Mutations identified in a cohort of Mexican patients with lysosomal acid lipase deficiency

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The new sequences are marked by black triangle and genotype D references by black square." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Seyed Y. Hosseini, Neda Sanaei, Mohamad-Reza Fattahi, Seyed A. Malek-Hosseini, Jamal Sarvari" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Seyed Y." "apellidos" => "Hosseini" ] 1 => array:2 [ "nombre" => "Neda" "apellidos" => "Sanaei" ] 2 => array:2 [ "nombre" => "Mohamad-Reza" "apellidos" => "Fattahi" ] 3 => array:2 [ "nombre" => "Seyed A." 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Cebolla" "autores" => array:6 [ 0 => array:4 [ "nombre" => "Alejandra" "apellidos" => "Consuelo-Sánchez" "email" => array:1 [ 0 => "draalejandraconsuelo@yahoo.com.mx" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Rodrigo" "apellidos" => "Vázquez-Frias" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Alejandra" "apellidos" => "Reyes-De La Rosa" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "Carlos P." "apellidos" => "Acosta-Rodríguez-Bueno" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "María P." 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"apellidos" => "Cebolla" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Department of Gastroenterology and Nutrition, Hospital Infantil de México Federico Gómez, Mexico City, Mexico" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Genetics, Hospital Infantil de México Federico Gómez, Mexico City, Mexico" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Group of Haematological and Metabolic Diseases, Translational Research Unit, Miguel Servet University Hospital, Zaragoza, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author at: Hospital Infantil de México Federico Gómez, Gastroenterology Research Office, Dr. Márquez 162, Doctores, Cuauhtémoc, 06720 México City, Mexico." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1372 "Ancho" => 2667 "Tamanyo" => 138944 ] ] "descripcion" => array:1 [ "en" => "LIPA gene. Location of variants found in the patients analyzed." ] ] ] "textoCompleto" => "1IntroductionLysosomal acid lipase deficiency (LAL-D) (MIM <a href="omim:278000">278000</a>) is an autosomal recessive disorder caused by mutations in the LIPA gene (MIM <a href="omim:613497">613497</a>) <a class="elsevierStyleCrossRef" href="#bib0105">[1]</a>, located on the long arm of chromosome 10 (10q23.31) <a class="elsevierStyleCrossRef" href="#bib0110">[2]</a>. In 1994, Aslanidis and collaborators <a class="elsevierStyleCrossRef" href="#bib0110">[2]</a> described that the gene was made up of 10 exons and measured 45kb <a class="elsevierStyleCrossRefs" href="#bib0115">[3,4]</a>. Intron 3 is characteristically wider than the rest (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) <a class="elsevierStyleCrossRefs" href="#bib0125">[5,6]</a>. The gene codes for the lysosomal acid lipase (LAL) protein, responsible for the hydrolysis of cholesteryl esters and triglycerides that have been internalized by the cell through lipoprotein endocytosis <a class="elsevierStyleCrossRef" href="#bib0135">[7]</a>; the misfunctioning of this enzyme leads to an accumulation of cholesteryl esters and triglycerides in the hepatocytes, intestine, adrenal glands and in the cells of the monocyte–macrophage system <a class="elsevierStyleCrossRef" href="#bib0140">[8]</a>.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Up until now, more than 59 gene mutations have been described, which together are the cause of a wide clinical spectrum (Human Gene Mutation Database, Institute of Medical Genetics at the University of Cardiff, <a href="http://www.hgmd.cf.ac.uk/">www.hgmd.cf.ac.uk</a>). A recurring pathogenic variant in which there is a substitution of guanine for adenine in position 894 of cDNA (c.894G>A) has been reported within European populations with a frequency of around 60% <a class="elsevierStyleCrossRef" href="#bib0145">[9]</a>. This protein-level alteration would not produce a change in the amino acid (p.Gln298Gln) due to redundancy in the genetic code; nevertheless, mRNA is generated before the synthesis of amino acid, in which the substitution of guanine for adenine modifies the splicing of exon 8, leading to the deletion of 24 amino acids (p.delS275_Q298) <a class="elsevierStyleCrossRef" href="#bib0150">[10]</a>. This alteration is known as E8SJM-1G>A (Exon 8 Splice Junction Mutation), and this protein-level change can be found in the literature as either p.Gln298Gln or p.delS275_Q298, without distinction <a class="elsevierStyleCrossRef" href="#bib0155">[11]</a>. There have also been described small deletions/insertions, inverted mutations, being less common than large deletions and directionless mutations <a class="elsevierStyleCrossRef" href="#bib0160">[12]</a>.Clinically, LAL-D results in two main phenotypes: Wolman disease (WD) (MIM <a href="omim:278000">278000</a>), with early onset in the neonatal stage, and which corresponds to a fulminant subtype of the disease; and cholesteryl ester storage disease (CESD), which normally has a later onset, although it may present itself from infancy up to adulthood with a chronic evolution, but which without treatment may finally turn fatal <a class="elsevierStyleCrossRefs" href="#bib0165">[13,14]</a>. It has been noted that when patients present a clinical picture beginning in the first months of life, it is due to directionless variants, such as in c.129C>G, which causes a codon for premature birth in position 43 of the amino acid (p,Tyr43*) <a class="elsevierStyleCrossRef" href="#bib0175">[15]</a> or in those that affect the reading frame (like c.414dup;p.Phe139llefs*7) <a class="elsevierStyleCrossRef" href="#bib0180">[16]</a>, in contrast to those that manifest themselves clinically in the first decade of life or in adulthood, where the variants found have a lesser effect on the sequence of amino acids and produce an enzyme with certain residual activity (such as c.386A>G;p.His129Arg) <a class="elsevierStyleCrossRef" href="#bib0175">[15]</a>. However, despite these findings, no one has been able to definitively establish a clear phenotype-genotype relationship <a class="elsevierStyleCrossRefs" href="#bib0155">[11,17,18]</a>.The goal of this study is to describe the mutations that are present in Mexican patients with a diagnosis of LAL-D.2Materials and methodsThis is a descriptive study which included every patient with LAL-D treated at the Federico Gómez Children's Hospital of Mexico (HIMFG, in Spanish) from January 2000 to June 2017. DNA genomes were obtained from peripheral blood from all pediatric patients with a diagnosis of LAL-D that had been confirmed by enzyme activity while capillary sequencing of the LIPA gene was carried out by the Molecular Development Laboratory at University of Washington, Department of Pediatrics in Seattle, by the Haemetological and Metabolic Diseases Group Translational Research Unit, of the Instituto de Investigación Sanitaria (IIS) Aragón, GIIS-012 CIBER Rare diseases (CIBERER) or at Neurogenetics DNA DiagnosticLaboratory, Massachusetts General Hospital, Boston, MA. All of the parents agreed to participate with their informed consent and patients eight years or older agreed to participate with their informed assent. Furthermore, the Research, Ethics, and Biosecurity Committees of the HIMFG gave their approval.3ResultsSixteen patients with LAL-D were identified, eight of whom were male. The median age at the time of diagnosis was 6.3 years old with an RIC of 4. All of the patients manifested the cholesteryl ester accumulation variant of LAL-D, while none had presented early onset or Wolman disease. Eight distinct varieties in the LIPA gene sequence were found: four pathogenic variants (c.260G>T;p.Gly87Val, c.386A>G;p.His129Arg, c.894G>A;p.delS275_Q298, c.1024G>A;p.Gly342Arg) and four variants previously reported as probably pathogenic or of unknown effect (c.67G>A;p.Gly23Arg, c.253C>A;p.Gln85Lys, c.294C>G;p.Asn98Lys, c.894G>C; p.Gln298His). In six individuals, the variants were found in the homozygous state and ten were compound heterozygous. The eight variants were inverted, with four found on exon 4 and the others on exons 2, 8 and 10 (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> and <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Four families were found among 15 of the individuals (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Individuals 3 and 4 are siblings from Mexico City, without antecedents of consanguinity. Two inverted variants were reported in them that produce a protein-level change (c.253C>A;p.Gln85Lys and c.294C>G;p.Asn98Lys) considered probably pathogenic. Individuals 5 and 13 are brothers belonging to a family from Villahermosa, Tabasco, also without antecedents of consanguinity. These patients were homozygous for the variant c.245C>A;pGly85Lys (reported as probably pathogenic). Individuals 6, 7 and 9 were members of the same family, heralding from Querétaro (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). The pathogenic variant E8SJM-1G>A (c.894G>A; p.delS275_Q298) was found in these patients in the homozygous state. Family 4 was made up of individuals 8 and 16. Patient 16 is the mother of patient 8; the initial diagnosis was made in patient 8. Patient 16 had remained asymptomatic; however, as part of the preparation for the study of patients with a diagnosis of LAL-D, their parents’ enzyme activity was measured. Patient 16 was found to have diminished enzyme activity, as well as hepatomegaly and dyslipidemia; for those reasons it was decided to undertake a LIPA gene capillary sequencing. The study found that individuals 8 and 16 are compound heterozygote and that both share the pathogenic variant E8SJM-1G>A (c.894G>A;p.delS275_Q298) in the heterozygous state. Individual 8 additionally presents the pathogenic variant c.1024G>A; p.Gly342Arg in the heterozygous state, which demonstrated that it had been inherited from the father (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Furthermore, patient 16 presents the probably pathogenic variant c.894G>C;p.Gln298His in the heterozygous state.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>4DiscussionThis study describes 16 Mexican individuals with a diagnosis of LAL-D. It represents the first reported cohort of Mexican patients and the largest in Latin America. Eight distinct variants were detected in the 16 individuals analyzed. The patients hail from different states of the country; despite this, the variant c.386A>G;p.His129Arg was found in six individuals, which represents 37.5% of our population. It was found in the heterozygous state in two patients (individuals 1 and 15, <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) and in the homozygous state in four patients (individuals 2, 11, 12 and 14, <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). None of the six individuals belong to the same family or to nearby locations. This variant has been previously reported in the literature and has been designated pathogenic, especially related to the CESD clinical setting. The frequency of this variant in the general European population was given as 0.009 <a class="elsevierStyleCrossRef" href="#bib0175">[15]</a>, which differs with what appears in this cohort of Mexican patients in which a much greater frequency is observed.On the other hand, the variant E8SJM-1G>A (c.894G>A; p.delS275_Q298), which is more common in European populations, was only found in four individuals among our population, three of whom belong to the same family and presented it in the homozygous state. Scott and collaborators reported that the frequency of the variant E8SJM-1G>A (c.894G>A; p.delS275_Q298) depends on the ethnic group being studied, which could explain the lower frequency discovered in our population <a class="elsevierStyleCrossRef" href="#bib0195">[19]</a>. Due to the unequal distribution of this variant, directed screening is not currently recommended for this alteration in those individuals with a clinical suspicion of LAL-D, but rather a complete gene sequencing <a class="elsevierStyleCrossRef" href="#bib0155">[11]</a>.The variant c.67G>A;p.Gly23Arg was found in the heterozygous state in three patients, all of whom come from different regions of the country. This variant has been considered as probably benign by bioinformatic prediction (SIFT and PolyPhen); there are two reports, however, in international databases (<a href="http://www.ncbi.nlm.nih.gov/">www.ncbi.nlm.nih.gov</a>), of two patients with this variant and Wolman disease. Due to this precedent and the three patients analyzed in this cohort who show a characteristic clinical picture for LAL-D, this could suggest that is a pathogenic variant.Patients 3 and 4 were previously described by Santillán-Hernández and collaborators, and they currently remain in treatment at our institution. These two sisters are compound heterozygote (c.253C>A;p.Gly85Lys and c.294C>G; p.Asn98Lys), and the variants found had not been previously reported in the literature; nevertheless, through models that predict the protein-level alteration along with the low enzyme activity present, it was concluded that these variants are probably pathogenic <a class="elsevierStyleCrossRef" href="#bib0200">[20]</a>. This study describes another two siblings with the variant c.253C>A;p.Gly85Lys in the homozygous state with a medical history of LAL-D and low enzyme activity; when taken together with evidence from the literature, it suggests that this variant can be considered pathogenic.The variant c.894G>C;pGln298His has previously been designated as probably pathogenic, a patient having been reported in an international database with clinical characteristics compatible with LAL-D (<a href="http://www.ncbi.nlm.nih.gov/">www.ncbi.nlm.nih.gov</a>). The PolyPhen-2 prediction model reports it as probably harmful, while SIFT as harmful. Individual 16's report with the presence of this variant contributes evidence for considering it a pathogenic variant.The rest of the variants found in this patient cohort (c.260G>T;p.Gly87Val, c.386A>G;p.His129Arg and c.1024G>A;p.Gly342Arg) had previously been reported in the literature and designated as pathogenic (Human Gene Mutation Database, Institute of Medical Genetics at the University of Cardiff, <a href="http://www.hgmd.cf.ac.uk/">www.hgmd.cf.ac.uk</a>).This is the largest study of pediatric patients with LAL-D in Latin America that describes found mutations. Mexican patients present a different frequency of mutations associated with LAL-D in comparison to European populations. The report on patients with variations previously referred to as probably pathogenic or of unknown effect along with characteristic clinical manifestations of LAL-D provide evidence for considering them pathogenic. Given the limited number of patients, we could not conclude that there exists a correlation between the genotype and phenotype of the disease.AbbreviationsAadenineAsnasparagineArgarginineCcytosinecDNAcomplementary deoxyribonucleic acidCESDcholesteryl ester storage diseaseDNAdeoxyribonucleic acidE8SJMExon 8 Splice Junction MutationGguanineGlnglutamineGlyglycineHIMFGHospital Infantil de México Federico Gómez (in spanish)HishistidinekbkilobaseLAL-Dlysosomal acid lipase deficiencyLIPAlipase A, lysosomal acid typeLyslysinemRNAmessenger ribonucleic acidPhephenylalaninePolyPhenpolymorphism phenotypingQglutamineRICinterquartile rangeSserineSIFTsorting intolerant from tolerantTthymineTyrtyrosineValvalineWDWolman diseaseFundingThere are no financial disclosures to declare.Authors’ contributionsDr ACS and Dr RVF participated equally and sufficiently in the intellectual content, assembled the research protocol, contribute analyzing the data, write the paper, review the statistical analysis and approved the final manuscript as submitted.Dr ARR contributes analyzing the data, writes the paper and approved the final manuscript as submitted.Dr CPAB, MPOV and JJC contribute analyzing the evidence, and approved the final manuscript as submitted.Conflicts of interestThe authors have no conflicts of interest to declare.Informed patient consentAll of the parents agreed to participate with their informed consent and patients eight years or older agreed to participate with their informed assent, including publication of the case details." 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Up until now, more than 59 mutations have been described and which are the cause of a very wide clinical spectrum. The goal of this study was to identify the mutations present in Mexican pediatric patients with a diagnosis of LAL-D. Materials and methodsA cross-sectional study was carried out which included all the pediatric patients with LAL-D treated in a tertiary hospital in Mexico from January 2000 to June 2017. ResultsSixteen patients with LAL-D were identified with a disease phenotype marked by the accumulation of cholesteryl esters. Eight distinct variants in the LIPA gene sequence were found, four pathogenic variants and four probably pathogenic. In six individuals, the variants were found in the homozygous state and ten were compound heterozygous. The eight variants were inverted, with five found on exon 4 and the others on exons 2, 8 and 10. The variant c.386A>G;p.His129Arg was the most common, being found in six of the 16 individuals (37.5%), making it much more frequent than what had previously been reported in the literature in proportion to the rest of the variants. The mutation known as E8SJM, which has been the mostly frequently found at the international level, was not the most common among this group of Mexican patients.In conclusion, Mexican patients present a different frequency of mutations associated with LAL-D in comparison to European populations." "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] ] ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1372 "Ancho" => 2667 "Tamanyo" => 138944 ] ] "descripcion" => array:1 [ "en" => "LIPA gene. Location of variants found in the patients analyzed." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1204 "Ancho" => 2083 "Tamanyo" => 44896 ] ] "descripcion" => array:1 [ "en" => "Family cases." ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "WD, Wolman disease; CESD, Cholesteryl Ester Storage Disease." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Patient \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Variant \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Change at the protein level \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Effect/phenotype reported<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.260G>Tc.386A>Gc.67G>A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HeterozygousHeterozygousHeterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p.Gly87Valp.His129Argp.Gly23Arg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pathogenic/WD, CESDPathogenic/CESDUnknown effect/WD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.386A>G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Homozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p.His129Arg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pathogenic/CESD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.253C>Ac.294C>G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HeterozygousHeterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p.Gln85Lysp.Asn98Lys \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Probably pathogenicProbably pathogenic \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.253C>Ac.294C>G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HeterozygousHeterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p.Gly85Lysp.Asn98Lys \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Probably pathogenicProbably pathogenic \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.253C>A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Homozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p.Gly85Lys \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Probably pathogenic \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.894G>A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Homozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p.delS275_Q298 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pathogenic/CESD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.894G>A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Homozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p.delS275_Q298 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pathogenic/CESD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.1024G>Ac.894G>A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HeterozygousHeterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p.Gly342Argp.delS275_Q298 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pathogenic/CESDPathogenic/CESD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.894G>A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Homozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p.delS275_Q298 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pathogenic/CESD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.67G>Ac.260G>T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HeterozygousHeterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p.Gly23Argp.Gly87Val \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Unknown effect/WDPathogenic/WD, CESD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.386A>G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Homozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p.His129Arg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pathogenic/CESD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.386A>G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Homozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p.His129Arg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pathogenic/CESD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.253C>A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Homozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p.Gly85Lys \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Probably pathogenic \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.386A>G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Homozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p.His129Arg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pathogenic/CESD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.67G>Ac.386A>G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HeterozygousHeterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p.Gly23Argp.His129Arg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Unknown effect/WDPathogenic/CESD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.894G>Ac.894G>C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HeterozygousHeterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p.delSer275_Gln298p.Gln298His \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pathogenic/CESDProbably pathogenic/WD \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2106823.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Patients previously reported in Santillán-Hernández et al. <a class="elsevierStyleCrossRef" href="#bib0200">[20]</a>." ] ] ] "descripcion" => array:1 [ "en" => "Variants of LIPA gene mutations found in the Mexican patients analyzed." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bib0105" "etiqueta" => "[1]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Lysosomal acid lipase deficiency: diagnosis and treatment of Wolman and Cholesteryl Ester Storage Diseases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "A.F. 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Alejandra Consuelo-Sáncheza,

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draalejandraconsuelo@yahoo.com.mx

Corresponding author at: Hospital Infantil de México Federico Gómez, Gastroenterology Research Office, Dr. Márquez 162, Doctores, Cuauhtémoc, 06720 México City, Mexico.

, Rodrigo Vázquez-Friasa, Alejandra Reyes-De La Rosab, Carlos P. Acosta-Rodríguez-Buenoa, María P. Ortal-Vitea, Jorge J. Cebollac

a Department of Gastroenterology and Nutrition, Hospital Infantil de México Federico Gómez, Mexico City, Mexico

b Department of Genetics, Hospital Infantil de México Federico Gómez, Mexico City, Mexico

c Group of Haematological and Metabolic Diseases, Translational Research Unit, Miguel Servet University Hospital, Zaragoza, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">1</span><span class="elsevierStyleSectionTitle" id="sect0030">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Lysosomal acid lipase deficiency &#40;LAL-D&#41; &#40;MIM <a href="omim:278000">278000</a>&#41; is an autosomal recessive disorder caused by mutations in the LIPA gene &#40;MIM <a href="omim:613497">613497</a>&#41; <a class="elsevierStyleCrossRef" href="#bib0105">&#91;1&#93;</a>&#44; located on the long arm of chromosome 10 &#40;10q23&#46;31&#41; <a class="elsevierStyleCrossRef" href="#bib0110">&#91;2&#93;</a>&#46; In 1994&#44; Aslanidis and collaborators <a class="elsevierStyleCrossRef" href="#bib0110">&#91;2&#93;</a> described that the gene was made up of 10 exons and measured 45<span class="elsevierStyleHsp" style=""></span>kb <a class="elsevierStyleCrossRefs" href="#bib0115">&#91;3&#44;4&#93;</a>&#46; Intron 3 is characteristically wider than the rest &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41; <a class="elsevierStyleCrossRefs" href="#bib0125">&#91;5&#44;6&#93;</a>&#46; The gene codes for the lysosomal acid lipase &#40;LAL&#41; protein&#44; responsible for the hydrolysis of cholesteryl esters and triglycerides that have been internalized by the cell through lipoprotein endocytosis <a class="elsevierStyleCrossRef" href="#bib0135">&#91;7&#93;</a>&#59; the misfunctioning of this enzyme leads to an accumulation of cholesteryl esters and triglycerides in the hepatocytes&#44; intestine&#44; adrenal glands and in the cells of the monocyte&#8211;macrophage system <a class="elsevierStyleCrossRef" href="#bib0140">&#91;8&#93;</a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">Up until now&#44; more than 59 gene mutations have been described&#44; which together are the cause of a wide clinical spectrum &#40;Human Gene Mutation Database&#44; Institute of Medical Genetics at the University of Cardiff&#44; <a href="http://www.hgmd.cf.ac.uk/">www&#46;hgmd&#46;cf&#46;ac&#46;uk</a>&#41;&#46; A recurring pathogenic variant in which there is a substitution of guanine for adenine in position 894 of cDNA &#40;c&#46;894G&#62;A&#41; has been reported within European populations with a frequency of around 60&#37; <a class="elsevierStyleCrossRef" href="#bib0145">&#91;9&#93;</a>&#46; This protein-level alteration would not produce a change in the amino acid &#40;p&#46;Gln298Gln&#41; due to redundancy in the genetic code&#59; nevertheless&#44; mRNA is generated before the synthesis of amino acid&#44; in which the substitution of guanine for adenine modifies the splicing of exon 8&#44; leading to the deletion of 24 amino acids &#40;p&#46;delS275&#95;Q298&#41; <a class="elsevierStyleCrossRef" href="#bib0150">&#91;10&#93;</a>&#46; This alteration is known as E8SJM<span class="elsevierStyleSup">-1G&#62;A</span> &#40;Exon 8 Splice Junction Mutation&#41;&#44; and this protein-level change can be found in the literature as either p&#46;Gln298Gln or p&#46;delS275&#95;Q298&#44; without distinction <a class="elsevierStyleCrossRef" href="#bib0155">&#91;11&#93;</a>&#46; There have also been described small deletions&#47;insertions&#44; inverted mutations&#44; being less common than large deletions and directionless mutations <a class="elsevierStyleCrossRef" href="#bib0160">&#91;12&#93;</a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Clinically&#44; LAL-D results in two main phenotypes&#58; Wolman disease &#40;WD&#41; &#40;MIM <a href="omim:278000">278000</a>&#41;&#44; with early onset in the neonatal stage&#44; and which corresponds to a fulminant subtype of the disease&#59; and cholesteryl ester storage disease &#40;CESD&#41;&#44; which normally has a later onset&#44; although it may present itself from infancy up to adulthood with a chronic evolution&#44; but which without treatment may finally turn fatal <a class="elsevierStyleCrossRefs" href="#bib0165">&#91;13&#44;14&#93;</a>&#46; It has been noted that when patients present a clinical picture beginning in the first months of life&#44; it is due to directionless variants&#44; such as in c&#46;129C&#62;G&#44; which causes a codon for premature birth in position 43 of the amino acid &#40;p&#44;Tyr43&#42;&#41; <a class="elsevierStyleCrossRef" href="#bib0175">&#91;15&#93;</a> or in those that affect the reading frame &#40;like c&#46;414dup&#59;p&#46;Phe139llefs&#42;7&#41; <a class="elsevierStyleCrossRef" href="#bib0180">&#91;16&#93;</a>&#44; in contrast to those that manifest themselves clinically in the first decade of life or in adulthood&#44; where the variants found have a lesser effect on the sequence of amino acids and produce an enzyme with certain residual activity &#40;such as c&#46;386A&#62;G&#59;p&#46;His129Arg&#41; <a class="elsevierStyleCrossRef" href="#bib0175">&#91;15&#93;</a>&#46; However&#44; despite these findings&#44; no one has been able to definitively establish a clear phenotype-genotype relationship <a class="elsevierStyleCrossRefs" href="#bib0155">&#91;11&#44;17&#44;18&#93;</a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The goal of this study is to describe the mutations that are present in Mexican patients with a diagnosis of LAL-D&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2</span><span class="elsevierStyleSectionTitle" id="sect0035">Materials and methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">This is a descriptive study which included every patient with LAL-D treated at the Federico G&#243;mez Children&#39;s Hospital of Mexico &#40;HIMFG&#44; in Spanish&#41; from January 2000 to June 2017&#46; DNA genomes were obtained from peripheral blood from all pediatric patients with a diagnosis of LAL-D that had been confirmed by enzyme activity while capillary sequencing of the LIPA gene was carried out by the Molecular Development Laboratory at University of Washington&#44; Department of Pediatrics in Seattle&#44; by the Haemetological and Metabolic Diseases Group Translational Research Unit&#44; of the Instituto de Investigaci&#243;n Sanitaria &#40;IIS&#41; Arag&#243;n&#44; GIIS-012 CIBER Rare diseases &#40;CIBERER&#41; or at Neurogenetics DNA Diagnostic</p><p id="par0030" class="elsevierStylePara elsevierViewall">Laboratory&#44; Massachusetts General Hospital&#44; Boston&#44; MA&#46; All of the parents agreed to participate with their informed consent and patients eight years or older agreed to participate with their informed assent&#46; Furthermore&#44; the Research&#44; Ethics&#44; and Biosecurity Committees of the HIMFG gave their approval&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3</span><span class="elsevierStyleSectionTitle" id="sect0040">Results</span><p id="par0035" class="elsevierStylePara elsevierViewall">Sixteen patients with LAL-D were identified&#44; eight of whom were male&#46; The median age at the time of diagnosis was 6&#46;3 years old with an RIC of 4&#46; All of the patients manifested the cholesteryl ester accumulation variant of LAL-D&#44; while none had presented early onset or Wolman disease&#46; Eight distinct varieties in the LIPA gene sequence were found&#58; four pathogenic variants &#40;c&#46;260G&#62;T&#59;p&#46;Gly87Val&#44; c&#46;386A&#62;G&#59;p&#46;His129Arg&#44; c&#46;894G&#62;A&#59;p&#46;delS275&#95;Q298&#44; c&#46;1024G&#62;A&#59;p&#46;Gly342Arg&#41; and four variants previously reported as probably pathogenic or of unknown effect &#40;c&#46;67G&#62;A&#59;p&#46;Gly23Arg&#44; c&#46;253C&#62;A&#59;p&#46;Gln85Lys&#44; c&#46;294C&#62;G&#59;p&#46;Asn98Lys&#44; c&#46;894G&#62;C&#59; p&#46;Gln298His&#41;&#46; In six individuals&#44; the variants were found in the homozygous state and ten were compound heterozygous&#46; The eight variants were inverted&#44; with four found on exon 4 and the others on exons 2&#44; 8 and 10 &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> and <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">Four families were found among 15 of the individuals &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Individuals 3 and 4 are siblings from Mexico City&#44; without antecedents of consanguinity&#46; Two inverted variants were reported in them that produce a protein-level change &#40;c&#46;253C&#62;A&#59;p&#46;Gln85Lys and c&#46;294C&#62;G&#59;p&#46;Asn98Lys&#41; considered probably pathogenic&#46; Individuals 5 and 13 are brothers belonging to a family from Villahermosa&#44; Tabasco&#44; also without antecedents of consanguinity&#46; These patients were homozygous for the variant c&#46;245C&#62;A&#59;pGly85Lys &#40;reported as probably pathogenic&#41;&#46; Individuals 6&#44; 7 and 9 were members of the same family&#44; heralding from Quer&#233;taro &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; The pathogenic variant E8SJM<span class="elsevierStyleSup">-1G&#62;A</span> &#40;c&#46;894G&#62;A&#59; p&#46;delS275&#95;Q298&#41; was found in these patients in the homozygous state&#46; Family 4 was made up of individuals 8 and 16&#46; Patient 16 is the mother of patient 8&#59; the initial diagnosis was made in patient 8&#46; Patient 16 had remained asymptomatic&#59; however&#44; as part of the preparation for the study of patients with a diagnosis of LAL-D&#44; their parents&#8217; enzyme activity was measured&#46; Patient 16 was found to have diminished enzyme activity&#44; as well as hepatomegaly and dyslipidemia&#59; for those reasons it was decided to undertake a LIPA gene capillary sequencing&#46; The study found that individuals 8 and 16 are compound heterozygote and that both share the pathogenic variant E8SJM<span class="elsevierStyleSup">-1G&#62;A</span> &#40;c&#46;894G&#62;A&#59;p&#46;delS275&#95;Q298&#41; in the heterozygous state&#46; Individual 8 additionally presents the pathogenic variant c&#46;1024G&#62;A&#59; p&#46;Gly342Arg in the heterozygous state&#44; which demonstrated that it had been inherited from the father &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Furthermore&#44; patient 16 presents the probably pathogenic variant c&#46;894G&#62;C&#59;p&#46;Gln298His in the heterozygous state&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">4</span><span class="elsevierStyleSectionTitle" id="sect0045">Discussion</span><p id="par0045" class="elsevierStylePara elsevierViewall">This study describes 16 Mexican individuals with a diagnosis of LAL-D&#46; It represents the first reported cohort of Mexican patients and the largest in Latin America&#46; Eight distinct variants were detected in the 16 individuals analyzed&#46; The patients hail from different states of the country&#59; despite this&#44; the variant c&#46;386A&#62;G&#59;p&#46;His129Arg was found in six individuals&#44; which represents 37&#46;5&#37; of our population&#46; It was found in the heterozygous state in two patients &#40;individuals 1 and 15&#44; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; and in the homozygous state in four patients &#40;individuals 2&#44; 11&#44; 12 and 14&#44; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; None of the six individuals belong to the same family or to nearby locations&#46; This variant has been previously reported in the literature and has been designated pathogenic&#44; especially related to the CESD clinical setting&#46; The frequency of this variant in the general European population was given as 0&#46;009 <a class="elsevierStyleCrossRef" href="#bib0175">&#91;15&#93;</a>&#44; which differs with what appears in this cohort of Mexican patients in which a much greater frequency is observed&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">On the other hand&#44; the variant E8SJM<span class="elsevierStyleSup">-1G&#62;A</span> &#40;c&#46;894G&#62;A&#59; p&#46;delS275&#95;Q298&#41;&#44; which is more common in European populations&#44; was only found in four individuals among our population&#44; three of whom belong to the same family and presented it in the homozygous state&#46; Scott and collaborators reported that the frequency of the variant E8SJM<span class="elsevierStyleSup">-1G&#62;A</span> &#40;c&#46;894G&#62;A&#59; p&#46;delS275&#95;Q298&#41; depends on the ethnic group being studied&#44; which could explain the lower frequency discovered in our population <a class="elsevierStyleCrossRef" href="#bib0195">&#91;19&#93;</a>&#46; Due to the unequal distribution of this variant&#44; directed screening is not currently recommended for this alteration in those individuals with a clinical suspicion of LAL-D&#44; but rather a complete gene sequencing <a class="elsevierStyleCrossRef" href="#bib0155">&#91;11&#93;</a>&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The variant c&#46;67G&#62;A&#59;p&#46;Gly23Arg was found in the heterozygous state in three patients&#44; all of whom come from different regions of the country&#46; This variant has been considered as probably benign by bioinformatic prediction &#40;SIFT and PolyPhen&#41;&#59; there are two reports&#44; however&#44; in international databases &#40;<a href="http://www.ncbi.nlm.nih.gov/">www&#46;ncbi&#46;nlm&#46;nih&#46;gov</a>&#41;&#44; of two patients with this variant and Wolman disease&#46; Due to this precedent and the three patients analyzed in this cohort who show a characteristic clinical picture for LAL-D&#44; this could suggest that is a pathogenic variant&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Patients 3 and 4 were previously described by Santill&#225;n-Hern&#225;ndez and collaborators&#44; and they currently remain in treatment at our institution&#46; These two sisters are compound heterozygote &#40;c&#46;253C&#62;A&#59;p&#46;Gly85Lys and c&#46;294C&#62;G&#59; p&#46;Asn98Lys&#41;&#44; and the variants found had not been previously reported in the literature&#59; nevertheless&#44; through models that predict the protein-level alteration along with the low enzyme activity present&#44; it was concluded that these variants are probably pathogenic <a class="elsevierStyleCrossRef" href="#bib0200">&#91;20&#93;</a>&#46; This study describes another two siblings with the variant c&#46;253C&#62;A&#59;p&#46;Gly85Lys in the homozygous state with a medical history of LAL-D and low enzyme activity&#59; when taken together with evidence from the literature&#44; it suggests that this variant can be considered pathogenic&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The variant c&#46;894G&#62;C&#59;pGln298His has previously been designated as probably pathogenic&#44; a patient having been reported in an international database with clinical characteristics compatible with LAL-D &#40;<a href="http://www.ncbi.nlm.nih.gov/">www&#46;ncbi&#46;nlm&#46;nih&#46;gov</a>&#41;&#46; The PolyPhen-2 prediction model reports it as probably harmful&#44; while SIFT as harmful&#46; Individual 16&#39;s report with the presence of this variant contributes evidence for considering it a pathogenic variant&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">The rest of the variants found in this patient cohort &#40;c&#46;260G&#62;T&#59;p&#46;Gly87Val&#44; c&#46;386A&#62;G&#59;p&#46;His129Arg and c&#46;1024G&#62;A&#59;p&#46;Gly342Arg&#41; had previously been reported in the literature and designated as pathogenic &#40;Human Gene Mutation Database&#44; Institute of Medical Genetics at the University of Cardiff&#44; <a href="http://www.hgmd.cf.ac.uk/">www&#46;hgmd&#46;cf&#46;ac&#46;uk</a>&#41;&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">This is the largest study of pediatric patients with LAL-D in Latin America that describes found mutations&#46; Mexican patients present a different frequency of mutations associated with LAL-D in comparison to European populations&#46; The report on patients with variations previously referred to as probably pathogenic or of unknown effect along with characteristic clinical manifestations of LAL-D provide evidence for considering them pathogenic&#46; Given the limited number of patients&#44; we could not conclude that there exists a correlation between the genotype and phenotype of the disease&#46;<span class="elsevierStyleDefList"><span class="elsevierStyleSectionTitle" id="sect0050">Abbreviations</span><span class="elsevierStyleDefTerm">A</span><span class="elsevierStyleDefDescription"><p id="par0080" class="elsevierStylePara elsevierViewall">adenine</p></span><span class="elsevierStyleDefTerm">Asn</span><span class="elsevierStyleDefDescription"><p id="par0085" class="elsevierStylePara elsevierViewall">asparagine</p></span><span class="elsevierStyleDefTerm">Arg</span><span class="elsevierStyleDefDescription"><p id="par0090" class="elsevierStylePara elsevierViewall">arginine</p></span><span class="elsevierStyleDefTerm">C</span><span class="elsevierStyleDefDescription"><p id="par0095" class="elsevierStylePara elsevierViewall">cytosine</p></span><span class="elsevierStyleDefTerm">cDNA</span><span class="elsevierStyleDefDescription"><p id="par0100" class="elsevierStylePara elsevierViewall">complementary deoxyribonucleic acid</p></span><span class="elsevierStyleDefTerm">CESD</span><span class="elsevierStyleDefDescription"><p id="par0105" class="elsevierStylePara elsevierViewall">cholesteryl ester storage disease</p></span><span class="elsevierStyleDefTerm">DNA</span><span class="elsevierStyleDefDescription"><p id="par0110" class="elsevierStylePara elsevierViewall">deoxyribonucleic acid</p></span><span class="elsevierStyleDefTerm">E8SJM</span><span class="elsevierStyleDefDescription"><p id="par0115" class="elsevierStylePara elsevierViewall">Exon 8 Splice Junction Mutation</p></span><span class="elsevierStyleDefTerm">G</span><span class="elsevierStyleDefDescription"><p id="par0120" class="elsevierStylePara elsevierViewall">guanine</p></span><span class="elsevierStyleDefTerm">Gln</span><span class="elsevierStyleDefDescription"><p id="par0125" class="elsevierStylePara elsevierViewall">glutamine</p></span><span class="elsevierStyleDefTerm">Gly</span><span class="elsevierStyleDefDescription"><p id="par0130" class="elsevierStylePara elsevierViewall">glycine</p></span><span class="elsevierStyleDefTerm">HIMFG</span><span class="elsevierStyleDefDescription"><p id="par0135" class="elsevierStylePara elsevierViewall">Hospital Infantil de M&#233;xico Federico G&#243;mez &#40;in spanish&#41;</p></span><span class="elsevierStyleDefTerm">His</span><span class="elsevierStyleDefDescription"><p id="par0140" class="elsevierStylePara elsevierViewall">histidine</p></span><span class="elsevierStyleDefTerm">kb</span><span class="elsevierStyleDefDescription"><p id="par0145" class="elsevierStylePara elsevierViewall">kilobase</p></span><span class="elsevierStyleDefTerm">LAL-D</span><span class="elsevierStyleDefDescription"><p id="par0150" class="elsevierStylePara elsevierViewall">lysosomal acid lipase deficiency</p></span><span class="elsevierStyleDefTerm">LIPA</span><span class="elsevierStyleDefDescription"><p id="par0155" class="elsevierStylePara elsevierViewall">lipase A&#44; lysosomal acid type</p></span><span class="elsevierStyleDefTerm">Lys</span><span class="elsevierStyleDefDescription"><p id="par0160" class="elsevierStylePara elsevierViewall">lysine</p></span><span class="elsevierStyleDefTerm">mRNA</span><span class="elsevierStyleDefDescription"><p id="par0165" class="elsevierStylePara elsevierViewall">messenger ribonucleic acid</p></span><span class="elsevierStyleDefTerm">Phe</span><span class="elsevierStyleDefDescription"><p id="par0170" class="elsevierStylePara elsevierViewall">phenylalanine</p></span><span class="elsevierStyleDefTerm">PolyPhen</span><span class="elsevierStyleDefDescription"><p id="par0175" class="elsevierStylePara elsevierViewall">polymorphism phenotyping</p></span><span class="elsevierStyleDefTerm">Q</span><span class="elsevierStyleDefDescription"><p id="par0180" class="elsevierStylePara elsevierViewall">glutamine</p></span><span class="elsevierStyleDefTerm">RIC</span><span class="elsevierStyleDefDescription"><p id="par0185" class="elsevierStylePara elsevierViewall">interquartile range</p></span><span class="elsevierStyleDefTerm">S</span><span class="elsevierStyleDefDescription"><p id="par0190" class="elsevierStylePara elsevierViewall">serine</p></span><span class="elsevierStyleDefTerm">SIFT</span><span class="elsevierStyleDefDescription"><p id="par0195" class="elsevierStylePara elsevierViewall">sorting intolerant from tolerant</p></span><span class="elsevierStyleDefTerm">T</span><span class="elsevierStyleDefDescription"><p id="par0200" class="elsevierStylePara elsevierViewall">thymine</p></span><span class="elsevierStyleDefTerm">Tyr</span><span class="elsevierStyleDefDescription"><p id="par0205" class="elsevierStylePara elsevierViewall">tyrosine</p></span><span class="elsevierStyleDefTerm">Val</span><span class="elsevierStyleDefDescription"><p id="par0210" class="elsevierStylePara elsevierViewall">valine</p></span><span class="elsevierStyleDefTerm">WD</span><span class="elsevierStyleDefDescription"><p id="par0215" class="elsevierStylePara elsevierViewall">Wolman disease</p></span></span></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Funding</span><p id="par0220" class="elsevierStylePara elsevierViewall">There are no financial disclosures to declare&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Authors&#8217; contributions</span><p id="par0225" class="elsevierStylePara elsevierViewall">Dr ACS and Dr RVF participated equally and sufficiently in the intellectual content&#44; assembled the research protocol&#44; contribute analyzing the data&#44; write the paper&#44; review the statistical analysis and approved the final manuscript as submitted&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Dr ARR contributes analyzing the data&#44; writes the paper and approved the final manuscript as submitted&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">Dr CPAB&#44; MPOV and JJC contribute analyzing the evidence&#44; and approved the final manuscript as submitted&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conflicts of interest</span><p id="par0240" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Informed patient consent</span><p id="par0245" class="elsevierStylePara elsevierViewall">All of the parents agreed to participate with their informed consent and patients eight years or older agreed to participate with their informed assent&#44; including publication of the case details&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Lysosomal acid lipase deficiency &#40;LAL-D&#41; is an autosomal recessive disease caused by mutations in the LIPA gene&#44; located on the long arm of chromosome 10 &#40;10q23&#46;31&#41;&#46; Up until now&#44; more than 59 mutations have been described and which are the cause of a very wide clinical spectrum&#46; The goal of this study was to identify the mutations present in Mexican pediatric patients with a diagnosis of LAL-D&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Materials and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A cross-sectional study was carried out which included all the pediatric patients with LAL-D treated in a tertiary hospital in Mexico from January 2000 to June 2017&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Sixteen patients with LAL-D were identified with a disease phenotype marked by the accumulation of cholesteryl esters&#46; Eight distinct variants in the LIPA gene sequence were found&#44; four pathogenic variants and four probably pathogenic&#46; In six individuals&#44; the variants were found in the homozygous state and ten were compound heterozygous&#46; The eight variants were inverted&#44; with five found on exon 4 and the others on exons 2&#44; 8 and 10&#46; The variant c&#46;386A&#62;G&#59;p&#46;His129Arg was the most common&#44; being found in six of the 16 individuals &#40;37&#46;5&#37;&#41;&#44; making it much more frequent than what had previously been reported in the literature in proportion to the rest of the variants&#46; The mutation known as E8SJM&#44; which has been the mostly frequently found at the international level&#44; was not the most common among this group of Mexican patients&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">In conclusion&#44; Mexican patients present a different frequency of mutations associated with LAL-D in comparison to European populations&#46;</p></span>"
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        "etiqueta" => "Fig&#46; 2"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Patient&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Variant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Change at the protein level&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Effect&#47;phenotype reported<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;260G&#62;Tc&#46;386A&#62;Gc&#46;67G&#62;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HeterozygousHeterozygousHeterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">p&#46;Gly87Valp&#46;His129Argp&#46;Gly23Arg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pathogenic&#47;WD&#44; CESDPathogenic&#47;CESDUnknown effect&#47;WD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;386A&#62;G&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Homozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">p&#46;His129Arg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pathogenic&#47;CESD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;253C&#62;Ac&#46;294C&#62;G&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HeterozygousHeterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">p&#46;Gln85Lysp&#46;Asn98Lys&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Probably pathogenicProbably pathogenic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;253C&#62;Ac&#46;294C&#62;G&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HeterozygousHeterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">p&#46;Gly85Lysp&#46;Asn98Lys&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Probably pathogenicProbably pathogenic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;253C&#62;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Homozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">p&#46;Gly85Lys&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Probably pathogenic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;894G&#62;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Homozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">p&#46;delS275&#95;Q298&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pathogenic&#47;CESD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;894G&#62;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Homozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">p&#46;delS275&#95;Q298&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pathogenic&#47;CESD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;1024G&#62;Ac&#46;894G&#62;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HeterozygousHeterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">p&#46;Gly342Argp&#46;delS275&#95;Q298&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pathogenic&#47;CESDPathogenic&#47;CESD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;894G&#62;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Homozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">p&#46;delS275&#95;Q298&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pathogenic&#47;CESD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;67G&#62;Ac&#46;260G&#62;T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HeterozygousHeterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">p&#46;Gly23Argp&#46;Gly87Val&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Unknown effect&#47;WDPathogenic&#47;WD&#44; CESD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;386A&#62;G&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Homozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">p&#46;His129Arg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pathogenic&#47;CESD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;386A&#62;G&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Homozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">p&#46;His129Arg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Pathogenic&#47;CESD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">13&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">c&#46;253C&#62;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Homozygous&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  """
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Variants of LIPA gene mutations found in the Mexican patients analyzed&#46;</p>"
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Article information

ISSN: 16652681
Original language: English

DOI:10.1016/j.aohep.2018.07.005

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	3	0	3
2024 October	17	5	22
2024 September	20	5	25
2024 August	21	3	24
2024 July	11	2	13
2024 June	11	6	17
2024 May	13	5	18
2024 April	19	25	44
2024 March	23	11	34
2024 February	13	5	18
2024 January	14	5	19
2023 December	18	9	27
2023 November	17	9	26
2023 October	13	14	27
2023 September	14	8	22
2023 August	11	8	19
2023 July	29	13	42
2023 June	19	7	26
2023 May	40	2	42
2023 April	55	5	60
2023 March	75	5	80
2023 February	19	6	25
2023 January	26	8	34
2022 December	37	11	48
2022 November	18	12	30
2022 October	23	6	29
2022 September	26	9	35
2022 August	21	10	31
2022 July	27	7	34
2022 June	37	8	45
2022 May	36	17	53
2022 April	23	22	45
2022 March	30	12	42
2022 February	12	4	16
2022 January	27	5	32
2021 December	28	13	41
2021 November	12	8	20
2021 October	37	16	53
2021 September	22	11	33
2021 August	18	8	26
2021 July	25	5	30
2021 June	12	6	18
2021 May	18	19	37
2021 April	27	31	58
2021 March	11	3	14
2021 February	6	7	13
2021 January	15	9	24
2020 December	11	8	19
2020 November	11	5	16
2020 October	13	5	18
2020 September	19	9	28
2020 August	10	5	15
2020 July	8	8	16
2020 June	10	1	11
2020 May	13	10	23
2020 April	11	1	12
2020 March	22	5	27
2020 February	13	7	20
2020 January	10	7	17
2019 December	12	2	14
2019 November	16	3	19
2019 October	16	5	21
2019 September	17	9	26
2019 August	29	7	36
2019 July	28	33	61
2019 June	6	21	27
2019 May	12	16	28

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