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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Our knowledge of spinal muscular atrophy &#40;SMA&#41; has advanced considerably since the earliest descriptions done by Werdnig&#44; in 1891&#44; and Hoffmann&#44; in 1893&#46; We know that it is due to a defect in the translation of the telomeric survival motor neuron &#40;SMN&#41; protein&#44; which seems to play a role in several essential cellular functions &#40;RNA metabolism&#44; processing&#44; and splicing&#41; and other functions more specifically related to the survival of alpha motor neurons &#40;apoptosis&#44; axonal transport&#41; in the anterior horn of the spinal cord&#46; The SMN protein is encoded by the <span class="elsevierStyleItalic">SMN1</span> and <span class="elsevierStyleItalic">SMN2</span> genes&#46; The literature describes a worldwide incidence of approximately 1 in 10&#44;000 live births&#44; with 1 out of 40 people being carriers of the disease&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The classical clinical picture of SMA is predominantly proximal muscle weakness and atrophy&#44; with ages of onset and severity that vary depending on the clinical type of SMA&#46; Traditionally&#44; the classification of SMA comprised 3 types&#58; infantile&#44; juvenile&#44; and adult&#46; At present&#44; the International Consensus Statement for Standard Care in SMA<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">1&#44;2</span></a> classifies it into more types based on the age of onset and clinical course&#44; dividing type III into subtypes according to the age of onset&#46; Type IV was added for adult-onset cases&#44; and type 0 for cases with prenatal onset&#44; which result in death within the first weeks of life &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; While there is clinical variability among individuals in each type and up to 25&#37; of the patients cannot be categorised&#44; this classification is useful for clinical practice and prognosis&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">The gene involved in SMA&#44; discovered in 1995&#44;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">3</span></a> is located in the long arm of chromosome 5 &#40;5q11&#46;1-13&#46;3&#41;&#46; It has been named <span class="elsevierStyleItalic">SMN</span> for &#8220;survival motor neuron&#8221;&#46; Humans have two nearly identical copies of this gene that have been called <span class="elsevierStyleItalic">SMN1</span> and <span class="elsevierStyleItalic">SMN2</span>&#46; They differ in a single nucleotide at the beginning of exon 7 &#40;C in <span class="elsevierStyleItalic">SMN1</span> and T in <span class="elsevierStyleItalic">SMN2</span>&#41; that is important in the splicing of the SMN RNA&#46; We do not know why this ubiquitous protein causes this highly selective neuronal disease&#46; Deletions in <span class="elsevierStyleItalic">SMN1</span> cause SMA&#46; Approximately 95&#37; of SMA patients have homozygous absence of exons 7 and 8 of the <span class="elsevierStyleItalic">SMN1</span> gene&#44; and about 5&#37; are compound heterozygous for absence of exons 7 and 8 in one <span class="elsevierStyleItalic">SMN1</span> allele and a point mutation in the other&#46; Deletions in the <span class="elsevierStyleItalic">SMN2</span> gene do not cause the disease&#59; instead&#44; it is the number of copies of this gene&#44; which may vary&#44; that has an effect on the phenotype and determines the severity of SMA&#44; with a greater number of <span class="elsevierStyleItalic">SMN2</span> copies correlating to a milder phenotype&#44; although there are other factors at play&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">4&#44;5</span></a> In this regard&#44; it has been hypothesised that the disease could be treated with gene therapy by induced overexpression of the <span class="elsevierStyleItalic">SMN2</span> gene&#44; and the day when this terrible disease can be mitigated may not be far away&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">6&#44;7</span></a>Another genetic approach that was successful in an experimental study was the insertion of the <span class="elsevierStyleItalic">SMN</span> gene by means of viral vectors in the genome of a mouse model of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">8</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Other forms of disease with clinical features that overlap with SMA&#44; with subtle differences&#44; are associated to different genes&#46; Cases associated with chromosome 11 alterations have been described &#40;spinal muscular atrophy with respiratory distress type 1 &#91;SMARD1&#93;&#41;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#44;10</span></a> as well as cases of early-onset recessive X-linked disease in males &#40;Kennedy&#39;s disease&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">11&#44;12</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The aim of this study was to determine the present incidence of SMA in our population&#44; its genotype distribution&#44; and its epidemiological and clinical characteristics in the past 25 years in the context of our current knowledge&#44; and to assess the level of care and the outcomes of SMA in our setting based on the international consensus&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">1&#44;2</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">We performed a retrospective descriptive study by reviewing the clinical histories of patients with a clinical and neurophysiological diagnosis of spinal muscular atrophy assessed in our hospital in the past 25 years &#40;from 1987 to early 2013&#41;&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">We collected data for epidemiological&#44; clinical and genetic variables&#44; the supportive care received&#44; 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the number of copies of the <span class="elsevierStyleItalic">SMN</span> gene was quantified by multiplex ligation-dependent probe amplification&#46; In patients with a single copy of the <span class="elsevierStyleItalic">SMN1</span> gene &#40;the other copy may be inactivated by a mutation&#41; we sequenced the DNA of the coding part of the <span class="elsevierStyleItalic">SMN1</span> gene to detect potential deletions&#44; duplications and point mutations&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Overall epidemiological results</span><p id="par0050" class="elsevierStylePara elsevierViewall">We found 37 patients who met the inclusion criteria&#44; which amounts to an approximate incidence in our reference population and year of 1&#46;41 cases per 15&#44;000 live births &#40;1 case per 10&#44;638 live births&#41;&#46; Fourteen patients were diagnosed between 1987 and 1999&#44; while the number of diagnoses rose to 23 for the 2000 to 2013 interval&#44; showing a clear increase in the number of diagnosed cases&#46; Before 1995&#44; cases were diagnosed by the identification of carriers in the family in 3 cases&#44; and in other 3 the genetics of the patients were studied at a later point&#44; as 2 of these patients had SMA type II and the other one SMA type III&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Most patients came from our reference area &#40;31&#47;37&#41;&#46; The male sex predominated&#44; with 23 cases in male patients and a 1&#46;6 to 1 male to female ratio&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The mean age at the onset of symptoms was 2&#46;2 months for type I SMA &#40;range&#44; 0&#8211;7 months&#41; and 11&#46;2 months for type II &#40;range&#44; 6&#8211;18 months&#41;&#46; On the other hand&#44; the only patient diagnosed with type III SMA was 12 months of age at the clinical onset&#44; while the patient diagnosed with spinal muscular atrophy with respiratory distress &#40;SMARD1&#41; developed symptoms in the first month of life&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Clinical results</span><p id="par0065" class="elsevierStylePara elsevierViewall">The most frequent type of SMA was type I&#44; found in 26 patients&#44; and followed by type II in 9&#46; One case was diagnosed as type III SMA and another as SMARD1&#46; There were no cases of X-linked inheritance &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">The presenting symptom in most patients was hypotonia&#44; which occurred in 27 out of the 37 cases&#44; followed by motor delay in 5 of the 37 cases&#46; In 4 patients&#44; type I SMA was associated with sucking and swallowing difficulties&#44; and 2 of them had episodes of choking&#59; another patient&#44; who had type I SMA&#44; was diagnosed following a life-threatening episode of apnoea&#46; None of our patients had onset with arthrogryposis&#44; nor they met the criteria for type 0 SMA&#46; The presenting symptom in 3 patients was respiratory distress associated with intercurrent infection&#44; and gait disorder in 2 patients &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">There were a total of 92 documented pregnancies in the families of the patients&#44; which included 9 cases of spontaneous miscarriage and one case of voluntary termination of pregnancy&#46; The nine miscarriages occurred in the families of 18 patients with type I SMA who were being followed up in our hospital &#40;families in which there were a total of 47 pregnancies&#44; corresponding to a 19&#46;1&#37; spontaneous miscarriage rate in this group&#41;&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Seven of the 37 patients had a family history of SMA&#44; and 3 had a family history of idiopathic muscle weakness&#46; In 4 patients there was a family history of neonatal death&#59; 3 of these deaths occurred in the early neonatal period in siblings of one of the patients&#44; who had onset with hypotonia at 8 days of age&#46; The remaining 23 cases had no family history of neurological disease or associated symptoms &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Genetic testing</span><p id="par0085" class="elsevierStylePara elsevierViewall">Genetic testing was carried out in 36 patients&#46; The number of copies of the <span class="elsevierStyleItalic">SMN2</span> gene could not be determined in most patients&#46; The most frequent genetic alteration was the homozygous deletion of exons 7 and 8 of the <span class="elsevierStyleItalic">SMN1</span> gene&#44; found in 31 out of the 36 cases&#44; while 5 patients had atypical genetics&#46; Four patients had compound heterozygous mutations with a classical deletion in one copy of the <span class="elsevierStyleItalic">SMN1</span> gene and a non-functional truncated copy of the other resulting from different mutations&#58; deletion of exons 1&#8211;6 in two cases&#44; deletion of exon 1 in one case&#44; and a 773insC mutation in the remaining case&#46; Lastly&#44; the patient diagnosed with SMA with respiratory distress had polymorphic changes in the <span class="elsevierStyleItalic">IGHMPB2</span> gene of chromosome 11 &#40;ex 1-T57C&#59; ex 6-C714A and G823A&#59; ex 8-C1104T&#59; ex 9-A&#43;18G&#59; ex 13-A2011G and C2316T&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarises the epidemiological&#44; clinical&#44; neurophysiological and outcome characteristics of the 5 cases with atypical genetics&#46; In six families&#44; a genetic diagnosis was made prenatally in subsequent pregnancies &#40;16&#46;2&#37;&#41;&#44; leading to the identification of the disease in 4 pregnancies&#44; carrier status in 2 pregnancies&#44; and healthy non-carrier status in the remaining 2 pregnancies &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Management and outcome</span><p id="par0095" class="elsevierStylePara elsevierViewall">Twenty-five patients were followed up at our hospital&#44; 7 of them through at-home hospital care&#46; Most of them had SMA type I &#40;18 patients&#41;&#46; The supportive care they received included motor physical therapy and rehabilitation &#40;15 patients&#41;&#44; respiratory physical therapy &#40;8 patients&#41; or basic respiratory care such as secretion management and aspiration &#40;5 patients&#41;&#46; Two patients received at-home oxygen therapy through low-flow nasal cannulae at 6 and 7 months&#44; and noninvasive ventilation was initiated in one patient at 8 months&#46; Two patients were treated with invasive mechanical ventilation with tracheostomy&#46; One of them was the patient diagnosed with SMARD1&#44; in whom invasive ventilatory support was initiated before the diagnosis was confirmed&#46; The second one was a SMA type II patient in whom a proactive intervention was performed in agreement with the family after prolonged invasive mechanical ventilation&#59; the tracheostomy was performed at age 12 months&#44; and after discharge from the hospital at 4 years of age the follow-up consisted of at-home hospital care until the patient&#39;s death at 14 years of age&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">As for nutritional management&#44; 4 patients required enteral nutrition&#44; delivered at home through a nasogastric tube&#44; and a gastrostomy was performed in one patient &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41;&#46; The parents of one other patient refused to have a gastrostomy performed&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">We know that 18 out of the total 25 patients followed up in our hospital died&#44; and most of them had SMA type I &#40;only one patient with SMA type II died during this period&#41;&#46; The median survival in our series for type I patients was 8&#46;0 months &#40;range&#44; 1&#46;5&#8211;44 months&#41; and 15&#46;8 years for type II &#40;range&#44; 3&#8211;25&#46;8 years&#41;&#46; An important fact is that 22 of the 25 patients with SMA type I followed up died before 24 months of age&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Discussion</span><p id="par0110" class="elsevierStylePara elsevierViewall">At the end of the 25 years under study&#44; the incidence in the reference population and year was similar to those described in other series&#44; which suggests a stable genetic penetrance for this disease in our population&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">13</span></a> SMA type I accounted for 70&#46;3&#37; of the cases&#59; the genetic defect in most of these patients &#40;31&#47;36&#41; was a homozygous deletion in the <span class="elsevierStyleItalic">SMN1</span> gene&#59; the mean survival was less than one year for type I&#44; somewhat below what is reported in the literature&#59; and there was a predominance of male patients in our series&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Hypotonia in infancy continues to be the most common clinical presentation &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; although in some cases &#40;3 in our series&#41; the presenting symptom is respiratory distress&#46; The age of clinical onset in patients with SMA type I was 2&#46;2 months&#46; While the diagnosis was made relatively early&#44; at present it is believed that this is not early enough to achieve the benefits expected of emerging therapeutic approaches&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">14&#8211;17</span></a> The usefulness of neonatal screening for offering specific patients participation in clinical trials is being considered&#46; This approach has already been implemented and there are studies on the subject&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">18</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">We found a spontaneous miscarriage rate of 19&#46;1&#37; in the families of patients with SMA type I&#44; at the upper limit of the range described for the general population &#40;10&#8211;20&#37;&#41;&#46; However&#44; this figure may underestimate the actual rate of spontaneous miscarriage associated with this disease&#44; as we have no information on the occurrence of subsequent miscarriages in families that were not followed up in our hospital&#46; Although this has been described before&#44; there are very few published studies on the association of SMA with spontaneous miscarriage&#44; and we did not find any systematic reviews on this matter&#46; A published case associated foetal death to foetal akinesia-deformation sequence&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">19</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Only one of our patients had a form of SMA unrelated to the <span class="elsevierStyleItalic">SMN</span> gene&#46; The patient was diagnosed with SMARD1&#46; The polymorphisms found in this patient had never been described before&#46; We assumed they were involved in the aetiology based on their location in chromosome 11 and the patient&#39;s clinical features&#46; The management of this case involved early ventilatory support with tracheostomy due to its onset with severe respiratory distress for which no initial clinical diagnosis was made&#44; as the patient followed the natural course of this disease in its early stages with severe respiratory problems and predominantly distal involvement&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">20</span></a> Several publications debate the use of invasive respiratory support in SMA type I&#44; which poses an ethical dilemma that has yet to be resolved&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">21</span></a> Since 2007 there is a standard of care consensus<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">22</span></a> that aims to improve the quality of life of SMA patients&#44; although according to several studies in different countries its introduction has raised controversy&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">23</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">In our experience&#44; implementing this standard of care&#44; as we have done in recent years&#44; requires the coordinated effort of the various specialties involved&#44; as well as adequate development of at-home hospital care&#46; It requires&#44; at least&#44; the universalisation of at-home oxygen therapy&#44; gastrostomy and noninvasive ventilatory support during the course of the disease&#44; in addition to the optimisation of orthopaedic measures to prevent bizarre deformities&#44; while adjusting care to the wishes and expectations of the parents&#46; It remains to be seen whether this approach increases survival&#44; and while this is not the goal of the care&#44; it could have this logical result&#46; Patient associations support this standard of care&#44; which must be taken into account by paediatricians&#46; The median survival for type I patients was 8 months&#44; lower than the figures published to date&#44; which was probably due to our late introduction of active nutritional and respiratory support&#46; This precludes us from drawing conclusions about overall survival&#44; although this approach seems to alleviate the anxiety of parents in regards to the suffering of their child&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">In our series&#44; tracheostomy was performed in only two patients&#46; One was the patient with SMARD1&#44; who had it for the reasons stated above&#44; and the other one a patient with SMA type II&#44; in whom it was more likely to be indicated given the slower course of the disease&#46; Nutritional support was only provided to one patient&#44; after the parents agreed&#44; through a scheduled gastrostomy at 16 months of age&#46; A cough assist machine was used in two patients with SMA type I at 8 and 23 months of age&#44; resulting in different degrees of satisfaction&#44; as in one case it worsened the patient&#39;s condition and the parents decided to discontinue its use&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">The genetic mutations found in our series are similar to those reported in the literature &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; In 2011&#44; the only 2 families in which the truncated copy of the <span class="elsevierStyleItalic">SMN1</span> gene with the deletion of exons 1&#8211;6 was detected came from the same geographical region&#44; and in both cases the copy was inherited from the father&#46; Analysis of the polymorphic markers linked to the <span class="elsevierStyleItalic">SMN1</span> locus and of multilocus markers &#40;272 and 212&#41; revealed that the fathers of the two patients had the same haplotype&#44; which suggested that both chromosomes shared a common ancestor&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conclusions and comments</span><p id="par0145" class="elsevierStylePara elsevierViewall">To conclude&#44; our series shows a classical clinical course with a relatively early onset and a stable population incidence of approximately 1 case per 10&#44;000 live births per year&#46; Most patients had a typical genetic basis&#44; and there was a predominance of males&#46; Approximately 1 in 10 patients had a mutation other than the classical mutation in the <span class="elsevierStyleItalic">SMN</span> gene&#46; Only one of the 37 patients in our series had a mutation in a gene other than the <span class="elsevierStyleItalic">SMN</span> gene that corresponded to a case of SMARD1&#46; The overall survival in our series was below that described previously&#46; The level of care has increased in line with social and welfare demands in recent years&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">We believe that multicentre cooperation is needed to adequately address the research and management of this disease&#44; for which there is an increasingly hopeful future&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflicts of interest</span><p id="par0155" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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    "fechaRecibido" => "2014-01-30"
    "fechaAceptado" => "2014-06-25"
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          "clase" => "keyword"
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            0 => "Spinal muscular atrophy"
            1 => "Spinal muscular atrophy"
            2 => "Spinal muscular atrophy with respiratory distress type 1"
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          "palabras" => array:3 [
            0 => "Atrofia muscular espinal"
            1 => "Atrofia espinal infantil"
            2 => "Atrofia muscular espinal con distr&#233;s respiratorio"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To determine the incidence of spinal muscular atrophy &#40;SMA&#41; in our study population and genetic distribution and epidemiological and clinical characteristics and to analyse the level of care and development&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and method</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Retrospective descriptive study of patients treated in our hospital in the past 25 years &#40;from 1987 to early 2013&#41;&#44; with a clinical and neurophysiological diagnosis of SMA&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A total of 37 patients were found&#44; representing an incidence for our reference population and year of 1 case per 10&#44;000 live births&#46; Males predominated &#40;male&#47;female ratio&#58; 1&#46;6&#47;1&#41;&#46; The type of SMA diagnosed more frequently was type I &#40;26 cases&#41;&#44; followed by type II &#40;9 cases&#41;&#44; one case with SMA type III&#44; and one case of spinal muscular atrophy with respiratory distress type 1 &#40;SMARD1&#41;&#46; The most frequent genetic alteration was homozygous deletion of exons 7 and 8 of SMN1 gene in 31 cases&#44; while five patients had atypical genetics&#46; The median survival for type I was 8&#46;0 months and 15&#46;8 years for type <span class="elsevierStyleSmallCaps">ii</span>&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The incidence in our population remains stable at around 1&#47;10&#44;000&#46; Most cases presented with&#44; predominantly male&#44; typical genetics&#46; In approximately 1&#47;10 patients the genetic alteration was different from the classical one to the SMN gene&#46; The prevalence of AME unrelated SMN gene was 1&#47;37&#46; The level of care has increased in line with social and welfare demands in recent years&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Conocer la incidencia de la atrofia espinal infantil &#40;AME&#41; en nuestra poblaci&#243;n y estudiar la distribuci&#243;n gen&#233;tica y las caracter&#237;sticas epidemiol&#243;gicas y cl&#237;nicas&#44; el nivel de cuidados y su evoluci&#243;n&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todo</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio descriptivo retrospectivo de los pacientes atendidos en nuestro hospital en los &#250;ltimos 25 a&#241;os &#40;1987&#8211;2013&#41;&#44; con diagn&#243;stico cl&#237;nico y neurofisiol&#243;gico de AME&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se hall&#243; a 37 pacientes&#44; lo que supone una incidencia aproximada de 1&#47;10&#44;000 reci&#233;n nacidos vivos&#46; Predominaba el sexo masculino &#40;relaci&#243;n var&#243;n&#47;mujer&#58; 1&#44;6&#47;1&#41;&#46; El tipo de AME diagnosticado m&#225;s frecuentemente fue el tipo <span class="elsevierStyleSmallCaps">i</span> &#40;26 casos&#41;&#44; seguido del tipo <span class="elsevierStyleSmallCaps">ii</span> &#40;9 casos&#41;&#44; un caso de AME tipo <span class="elsevierStyleSmallCaps">iii</span>&#44; y otro caso de <span class="elsevierStyleItalic">spinal muscular atrophy with respiratory distress type 1</span> &#40;SMARD 1&#41;&#46; La alteraci&#243;n gen&#233;tica m&#225;s frecuente fue la deleci&#243;n en homocigosis de exones 7 y 8 del gen SMN1&#44; en 31 casos&#44; mientras que 5 pacientes presentaban una gen&#233;tica at&#237;pica&#46; La mediana de supervivencia para el tipo <span class="elsevierStyleSmallCaps">i</span> fue de 8&#44;0 meses y de 15&#44;8 a&#241;os para el tipo <span class="elsevierStyleSmallCaps">ii</span>&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La incidencia en nuestra poblaci&#243;n permanece estable en torno a 1&#47;10&#44;000&#46; La mayor&#237;a de los casos presenta una gen&#233;tica t&#237;pica con predominio de varones&#46; En aproximadamente 1&#47;10 pacientes la alteraci&#243;n gen&#233;tica fue diferente de la cl&#225;sica&#46; La prevalencia de AME no relacionadas con el gen SMN fue de 1&#47;37&#46; El nivel de cuidados se ha incrementado en los &#250;ltimos a&#241;os&#44; en consonancia con las demandas sociales y asistenciales&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Rodr&#237;guez AM&#44; Mart&#237;nez PLM&#44; Fern&#225;ndez JMR&#44; Cardona AU&#44; Ant&#243;n JM&#46; Atrofia muscular espinal&#58; revisi&#243;n de nuestra casu&#237;stica en los &#250;ltimos 25 a&#241;os&#46; An Pediatr &#40;Barc&#41;&#46; 2015&#59;82&#58;159&#8211;165&#46;</p>"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Prenatal genetic diagnosis in subsequent pregnancies&#46;</p>"
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Supportive care received by patients followed up in our centre&#46; Motor rehabilitation&#44; respiratory physical therapy&#44; basic respiratory care&#44; low-flow oxygen therapy&#44; noninvasive mechanical ventilation &#40;NIMV&#41;&#44; invasive mechanical ventilation &#40;IMV&#41;&#44; enteral nutrition through nasogastric tube &#40;NGT&#41; or gastrostomy&#46;</p>"
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                  <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="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Age at onset&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical course&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Age at death&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Number of <span class="elsevierStyleItalic">SNM2</span> copies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Prenatal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Respiratory support&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1 month&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">i</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#8211;6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Never sit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;2 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">ii</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;18 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Never stand&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;2 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#44; 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">iii</span>a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;18 months&#44; &#60;3 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Stand and walk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Adult&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#44; 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">iii</span>b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;3 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Stand and walk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Adult&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">iv</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;21 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Stand and walk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Adult&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#8211;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Classification of spinal muscular atrophy&#46;</p>"
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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="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Case&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Age at onset&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical presentation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Neurophysiology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Genetics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Outcome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">III</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Motor delay&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Chronic symptoms of severe partial denervation in lower limb muscles and milder in upper limbs&#46; Fibrillation potentials and positive sharp waves&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Deletion in one copy of the SMN1 gene<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>truncated copy by deletion of exons 1&#8211;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Loss of standing&#47;walking at 18 months&#46; Scoliosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">II</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Difficulty standing&#44; unable to walk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Loss of motor unit potentials&#44; chronic signs of severe partial denervation in proximal muscles of lower limbs and less severe in upper limbs&#46; Few fibrillation potentials and positive sharp waves&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Deletion of one copy of the <span class="elsevierStyleItalic">SMN1</span> gene<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>truncated copy by 773insC mutation in exon 6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Loss of standing at 60 months&#46; Scoliosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SMARD1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Birth&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Respiratory distress&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Marked signs of denervation with fibrillation and positive waves with predominance of distal muscles of limbs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Polymorphic alterations in the <span class="elsevierStyleItalic">IGHMPB2</span> gene &#40;ex 1-T57C&#59; ex 6-C714A and G823A&#59; ex 8-C1104T&#59; ex 9-A&#43;18G&#59; ex 13-A2011G and C2316T&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tracheostomy and prolonged mechanical ventilation&#46; Death at 44 months of age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">I</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypotonia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Fibrillations and positive sharp waves&#44; very reduced tracings with small amplitude&#44; increased polyphasic motor unit potentials&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Heterozygous deletion in <span class="elsevierStyleItalic">SMN1</span> gene &#40;deletion of exons 1&#8211;6 and deletion of exons 7&#8211;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Death at 7 months of age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">I</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypotonia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Motor disorder with spontaneous fibrillations&#44; signs of denervation with proximal muscle predominance&#44; normal NCV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Deletion in one copy of the <span class="elsevierStyleItalic">SMN1</span> gene <span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>truncated copy due to exon 1 deletion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Death at 8&#46;5 months of age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Epidemiological&#44; clinical&#44; neurophysiological and clinical course characteristics of atypical genetics cases&#46;</p>"
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:23 [
            0 => array:3 [
              "identificador" => "bib0120"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
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                      "autores" => array:1 [
                        0 => array:3 [
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                          "etal" => false
                          "autores" => array:2 [
                            0 => "H&#46; Roper"
                            1 => "R&#46; Quinlivan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/adc.2009.166512"
                      "Revista" => array:6 [
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                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19819869"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
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              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                  "host" => array:1 [
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                            2 => "S&#46; Reboullet"
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                            4 => "P&#46; Burlet"
                            5 => "L&#46; Viollet"
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            3 => array:3 [
              "identificador" => "bib0135"
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              "referencia" => array:1 [
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                  "contribucion" => array:1 [
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                      "titulo" => "A positive modifier of spinal muscular atrophy in the SMN2 gene"
                      "autores" => array:1 [
                        0 => array:2 [
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ajhg.2009.08.002"
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                        "fecha" => "2009"
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            ]
            4 => array:3 [
              "identificador" => "bib0140"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Correlation of PLS3 expression with disease severity in children with spinal muscular atrophy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "C&#46; Yanyan"
                            1 => "Q&#46; Yujin"
                            2 => "B&#46; Jinli"
                            3 => "J&#46; Yuwei"
                            4 => "W&#46; Hong"
                            5 => "S&#46; Fang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/jhg.2013.111"
                      "Revista" => array:6 [
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                        "volumen" => "59"
                        "paginaInicial" => "24"
                        "paginaFinal" => "27"
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Original Article
Infantile spinal atrophy: Our experience in the last 25 years
Atrofia muscular espinal: revisión de nuestra casuística en los últimos 25 años
A. Madrid Rodríguez
Corresponding author
auroramadrid_2000@yahoo.es

Corresponding author.
, P.L. Martínez Martínez, J.M. Ramos Fernández, A. Urda Cardona, J. Martínez Antón
Servicio de Pediatría, Hospital Materno Infantil, Hospital Regional Universitario de Málaga, Málaga, Spain
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with 1 out of 40 people being carriers of the disease&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The classical clinical picture of SMA is predominantly proximal muscle weakness and atrophy&#44; with ages of onset and severity that vary depending on the clinical type of SMA&#46; Traditionally&#44; the classification of SMA comprised 3 types&#58; infantile&#44; juvenile&#44; and adult&#46; At present&#44; the International Consensus Statement for Standard Care in SMA<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">1&#44;2</span></a> classifies it into more types based on the age of onset and clinical course&#44; dividing type III into subtypes according to the age of onset&#46; Type IV was added for adult-onset cases&#44; and type 0 for cases with prenatal onset&#44; which result in death within the first weeks of life &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; While there is clinical variability among individuals in each type and up to 25&#37; of the patients cannot be categorised&#44; this classification is useful for clinical practice and prognosis&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">The gene involved in SMA&#44; discovered in 1995&#44;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">3</span></a> is located in the long arm of chromosome 5 &#40;5q11&#46;1-13&#46;3&#41;&#46; It has been named <span class="elsevierStyleItalic">SMN</span> for &#8220;survival motor neuron&#8221;&#46; Humans have two nearly identical copies of this gene that have been called <span class="elsevierStyleItalic">SMN1</span> and <span class="elsevierStyleItalic">SMN2</span>&#46; They differ in a single nucleotide at the beginning of exon 7 &#40;C in <span class="elsevierStyleItalic">SMN1</span> and T in <span class="elsevierStyleItalic">SMN2</span>&#41; that is important in the splicing of the SMN RNA&#46; We do not know why this ubiquitous protein causes this highly selective neuronal disease&#46; Deletions in <span class="elsevierStyleItalic">SMN1</span> cause SMA&#46; Approximately 95&#37; of SMA patients have homozygous absence of exons 7 and 8 of the <span class="elsevierStyleItalic">SMN1</span> gene&#44; and about 5&#37; are compound heterozygous for absence of exons 7 and 8 in one <span class="elsevierStyleItalic">SMN1</span> allele and a point mutation in the other&#46; Deletions in the <span class="elsevierStyleItalic">SMN2</span> gene do not cause the disease&#59; instead&#44; it is the number of copies of this gene&#44; which may vary&#44; that has an effect on the phenotype and determines the severity of SMA&#44; with a greater number of <span class="elsevierStyleItalic">SMN2</span> copies correlating to a milder phenotype&#44; although there are other factors at play&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">4&#44;5</span></a> In this regard&#44; it has been hypothesised that the disease could be treated with gene therapy by induced overexpression of the <span class="elsevierStyleItalic">SMN2</span> gene&#44; and the day when this terrible disease can be mitigated may not be far away&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">6&#44;7</span></a>Another genetic approach that was successful in an experimental study was the insertion of the <span class="elsevierStyleItalic">SMN</span> gene by means of viral vectors in the genome of a mouse model of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">8</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Other forms of disease with clinical features that overlap with SMA&#44; with subtle differences&#44; are associated to different genes&#46; Cases associated with chromosome 11 alterations have been described &#40;spinal muscular atrophy with respiratory distress type 1 &#91;SMARD1&#93;&#41;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#44;10</span></a> as well as cases of early-onset recessive X-linked disease in males &#40;Kennedy&#39;s disease&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">11&#44;12</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The aim of this study was to determine the present incidence of SMA in our population&#44; its genotype distribution&#44; and its epidemiological and clinical characteristics in the past 25 years in the context of our current knowledge&#44; and to assess the level of care and the outcomes of SMA in our setting based on the international consensus&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">1&#44;2</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">We performed a retrospective descriptive study by reviewing the clinical histories of patients with a clinical and neurophysiological diagnosis of spinal muscular atrophy assessed in our hospital in the past 25 years &#40;from 1987 to early 2013&#41;&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">We collected data for epidemiological&#44; clinical and genetic variables&#44; the supportive care received&#44; and survival&#46; The variables analysed were age at clinical onset and age at death&#44; sex&#44; family history of relatives that had the disease&#44; initial symptoms&#44; neurophysiological examinations&#44; genetic testing&#44; type of SMA&#44; subsequent prenatal diagnostic examinations&#44; supportive care received&#44; and survival&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The molecular analysis involved amplification of exons 7 and 8 of the <span class="elsevierStyleItalic">SMN1</span> gene by polymerase chain reaction from blood DNA samples from patients with suspected SMA&#46; The <span class="elsevierStyleItalic">SMN1</span> and <span class="elsevierStyleItalic">SMN2</span> genes were differentiated by restriction fragment length polymorphism analysis&#46; The absence of one of the 3 restriction fragments was interpreted as a homozygous deletion of exon 7 of the <span class="elsevierStyleItalic">SMN1</span> gene&#46; The homozygous deletion of exon 8 of the <span class="elsevierStyleItalic">SMN1</span> gene was evinced by the absence of the 189-bp band of the <span class="elsevierStyleItalic">SMN1</span> gene that was not digested in the presence of the 2 restriction fragments of the <span class="elsevierStyleItalic">SMN2</span> gene&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">In cases in which homozygous deletions were not detected&#44; the number of copies of the <span class="elsevierStyleItalic">SMN</span> gene was quantified by multiplex ligation-dependent probe amplification&#46; In patients with a single copy of the <span class="elsevierStyleItalic">SMN1</span> gene &#40;the other copy may be inactivated by a mutation&#41; we sequenced the DNA of the coding part of the <span class="elsevierStyleItalic">SMN1</span> gene to detect potential deletions&#44; duplications and point mutations&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Overall epidemiological results</span><p id="par0050" class="elsevierStylePara elsevierViewall">We found 37 patients who met the inclusion criteria&#44; which amounts to an approximate incidence in our reference population and year of 1&#46;41 cases per 15&#44;000 live births &#40;1 case per 10&#44;638 live births&#41;&#46; Fourteen patients were diagnosed between 1987 and 1999&#44; while the number of diagnoses rose to 23 for the 2000 to 2013 interval&#44; showing a clear increase in the number of diagnosed cases&#46; Before 1995&#44; cases were diagnosed by the identification of carriers in the family in 3 cases&#44; and in other 3 the genetics of the patients were studied at a later point&#44; as 2 of these patients had SMA type II and the other one SMA type III&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Most patients came from our reference area &#40;31&#47;37&#41;&#46; The male sex predominated&#44; with 23 cases in male patients and a 1&#46;6 to 1 male to female ratio&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The mean age at the onset of symptoms was 2&#46;2 months for type I SMA &#40;range&#44; 0&#8211;7 months&#41; and 11&#46;2 months for type II &#40;range&#44; 6&#8211;18 months&#41;&#46; On the other hand&#44; the only patient diagnosed with type III SMA was 12 months of age at the clinical onset&#44; while the patient diagnosed with spinal muscular atrophy with respiratory distress &#40;SMARD1&#41; developed symptoms in the first month of life&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Clinical results</span><p id="par0065" class="elsevierStylePara elsevierViewall">The most frequent type of SMA was type I&#44; found in 26 patients&#44; and followed by type II in 9&#46; One case was diagnosed as type III SMA and another as SMARD1&#46; There were no cases of X-linked inheritance &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">The presenting symptom in most patients was hypotonia&#44; which occurred in 27 out of the 37 cases&#44; followed by motor delay in 5 of the 37 cases&#46; In 4 patients&#44; type I SMA was associated with sucking and swallowing difficulties&#44; and 2 of them had episodes of choking&#59; another patient&#44; who had type I SMA&#44; was diagnosed following a life-threatening episode of apnoea&#46; None of our patients had onset with arthrogryposis&#44; nor they met the criteria for type 0 SMA&#46; The presenting symptom in 3 patients was respiratory distress associated with intercurrent infection&#44; and gait disorder in 2 patients &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">There were a total of 92 documented pregnancies in the families of the patients&#44; which included 9 cases of spontaneous miscarriage and one case of voluntary termination of pregnancy&#46; The nine miscarriages occurred in the families of 18 patients with type I SMA who were being followed up in our hospital &#40;families in which there were a total of 47 pregnancies&#44; corresponding to a 19&#46;1&#37; spontaneous miscarriage rate in this group&#41;&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Seven of the 37 patients had a family history of SMA&#44; and 3 had a family history of idiopathic muscle weakness&#46; In 4 patients there was a family history of neonatal death&#59; 3 of these deaths occurred in the early neonatal period in siblings of one of the patients&#44; who had onset with hypotonia at 8 days of age&#46; The remaining 23 cases had no family history of neurological disease or associated symptoms &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Genetic testing</span><p id="par0085" class="elsevierStylePara elsevierViewall">Genetic testing was carried out in 36 patients&#46; The number of copies of the <span class="elsevierStyleItalic">SMN2</span> gene could not be determined in most patients&#46; The most frequent genetic alteration was the homozygous deletion of exons 7 and 8 of the <span class="elsevierStyleItalic">SMN1</span> gene&#44; found in 31 out of the 36 cases&#44; while 5 patients had atypical genetics&#46; Four patients had compound heterozygous mutations with a classical deletion in one copy of the <span class="elsevierStyleItalic">SMN1</span> gene and a non-functional truncated copy of the other resulting from different mutations&#58; deletion of exons 1&#8211;6 in two cases&#44; deletion of exon 1 in one case&#44; and a 773insC mutation in the remaining case&#46; Lastly&#44; the patient diagnosed with SMA with respiratory distress had polymorphic changes in the <span class="elsevierStyleItalic">IGHMPB2</span> gene of chromosome 11 &#40;ex 1-T57C&#59; ex 6-C714A and G823A&#59; ex 8-C1104T&#59; ex 9-A&#43;18G&#59; ex 13-A2011G and C2316T&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarises the epidemiological&#44; clinical&#44; neurophysiological and outcome characteristics of the 5 cases with atypical genetics&#46; In six families&#44; a genetic diagnosis was made prenatally in subsequent pregnancies &#40;16&#46;2&#37;&#41;&#44; leading to the identification of the disease in 4 pregnancies&#44; carrier status in 2 pregnancies&#44; and healthy non-carrier status in the remaining 2 pregnancies &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Management and outcome</span><p id="par0095" class="elsevierStylePara elsevierViewall">Twenty-five patients were followed up at our hospital&#44; 7 of them through at-home hospital care&#46; Most of them had SMA type I &#40;18 patients&#41;&#46; The supportive care they received included motor physical therapy and rehabilitation &#40;15 patients&#41;&#44; respiratory physical therapy &#40;8 patients&#41; or basic respiratory care such as secretion management and aspiration &#40;5 patients&#41;&#46; Two patients received at-home oxygen therapy through low-flow nasal cannulae at 6 and 7 months&#44; and noninvasive ventilation was initiated in one patient at 8 months&#46; Two patients were treated with invasive mechanical ventilation with tracheostomy&#46; One of them was the patient diagnosed with SMARD1&#44; in whom invasive ventilatory support was initiated before the diagnosis was confirmed&#46; The second one was a SMA type II patient in whom a proactive intervention was performed in agreement with the family after prolonged invasive mechanical ventilation&#59; the tracheostomy was performed at age 12 months&#44; and after discharge from the hospital at 4 years of age the follow-up consisted of at-home hospital care until the patient&#39;s death at 14 years of age&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">As for nutritional management&#44; 4 patients required enteral nutrition&#44; delivered at home through a nasogastric tube&#44; and a gastrostomy was performed in one patient &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41;&#46; The parents of one other patient refused to have a gastrostomy performed&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">We know that 18 out of the total 25 patients followed up in our hospital died&#44; and most of them had SMA type I &#40;only one patient with SMA type II died during this period&#41;&#46; The median survival in our series for type I patients was 8&#46;0 months &#40;range&#44; 1&#46;5&#8211;44 months&#41; and 15&#46;8 years for type II &#40;range&#44; 3&#8211;25&#46;8 years&#41;&#46; An important fact is that 22 of the 25 patients with SMA type I followed up died before 24 months of age&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Discussion</span><p id="par0110" class="elsevierStylePara elsevierViewall">At the end of the 25 years under study&#44; the incidence in the reference population and year was similar to those described in other series&#44; which suggests a stable genetic penetrance for this disease in our population&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">13</span></a> SMA type I accounted for 70&#46;3&#37; of the cases&#59; the genetic defect in most of these patients &#40;31&#47;36&#41; was a homozygous deletion in the <span class="elsevierStyleItalic">SMN1</span> gene&#59; the mean survival was less than one year for type I&#44; somewhat below what is reported in the literature&#59; and there was a predominance of male patients in our series&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Hypotonia in infancy continues to be the most common clinical presentation &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; although in some cases &#40;3 in our series&#41; the presenting symptom is respiratory distress&#46; The age of clinical onset in patients with SMA type I was 2&#46;2 months&#46; While the diagnosis was made relatively early&#44; at present it is believed that this is not early enough to achieve the benefits expected of emerging therapeutic approaches&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">14&#8211;17</span></a> The usefulness of neonatal screening for offering specific patients participation in clinical trials is being considered&#46; This approach has already been implemented and there are studies on the subject&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">18</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">We found a spontaneous miscarriage rate of 19&#46;1&#37; in the families of patients with SMA type I&#44; at the upper limit of the range described for the general population &#40;10&#8211;20&#37;&#41;&#46; However&#44; this figure may underestimate the actual rate of spontaneous miscarriage associated with this disease&#44; as we have no information on the occurrence of subsequent miscarriages in families that were not followed up in our hospital&#46; Although this has been described before&#44; there are very few published studies on the association of SMA with spontaneous miscarriage&#44; and we did not find any systematic reviews on this matter&#46; A published case associated foetal death to foetal akinesia-deformation sequence&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">19</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Only one of our patients had a form of SMA unrelated to the <span class="elsevierStyleItalic">SMN</span> gene&#46; The patient was diagnosed with SMARD1&#46; The polymorphisms found in this patient had never been described before&#46; We assumed they were involved in the aetiology based on their location in chromosome 11 and the patient&#39;s clinical features&#46; The management of this case involved early ventilatory support with tracheostomy due to its onset with severe respiratory distress for which no initial clinical diagnosis was made&#44; as the patient followed the natural course of this disease in its early stages with severe respiratory problems and predominantly distal involvement&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">20</span></a> Several publications debate the use of invasive respiratory support in SMA type I&#44; which poses an ethical dilemma that has yet to be resolved&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">21</span></a> Since 2007 there is a standard of care consensus<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">22</span></a> that aims to improve the quality of life of SMA patients&#44; although according to several studies in different countries its introduction has raised controversy&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">23</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">In our experience&#44; implementing this standard of care&#44; as we have done in recent years&#44; requires the coordinated effort of the various specialties involved&#44; as well as adequate development of at-home hospital care&#46; It requires&#44; at least&#44; the universalisation of at-home oxygen therapy&#44; gastrostomy and noninvasive ventilatory support during the course of the disease&#44; in addition to the optimisation of orthopaedic measures to prevent bizarre deformities&#44; while adjusting care to the wishes and expectations of the parents&#46; It remains to be seen whether this approach increases survival&#44; and while this is not the goal of the care&#44; it could have this logical result&#46; Patient associations support this standard of care&#44; which must be taken into account by paediatricians&#46; The median survival for type I patients was 8 months&#44; lower than the figures published to date&#44; which was probably due to our late introduction of active nutritional and respiratory support&#46; This precludes us from drawing conclusions about overall survival&#44; although this approach seems to alleviate the anxiety of parents in regards to the suffering of their child&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">In our series&#44; tracheostomy was performed in only two patients&#46; One was the patient with SMARD1&#44; who had it for the reasons stated above&#44; and the other one a patient with SMA type II&#44; in whom it was more likely to be indicated given the slower course of the disease&#46; Nutritional support was only provided to one patient&#44; after the parents agreed&#44; through a scheduled gastrostomy at 16 months of age&#46; A cough assist machine was used in two patients with SMA type I at 8 and 23 months of age&#44; resulting in different degrees of satisfaction&#44; as in one case it worsened the patient&#39;s condition and the parents decided to discontinue its use&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">The genetic mutations found in our series are similar to those reported in the literature &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; In 2011&#44; the only 2 families in which the truncated copy of the <span class="elsevierStyleItalic">SMN1</span> gene with the deletion of exons 1&#8211;6 was detected came from the same geographical region&#44; and in both cases the copy was inherited from the father&#46; Analysis of the polymorphic markers linked to the <span class="elsevierStyleItalic">SMN1</span> locus and of multilocus markers &#40;272 and 212&#41; revealed that the fathers of the two patients had the same haplotype&#44; which suggested that both chromosomes shared a common ancestor&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conclusions and comments</span><p id="par0145" class="elsevierStylePara elsevierViewall">To conclude&#44; our series shows a classical clinical course with a relatively early onset and a stable population incidence of approximately 1 case per 10&#44;000 live births per year&#46; Most patients had a typical genetic basis&#44; and there was a predominance of males&#46; Approximately 1 in 10 patients had a mutation other than the classical mutation in the <span class="elsevierStyleItalic">SMN</span> gene&#46; Only one of the 37 patients in our series had a mutation in a gene other than the <span class="elsevierStyleItalic">SMN</span> gene that corresponded to a case of SMARD1&#46; The overall survival in our series was below that described previously&#46; The level of care has increased in line with social and welfare demands in recent years&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">We believe that multicentre cooperation is needed to adequately address the research and management of this disease&#44; for which there is an increasingly hopeful future&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflicts of interest</span><p id="par0155" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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            2 => "Spinal muscular atrophy with respiratory distress type 1"
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            0 => "Atrofia muscular espinal"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To determine the incidence of spinal muscular atrophy &#40;SMA&#41; in our study population and genetic distribution and epidemiological and clinical characteristics and to analyse the level of care and development&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and method</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Retrospective descriptive study of patients treated in our hospital in the past 25 years &#40;from 1987 to early 2013&#41;&#44; with a clinical and neurophysiological diagnosis of SMA&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A total of 37 patients were found&#44; representing an incidence for our reference population and year of 1 case per 10&#44;000 live births&#46; Males predominated &#40;male&#47;female ratio&#58; 1&#46;6&#47;1&#41;&#46; The type of SMA diagnosed more frequently was type I &#40;26 cases&#41;&#44; followed by type II &#40;9 cases&#41;&#44; one case with SMA type III&#44; and one case of spinal muscular atrophy with respiratory distress type 1 &#40;SMARD1&#41;&#46; The most frequent genetic alteration was homozygous deletion of exons 7 and 8 of SMN1 gene in 31 cases&#44; while five patients had atypical genetics&#46; The median survival for type I was 8&#46;0 months and 15&#46;8 years for type <span class="elsevierStyleSmallCaps">ii</span>&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The incidence in our population remains stable at around 1&#47;10&#44;000&#46; Most cases presented with&#44; predominantly male&#44; typical genetics&#46; In approximately 1&#47;10 patients the genetic alteration was different from the classical one to the SMN gene&#46; The prevalence of AME unrelated SMN gene was 1&#47;37&#46; The level of care has increased in line with social and welfare demands in recent years&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Conocer la incidencia de la atrofia espinal infantil &#40;AME&#41; en nuestra poblaci&#243;n y estudiar la distribuci&#243;n gen&#233;tica y las caracter&#237;sticas epidemiol&#243;gicas y cl&#237;nicas&#44; el nivel de cuidados y su evoluci&#243;n&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todo</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio descriptivo retrospectivo de los pacientes atendidos en nuestro hospital en los &#250;ltimos 25 a&#241;os &#40;1987&#8211;2013&#41;&#44; con diagn&#243;stico cl&#237;nico y neurofisiol&#243;gico de AME&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se hall&#243; a 37 pacientes&#44; lo que supone una incidencia aproximada de 1&#47;10&#44;000 reci&#233;n nacidos vivos&#46; Predominaba el sexo masculino &#40;relaci&#243;n var&#243;n&#47;mujer&#58; 1&#44;6&#47;1&#41;&#46; El tipo de AME diagnosticado m&#225;s frecuentemente fue el tipo <span class="elsevierStyleSmallCaps">i</span> &#40;26 casos&#41;&#44; seguido del tipo <span class="elsevierStyleSmallCaps">ii</span> &#40;9 casos&#41;&#44; un caso de AME tipo <span class="elsevierStyleSmallCaps">iii</span>&#44; y otro caso de <span class="elsevierStyleItalic">spinal muscular atrophy with respiratory distress type 1</span> &#40;SMARD 1&#41;&#46; La alteraci&#243;n gen&#233;tica m&#225;s frecuente fue la deleci&#243;n en homocigosis de exones 7 y 8 del gen SMN1&#44; en 31 casos&#44; mientras que 5 pacientes presentaban una gen&#233;tica at&#237;pica&#46; La mediana de supervivencia para el tipo <span class="elsevierStyleSmallCaps">i</span> fue de 8&#44;0 meses y de 15&#44;8 a&#241;os para el tipo <span class="elsevierStyleSmallCaps">ii</span>&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La incidencia en nuestra poblaci&#243;n permanece estable en torno a 1&#47;10&#44;000&#46; La mayor&#237;a de los casos presenta una gen&#233;tica t&#237;pica con predominio de varones&#46; En aproximadamente 1&#47;10 pacientes la alteraci&#243;n gen&#233;tica fue diferente de la cl&#225;sica&#46; La prevalencia de AME no relacionadas con el gen SMN fue de 1&#47;37&#46; El nivel de cuidados se ha incrementado en los &#250;ltimos a&#241;os&#44; en consonancia con las demandas sociales y asistenciales&#46;</p></span>"
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      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Rodr&#237;guez AM&#44; Mart&#237;nez PLM&#44; Fern&#225;ndez JMR&#44; Cardona AU&#44; Ant&#243;n JM&#46; Atrofia muscular espinal&#58; revisi&#243;n de nuestra casu&#237;stica en los &#250;ltimos 25 a&#241;os&#46; An Pediatr &#40;Barc&#41;&#46; 2015&#59;82&#58;159&#8211;165&#46;</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Classification of spinal muscular atrophy in our series&#46;</p>"
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Family history of neurologic disorders or death during childhood&#46;</p>"
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Supportive care received by patients followed up in our centre&#46; Motor rehabilitation&#44; respiratory physical therapy&#44; basic respiratory care&#44; low-flow oxygen therapy&#44; noninvasive mechanical ventilation &#40;NIMV&#41;&#44; invasive mechanical ventilation &#40;IMV&#41;&#44; enteral nutrition through nasogastric tube &#40;NGT&#41; or gastrostomy&#46;</p>"
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                  <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="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Age at onset&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical course&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Age at death&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Number of <span class="elsevierStyleItalic">SNM2</span> copies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Prenatal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Respiratory support&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1 month&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">i</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#8211;6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Never sit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;2 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">ii</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;18 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Never stand&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;2 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#44; 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">iii</span>a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;18 months&#44; &#60;3 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Stand and walk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Adult&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#44; 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">iii</span>b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;3 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Stand and walk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Adult&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">iv</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;21 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Stand and walk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Adult&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#8211;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Classification of spinal muscular atrophy&#46;</p>"
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                  <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="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Case&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Age at onset&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical presentation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Neurophysiology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Genetics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Outcome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">III</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Motor delay&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Chronic symptoms of severe partial denervation in lower limb muscles and milder in upper limbs&#46; Fibrillation potentials and positive sharp waves&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Deletion in one copy of the SMN1 gene<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>truncated copy by deletion of exons 1&#8211;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Loss of standing&#47;walking at 18 months&#46; Scoliosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">II</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Difficulty standing&#44; unable to walk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Loss of motor unit potentials&#44; chronic signs of severe partial denervation in proximal muscles of lower limbs and less severe in upper limbs&#46; Few fibrillation potentials and positive sharp waves&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Deletion of one copy of the <span class="elsevierStyleItalic">SMN1</span> gene<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>truncated copy by 773insC mutation in exon 6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Loss of standing at 60 months&#46; Scoliosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SMARD1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Birth&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Respiratory distress&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Marked signs of denervation with fibrillation and positive waves with predominance of distal muscles of limbs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Polymorphic alterations in the <span class="elsevierStyleItalic">IGHMPB2</span> gene &#40;ex 1-T57C&#59; ex 6-C714A and G823A&#59; ex 8-C1104T&#59; ex 9-A&#43;18G&#59; ex 13-A2011G and C2316T&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tracheostomy and prolonged mechanical ventilation&#46; Death at 44 months of age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">I</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypotonia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Fibrillations and positive sharp waves&#44; very reduced tracings with small amplitude&#44; increased polyphasic motor unit potentials&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Heterozygous deletion in <span class="elsevierStyleItalic">SMN1</span> gene &#40;deletion of exons 1&#8211;6 and deletion of exons 7&#8211;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Death at 7 months of age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">I</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypotonia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Motor disorder with spontaneous fibrillations&#44; signs of denervation with proximal muscle predominance&#44; normal NCV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Deletion in one copy of the <span class="elsevierStyleItalic">SMN1</span> gene <span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>truncated copy due to exon 1 deletion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Death at 8&#46;5 months of age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Epidemiological&#44; clinical&#44; neurophysiological and clinical course characteristics of atypical genetics cases&#46;</p>"
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    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
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Article information
ISSN: 23412879
Original language: English
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