Molecular and clinical characterization of a series of patients with childhood-onset lysosomal acid lipase deficiency. Retrospective investigations, follow-up and detection of two novel LIPA pathogenic variants

Atherosclerosis. 2017 Oct:265:124-132. doi: 10.1016/j.atherosclerosis.2017.08.021. Epub 2017 Aug 26.


Background and aims: Childhood/Adult-onset Lysosomal Acid Lipase Deficiency (LAL-D) is a recessive disorder due to loss of function variants of LAL, the enzyme which hydrolyses cholesteryl esters, derived from internalized apoB containing lipoproteins. The disease is characterized by multi-organ involvement including the liver, spleen, intestine and cardiovascular system. The aim of this study was the clinical and molecular characterization of 14 (13 unrelated) previously unreported patients with childhood-onset LAL-D.

Methods: Data collected included clinical and laboratory investigations, liver imaging, liver biopsy and LIPA gene analysis. The response to lipid-lowering medications, liver transplantation and enzyme replacement therapy (ERT) was reported for some patients.

Results: LAL-D was suspected at 4.4 ± 3.3 years of age for the presence of hepatomegaly, elevated serum transaminases and hypercholesterolemia, and was confirmed by liver biopsy/imaging and LAL assay. The follow up period ranged from 3 to 40 years (mean 7.8 ± 4.0 years in 13 cases). Patients treated with statins with or without ezetimibe showed 28% reduction of plasma LDL-cholesterol without a tangible effect on liver enzymes; some patients receiving ERT showed normalized lipoprotein profile and transaminase levels. The common c.894G > A variant was observed in homozygosity or compound heterozygosity in 10 patients. We found seven previously reported variants: p.(Trp140*), p.(Arg218*), p.(Gly266*), p.(Thr288Ile), p.(Leu294Ser), p.(His295Tyr) and p.(Gly342Arg) and two novel variants: p.(Asp345Asn), affecting the LAL catalytic triad, and c.229+3A > C, affecting splicing. Homozygosity for p.(Thr288Ile) or c.229+3A > C was associated with a severe phenotype.

Conclusions: This study provides additional data on the features of childhood-onset LAL-D and describes two novel pathogenic variants of the LIPA gene.

Keywords: Cholesteryl ester storage disease; LIPA gene variants; Liver disease; Lysosomal acid lipase deficiency.

Publication types

  • Multicenter Study

MeSH terms

  • Adolescent
  • Age of Onset
  • Biomarkers / blood
  • Biopsy
  • Child
  • Child, Preschool
  • Cholesterol, LDL / blood
  • DNA Mutational Analysis
  • Enzyme Replacement Therapy
  • Europe
  • Female
  • Follow-Up Studies
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Haplotypes
  • Hepatomegaly / diagnosis
  • Hepatomegaly / enzymology
  • Hepatomegaly / genetics
  • Hepatomegaly / therapy
  • Heterozygote
  • Homozygote
  • Humans
  • Hypercholesterolemia / diagnosis
  • Hypercholesterolemia / drug therapy
  • Hypercholesterolemia / enzymology
  • Hypercholesterolemia / genetics
  • Hypolipidemic Agents / therapeutic use
  • Infant
  • Liver / diagnostic imaging
  • Liver / pathology
  • Liver / surgery
  • Liver Function Tests
  • Liver Transplantation
  • Male
  • Mutation*
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Retrospective Studies
  • Sterol Esterase / deficiency
  • Sterol Esterase / genetics*
  • Sterol Esterase / therapeutic use
  • Time Factors
  • Treatment Outcome
  • Wolman Disease / diagnosis
  • Wolman Disease / enzymology
  • Wolman Disease / genetics*
  • Wolman Disease / therapy


  • Biomarkers
  • Cholesterol, LDL
  • Hypolipidemic Agents
  • LIPA protein, human
  • Sterol Esterase