Prevalence of Cholesteryl Ester Storage Disease

Abstract

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 27, No. 8Prevalence of Cholesteryl Ester Storage Disease Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBPrevalence of Cholesteryl Ester Storage Disease Sandro Muntoni, Heiko Wiebusch, Marianne Jansen-Rust, Stephan Rust, Udo Seedorf, Helmut Schulte, Klaus Berger, Harald Funke and Gerd Assmann Sandro MuntoniSandro Muntoni From the Department of Toxicology, Oncology, and Molecular Pathology Unit (S.M.), University of Cagliari, Italy; the Leibniz Institute of Arteriosclerosis Research (S.M., M.J.-R., S.R., U.S., H.S., H.F., G.A.), University of Münster, Germany; the Institute of Clinical Chemistry and Laboratory Medicine (H.W., G.A.), University Hospital Münster, Germany; the Department of Molecular Haemostaseology (H.F.), University of Jena, Germany; and the Institute of Epidemiology and Social Medicine (K.B.), University of Münster, Germany. Search for more papers by this author , Heiko WiebuschHeiko Wiebusch From the Department of Toxicology, Oncology, and Molecular Pathology Unit (S.M.), University of Cagliari, Italy; the Leibniz Institute of Arteriosclerosis Research (S.M., M.J.-R., S.R., U.S., H.S., H.F., G.A.), University of Münster, Germany; the Institute of Clinical Chemistry and Laboratory Medicine (H.W., G.A.), University Hospital Münster, Germany; the Department of Molecular Haemostaseology (H.F.), University of Jena, Germany; and the Institute of Epidemiology and Social Medicine (K.B.), University of Münster, Germany. Search for more papers by this author , Marianne Jansen-RustMarianne Jansen-Rust From the Department of Toxicology, Oncology, and Molecular Pathology Unit (S.M.), University of Cagliari, Italy; the Leibniz Institute of Arteriosclerosis Research (S.M., M.J.-R., S.R., U.S., H.S., H.F., G.A.), University of Münster, Germany; the Institute of Clinical Chemistry and Laboratory Medicine (H.W., G.A.), University Hospital Münster, Germany; the Department of Molecular Haemostaseology (H.F.), University of Jena, Germany; and the Institute of Epidemiology and Social Medicine (K.B.), University of Münster, Germany. Search for more papers by this author , Stephan RustStephan Rust From the Department of Toxicology, Oncology, and Molecular Pathology Unit (S.M.), University of Cagliari, Italy; the Leibniz Institute of Arteriosclerosis Research (S.M., M.J.-R., S.R., U.S., H.S., H.F., G.A.), University of Münster, Germany; the Institute of Clinical Chemistry and Laboratory Medicine (H.W., G.A.), University Hospital Münster, Germany; the Department of Molecular Haemostaseology (H.F.), University of Jena, Germany; and the Institute of Epidemiology and Social Medicine (K.B.), University of Münster, Germany. Search for more papers by this author , Udo SeedorfUdo Seedorf From the Department of Toxicology, Oncology, and Molecular Pathology Unit (S.M.), University of Cagliari, Italy; the Leibniz Institute of Arteriosclerosis Research (S.M., M.J.-R., S.R., U.S., H.S., H.F., G.A.), University of Münster, Germany; the Institute of Clinical Chemistry and Laboratory Medicine (H.W., G.A.), University Hospital Münster, Germany; the Department of Molecular Haemostaseology (H.F.), University of Jena, Germany; and the Institute of Epidemiology and Social Medicine (K.B.), University of Münster, Germany. Search for more papers by this author , Helmut SchulteHelmut Schulte From the Department of Toxicology, Oncology, and Molecular Pathology Unit (S.M.), University of Cagliari, Italy; the Leibniz Institute of Arteriosclerosis Research (S.M., M.J.-R., S.R., U.S., H.S., H.F., G.A.), University of Münster, Germany; the Institute of Clinical Chemistry and Laboratory Medicine (H.W., G.A.), University Hospital Münster, Germany; the Department of Molecular Haemostaseology (H.F.), University of Jena, Germany; and the Institute of Epidemiology and Social Medicine (K.B.), University of Münster, Germany. Search for more papers by this author , Klaus BergerKlaus Berger From the Department of Toxicology, Oncology, and Molecular Pathology Unit (S.M.), University of Cagliari, Italy; the Leibniz Institute of Arteriosclerosis Research (S.M., M.J.-R., S.R., U.S., H.S., H.F., G.A.), University of Münster, Germany; the Institute of Clinical Chemistry and Laboratory Medicine (H.W., G.A.), University Hospital Münster, Germany; the Department of Molecular Haemostaseology (H.F.), University of Jena, Germany; and the Institute of Epidemiology and Social Medicine (K.B.), University of Münster, Germany. Search for more papers by this author , Harald FunkeHarald Funke From the Department of Toxicology, Oncology, and Molecular Pathology Unit (S.M.), University of Cagliari, Italy; the Leibniz Institute of Arteriosclerosis Research (S.M., M.J.-R., S.R., U.S., H.S., H.F., G.A.), University of Münster, Germany; the Institute of Clinical Chemistry and Laboratory Medicine (H.W., G.A.), University Hospital Münster, Germany; the Department of Molecular Haemostaseology (H.F.), University of Jena, Germany; and the Institute of Epidemiology and Social Medicine (K.B.), University of Münster, Germany. Search for more papers by this author and Gerd AssmannGerd Assmann From the Department of Toxicology, Oncology, and Molecular Pathology Unit (S.M.), University of Cagliari, Italy; the Leibniz Institute of Arteriosclerosis Research (S.M., M.J.-R., S.R., U.S., H.S., H.F., G.A.), University of Münster, Germany; the Institute of Clinical Chemistry and Laboratory Medicine (H.W., G.A.), University Hospital Münster, Germany; the Department of Molecular Haemostaseology (H.F.), University of Jena, Germany; and the Institute of Epidemiology and Social Medicine (K.B.), University of Münster, Germany. Search for more papers by this author Originally published1 Aug 2007https://doi.org/10.1161/ATVBAHA.107.146639Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1866–1868Cholesteryl ester storage disease (CESD) is an autosomal recessive chronic liver disease caused by lysosomal acid lipase (LAL) deficiency. The gene is located on chromosome 10q23.2-q23.3, and the enzyme is essential for triglycerides and cholesteryl ester hydrolysis in lysosomes. CESD is characterized by hypercholesterolemia, hypertriglyceridemia, HDL deficiency, and abnormal lipid deposition in many organs. In the liver this results in hepatomegaly caused by hepatic steatosis and fibrosis that can lead to micronodular cirrhosis.1 Disease onset takes place during childhood or adolescence. Males and females are affected in about equal numbers. Patients rarely reach the age of 30. Biochemically, the disorder is recognized by largely reduced lysosomal acid lipase activity.2,3 Complete absence of LAL activity causes Wolman Disease, which is normally fatal within the first 6 months of life.1,4 Several groups have identified mutations in the LAL gene underlying CESD and Wolman disease.5–9 Mutations causing Wolman disease produce an enzyme with no residual activity or no enzyme at all, whereas CESD-causing mutations encode for LAL which retains some enzyme activity.4,10 A G-to-A transition at position −1 of the exon 8 splice donor (E8SJM, Exon 8 Splice Junction Mutation) leads to an in-frame deletion of exon 8. The resulting protein is 24 amino acids shorter and has no residual LAL activity, however E8SJM does not cause Wolman Disease because 2% to 4% of normally spliced LAL is present in homozygote carriers.11,12 The vast majority of CESD patients described to date are E8SJM carriers.3,11–17 This observation provided the possibility to obtain a good estimate for the prevalence of CESD in the general population by performing a genetic E8SJM screening.We therefore screened for the mutations in a test cohort of 1152 individuals from the PROCAM (PROspective CArdiovascular Münster)-Study of North-Western Germany and 2 validation cohorts, 1 from the city of Münster (PROCAM, n=478) and 1 from the MEMO-Study18 cohort (n=376), which is a follow-up of the WHO-MONICA project from Augsburg (Southern Germany). The study was approved by an institutional review committee, and informed consent was obtained from all participants. EDTA blood was collected and organized in pools of 8 individuals using equal amounts of leukocytes from each participant. In case a pool of 8 was tested positive, each participant’s DNA was individually extracted using standard procedures and subjected to an individual genotyping test. No further analysis was performed on negative pools.Pooled DNA screening was facilitated using a previously published allele-selective polymerase chain reaction (PCR) procedure.19 The reaction (50 μL volume) was carried out in a single tube using the following protocol: 0.015 μmol/L wild-type selective primer (5′-AACCCCAAATGCACTCCTGGAATGACTCCC-3′), 0.2 μmol/L mutation (E8SJM) selective primer (5′-TCTGATGTTGATTTTACATGCGGCCCAAATGCACTCCTGGAATGTCTATT-3′), 0.1 μmol/L common primer (5′-CACATACTTGAGATTATGGCTCTAGTT-3′) with 12.5 μmol/L d-NTP in a standard PCR buffer. The PCR initial denaturation step (95°C, 30 sec) was followed by 47 cycles of 94°C (30 sec), 64°C (45 sec), and 72°C (45 sec). PCR product(s) were separated by agarose gel electrophoresis, ethidium bromide stained, and photographed after transillumination with UV light. A 219-bp fragment indicated the presence of the wild-type allele (Figure A, No. 1), whereas a 239-bp fragment identified the mutant allele (Figure A, No. 3). Both bands were simultaneously present in heterozygote individuals (Figure A, No. 2; Figure C, No. 2) or if a pool of 8 contained at least 1 mutant of its 16 alleles (Figure B, No. 2 and 5). Two known LAL polymorphisms (thr[-6]pro and gly2arg) were monitored and recorded for future studies using a previously published method.20Download figureDownload PowerPointScreening analysis of the E8SJM mutation in LAL by allele-selective PCR. Panel A shows the results of a wild-type individual (No.1, 219-bp fragment only), a E8SJM heterozygote (No. 2; 219- and 239-bp fragments), and a E8SJM homozygote (No. 3; 239-bp fragment only) together with a DNA size marker (SM). Panel B shows the analysis of 8 DNA pools, each representing 8 individual DNA samples in equimolar amounts (No. 1–8). Lane C denotes a negative control. Lanes 1/8, 1/16, and 1/32 show positive control pools where the E8SJM-allele is diluted 8-, 16-, and 32-fold with wild-type alleles, the later 2 for sensitivity purpose only. The pools in lanes No. 2 and 5 each contain at least 1 carrier of the E8SJM allele. Panel C shows the subsequent analysis of all 8 individual DNA samples from a positive pool (here No. 5 of panel B) that confirmed the presence of exactly 1 E8SJM-carrier in each of the 2 positive pools (No. 2 and 5, panel B). For comparison, 2 positive (+C) and 2 negative (−C) control samples are shown. For all panels, a negative image of the original Polaroid was chosen for display reasons.DNA from all E8SJM carriers was subjected to sequencing analysis for further confirmation, using a previously reported protocol.3 Plasma lipids and lipoproteins were determined from fasted blood samples by CDC-controlled laboratory procedures.A current literature review revealed that about half of all reported CESD cases so far were E8SJM carriers. Therefore, a screening for this mutation should yield a fairly reliable estimate of the CESD frequency in the population. With the use of our allele-selective PCR pool-screening procedure, 3 geographically different cohorts (from Northern and Southern Germany) were analyzed for the presence of E8SJM. In all 3 cohorts, comprising 2023 individuals, 10 heterozygous carriers were identified (allele frequency: 0.0025). In the test cohort from Northern Germany the allele frequency was 0.0026 (Eastern Westphalia, 6 carriers in 1152), and in the validation cohorts it was 0.0020 (Münster, 2 in 495) and from Southern Germany 0.0027 (Augsburg, 2 in 376). The combined E8SJM allele frequency of 0.0025 translates into a carrier frequency of about 1 in 200 or 5000 per million in the general population.Assuming Hardy-Weinberg equilibrium, the homozygote carrier frequency can be estimated to 6 per million. Applying these results to the German general population, about 91 E8SJM homozygotes aged 18 years or younger would be expected. Under the assumption that this mutation represents about 50% of all CESD-causing mutations, the prevalence of CESD (homozygotes or compound heterozygotes) among German newborns is estimated at 25 per million, or a total of 366 cases under the age of 18. This estimate is in apparent conflict with the small number of CESD cases reported in the literature.1,21 Even after considering a higher E8SJM prevalence in CESD, for example Lohse et al22 found E8SJM carriers in 70% of Czech CESD patients, 13 or more cases per million newborns would be expected.Because most of the reported E8SJM carriers are of European or North American origin, it can be expected that this mutation strongly impacts CESD formation in these countries. Furthermore, a large number of family studies reported so far have never identified a CESD-free E8SJM homozygote. We interpret these findings as evidence for a high penetrance of the mutation and conclude that the here identified disparity between expected and reported cases indicates that CESD should be largely under-diagnosed in Europe and North America.We therefore suggest that CESD should more often be considered as a differential diagnosis in liver diseases of unknown (nonalcoholic steatohepatitis or NASH) or known (alcoholic steatohepatitis) origin and in dyslipidemic patients with combined hyperlipidemia and low HDL-cholesterol (Familial Combined Hyperlipidemia). Awareness of the disease combined with efficient diagnostic tools should facilitate the correct diagnosis and therapy1,23,24,25,26 of CESD.DisclosuresNone.FootnotesCorrespondence to Sandro Muntoni, Dipartimento di Tossicologia, Sezione di Oncologia e Patologia Molecolare, Via Porcell 4, 09124 Cagliari, Italy. E-mail [email protected] References 1 Assmann G, Seedorf U. Acid lipase deficiency: Wolman disease and cholesterol ester storage disease. Sciver CR, Beuadet LA, Sly WS, Valle D. The Metabolic & Molecular Bases of Inherited Disease (8th edition) 2001; 3551–3572. New York, McGraw-Hill.Google Scholar2 Patrick AD, Lake BD. Deficiency of an acid lipase in Wolman’s disease. Nature. 1969; 222: 1067–1068.CrossrefMedlineGoogle Scholar3 Seedorf U, Wiebusch H, Muntoni Sa, Christensen NC, Skovby F, Nickel V, Roskos M, Funke H, Ose L, Assmann G. A novel variant of lysosomal acid lipase (Leu336–>Pro) associated with acid lipase deficiency and cholesterol ester storage disease. Arterioscler Thromb Vasc Biol. 1995; 15: 773–778.CrossrefMedlineGoogle Scholar4 Aslanidis C, Ries S, Fehringer P, Buchler C, Klima H, Schmitz G. Genetic and biochemical evidence that CESD and Wolman disease are distinguished by residual lysosomal acid lipase activity. Genomics. 1996; 33: 85–93.CrossrefMedlineGoogle Scholar5 Du H, Sheriff S, Bezerra J, Leonova T, Grabowski GA, Sheriff S, Du H, Grabowski GA. Molecular and enzymatic analyses of lysosomal acid lipase in cholesteryl ester storage disease. Review. Mol Genet Metab. 1998; 64: 126–134.CrossrefMedlineGoogle Scholar6 vom Dahl S, Harzer K, Rolfs A, Albrecht B, Niederau C, Vogt C, van Weely S, Aerts J, Muller G, Haussinger D. Hepatosplenomegalic lipidosis: what unless Gaucher? Adult cholesteryl ester storage disease (CESD) with anemia, mesenteric lipodystrophy, increased plasma chitotriosidase activity and a homozygous lysosomal acid lipase -1 exon 8 splice junction mutation. J Hepatol. 1999; 31: 741–746.CrossrefMedlineGoogle Scholar7 Anderson RA, Bryson GM, Parks JS. Lysosomal acid lipase mutations that determine phenotype in Wolman and cholesterol ester storage disease. Mol Genet Metab. 1999; 68: 333–345.CrossrefMedlineGoogle Scholar8 Elleder M, Chlumska A, Hyanek J, Poupetova H, Ledvinova J, Maas S, Lohse P. Subclinical course of cholesteryl ester storage disease in an adult with hypercholesterolemia, accelerated atherosclerosis, and liver cancer. J Hepatol. 2000; 32: 528–534.CrossrefMedlineGoogle Scholar9 Drebber U, Andersen M, Kasper HU, Lohse P, Stolte M, Dienes HP. Severe chronic diarrhea and weight loss in cholesteryl ester storage disease: a case report. World J Gastroenterol. 2005; 11: 2364–2366.CrossrefMedlineGoogle Scholar10 Pagani F, Pariyarath R, Garcia R, Stuani C, Burlina AB, Ruotolo G, Rabusin M, Baralle FE. New lysosomal acid lipase gene mutants explain the phenotype of Wolman disease and cholesteryl ester storage disease. J Lipid Res. 1998; 39: 1382–1388.CrossrefMedlineGoogle Scholar11 Muntoni S, Wiebusch H, Funke H, Ros E, Seedorf, Assmann G. Homozygosity for a splice junction mutation in exon 8 of the gene encoding lysosomal acid lipase in a Spanish kindred with cholesterol ester storage disease (CESD). Hum Genet. 1995; 95: 491–494.CrossrefMedlineGoogle Scholar12 Pagani F, Garcia R, Pariyarath R, Stuani C, Gridelli B, Paone G, Baralle FE. Expression of lysosomal acid lipase mutants detected in three patients with cholesteryl ester storage disease. Hum Mol Genet. 1996; 5: 1611–1617.CrossrefMedlineGoogle Scholar13 Klima H, Ullrich K, Aslanidis C, Fehringer P, Lackner KJ, Schmitz G. A splice junction mutation causes deletion of a 72-base exon from the mRNA for lysosomal acid lipase in a patient with cholesteryl ester storage disease. J Clin Invest. 1993; 92: 2713–2718.CrossrefMedlineGoogle Scholar14 Gasche C, Aslanidis C, Kain R, Exner M, Helbich T, Dejaco C, Schmitz G, Ferenci P. A novel variant of lysosomal acid lipase in cholesteryl ester storage disease associated with mild phenotype and improvement on lovastatin. J Hepatol. 1997; 27: 744–750.CrossrefMedlineGoogle Scholar15 Redonnet-Vernhet I, Chatelut M, Salvayre R, Levade T. A novel lysosomal acid lipase gene mutation in a patient with cholesteryl ester storage disease. Hum Mutat. 1998; 11: 335–336.MedlineGoogle Scholar16 Redonnet-Vernhet I, Chatelut M, Basile JP, Salvayre R, Levade T. Cholesteryl ester storage disease: relationship between molecular defects and in situ activity of lysosomal acid lipase. Biochem Mol Med. 1997; 62: 42–49.CrossrefMedlineGoogle Scholar17 Ameis D, Brockmann G, Knoblich R, Merkel M, Ostlund RE Jr, Yang JW, Coates PM, Cortner JA, Feinman SV, Greten H. A 5′ splice-region mutation and a dinucleotide deletion in the lysosomal acid lipase gene in two patients with cholesteryl ester storage disease. J Lipid Res. 1995; 36: 241–250.CrossrefMedlineGoogle Scholar18 Rothdach AJ, Trenkwalder C, Haberstock J, Keil U, Berger K. Prevalence and risk factors of RLS in an elderly population: The MEMO Study. Neurology. 2000; 54: 1064–1068.CrossrefMedlineGoogle Scholar19 Rust S, Funke H, Assmann G. Mutagenically separated PCR (MS-PCR): a highly specific one step procedure for easy mutation detection. Nucleic Acids Res. 1993; 21: 3623–3629.CrossrefMedlineGoogle Scholar20 Muntoni S, Wiebusch H, Funke H, Seedorf U, Roskos M, Shulte H, Saku K, Arakawa K, Balestrieri A, Assmann G. A missense mutation (Thr-6Pro) in the lysosomal acid lipase (LAL) gene is present with a high frequency in three different ethnic populations: impact on serum lipoprotein concentrations. Hum Genet. 1996; 97: 265–267.CrossrefMedlineGoogle Scholar21 Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. J Am Med Assoc. 1999; 281: 249–254.CrossrefMedlineGoogle Scholar22 Lohse P, Maas S, Lohse P, Elleder M, Kirk JM, Besley Guy TN, Seidel D. Compound heterozygosity for a Wolman mutation is frequent among patients with cholesteryl ester storage disease. J Lipid Res. 2000; 41: 23–31.CrossrefMedlineGoogle Scholar23 Levy R, Ostlund RE Jr, Schonfeld G, Wong P, and Semenkovich CF. Cholesteryl ester storage disease: complex molecular effects of chronic lovastatin therapy. J Lipid Res. 1992; 33: 1005–1015.CrossrefMedlineGoogle Scholar24 Rassoul F, Richter V, Lohse P, Naumann A, Purschwitz K, Keller E. Long- term administration of the 3hydroxy3methylglutaryl (HMG)-coenzymeA (CoA) reductase inhibitor lovastatin in two patients with cholesteryl ester storage disease. Int J Clin Pharmacol Ther. 2001; 39 (5): 199–204.CrossrefMedlineGoogle Scholar25 Tadiboyina VT, Liu DM, Miskie BA, Wang J, Hegele RA. Treatment of dyslipidemia with lovastatin and ezetimibe in an adolescent with cholesterol ester storage disease. Lipids Health Dis. 2005; 4: 26.CrossrefMedlineGoogle Scholar26 Hong D, Heur M, Witte D, Ameis D, Grabowski GA. Lysosomal acid lipase deficiency: Correction of lipid storage by adenovirus-mediated gene transfer in mice. Hum Gene Ther. 2002; 13: 11: 1361–1372.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Ramakrishna S, Kasala M, Perumal K, Malleeswaran S, Patcha R and Varghese J (2022) Living-Donor Liver Transplantation for Late-Onset Lysosomal Acid Lipase Deficiency, Journal of Clinical and Experimental Hepatology, 10.1016/j.jceh.2021.06.022, 12:2, (672-676), Online publication date: 1-Mar-2022. Grabowski G and Du H (2022) Lysosomal acid lipase: Roles in rare deficiency diseases, myeloid cell biology, innate immunity, and common neutral lipid diseases Cholesterol, 10.1016/B978-0-323-85857-1.00022-5, (639-673), . Davison J, E. Humphries S, G. Winchester B and Mole S (2021) Prenatal Diagnosis of Disorders of Lipid Metabolism Genetic Disorders and the Fetus, 10.1002/9781119676980.ch25, (910-981), Online publication date: 26-Jul-2021. Mistry P, Thurberg B and Grabowski G (2021) Lysosomal Storage Disorders in Children Liver Disease in Children, 10.1017/9781108918978.032, (570-592) Parham J and Underberg J (2021) Lysosomal Acid Lipase Deficiency Therapeutic Lipidology, 10.1007/978-3-030-56514-5_21, (405-416), . Teixeira da Costa L (2021) On the possible existence of a liver LDL-ostat, and its malfunctioning in familial hypercholesterolemia, Medical Hypotheses, 10.1016/j.mehy.2021.110500, 147, (110500), Online publication date: 1-Feb-2021. Rashu E, Junker A, Danielsen K, Dahl E, Hamberg O, Borgwardt L, Christensen V, Albrechtsen N and Gluud L (2020) Cholesteryl ester storage disease of clinical and genetic characterisation: A case report and review of literature, World Journal of Clinical Cases, 10.12998/wjcc.v8.i9.1642, 8:9, (1642-1650), Online publication date: 6-May-2020. Lackner C and Knisely A (2020) Hereditäre Lebererkrankungen Pathologie, 10.1007/978-3-642-04557-8_4, (63-116), . Nascimbeni F, Dionisi Vici C, Vespasiani Gentilucci U, Angelico F, Nobili V, Petta S and Valenti L (2020) AISF update on the diagnosis and management of adult-onset lysosomal storage diseases with hepatic involvement, Digestive and Liver Disease, 10.1016/j.dld.2019.12.005, 52:4, (359-367), Online publication date: 1-Apr-2020. Gomaraschi M, Bonacina F and Norata G (2019) Lysosomal Acid Lipase: From Cellular Lipid Handler to Immunometabolic Target, Trends in Pharmacological Sciences, 10.1016/j.tips.2018.12.006, 40:2, (104-115), Online publication date: 1-Feb-2019. Cebolla J, Irún P, Mozas P and Giraldo P (2019) Evaluation of two approaches to lysosomal acid lipase deficiency patient identification: An observational retrospective study, Atherosclerosis, 10.1016/j.atherosclerosis.2019.03.013, 285, (49-54), Online publication date: 1-Jun-2019. Pericleous M, Kelly C, Ala A and Schilsky M (2019) The Epidemiology of Rare Hereditary Metabolic Liver Diseases Clinical Epidemiology of Chronic Liver Diseases, 10.1007/978-3-319-94355-8_17, (307-330), . Benevides G, Miura I, Person N, Pugliese R, Danesi V, Lima F and Porta G (2019) Lysosomal acid lipase deficiency in Brazilian children: a case series, Jornal de Pediatria (Versão em Português), 10.1016/j.jpedp.2018.08.016, 95:5, (552-558), Online publication date: 1-Sep-2019. Kuloglu Z, Kansu A, Selbuz S, Kalaycı A, Şahin G, Kirsaclioglu C, Demirören K, Dalgıç B, Kasırga E, Önal Z and İşlek A (2019) The Frequency of Lysosomal Acid Lipase Deficiency in Children With Unexplained Liver Disease, Journal of Pediatric Gastroenterology & Nutrition, 10.1097/MPG.0000000000002224, 68:3, (371-376), Online publication date: 1-Mar-2019. Angel G, Hutchinson A, Jain N, Forbes C and Reynders J (2019) Large‐scale functional LIPA variant characterization to improve birth prevalence estimates of lysosomal acid lipase deficiency , Human Mutation, 10.1002/humu.23837, 40:11, (2007-2020), Online publication date: 1-Nov-2019. Ashfield-Watt P, Haralambos K, Edwards R, Townsend D, Gingell R, Wa Li K, Humphries S and McDowell I (2018) Estimation of the prevalence of cholesteryl ester storage disorder in a cohort of patients with clinical features of familial hypercholesterolaemia, Annals of Clinical Biochemistry: International Journal of Laboratory Medicine, 10.1177/0004563218793165, 56:1, (112-117), Online publication date: 1-Jan-2019. Consuelo-Sánchez A, Vázquez-Frias R, Reyes-De La Rosa A, Acosta-Rodríguez-Bueno C, Ortal-Vite M and Cebolla J (2019) Mutations identified in a cohort of Mexican patients with lysosomal acid lipase deficiency, Annals of Hepatology, 10.1016/j.aohep.2018.07.005, 18:4, (646-650), Online publication date: 1-Jul-2019. Cappuccio G, Donti T, Hubert L, Sun Q and Elsea S (2019) Opening a window on lysosomal acid lipase deficiency: Biochemical, molecular, and epidemiological insights, Journal of Inherited Metabolic Disease, 10.1002/jimd.12057, 42:3, (509-518), Online publication date: 1-May-2019. Schonfeld E and Brown R (2019) Genetic Causes of Liver Disease, Medical Clinics of North America, 10.1016/j.mcna.2019.07.003, 103:6, (991-1003), Online publication date: 1-Nov-2019. Carter A, Brackley S, Gao J and Mann J (2019) The global prevalence and genetic spectrum of lysosomal acid lipase deficiency: A rare condition that mimics NAFLD, Journal of Hepatology, 10.1016/j.jhep.2018.09.028, 70:1, (142-150), Online publication date: 1-Jan-2019. Benevides G, Miura I, Person N, Pugliese R, Danesi V, Lima F and Porta G (2019) Lysosomal acid lipase deficiency in Brazilian children: a case series, Jornal de Pediatria, 10.1016/j.jped.2018.05.016, 95:5, (552-558), Online publication date: 1-Sep-2019. Vinje T, Wierød L, Leren T and Strøm T (2018) Prevalence of cholesteryl ester storage disease among hypercholesterolemic subjects and functional characterization of mutations in the lysosomal acid lipase gene, Molecular Genetics and Metabolism, 10.1016/j.ymgme.2017.11.008, 123:2, (169-176), Online publication date: 1-Feb-2018. Reynolds T, Mewies C, Hamilton J and Wierzbicki A (2018) Identification of rare diseases by screening a population selected on the basis of routine pathology results—the PATHFINDER project: lysosomal acid lipase/cholesteryl ester storage disease substudy, Journal of Clinical Pathology, 10.1136/jclinpath-2017-204727, 71:7, (608-613), Online publication date: 1-Jul-2018. Vázquez-Frias R, García-Ortiz J, Valencia-Mayoral P, Castro-Narro G, Medina-Bravo P, Santillán-Hernández Y, Flores-Calderón J, Mehta R, Arellano-Valdés C, Carbajal-Rodríguez L, Navarrete-Martínez J, Urbán-Reyes M, Valadez-Reyes M, Zárate-Mondragón F and Consuelo-Sánchez A (2018) Mexican consensus on lysosomal acid lipase deficiency diagnosis, Revista de Gastroenterología de México (English Edition), 10.1016/j.rgmxen.2018.01.001, 83:1, (51-61), Online publication date: 1-Jan-2018. Hannah-Shmouni F and Stratakis C (2018) An overview of inborn errors of metabolism manifesting with primary adrenal insufficiency, Reviews in Endocrine and Metabolic Disorders, 10.1007/s11154-018-9447-2, 19:1, (53-67), Online publication date: 1-Mar-2018. Sathiyakumar V, Kapoor K, Jones S, Banach M, Martin S and Toth P (2018) Novel Therapeutic Targets for Managing Dyslipidemia, Trends in Pharmacological Sciences, 10.1016/j.tips.2018.06.001, 39:8, (733-747), Online publication date: 1-Aug-2018. Oynotkinova O, Nikonov E, Baranov A, Krukov E and Doroshko M (2018) Lysosomal acid lipase deficiency - underestimated cause of dislipidemia. what's new?, Dokazatel'naya gastroenterologiya, 10.17116/dokgastro2018704165, 7:4, (65), . Vázquez-Frias R, García-Ortiz J, Valencia-Mayoral P, Castro-Narro G, Medina-Bravo P, Santillán-Hernández Y, Flores-Calderón J, Mehta R, Arellano-Valdés C, Carbajal-Rodríguez L, Navarrete-Martínez J, Urbán-Reyes M, Valadez-Reyes M, Zárate-Mondragón F and Consuelo- Sánchez A (2018) Consenso mexicano sobre el diagnóstico de la deficiencia de lipasa ácida lisosomal, Revista de Gastroenterología de México, 10.1016/j.rgmx.2017.08.001, 83:1, (51-61), Online publication date: 1-Jan-2018. Draijer L, Bosch A, Wiegman A, Sjouke B, Benninga M and Koot B (2018) Screening for lysosomal acid lipase deficiency: A retrospective data mining study and evaluation of screening criteria, Atherosclerosis, 10.1016/j.atherosclerosis.2018.09.023, 278, (174-179), Online publication date: 1-Nov-2018. Morris G, Braund P, Moore J, Samani N, Codd V and Webb T (2017) Coronary Artery Disease–Associated LIPA Coding Variant rs1051338 Reduces Lysosomal Acid Lipase Levels and Activity in Lysosomes, Arteriosclerosis, Thrombosis, and Vascular Biology, 37:6, (1050-1057), Online publication date: 1-Jun-2017. Schonfeld E and Brown R (2017) Genetic Testing in Liver Disease, Clinics in Liver Dise