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Original article
A variant in GRN of Spanish origin presenting with heterogeneous phenotypes
Una variante en GRN de origen Español con presentación fenotípica heterogénea
M. Menéndez-Gonzáleza,b,c,
,1
, A. García-Martíneza,1, I. Fernández-Vegab,d,e, A. Pitiotf, V. Álvarezb,g
a Department of Neurology, Hospital Universitario Central de Asturias, Spain
b Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Spain
c Department of Medicine, Universidad de Oviedo, Spain
d Department of Pathology Anatomy, Hospital Universitario Central de Asturias, Spain
e Department of Surgery, Universidad de Oviedo, Spain
f Laboratory of Molecular Oncology, Hospital Universitario Central de Asturias, Spain
g Laboratory of Genetics, Hospital Universitario Central de Asturias, Spain
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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">Frontotemporal lobar degeneration &#40;FTLD&#41; is characterized by remarkable heterogeneity from a clinical&#44; pathological&#44; and genetic point of view&#46; Progranulin &#40;<span class="elsevierStyleItalic">GRN</span>&#41;&#44; microtubule-associated protein tau &#40;<span class="elsevierStyleItalic">MAPT</span>&#41;&#44; and chromosome 9 open reading frame 72 &#40;<span class="elsevierStyleItalic">C9orf72</span>&#41; account for most familial cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a><span class="elsevierStyleItalic">GRN</span> mutations account for 4&#46;5&#37; to 10&#37; of FTLD cases&#44; but this proportion increases to 22&#37; in patients with positive family history&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleItalic">GRN</span> mutations may cause any subtype of FTD&#44; including behavioral variant &#40;BvFTD&#41; and different forms of primary progressive aphasias &#40;PPA&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a> Patients often present with an extensive phenotypic variability&#44; even among different members of the same kindred carrying an identical disease mutation&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#8211;10</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">GRN</span> gene encodes a secreted precursor protein &#40;progranulin&#44; PGRN&#41; composed of a signal peptide and 7&#46;5 tandem repeats of highly conserved motifs containing 12 cysteines that can be proteolytically cleaved to form a family of granulin peptides A to G&#46; Their biological roles&#44; mediated by either the whole protein or its proteolytic cleavage product&#44; include cell proliferation&#44; inflammation&#44; lysosome function&#44; neurite outgrowth&#44; neuronal survival&#44; and metabolic homeostasis&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Most <span class="elsevierStyleItalic">GRN</span> mutations identified to date are predicted to cause the pathology via a haploinsufficiency mechanism by creating premature stop codons&#44; which in turn result in nonsense-mediated decay &#40;NMD&#41;&#46; How a decrease in the levels of GRN causes neurodegenerative processes is not fully understood&#44; as different potential pathways might be involved&#46; PGRN has anti-inflammatory properties&#44; while granulin peptides have pro-inflammatory properties&#46; The upregulation of <span class="elsevierStyleItalic">GRN</span> in activated microglia suggests PGRN might be involved in neurodegeneration through proinflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Finally&#44; <span class="elsevierStyleItalic">GRN</span> mutant neurons have reduced lysosomal GCase activity&#44; leading to impaired processing of prosaposin&#44; which also may contribute to pathogenesis from <span class="elsevierStyleItalic">GRN</span> mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">To date&#44; more than 170 <span class="elsevierStyleItalic">GRN</span> mutations have been described&#44; most of which led to reduced function or decreased expression of the protein PGRN&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;15</span></a> Among these&#44; there has been described an infrequent splice site variant c&#46;1414-1G&#62;T in 2 Hispanic families in the American continent&#46; The variant is predicted to affect an acceptor splice site and is categorized as a likely pathogenic variant&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Although no studies of progranulin levels in plasma or cDNA have been published&#44; a similar variant &#40;c&#46;1414-2A&#62;G&#41; affects the same core splice-site&#44; and <span class="elsevierStyleItalic">ex vivo</span> splicing assays confirmed that the mutation c&#46;1414-2A&#62;G affects splicing of the exon&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Moreover&#44; homozygous carriers of this variant &#40;members of one of the families described in this report&#41; were previously reported to develop retinal degeneration&#44; hearing loss&#44; and cognitive impairment in the spectrum of Usher syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Our work describes the clinical and neuroimaging features of 5 Spanish families carrying the variant c&#46;1414-1G&#62;T in the <span class="elsevierStyleItalic">GRN</span> gene&#46; We present the clinical&#44; neuroimaging&#44; and laboratory findings&#44; including plasmatic progranulin levels and an RNA study when available&#46; We also present the neuropathologic findings in one case&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Method</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Subjects</span><p id="par0030" class="elsevierStylePara elsevierViewall">Subjects were assessed at the Neurology Service of Hospital Universitario Central de Asturias &#40;Oviedo&#41;&#44; and referred for genetic analysis to the Genetics Laboratory of Hospital Universitario Central de Asturias&#46; Written informed consent was given for all index cases or their legal guardian according to the Declaration of Helsinki&#46; The informed consent form for genetic studies was approved by the Ethical Committee of Principado de Asturias&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The diagnostic workup of index cases included patient and family medical records&#44; detailed history-taking&#44; neurological examination&#44; cognitive assessment&#44; and neuroimaging as decided by the clinician in charge of the patient&#46; Genealogical trees were drawn from the information provided by index cases or their relatives&#46; Genetic testing was made for the most common genes leading to cognitive impairment&#44; including <span class="elsevierStyleItalic">c9orf72&#44; GRN&#44; MAPT&#44; PS1&#44; PS2&#44;</span> and <span class="elsevierStyleItalic">APP&#46;</span></p><p id="par0040" class="elsevierStylePara elsevierViewall">Genetic counseling was offered to the relatives of the index cases&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Genetic testing</span><p id="par0045" class="elsevierStylePara elsevierViewall">The genomic DNA was isolated from peripheral blood leukocytes&#46; In the diagnostic procedure of all index cases&#44; NGS &#40;Next Generation Sequencing&#41; for genes associated with neurodegenerative diseases was performed&#44; according to previously published procedures<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> &#40;<span class="elsevierStyleBold">Supplementary file 1</span>&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">In silico prediction</span><p id="par0050" class="elsevierStylePara elsevierViewall">MaxEntScan was used to predict the splicing effects&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> The variant was classified according to the American College of Medical Genetics and Genomics &#40;ACMG&#41; guidelines &#40;<a href="https://www.acmg.net/">https&#58;&#47;&#47;www&#46;acmg&#46;net&#47;</a>&#41;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Plasma progranulin dosage</span><p id="par0055" class="elsevierStylePara elsevierViewall">To determine the level of plasma progranulin&#44; an enzyme-immunoanalytical essay was performed in an external laboratory &#40;Reference Laboratory&#44; Spain&#41;&#46; The normal range level in this laboratory is 21&#46;8-53&#46;2&#160;ng&#47;mL&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095"><span class="elsevierStyleItalic">GRN</span> mRNA and cDNA analysis</span><p id="par0060" class="elsevierStylePara elsevierViewall">RNA from peripheral blood leukocytes was extracted using TRI Reagent&#8482; Solution &#40;Thermo Fisher Scientific&#44; Baltics UAB&#44; Vilnius&#44; Lithuania&#59; AM9738&#41; and was subsequently used for cDNA synthesis with RNA ImProm-II Reverse Transcriptase &#40;Promega Corporation&#44; Madison&#44; WI&#44; USA&#59; A3802&#41;&#44; according to the manufacturer&#8217;s instructions&#46; To study the effect of the c&#46;1414-1G&#62;T variant on the <span class="elsevierStyleItalic">GRN</span> transcript&#44; we performed a polymerase chain reaction using primers reported in <span class="elsevierStyleBold">Supplementary material 1&#46;</span> The amplification product was sequenced on an Applied Biosystems ABI3130 Genetic Analyzer using the BigDye Terminator 1&#46;1 Cycle Sequencing Kit according to the manufacturer&#8217;s instructions &#40;Thermo Fisher Scientific&#41;&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Molecular findings</span><p id="par0065" class="elsevierStylePara elsevierViewall">Targeted NGS was performed&#44; and we identified 7 symptomatic and 2 asymptomatic heterozygous carriers of the variant c&#46;1414-1G&#62;T in the <span class="elsevierStyleItalic">GRN</span> gene &#40;NM&#95;002087&#41;&#46; No other variants were identified<span class="elsevierStyleItalic">&#46; Ex vivo</span> splicing assays showed a loss of 20 amino acids in exon 12 in c&#46;1414-1G&#62;T carriers &#40;p&#46;Val468&#95;Ala492del&#59; c&#46; c1417&#95;1476del&#41; &#40;<span class="elsevierStyleBold">supplementary&#44; Fig&#46; 1</span>&#41;&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Clinical findings</span><p id="par0070" class="elsevierStylePara elsevierViewall">Next&#44; we summarize the main clinical features and neuroimaging findings of the 5 families where we found a variant c&#46;1414-1G&#62;T in the <span class="elsevierStyleItalic">GRN</span> gene <span class="elsevierStyleBold">&#40;Supplementa</span><span class="elsevierStyleBold">ry</span><span class="elsevierStyleBold">file 1</span>&#41;&#46; All subjects were white&#44; of Spanish origin&#44; were born in the Asturias region &#40;North Spain&#41; &#44;and were living in Spain or other European countries at the time of diagnosis&#46; In some families&#44; we have been able to draw the full family tree&#44; while in others we report the index case only&#44; with little information on other family members because there were no other members affected or information was inaccessible&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Family &#35;1&#58;</span> The index case is a woman who started at 59 years old with progressive behavioral changes dominated by apathy&#44; perseverative behaviour&#44; hyperorality&#44; lack of self-care&#44; and emotional flattening&#59; and soon later aphasia and dysexecutive syndrome leading to severe dementia in 4 years&#46; A brain CT scan showed bilateral but asymmetric frontotemporal atrophy&#44; much more marked on the left side&#44; that progressed to severe&#44; global&#44; asymmetric atrophy in 5 years &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; A brain SPECT scan showed severe hypoperfusion in the frontotemporal lobes&#46; She was diagnosed with behavioral variant FTD &#40;BvFTD&#41; and died 12 years after onset&#46; There were no family members diagnosed with neurodegenerative diseases&#46; An aunt had been diagnosed with a psychiatric disorder in early adulthood&#44; but we were unable to obtain more information on that case&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Family &#35;2&#58;</span> The index case is a 69-year-old woman with no relevant family history&#46; She started with difficulties naming objects and comprehending some words&#46; Neuropsychological assessment revealed low scores in naming drawings and surface dyslexia with spared repetition and speech&#46; She was diagnosed with semantic variant primary progressive aphasia &#40;svPPA&#41;&#46; The brain CT and MRI scans performed at diagnosis showed asymmetry of the frontal and occipital horns of the lateral ventricles&#46; An FDG-PET scan performed at diagnosis showed severe hypometabolism in the left frontal&#44; temporal&#44; and parietal cortices&#44; as well as in the left caudate&#44; putamen&#44; and thalamus nuclei and the right cerebellar cortex &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Plasmatic progranulin levels were normal &#40;30&#46;2&#160;ng&#47;mL&#41;&#46; Her 43-year-old daughter is asymptomatic&#46; She decided to undergo genetic testing after genetic counseling&#44; and was found to be a carrier of the variant c&#46;1414-1G&#62;T in the <span class="elsevierStyleItalic">GRN</span> gene&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Family &#35;3&#58;</span> The index case is a 62-year-old man with a family history of dementia&#58; his mother and a maternal uncle had been diagnosed with Alzheimer&#8217;s disease&#46; His father presented head tremor&#46; The patient started with a resting tremor of the right upper limb&#46; Specifically asked&#44; he admitted presenting hyposmia for at least 3 years&#46; The brain MRI and FDG-PET were both normal&#44; while the DaTSPECT scan revealed a mild decrease&#44; not significant&#44; in the density of presynaptic transporters of dopamine in neurons of the left putamen &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; This clinical picture remained stable for 3 years without the use of any dopaminergic medication&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Family &#35;4</span><span class="elsevierStyleBold">&#58;</span> The index case is a 57-year-old woman with no relevant medical history&#46; Her family started noticing subtle changes in behavior&#44; including emotional lability&#46; Months later she started with language difficulties and soon later dysphagia and some dyspnea when talking&#46; Then she became clumsy with her right hand&#46; Examination revealed severe dysarthria with no tongue atrophy or fasciculations&#46; Segmentary muscular balance in the limbs was normal&#46; The sensory exam showed no abnormalities&#46; Reflexes were brisk at all levels including bilateral clonus Achilles reflexes&#46; Abdominal reflex and plantar reflexes were negative&#46; Gait was normal&#46; The score in the ALSFRS-R was 41&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Routine laboratory blood tests were normal&#46; Brain and cervical spine MRI only showed a pineal cyst of 15&#160;mm and a C5-C5 discal hernia without myelopathy&#46; The first EMG was normal but showed mild alterations in the median nerve suggestive of entrapment in the carpal tunnel&#46; The second EMG&#44; 6 months later&#44; showed active denervation signs including spontaneous fasciculations in the bulbar&#44; cervical&#44; thoracic&#44; and lumbar segments&#44; more prominent on the right side&#44; without involvement of the sensory nerves but with bilateral focal neuropathy of the median nerve at the carpal tunnel&#46; Motor-evoked potentials showed altered efferent pathway conduction in the upper limbs only&#46; An FDG-PET scan showed hypometabolism in the frontotemporal lobes&#44; more intense on the left side&#46; Around 12 months after onset&#44; the patient started with painful spasms that were treated with oral levetiracetam&#44; clonazepam&#44; and baclofen&#44; with no improvement&#46; Her mental and motor status deteriorated rapidly&#44; and she died within a few weeks&#46; Autopsy &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41; revealed findings compatible with FTD-ALS with inclusions of TDP-43 type A&#46; There was an intense loss of motor neurons in the anterior horns in all 3 spinal cord segments&#44; particularly in the cervical and thoracic segments&#46; The remaining neurons showed degenerative signs such as central chromatolysis and were surrounded by areas of gliosis and sclerosis&#46; Immunohistochemistry showed a variable number of TDP-43positive cytoplasmatic inclusions&#44; mostly filiform types&#46; Other motor neurons showed a lack of expression of TDP-43 in the nucleus&#46; Remarkably&#44; there was a moderate-intense mobilization of CD68 positive cells from the microglial-macrophagic system in the white matter of the spinal cord&#44; corresponding to the brainstem corticospinal tracts&#44; displaying an intense loss of the motor neurons in the hyoglossus nuclei&#44; with some neuronophagia&#46; At the encephalic level&#44; conventional staining showed signs of degeneration with neuronal loss in the frontotemporal lobes and micro-spongiosis in the most superficial layers&#46; Immunohistochemistry showed TDP-43&#8211;positive intracytoplasmic inclusions&#44; mostly granular and rounded&#44; in the most superficial layers of the frontal cortex &#40;layer 2&#41;&#44; with isolated positive short dystrophic neurites&#46; No intranuclear TDP-43&#8211;positive inclusions were observed&#46; The hippocampus was scarcely affected&#44; with some intracytoplasmic TDP-43&#8211;positive inclusions in the gyrus dentatus&#46; There was no immunoreactivity for AT8 nor beta-amyloid in the cortex or the limbic system&#46; The anti-ubiquitin antibody correlated with the TDP-43&#8211;positive inclusions&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Segregation studies on living family members found that her mother &#40;86 years old&#44; diagnosed with unspecified dementia&#41;&#44; a brother &#40;54 years old&#44; asymptomatic&#41;&#44; and a sister &#40;66 years old&#44; asymptomatic&#41; were all heterozygous carriers of the c&#46;1414-1G&#62;T variant &#40;<span class="elsevierStyleBold">Supplementa</span><span class="elsevierStyleBold">ry</span><span class="elsevierStyleBold">file 2&#44;</span><a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Family &#35;5&#46;</span> Index case &#40;individual II&#46;4 in supplemental file 2&#44; figure 2&#41; is a woman who started with cognitive impairment at 76 years old&#44; mainly memory complaints and language difficulties&#46; The neuropsychological assessment confirmed low scores in naming tasks&#44; comprehension of sentences&#44; and verbal memory&#46; CT was normal while the brain SPECT showed mild-moderate hypoactivity in the frontotemporal regions&#44; more marked in the right hemisphere&#44; and irregularities in the perfusion of parietal lobes &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41;&#46; She progressed slowly and died 8 years later&#46; No specific diagnosis was made&#44; other than &#8220;cognitive impairment of probable neurodegenerative origin&#8221;&#46; Another member of this family &#40;the younger sister&#44; II&#46;5&#44; <span class="elsevierStyleBold">Supplementary file 2</span>&#44; Fig&#46; 2&#41; had been assessed independently at another Spanish hospital and diagnosed with Usher-like phenotype&#44; as she presented with late-onset retinal degeneration with very rapid progression and hearing loss&#44; as well as uncharacterized cognitive impairment&#46; She was found to be a homozygous carrier of this variant&#46; We were unable to test all members of this family&#59; but in some cases&#44; the genetic status could be inferred from descendants or known from a previous report&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> The parents of this sibling were a man who had died of lung cancer in his fifties and a woman with visual impairment of no specific diagnosis &#40;not clearly attributable to retinal degeneration&#41;&#46; The parents were not tested&#44; but as there were homozygosity among the sibling&#44; both progenitors must have been obligate carriers of the mutation&#46; Two of the mother&#8217;s brothers &#40;not shown in the pedigree&#41; had manifested behaviour changes compatible with FTD&#44; although they were not formally diagnosed&#46; The sibling of 6 includes the eldest sister&#44; a heterozygous carrier who died after a stroke and had visual impairment of no specific diagnosis&#59; and a brother &#40;second sibling&#41; who died with unspecified cognitive and visual impairment&#44; whose genetic status is unknown&#46; The younger and elder sisters of the index case &#40;the third and fifth siblings&#41; shared the phenotype of cognitive impairment&#44; hearing loss&#44; and retinal degeneration&#59; and both were found to be homozygous carriers of the variant&#46; Retinal degeneration was compatible with retinitis pigmentosa&#58; age at onset 40-45 years old&#44; with nyctalopia and photophobia&#59; constriction of visual fields evolving to tunnel vision with central vision only distinguishing shapes&#59; fundoscopy revealed thinning of central retinal vessels&#44; a scarce number of bone spicule pigments&#44; absence of foveal reflex&#44; and pale optic disc&#46; Finally&#44; the youngest sister in the sibling &#40;the only one who is still alive&#41; has no symptoms to date but was found to be an asymptomatic carrier&#46; Among the descendants of the sibling&#44; who are now in their fifties and sixties&#44; there are no reported cases of visual or cognitive impairment to date &#40;there is one man with hearing loss&#44; III&#46;3 in <span class="elsevierStyleBold">Supplementary file 2</span>&#44; Fig&#46; 2&#41;&#46; Some of the descendants decided after genetic counseling to get genetic testing done&#44; and some of them resulted to be asymptomatic carriers of the variant 1414-1G&#160;&#62;&#160;T in <span class="elsevierStyleItalic">GRN</span> gene history &#40;<span class="elsevierStyleBold">Supplementary file 2</span>&#44; Fig&#46; 2&#41;&#46; We measured the levels of plasmatic progranulin in one of the asymptomatic carriers &#40;the son of the index case&#58; III&#46;6 in supplementary file 2&#44; Fig&#46; 2&#41; and resulted within the normal range &#40;37&#46;5&#160;ng&#47;mL&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Discussion</span><p id="par0110" class="elsevierStylePara elsevierViewall">Here we report the main clinical&#44; laboratory&#44; and neuroimaging features of 5 Spanish families with the variant c&#46;1414-1G&#62;T in the <span class="elsevierStyleItalic">GRN</span> gene&#46; This variant was previously described in 2 Hispanic families in the American continent&#44; one of which had 20 affected individuals&#44; but it did not show perfect segregation&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> At that time&#44; the variant c&#46;1414-1G&#62;T in <span class="elsevierStyleItalic">GRN</span> had not been described in other patients or healthy subjects&#46; Later&#44; it was described as part of the spectrum of Usher syndrome in homozygous subjects<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> who are also members of family &#35;5 reported here&#41;&#46; Given it has only been reported in families of Hispanic origin&#44; and our families are all from the same region&#44; there might be a Spanish founder effect&#44; even though other genetic studies such as haplotype studies would be needed to confirm this point&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Characteristic phenotypic differences corresponding with specific gene variants increase our understanding of the genotype-phenotype relationship in the complex spectrum of neurodegenerative disorders&#44; particularly in familial FTLD&#44; where 3 genes are responsible for most cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> In our series&#44; information on some families is limited since this is a retrospective study&#44; and information was gathered from medical records and indirectly from other family members&#46; Even so&#44; our series further expands the spectrum of clinical symptoms in <span class="elsevierStyleItalic">GRN</span> mutations&#46; There were homozygous carriers clinically diagnosed with BvFTD&#44; with svPPA&#44; with rapidly progressive motor neuron disease &#40; pathologically documented&#41;&#44; and with tremor dominant parkinsonism&#59; and homozygous carriers diagnosed with retinal degeneration &#40;compatible with retinitis pigmentosa&#41;&#46; The latter phenotype was previously reported to be associated with hearing loss in some cases&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Motor neuron disease is uncommon among carriers of <span class="elsevierStyleItalic">GRN</span> mutations&#44;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> although this association has already been described in a few families&#44;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;21</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">The most common neuroimaging finding in our series was asymmetric atrophy of the frontal cortex with asymmetric enlargement of the ventricular horns&#44; a well-known characteristic of <span class="elsevierStyleItalic">GRN</span> mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> We also found severe cortical asymmetric hypometabolism with contralateral cerebellar diaschisis and normal DaTSPECT in a patient with tremor parkinsonism&#44; as previously reported in FTD with parkinsonism&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Clinical heterogeneity is well known in <span class="elsevierStyleItalic">GRN</span> mutations<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;5&#44;16&#44;24</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> and there might be different underlying pathological processes explaining this fact&#46; First&#44; <span class="elsevierStyleItalic">GRN</span> expression mediates neuroinflammation function related to general neurodegeneration&#44; which may be a shared mechanism for PD&#44; AD&#44; and ALS&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> In addition&#44; the <span class="elsevierStyleItalic">GRN</span> gene has recently been identified as a susceptibility gene for AD in a large GWAS study&#44;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> which may expand the phenotypic diversity&#46; Interestingly&#44; one of our families is associated with retinitis pigmentosa and it is known that homozygous mutations in <span class="elsevierStyleItalic">GRN</span> are associated with neuronal ceroid lipofuscinosis 11 &#40;CLN11&#41;&#44; a rare lysosomal-storage disorder characterized by cerebellar ataxia&#44; seizures&#44; retinitis pigmentosa&#44; and cognitive disorders&#44; usually beginning between 13 and 25 years of age&#46; Other homozygous patients present distinct delayed phenotypes of FTD and parkinsonism after 50 years&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> In the <span class="elsevierStyleItalic">CLN11</span> gene&#44; hallmarks of neuronal ceroid lipofuscinosis were present&#44; but TDP-43 cytoplasmic inclusions were absent&#44; which markedly differs from heterozygous mutations&#44; suggesting a pathological shift between lysosomal and TDP-43 pathologies depending on the mono- or bi-allelic status&#46; A dosage effect of <span class="elsevierStyleItalic">GRN</span> mutation is supported by the presence of residual levels of plasma PGRN and low levels of normal transcript detected in cases with a homozygous splice-site mutation and late-onset FTD<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> and from reports such as the present series&#44; where homozygous carriers developed retinal and brain degeneration while heterozygous carriers developed brain degeneration only or remained asymptomatic&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">The neuropathological study of the index case of family 4 shows typical findings of FTD-ALS TDP-43 subtype A&#44;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> which has been reported to be familial in up to 50&#37; of cases&#46; In our series&#44; family history was not particularly informative in some families&#44; with just one or a few members presenting neurodegenerative diseases&#46; Although this suggests incomplete penetrance of this variant&#44; as previously reported&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> the phenotypic heterogeneity of <span class="elsevierStyleItalic">GRN</span> mutations may hinder the identification of family members with related disorders in some cases&#46; Moreover&#44; the age of onset is also variable&#44; with carriers developing severe symptoms in their fifties while others remain asymptomatic in their sixties&#46; It has been shown that both modifier genes<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> and epigenetic marks<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> contribute to the increased progranulin expression in cases of reduced penetrance&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The variant c&#46;1414-1G&#62;T affects the last nucleotide of intron 11 within a core splice site and is predicted to alter an acceptor splice-site causing exon skipping&#46; Most <span class="elsevierStyleItalic">GRN</span> pathogenic variants are predicted to cause the pathology via a haploinsufficiency mechanism by creating premature stop codons&#44; which in turn result in NMD&#46; We showed that the heterozygous carriers of the variant c&#46;1414-1G&#62;T have a loss of 20 amino acids &#40;468 to 492&#41; in the exon 12 affecting PGRN domain D &#40;granulin D&#41;&#44; but no NMD was detected&#44; and the plasmatic levels of the protein were in the normal range according to the laboratory reference&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31&#44;32</span></a> However&#44; the fact that it is translated into protein does not mean the protein is completely functional&#46; Therefore&#44; functional studies should be performed to assess the functionality of the mutant protein&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Previous works demonstrated that cerebrospinal fluid progranulin levels do not correlate with its serum levels&#44; indicating differential regulation of its central and peripheral levels in neurodegeneration&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> It might be possible that the c&#46;1414-1G&#62;T variant causes a central nervous PGRN reduction or has a pathological mechanism similar to other pathogenic variants associated with normal progranulin levels&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> Future studies are needed to determine these possibilities&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">A recent study<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> showed that affected pathways in <span class="elsevierStyleItalic">GRN</span> mutation carriers extend beyond <span class="elsevierStyleItalic">GRN</span> and contribute to genetically unexplained forms of FTLD-TDP type A&#44; including dysregulation of the GABAergic signaling pathway and the potential involvement of astrocytic inflammation&#46; This study also provides new avenues for research into FTLD-TDP type A and GRN and potentially new therapeutic targets such as the GABAergic&#44; GDNF&#44; and sphingolipid pathways&#46; Other therapeutic strategies such as gene therapy targeting splicing sites may also be suitable&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">In conclusion&#44; the clinical pictures&#44; segregation data&#44; the absence of variant carriers among non-demented controls&#44; and splicing analyses strongly suggest that <span class="elsevierStyleItalic">GRN</span> c&#46;1414-1G&#62;T is a pathogenic variant&#46; Given it has only been reported in families of Hispanic origin&#44; and our families are all from the same region&#44; there might be a Hispanic founder effect&#46; As this variant seems to affect <span class="elsevierStyleItalic">GRN</span> gene splicing but not plasmatic levels of the progranulin protein&#44; there might be other pathogenic mechanisms apart from haploinsufficiency&#59; functional studies are needed to elucidate this question&#46; Phenotypes and disease progression can be diverse as in other <span class="elsevierStyleItalic">GRN</span> mutations&#44; while retinitis pigmentosa may be added to the clinical spectrum&#46; This variant should be considered for therapeutic strategies based on the GABAergic&#44; GDNF&#44; lysosomal function&#44; and sphingolipid pathways or for those based on restoring <span class="elsevierStyleItalic">GRN</span> functional levels&#44; either using enzymatic inhibition or using gene editing targeting splicing sites&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#8211;37</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Competing interests</span><p id="par0155" class="elsevierStylePara elsevierViewall">The authors report no competing interests&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Funding</span><p id="par0160" class="elsevierStylePara elsevierViewall">This research was funded by a grant from <span class="elsevierStyleGrantSponsor" id="gs0005">Instituto de Salud Carlos III</span> &#40;PI21&#47;00467&#44; co-funded by <span class="elsevierStyleGrantSponsor" id="gs0010">European Regional Development Fund</span>&#47;<span class="elsevierStyleGrantSponsor" id="gs0015">European Social Fund</span>&#41; to MMG and VA&#46;</p></span></span>"
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              "titulo" => "Subjects"
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            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Genetic testing"
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              "identificador" => "sec0025"
              "titulo" => "In silico prediction"
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              "identificador" => "sec0030"
              "titulo" => "Plasma progranulin dosage"
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              "identificador" => "sec0035"
              "titulo" => "GRN mRNA and cDNA analysis"
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          "titulo" => "Results"
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              "titulo" => "Molecular findings"
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              "titulo" => "Clinical findings"
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          "titulo" => "Discussion"
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          "titulo" => "Competing interests"
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          "titulo" => "Funding"
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          "identificador" => "xack630950"
          "titulo" => "Acknowledgments"
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          "titulo" => "References"
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    "tienePdf" => true
    "fechaRecibido" => "2022-07-12"
    "fechaAceptado" => "2022-09-19"
    "PalabrasClave" => array:2 [
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1566484"
          "palabras" => array:8 [
            0 => "Granulin"
            1 => "Frontotemporal dementia"
            2 => "Motor neuron disease"
            3 => "Parkinsonism"
            4 => "Progressive aphasia"
            5 => "Retinal degeneration"
            6 => "Gene dosage effect"
            7 => "Haploinsufficiency"
          ]
        ]
        1 => array:4 [
          "clase" => "abr"
          "titulo" => "Abbreviations"
          "identificador" => "xpalclavsec1566485"
          "palabras" => array:7 [
            0 => "ALS"
            1 => "CLN"
            2 => "FTD"
            3 => "GRN"
            4 => "NMD"
            5 => "PGRN"
            6 => "PPA"
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            0 => "Granulina"
            1 => "Demencia frontotemporal"
            2 => "Enfermedad de motoneurona"
            3 => "Parkinsonismo"
            4 => "Afasia progresiva primaria"
            5 => "Degeneraci&#243;n retiniana"
            6 => "Efecto de dosis g&#233;nica"
            7 => "Haploinsuficiencia"
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    "resumen" => array:2 [
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">The variant c&#46;1414-1G&#62;T in the <span class="elsevierStyleItalic">GRN</span> gene has previously been&#160;reported as probably pathogenic in subjects of Hispanic origin in the American continent&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">We report 5 families of Spanish origin carrying this variant&#44; including the clinical&#44; neuroimaging&#44; and laboratory findings&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Phenotypes were strikingly different&#44; including cases presenting with behavioral variant frontotemporal dementia&#44; semantic variant primary progressive aphasia&#44; rapidly progressive motor neuron disease &#40;pathologically documented&#41;&#44; and tremor-dominant parkinsonism&#46; Retinal degeneration has been found in homozygous carriers only&#46; <span class="elsevierStyleItalic">Ex vivo</span> splicing assays confirmed that the mutation c&#46;1414-1G&#62;T affects the splicing of the exon&#44; causing a loss of 20 amino acids in exon 11&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">We conclude that variant c&#46;1414-1G&#62;T of the <span class="elsevierStyleItalic">GRN</span> gene is pathogenic&#44; can lead to a variety of clinical presentations and to gene dosage effect&#44; and probably has a Spanish founder effect&#46;</p></span>"
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            "titulo" => "Introduction"
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            "titulo" => "Methods"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">La variante c&#46;1414-1G&#160;&#62;&#160;T en el gen <span class="elsevierStyleItalic">GRN</span> ha sido reportada previamente como probablemente patog&#233;nica en sujetos del continente Americano de origen Hispano&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Reportamos cinco familias de origen Espa&#241;ol portadoras de la mencionada variante&#46; Se presentan las caracter&#237;sticas cl&#237;nicas&#44; de neuroimagen y de laboratorio&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Los fenotipos encontrados difieren llamativamente entre los distintos casos&#44; incluyendo presentaci&#243;n como demencia frontotemporal variante conductual&#44; variante sem&#225;ntica de afasia progresiva primaria&#44; enfermedad de neurona motora r&#225;pidamente progresiva &#40;con confirmaci&#243;n neuropatol&#243;gico&#41; y parkinsonismo de predominio trem&#243;rico&#46; Degeneraci&#243;n retiniana fue evidenciada &#250;nicamente en portadores homocigotos&#46; Ensayos de splicing <span class="elsevierStyleItalic">ex vivo</span> confirman que la mutaci&#243;n c&#46;1414-1G&#160;&#62;&#160;T afecta el splicing del ex&#243;n&#44; causando una p&#233;rdida de 20 amino&#225;cidos en el ex&#243;n 11&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Concluimos que la variante c&#46;1414-1G&#160;&#62;&#160;T del gen <span class="elsevierStyleItalic">GRN</span> es patog&#233;nica&#44; puede causar presentaciones cl&#237;nicas diversas&#44; efecto de dosis g&#233;nica y probablemente represente un efecto fundador de origen Espa&#241;ol&#46;</p></span>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Neuroimaging from index case in family &#35;1&#46;</span> CT brain scan showing severe and asymmetric atrophy of the frontal and temporal lobes&#44; more intense on the left side&#46; <span class="elsevierStyleBold">A</span><span class="elsevierStyleBold">&#41;</span> Baseline&#44; at diagnosis&#46; <span class="elsevierStyleBold">B</span><span class="elsevierStyleBold">&#41;</span> Follow-up&#44; 5 years after diagnosis&#46;</p>"
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Neuroimaging from case index in family &#35;2&#46;</span> Brain FDG-PET scan showing severe hypometabolism in the left frontal&#44; temporal&#44; and parietal cortices&#44; as well as in the left caudate&#44; putamen&#44; and thalamus nuclei and the right cerebellar cortex&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Neuroimaging from index case in family &#35;3&#46;</span> DaT-SPECT showed a mild decrease&#44; not significant&#44; in the density of presynaptic transporters of dopamine in neurons of the left putamen&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Main neuropathological features of index case from family &#35;4&#46; A</span><span class="elsevierStyleBold">&#41;</span> Marked depletion of motor neurons from the anterior horn of the spinal cord &#40;hematoxylin and eosin stain&#41;&#46; <span class="elsevierStyleBold">B</span><span class="elsevierStyleBold">&#41;</span> Motor neuron filiform cytoplasmic inclusion was revealed by anti&#8211;TDP-43 in the spinal cord &#40;black arrow&#41;&#46; Other remaining motor neurons showed loss of normal nuclear staining &#40;red arrows&#41;&#46; <span class="elsevierStyleBold">C</span><span class="elsevierStyleBold">&#41;</span> Many small cortical neuronal paranuclear inclusions were detected with antibodies against TDP-43 &#40;black arrows&#41;&#46; Short cortical dystrophic neurites were observed with anti&#8211;TDP-43 &#40;black arrowheads&#41; Loss of normal nuclear staining of TDP-43 was noted &#40;red arrows&#41;&#46; <span class="elsevierStyleBold">D&#46;</span> Some hippocampal neuronal cytoplasmic inclusions in dentate granule cells were displayed &#40;black arrows&#41;&#46; Loss of normal nuclear staining of TDP-43 was noted &#40;red arrow&#41;&#46; Magnification &#215;400&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Neuroimaging study from case index in family &#35;5&#46;</span> SPECT brain scan showed mild-moderate hypoactivity in the frontotemporal regions&#44; more marked on the right hemisphere&#44; and irregularities in the perfusion of parietal lobes&#46;</p>"
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        "texto" => "<p id="par0165" class="elsevierStylePara elsevierViewall">We would like to thank patients and families for collaborating in this study and giving permission to publish the series of cases&#46;</p>"
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Article information
ISSN: 21735808
Original language: English
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