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Background: Lysosomal acid lipase deficiency (LALD, OMIM#278000) is a rare lysosomal disorder with an autosomal recessive inheritance. The main clinical manifestations are related to a progressive accumulation of cholesteryl esters, triglycerides or both within the lysosome in different organs such as the liver, spleen, and cardiovascular system. A wide range of clinical severity is associated with LALD including a severe very rare antenatal/neonatal/infantile phenotype named Wolman disease and a late-onset form named cholesteryl ester storage disease (CESD)., Methods: This study aimed to investigate a cohort of at-risk patients (4174) presenting with clinical or biological signs consistent with LALD using the assessment of LAL activity on dried blood spots., Results: LAL activity was lower than 0.05 nmol/punch/L (cut-off: 0.12) in 19 patients including 13 CESD and 6 Wolman. Molecular study has been conducted in 17 patients and succeeded in identifying 34 mutated alleles. Fourteen unique variants have been characterized, 7 of which are novel., Conclusion: This study allowed to identify a series of patients and expanded the molecular spectrum knowledge of LALD. Besides, a new screening criteria grid based on the clinical/biological data from our study and the literature has been proposed in order to enhance the diagnosis rate in at risk populations., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background & Aims: Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive condition that may present in a mild form (cholesteryl ester storage disease [CESD]), which mimics non-alcoholic fatty liver disease (NAFLD). It has been suggested that CESD may affect 1 in 40,000 and is under-diagnosed in NAFLD clinics. Therefore, we aimed to estimate the prevalence of LAL-D using analysis of genetic variation in LIPA., Methods: MEDLINE and EMBASE were systematically searched for previously reported disease variants and prevalence estimates. Previous prevalence estimates were meta-analysed. Disease variants in LIPA were annotated with allele frequencies from gnomAD and combined with unreported major functional variants found in humans. Pooled ethnicity-specific prevalences for LAL-D and CESD were calculated using the Hardy-Weinberg equation., Results: Meta-analysis of existing genetic studies estimated the prevalence of LAL-D as 1 per 160,000 (95% CI 1 per 65,025-761,652) using the allele frequency of c.894G>A in LIPA. A total of 98 previously reported disease variants in LIPA were identified, of which 32/98 were present in gnomAD, giving a prevalence of 1 per 307,482 (95% CI 257,672-366,865). Wolman disease was associated with more loss-of-function variants than CESD. When this was combined with 22 previously unreported major functional variants in LIPA identified in humans, the pooled prevalence of LAL-D was 1 per 177,452 (95% CI 149,467-210,683) with a carrier frequency of 1 per 421. The prevalence is lowest in those of East Asian, South Asian, and Finnish ancestry., Conclusion: Using 120 disease variants in LIPA, these data can reassure clinicians that LAL-D is an ultra-rare disorder. Given the therapeutic capability of sebelipase alpha, investigation for LAL-D might be included in second-line metabolic screening in NAFLD., Lay Summary: Lysosomal Acid Lipase Deficiency (LAL-D) is a rare genetic condition that can cause severe liver disease, but it is difficult to diagnose and sometimes can look like simple fatty liver. It was not clear how common LAL-D was and whether many cases were being missed. To study this, we searched for all genetic mutations that could cause LAL-D, calculated how common those mutations were, and added them up. This let us estimate that LAL-D affects roughly 1 in 175,000 people. We conclude that LAL-D is a very rare condition, but it is treatable so may be included in a 'second-line' of tests for causes of fatty liver., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Lysosomal acid lipase deficiency (LAL-D) is a lysosomal storage disorder. In severe cases, it can cause life-threatening organ failure due to lipid substrates accumulation. However, mild phenotypes of this disorder are increasingly recognized. The aim of this study is to determine the number of missed LAL-D patients in a large pediatric hospital population., Methods: In a retrospective data mining study, the medical files of children, who visited the outpatient clinic at a university hospital between 2000 and 2016, with high plasma low density lipoprotein cholesterol (LDL-C) levels, were evaluated. Previously developed LAL-D screening criteria, with lipid and alanine aminotransferase (ALT) values adjusted for children, were used to analyze which children are suspect for LAL-D. For suspicion of LAL-D, at least 3 out of 5 screening criteria had to be met. Subsequently data on presentation and follow-up were collected to determine if the clinical picture was compatible with LAL-D., Results: We identified 2037 children with high LDL-C levels. Of those, 36 children complied with ≥3 screening criteria. Thirty-one of those had an underlying disorder other than LAL-D that explained the abnormalities and, in the 5 remaining children, ALT and lipid levels normalized spontaneously, thus excluding LAL-D., Conclusions: This study shows that retrospective data mining is unlikely to yield a significant number of LAL-D cases in children. The screening algorithm adjusted for children seems useful and accurate in the selection of children for further testing, suggesting it can be applied prospectively, although further validation is warranted., (Copyright © 2018. Published by Elsevier B.V.)

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., (Copyright © 2017. Published by Elsevier B.V.)

Background: The childhood/adult-onset lysosomal acid lipase deficiency (LALD; late-onset LALD) is a rare genetic disease. Children present severe fatty liver disease with early cirrhosis. Before enzyme replacement therapy, statins were the standard treatment to improve the severe dyslipidemia. However, late-onset LALD should be considered as a systemic metabolic disease: chronic hyper-low-density lipoprotein and hypo-high-density lipoprotein cholesterolemia induces early atherosclerosis in addition to the liver morbidity., Objective: To assess 4 new pediatric cases of late-onset LALD with an evaluation of hepatic, metabolic, and vascular evolution under statin., Methods: Four patients were retrospectively described. Anthropometric data (weight, height, and body mass index) and laboratory data (LIPA mutations, acid lipase residual activity, liver and lipid profile, and homeostatic model assessment index) were collected. Liver histology was assessed by the noninvasive tests FibroScan and FibroTest and confirmed by liver biopsy. Vascular impact was followed up by carotid intima-media thickness (cIMT) assessment., Results: The 4 cases of late-onset LALD came from 2 families, each with a boy (aged 8.6 and 11 years at diagnosis) and a girl (aged 10.6 and 13 years at diagnosis). Treatment with statins was performed for 8 and 5 years, respectively, from diagnosis. Statins decreased the low-density lipoprotein cholesterol mean value of 40%. All children showed significant liver fibrosis (F3 [n = 3]; F2 [n = 1]). cIMT showed the following for all children: abnormal measures without improvement and atherosclerotic plaques. One child developed a deleterious metabolic phenotype with obesity and insulin resistance (homeostatic model assessment = 3.08) associated with higher mean hepatic transaminases (149 vs 98, 88, and 61 IU/L) and increased mean cIMT values (raising from 0.47 to 0.5 mm vs 0.43 and 0.43 mm)., Conclusion: Late-onset LALD is a rare metabolic disease with a larger impact than liver disease. Our work shows the importance of having a global metabolic view and to evaluate the cardiovascular impact of the new enzymatic treatment., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Niemann-Pick type C (NPC) is a progressive neurodegenerative disease characterized by lysosomal/endosomal accumulation of unesterified cholesterol and glycolipids. Recent studies have shown that plasma cholestane-3β,5α,6β-triol (CT) and 7-ketocholesterol (7-KC) could be potential biomarkers for the diagnosis of NPC patients. We aimed to know the sensitivity and specificity of these biomarkers for the diagnosis of NPC compared with other diseases that can potentially lead to oxysterol alterations. We studied 107 controls and 122 patients including 16 with NPC, 3 with lysosomal acid lipase (LAL) deficiency, 8 with other lysosomal diseases, 5 with galactosemia, 11 with cerebrotendinous xanthomatosis (CTX), 3 with Smith-Lemli-Opitz, 14 with peroxisomal biogenesis disorders, 19 with unspecific hepatic diseases, 13 with familial hypercholesterolemia, and 30 with neurological involvement and no evidence of an inherited metabolic disease. CT and 7-KC were analyzed by HPLC-ESI-MS/MS as mono-dimethylglycine derivatives. Levels of 7-KC were high in most of the studied diseases, whereas those of CT were only high in NPC, LAL, and CTX patients. Consequently, although CT is a sensitive biomarker of NPC disease, including those cases with doubtful filipin staining, it is not specific. 7-KC is a very unspecific biomarker., (Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.)

Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive lysosomal storage disease caused by deleterious mutations in the LIPA gene. The age at onset and rate of progression vary greatly and this may relate to the nature of the underlying mutations. Patients presenting in infancy have the most rapidly progressive disease, developing signs and symptoms in the first weeks of life and rarely surviving beyond 6 months of age. Children and adults typically present with some combination of dyslipidaemia, hepatomegaly, elevated transaminases, and microvesicular hepatosteatosis on biopsy. Liver damage with progression to fibrosis, cirrhosis and liver failure occurs in a large proportion of patients. Elevated low-density lipoprotein cholesterol levels and decreased high-density lipoprotein cholesterol levels are common features, and cardiovascular disease may manifest as early as childhood. Given that these clinical manifestations are shared with other cardiovascular, liver and metabolic diseases, it is not surprising that LAL-D is under-recognized in clinical practice. This article provides practical guidance to lipidologists, endocrinologists, cardiologists and hepatologists on how to recognize individuals with this life-limiting disease. A diagnostic algorithm is proposed with a view to achieving definitive diagnosis using a recently developed blood test for lysosomal acid lipase. Finally, current management options are reviewed in light of the ongoing development of enzyme replacement therapy with sebelipase alfa (Synageva BioPharma Corp., Lexington, MA, USA), a recombinant human lysosomal acid lipase enzyme., (Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

We describe a system for quantitative lipid analysis employing ternary gradient high-performance liquid chromatography with evaporative light scattering detection. This technique was applied to extracts of cultured fibroblasts, cultured lymphocytes, and leukocytes and to liver and spleen biopsy specimens. Separation of nonpolar lipids, glycolipids, phospholipids, and sphingolipids was achieved in a single run. Detection did not depend on the presence of any specific chemical reactions, uv absorption, or fluorescence. The sensitivity of the technique is well below 200 ng for individual lipids, and many individual lipid classes were detected in samples as small as 1 mg of total protein, the yield of a single flask of cultured skin fibroblasts. The characteristic stored lipids cholesterol ester and sphingomyelin were seen in excess in human fibroblast cultures from patients with Wolman's disease and Niemann-Pick disease, respectively. A biopsy spleen sample from a patient with Gaucher's disease showed a large glucosylceramide peak. This system provides a tool for detecting lipids that accumulate in tissues of patients with currently unidentified metabolic storage disorders.

The sterol composition of sera from patients with cerebrotendinous xanthomatosis (CTX) was investigated by gas chromatographic analysis of saponified extracts, using a polar (CP Wax 52CB) and an apolar (CP Sil 5CB) capillary column. Apart from already known sterols, the presence of increased amounts of 8-lathosterol (5 alpha-cholest-8(9)-en-3 beta-ol) and significant amounts of 8-dehydrocholesterol (cholesta-5,8-dien-3 beta-ol) were noticed. The latter compound has not been detected previously in human serum and possibly represents a hitherto unknown cholesterol precursor. The apparently elevated levels of delta 8-sterols in CTX serum suggests partial inhibition of migration of the 8,9 double bond to the 7,8 position in this condition. The concentration of 7-lathosterol, an indicator of cholesterol production rate, is also highly elevated in CTX serum and quickly returns to normal values after oral bile acid therapy. Determinations of serum lathosterol are not only useful in the follow-up of therapy of CTX patients, but also in the follow-up of hypercholesterolemic patients treated with either HMG-CoA reductase inhibitors or bile acid sequestrants.