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

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

doi:10.1016/j.atherosclerosis.2017.08.021

Cited by 22 publications

(24 citation statements)

References 26 publications

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“…Indeed, we showed that CESD patients had higher carotid IMT values, index of pre-clinical atherosclerosis, than controls. Consistently, although in the absence of a direct comparison with matched controls, carotid IMT values of CESD patients were found to be >75 th percentile of the general population with similar age and sex [4,5].…”

Section: Discussionmentioning

confidence: 80%

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LIPA gene mutations affect the composition of lipoproteins: Enrichment in ACAT-derived cholesteryl esters

et al. 2020

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Background and aimsCholesteryl ester storage disease (CESD) due to LIPA gene mutations is characterized by hepatic steatosis, hypercholesterolemia and hypoalphalipoproteinemia, exposing affected patients to an increased cardiovascular risk. Further insights into the impact of LIPA gene mutations on lipid/lipoprotein metabolism are limited. Aim of the study was to investigate the effect of carrying one or two mutant LIPA alleles on lipoprotein composition and function. MethodsLipoproteins were isolated from 6 adult CESD patients, 5 relatives carrying one mutant LIPA allele (carriers) and 12 sex/age matched controls. Lipid profile, lipoprotein mass composition and the fatty acid distribution of cholesteryl esters (CEs) were assessed. HDL function was evaluated as the ability to promote nitric oxide release by endothelial cells. ResultsDespite the lipid-lowering therapy, total cholesterol, LDL-cholesterol and triglycerides were increased in CESD patients compared to controls, while HDL-cholesterol was reduced.Carriers also displayed elevated total and LDL-cholesterol. Very low and intermediate density lipoproteins from CESD patients and carriers were enriched in CEs compared to the control ones, with a concomitant reduction of triglycerides. Fatty acid composition of CEs in serum and lipoproteins showed a depletion of linoleate content in CESD patients, due to the reduced LCAT activity. In CESD HDL, fatty acid distribution of CEs was shifted towards saturated ones, if compared to control HDL. The changes in HDL composition did not affect HDL ability to promote nitric oxide release by endothelial cells. ConclusionsLIPA gene mutations significantly affected plasma levels and lipid composition of lipoproteins, likely contributing to the increased cardiovascular risk of affected patients.

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Section: Discussionmentioning

confidence: 80%

“…Clinically, CESD patients present with hepatomegaly, splenomegaly, malabsorption and increased cardiovascular risk [3]. Consistently, carotid intima-media thickness (cIMT), a marker of preclinical atherosclerosis, is elevated in CESD patients; however, a direct comparison with age-and sex-matched controls is lacking [4,5].…”

Section: Introductionmentioning

confidence: 99%

LIPA gene mutations affect the composition of lipoproteins: Enrichment in ACAT-derived cholesteryl esters

et al. 2020

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“…Based upon our findings, we recommend performing LIPA analysis in patients with LAL activity below 12 pmol/min/mg protein for molecular confirmation. To date, 91 mutations and eight gross rearrangements involving the 10 exons of LIPA (exon 4 mainly involved), including those reported in the literature and loss‐of‐function mutations in ExAC, gnomAD, and ClinVar (Figure and Table S3) have been identified . Among the detected mutations in our cohort, c.309C>A (p.Ser103Arg) and c.856G>C (p.Ala286Pro) were novel causative mutations (Figure highlighted in red and Table ), as supported by SIFT, Polyphen, CADD, Mutation taster, LRT and biochemical data (reduced and deficient LAL activity in patients).…”

Section: Discussionmentioning

confidence: 99%

“…The disease onset and severity depend upon the amount of residual LAL activity, with partial enzymatic function leading to a more benign clinical course . Infantile‐onset LAL‐D typically presents in the first 6 months of life and is the most rapidly fatal presentation . Childhood/adult‐onset LAL‐D typically shows a heterogeneous phenotypic presentation, with an age of manifestation ranging from the first to the sixth decade.…”

Section: Introductionmentioning

confidence: 99%

Opening a window on lysosomal acid lipase deficiency: Biochemical, molecular, and epidemiological insights

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Donti

Hubert

et al. 2019

J of Inher Metab Disea

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Lysosomal acid lipase deficiency (LAL-D) is a multi-organ autosomal recessive disease caused by mutations in LIPA. We reviewed data from 681 samples (white blood cells [WBC] n = 625, fibroblasts = 30, liver = 4, amniocytes = 13, chorionic villus = 9) received for analysis of lysosomal acid lipase (LAL) activity over a 15-year period. LIPA sequencing was performed in 49 patients with reduced (n = 26) or deficient (n = 23) LAL activity. The Exome Aggregation Consortium and Genome Aggregation Database dataset were used for LAL-D prevalence calculations. LAL WBC activity was reduced in 67 patients (10.72%) and deficient in 37 (5.92%). The average of LAL activity ± margin of error (CI 95%) was 19.32 ± 0.86 pmol/min/mg for reduced activity patients and 5.90 ± 1.42 pmol/min/mg for deficient patients. The average age at diagnosis for LAL-D was 23.6 years with several patients older than age 30. The correlation between the age at diagnosis and LAL activity showed a significant moderate direct correlation (Pearson's r = 0.46, P < 0.005). Homozygous or compound heterozygous mutations were identified in 9 out of 23 patients with deficient results (detection rate 39.1%). The average LAL activity in molecularly confirmed patients was 4.02 ± 2.02 pmol/min/mg protein, while in molecularly negative patients was 13.886 ± 1.49 pmol/min/mg (P < 0.0001). Twenty-two different mutations were identified including two novel variants (c.309C>A and c.856G>C). A carrier frequency of approximately 1 in 350 was inferred. LAL activity in WBC is a validated tool for LAL-D diagnosis. Higher residual enzymatic activity might result in a milder phenotype leading to diagnosis delay. A cut-off below 12 pmol/min/mg protein might be useful to discriminate patients with LIPA mutations.

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“…Wild‐type LIPA complementary DNA (cDNA), along with 149 variants, were selected for in vitro functional assessment as follows. All missense, nonsense, and 1/2 base pair frameshift variants from the patients with LAL deficiency are reported in references (Himes et al, ; Hooper, Tran, Formby, & Burnett, ; Kuranobu et al, ; Pisciotta et al, ; Reiner et al, ; Ries et al,; Santillán‐Hernández et al, ; Scott et al, ; Valayannopoulos et al, ). This resulted in 47 known pathogenic variants from the literature being chosen.…”

Section: Methodsmentioning

confidence: 99%

Large‐scale functionalLIPAvariant characterization to improve birth prevalence estimates of lysosomal acid lipase deficiency

et al. 2019

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Lysosomal acid lipase (LAL) deficiency is an autosomal recessive disorder caused by LIPA gene mutations that disrupt LAL activity. We performed in vitro functional testing of 149 LIPA variants to increase the understanding of the variant effects on LAL deficiency and to improve disease prevalence estimates. Chosen variants had been reported in literature or population databases. Functional testing was done by plasmid transient transfection and LAL activity assessment. We assembled a set of 165 published LAL deficient patient genotypes to evaluate this assay's effectiveness to recapitulate genotype/phenotype relationships. Rapidly progressive LAL deficient patients showed negligible enzymatic activity (<1%), whereas patients with childhood/adult LAL deficiency typically have 1–7% average activity. We benchmarked six in silico variant effect prediction algorithms with these functional data. PolyPhen‐2 was shown to have a superior area under the receiver operating curve performance. We used functional data along with Genome Aggregation Database (gnomAD) allele frequencies to estimate LAL deficiency birth prevalence, yielding a range of 3.45–5.97 cases per million births in European‐ancestry populations. The low estimate only considers functionally assayed variants in gnomAD. The high estimate computes allele frequencies for variants absent in gnomAD, and uses in silico scores for unassayed variants. Prevalence estimates are lower than previously published, underscoring LAL deficiency's rarity.

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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

Cited by 22 publications

References 26 publications

LIPA gene mutations affect the composition of lipoproteins: Enrichment in ACAT-derived cholesteryl esters

LIPA gene mutations affect the composition of lipoproteins: Enrichment in ACAT-derived cholesteryl esters

Opening a window on lysosomal acid lipase deficiency: Biochemical, molecular, and epidemiological insights

Large‐scale functionalLIPAvariant characterization to improve birth prevalence estimates of lysosomal acid lipase deficiency

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