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Cholesteryl ester storage disease (CESD) is an autosomal recessive lysosomal lipid storage disorder caused by biallelic mutations in the LIPA gene, which encodes lysosomal acid lipase (LAL). Patients with CESD present variably with hepatomegaly, mixed hyperlipidemia (elevated LDL-cholesterol and triglycerides, low HDL-cholesterol), elevated transaminases, and progressive hepatic fibrosis leading to cirrhosis and premature atherosclerosis. The disorder spans a phenotypic continuum from severe infantile-onset Wolman disease with absent enzyme activity to adult-onset CESD with residual LAL activity. Early recognition relies on a high index of suspicion in patients with unexplained hepatomegaly and dyslipidemia.
Genetic evidence for LIPA-CESD comprises over 206 probands across more than 55 unrelated families, with autosomal recessive inheritance confirmed by cosegregation of pathogenic alleles and reduced LAL activity in carriers ([PMID:23403440]). The most common variant, c.894G>A (p.Gln298=), leads to exon 8 skipping and partial retention of correctly spliced transcript (approximately 3% of total LAL mRNA), resulting in attenuated enzyme function and the CESD phenotype ([PMID:8617513]). Additional missense, nonsense, frameshift, and splice-site mutations have been described, including p.His295Tyr ([PMID:7833918]) and p.Gly266Ter, demonstrating a wide variant spectrum in CESD.
Segregation analysis in multiple kindreds has documented over 55 affected sibships and extended relatives with biallelic LIPA mutations, and carrier parents consistently exhibit intermediate LAL activity, corroborating recessive transmission ([PMID:8254026]). Case series and population studies have identified compound heterozygotes and homozygotes for both founder and novel mutations in diverse ethnic groups, underscoring the importance of comprehensive LIPA sequencing when biochemical and clinical features are suggestive.
Functional studies provide moderate experimental evidence: in vitro expression of mutant LAL alleles reveals that exon 8 splice-site defects yield internally deleted proteins with <5% activity, while null alleles result in absent enzyme activity. Missense substitutions such as p.His295Tyr and Leu336Pro disrupt catalytic function or glycosylation and stability, as shown in fibroblast assays, insect cell expression, and enzymatic activity measurements ([PMID:7833918]; [PMID:8617513]). These assays confirm that residual LAL activity correlates with milder CESD phenotypes, whereas complete loss leads to Wolman disease.
No significant conflicting evidence has been reported; phenotypic variability aligns with the degree of residual enzyme activity and mutation type. Diagnostic delay is common due to overlapping features with more prevalent hepatic and metabolic disorders, but targeted genetic testing and enzyme assays enable definitive diagnosis.
Integration of genetic and functional findings establishes a definitive gene-disease relationship for LIPA and CESD, fulfilling criteria for extensive proband counts, consistent segregation, and concordant experimental data. Early diagnosis of CESD informs clinical management, including dietary and lipid-lowering interventions, and highlights candidates for enzyme replacement therapy. Key take-home: In patients with unexplained hepatomegaly and mixed dyslipidemia, measurement of LAL activity and LIPA genetic testing should be pursued to enable timely diagnosis and treatment.
Gene–Disease AssociationDefinitiveOver 206 patients in >55 families with consistent clinical and biochemical findings across multiple cohorts Genetic EvidenceStrong206 probands in 55 unrelated families; AR cosegregation with reduced LAL activity ([PMID:23403440]) Functional EvidenceModerateIn vitro and ex vivo assays demonstrate that splice-site and missense variants yield <5% residual activity correlating with phenotype ([PMID:7833918]; [PMID:8617513]) |