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Evaluation of two approaches to lysosomal acid lipase deficiency patient identification: An observational retrospective study

  • Jorge J. Cebolla
    Correspondence
    Corresponding author. Unidad de Investigación Traslacional, Instituto de Investigación Sanitaria Aragón (IIS Aragón), GIIS-012, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), CB/06/07/1036, Hospital Universitario Miguel Servet, P° Isabel La Católica 1-3, 50009, Zaragoza, Spain.
    Affiliations
    Instituto de Investigación Sanitaria Aragón (IIS Aragón), GIIS-012, Zaragoza, 50009, Spain

    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), CB/06/07/1036, Instituto de Salud Carlos III (ISCIII), Hospital Universitario Miguel Servet, Zaragoza, 50009, Spain

    Fundación Española para el Estudio y Terapéutica de la Enfermedad de Gaucher y Otras Lisosomales (FEETEG), Zaragoza, 50008, Spain

    Departamento de Bioquímica, Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, 50009, Spain
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  • Pilar Irún
    Affiliations
    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), CB/06/07/1036, Instituto de Salud Carlos III (ISCIII), Hospital Universitario Miguel Servet, Zaragoza, 50009, Spain
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  • Pilar Mozas
    Affiliations
    Departamento de Bioquímica, Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, 50009, Spain
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  • Pilar Giraldo
    Affiliations
    Instituto de Investigación Sanitaria Aragón (IIS Aragón), GIIS-012, Zaragoza, 50009, Spain

    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), CB/06/07/1036, Instituto de Salud Carlos III (ISCIII), Hospital Universitario Miguel Servet, Zaragoza, 50009, Spain

    Fundación Española para el Estudio y Terapéutica de la Enfermedad de Gaucher y Otras Lisosomales (FEETEG), Zaragoza, 50008, Spain
    Search for articles by this author

      Highlights

      • Plasma lysosomal storage disorder (LSD) biomarkers was a good approximation to identify lysosomal acid lipase deficiency (LALD) patients.
      • Combination of LSD biomarkers and lipid-liver profile (LLP) enhanced the power to identify LALD patients in natural history cohorts.
      • Lysosomal storage disease suspected patients was queried for LIPA mutations.
      • Novel LIPA mutations were found in this study.

      Abstract

      Background and aims

      Lysosomal acid lipase deficiency (LALD) leads to the accumulation of cholesteryl esters and/or triglycerides (TG) in lysosomes due to the lack of the enzyme codified by the LIPA gene. The most common symptoms are dyslipidaemia and hypertransaminasemia, together with manifestations common to other lysosomal storage disorders (LSDs), including visceromegalies and elevated plasma biomarkers. Alteration of the lipid-liver profile (LLP) has been widely applied as a criterion for LALD screening, but the usefulness of biomarkers has not yet been explored. Our purpose was to explore the utility of plasma chitotriosidase activity (ChT) and CCL18/PARC concentration in addition to LLP to identify LALD patients in an observational retrospective study of two different sample collections.

      Methods

      Biological samples refining: Collection 1 (primary hypercholesterolemia suspected) included unrelated individuals with hyperlipidaemia and without LDLR, APOB and PCSK9 gene mutations (Set 1), and Collection 2 (LSD suspected) included individuals without definitive LSD diagnosis (Set 2). We assessed plasma LLP (total cholesterol and its fractions, TG concentration and transaminases activities), as well as plasma ChT and CCL18/PARC. All subjects with anomalous LLP and/or biomarker levels were LIPA sequenced.

      Results

      Twenty-four subjects showed altered LLP and/or biomarkers. We identified two LALD patients (one homozygous and one compound heterozygous) and one carrier of a novel LIPA variant.

      Conclusions

      The measurement of plasma ChT and CCL18/PARC combined with LLP will be a useful approach to identifying LALD patients in retrospective LALD patient studies.

      Graphical abstract

      Abbreviations:

      ALT (alanine aminotransferase), AST (aspartate aminotransferase), CCL18/PARC (chemokine (CeC motif) ligand 18/pulmonary and activation-regulated chemokine), CESD (cholesteryl ester storage disease), c-HDL (high-density lipoproteins cholesterol), c-LDL (low-density lipoproteins cholesterol), c-VLDL (very low-density lipoproteins cholesterol), Chol (cholesterol), ChT (chitotriosidase activity), E8SJM (exon 8 splice junction mutation), FH (familial hypercholesterolemia), LALD (lysosomal acid lipase deficiency), LLP (lipid-liver profile), LSD (lysosomal storage disease), PH (primary hypercholesterolemia), SREBP (sterol regulatory element-binding protein), TChol (total cholesterol), TG (triglyceride), UTR (untranslated region)
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