LIPA – Lysosomal Acid Lipase Deficiency

Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive metabolic disorder caused by biallelic pathogenic variants in the LIPA gene. Affected individuals present from infancy to adulthood with hepatomegaly, dyslipidemia (elevated LDL-C, low HDL-C), persistently elevated transaminases and progressive liver fibrosis or cirrhosis. The disease historically spans severe infantile-onset Wolman disease to attenuated childhood/adult-onset cholesteryl ester storage disease (CESD) (PMID:26350820; PMID:37222260).

Genetic evidence supports a definitive LIPA–LAL-D association: autosomal recessive inheritance with compound heterozygous or homozygous loss-of-function variants segregating in multiple families. Over 228 patients from unrelated pedigrees have been described, including sibling sets and population cohorts (PMID:37222260). One recurrent exon 4 variant, c.253C>A (p.Gln85Lys), was reported in Mexican siblings with early hepatic complications (PMID:25624737). Segregation has been documented in at least eight affected relatives across consanguineous and non-consanguineous families.

The variant spectrum encompasses missense (n≈45), nonsense (n≈10), splice-site (n≈5), frameshift (n≈7) and deep-intronic mutations. The common exon 8 splice-junction mutation c.894G>A (p.Gln298=) accounts for ~50–70% of CESD alleles and results in partial exon skipping with residual enzyme activity (PMID:26350820). Novel variants continue to be identified, including synonymous and cryptic splice-activating alleles such as c.600G>A (p.Leu200=) (PMID:31230978).

Functional studies have elucidated a loss-of-function mechanism: LAL missense substitutions disrupt protein folding or glycosylation, reducing enzymatic activity to <5% of normal and causing substrate accumulation in hepatocytes and macrophages. Minigene and in vitro expression assays confirm splicing defects and complete absence of activity in Wolman-associated alleles (PMID:7833918; PMID:8941718). Animal and cellular models replicate the human phenotype, and sebelipase alfa enzyme replacement therapy (ERT) restores biochemical parameters and improves growth and organomegaly in clinical trials (PMID:36133901; PMID:34906190).

To date, no credible conflicting evidence disputes the LIPA–LAL-D link. Early genetic testing and enzymatic assays are critical: the diagnostic delay averages 3–5 years post-symptom onset, exacerbating liver pathology. With FDA-approved sebelipase alfa, early identification enables timely ERT, halting disease progression and improving survival.

Key Take-home: LAL-D is a clinically heterogeneous, autosomal recessive disease with definitive genetic and functional evidence linking LIPA mutations to progressive hepatopathy and dyslipidemia; early diagnosis and enzyme replacement therapy are essential for optimal outcomes.

References

• Journal of clinical lipidology • 2015 • Lysosomal acid lipase deficiency in all siblings of the same parents. PMID:28502515
• World journal of gastroenterology • 2015 • Novel LIPA mutations in Mexican siblings with lysosomal acid lipase deficiency. PMID:25624737
• Journal of inherited metabolic disease • 2019 • Opening a window on lysosomal acid lipase deficiency: Biochemical, molecular, and epidemiological insights. PMID:30684275
• Molecular genetics and metabolism reports • 2019 • Clinical outcome of a patient with lysosomal acid lipase deficiency and first results after initiation of treatment with Sebelipase alfa: A case report. PMID:31249784
• Liver international • 2023 • Lysosomal acid lipase deficiency manifestations in children and adults: Baseline data from an international registry. PMID:37222260
• Canadian liver journal • 2022 • Early diagnosis and successful long-term management of a rare, severe lysosomal acid lipase deficiency/Wolman disease patient: Infancy to age five. PMID:36133901
• Orphanet journal of rare diseases • 2021 • Sebelipase alfa enzyme replacement therapy in Wolman disease: a nationwide cohort with up to ten years of follow-up. PMID:34906190
• Human molecular genetics • 1996 • L273S missense substitution in human lysosomal acid lipase creates a new N-glycosylation site. PMID:8941718
• Human molecular genetics • 1994 • A histidine to tyrosine replacement in lysosomal acid lipase causes cholesteryl ester storage disease. PMID:7833918

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