysosomal acid lipase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Classification approved by the ClinGen Lysosomal Diseases GCEP on April 28, 2023.

Addendum: The original MONDO ID used for this curation, MONDO:0010204, was obsoleted and was replaced by the current MONDO ID, MONDO:0800449, on July 2, 2025. No other details were changed.

LIPA was first reported in relation to lysosomal acid lipase deficiency, an autosomal recessive lysosomal storage disorder, in 1993 (Klima H et al., PMID: 8254026). LIPA encodes a hydrolase, lysosomal acid lipase A (LAL), involved in the degradation of lysosomal cholesterol esters and triglycerides. Deficiency of LAL results in accumulation of cholesterol esters and triglycerides predominantly in the liver, spleen, adrenals, bone marrow, lymph nodes, and in macrophages throughout the body, particularly in the intestinal villi. Therefore, deficiency of LIPA is expected to result in reduced LAL activity which causes various symptoms such as hepatosplenomegaly, dyslipidemia, and liver failure. Lysosomal acid lipase deficiency has a phenotypic continuum and can be divided into two clinical phenotypes: infantile-onset Wolman disease and later-onset cholesterol ester storage disease. The diagnosis of lysosomal acid lipase deficiency 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 (Hoffman et al., 2015, PMID: 26225414).

Seven variants (1 frameshift, 2 splice site, 2 nonsense, 2 synonymous) that have been reported in seven probands across four publications (Bychkov IO, et al., 2019, PMID: 31230978; Fasano T, et al., 2012, PMID: 22227072; Aslanidis C, et al., 1996, PMID: 8617513; Lin P, et al., 2015, PMID: 25722898) are included in this curation. Individuals with significantly decreased enzyme activity (≤5% of controls) typically have the infantile phenotype, whereas individuals with less severely reduced residual enzymatic activity (2%-11% of controls) typically have the later-onset phenotype (Fasano T, et al., 2012, PMID: 22227072). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is loss of function.

This gene-disease relationship is also supported by experimental evidence including biochemical function of the LAL enzyme, animal models systems, rescue in animal models, and rescue in humans. Individuals with LAL deficiency show accumulation of cholesterol esters and triglycerides in the liver and spleen due to reduced or undetectable levels of LAL activity (Fasano T, et al., 2012, PMID: 22227072). LAL knockout mouse models exhibit loss of enzyme activity, massive accumulation of triglycerides and cholesteryl esters in several organs, and hepatomegaly which recapitulates the phenotype in humans with LAL deficiency (Du H, et al., 1998, PMID: 9700186). Gene therapy in mice dramatically lowered hepatosplenomegaly, liver and spleen triglyceride and cholesterol levels, and serum expression of markers of liver damage. Measures of liver inflammation and fibrosis were also reduced, and decreased LAL activity was corrected (Lam P, et al., 2022, PMID: 36092360). Enzyme therapy in mice with recombinant human LAL resulted in a significant improvement in organ size and tissue histology as well as significant decreases in cholesterol esters and triglycerides, extended life spans, and diminished liver fibrosis and macrophage proliferation (Sun Y, et al., 2014, PMID: 24837159). Long-term sebelipase alfa treatment in humans has been generally well-tolerated and has provided multiple benefits for patients with LAL deficiency including improvements in liver and lipid parameters, and liver histology was mostly stable or improved from baseline with treatment (Burton BK, et al., 2022, PMID: 34774639).

In summary, LIPA is definitively associated with lysosomal acid lipase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Classification approved by the ClinGen Lysosomal Diseases GCEP on April 28, 2023.

Addendum: The original MONDO ID used for this curation, MONDO:0010204, was obsoleted and was replaced by the current MONDO ID, MONDO:0800449, on July 2, 2025. No other details were changed.

Data provided by the ClinGen Prenatal GCEP from February 11, 2025 secondary analysis:

No changes to the original lumping and splitting decision. Prenatal presentation of Lysosomal Acid Lipase (LAL) deficiency, particularly Wolman disease, is primarily characterized by biochemical confirmation of deficient LAL activity in cultured amniotic or chorionic villus cells and significant lipid accumulation in fetal tissues such as hepatocytes, adrenal cells, and syncytiotrophoblasts. Ultrasound findings, only documented by Blitz et al. (2017, PMID: 28374935) and Ben-Haroush et al. (2003, PMID: 12666227), include hepatomegaly, fetal ascites, and adrenal calcifications, which are hallmark features of the disease. Genetic testing, although only once reported with prenatal presentation, can be conducted via CVS or amniocentesis to detect two pathogenic LIPA variants, particularly in high-risk populations. The evidence highlights that prenatal diagnosis relies on a combination of enzyme assays, genetic analysis, and imaging findings to confirm the condition.

Currently, there is no known association between Lysosomal acid lipase deficiency and pregnancy loss or infertility.