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

Livia Pisciotta, Giulia Tozzi, Lorena Travaglini, Roberta Taurisano, Tiziano Lucchi, Giuseppe Indolfi, Francesco Papadia, Maja Di Rocco, Lorenzo D'Antiga, Patricia Crock, Komal Vora, Scott Nightingale, Helen Michelakakis, Anastasia Garoufi, Lilia Lykopoulou, Stefano Bertolini, Sebastiano Calandra

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)124-132
Number of pages9
JournalAtherosclerosis
Volume265
DOIs
Publication statusPublished - Oct 1 2017

Keywords

  • Cholesteryl ester storage disease
  • LIPA gene variants
  • Liver disease
  • Lysosomal acid lipase deficiency

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Pisciotta, L., Tozzi, G., Travaglini, L., Taurisano, R., Lucchi, T., Indolfi, G., Papadia, F., Di Rocco, M., D'Antiga, L., Crock, P., Vora, K., Nightingale, S., Michelakakis, H., Garoufi, A., Lykopoulou, L., Bertolini, S., & Calandra, S. (2017). 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, 265, 124-132. https://doi.org/10.1016/j.atherosclerosis.2017.08.021