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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="GRN Frontotemporal Dementia" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2020/02/06" /><meta name="citation_author" content="Ging-Yuek Robin Hsiung" /><meta name="citation_author" content="Howard H Feldman" /><meta name="citation_pmid" content="20301545" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1371/" /><meta name="citation_keywords" content="FTD-GRN" /><meta name="citation_keywords" content="FTD-GRN" /><meta name="citation_keywords" content="Progranulin" /><meta name="citation_keywords" content="GRN" /><meta name="citation_keywords" content="GRN Frontotemporal Dementia" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="GRN Frontotemporal Dementia" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Ging-Yuek Robin Hsiung" /><meta name="DC.Contributor" content="Howard H Feldman" /><meta name="DC.Date" content="2020/02/06" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK1371/" /><meta name="description" content="The spectrum of GRN frontotemporal dementia (GRN-FTD) includes the behavioral variant (bvFTD), primary progressive aphasia (PPA; further subcategorized as progressive nonfluent aphasia [PNFA] and semantic dementia [SD]), and movement disorders with extrapyramidal features such as parkinsonism and corticobasal syndrome (CBS). A broad range of clinical features both within and between families is observed. The age of onset ranges from 35 to 87 years. Behavioral disturbances are the most common early feature, followed by progressive aphasia. Impairment in executive function manifests as loss of judgment and insight. In early stages, PPA often manifests as deficits in naming, word finding, or word comprehension. In late stages, affected individuals often become mute and lose their ability to communicate. Early findings of parkinsonism include rigidity, bradykinesia or akinesia (slowing or absence of movements), limb dystonia, apraxia (loss of ability to carry out learned purposeful movements), and disequilibrium. Late motor findings may include myoclonus, dysarthria, and dysphagia. Most affected individuals eventually lose the ability to walk. Disease duration is three to 12 years." /><meta name="og:title" content="GRN Frontotemporal Dementia" /><meta name="og:type" content="book" /><meta name="og:description" content="The spectrum of GRN frontotemporal dementia (GRN-FTD) includes the behavioral variant (bvFTD), primary progressive aphasia (PPA; further subcategorized as progressive nonfluent aphasia [PNFA] and semantic dementia [SD]), and movement disorders with extrapyramidal features such as parkinsonism and corticobasal syndrome (CBS). A broad range of clinical features both within and between families is observed. The age of onset ranges from 35 to 87 years. Behavioral disturbances are the most common early feature, followed by progressive aphasia. Impairment in executive function manifests as loss of judgment and insight. In early stages, PPA often manifests as deficits in naming, word finding, or word comprehension. In late stages, affected individuals often become mute and lose their ability to communicate. Early findings of parkinsonism include rigidity, bradykinesia or akinesia (slowing or absence of movements), limb dystonia, apraxia (loss of ability to carry out learned purposeful movements), and disequilibrium. Late motor findings may include myoclonus, dysarthria, and dysphagia. Most affected individuals eventually lose the ability to walk. 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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="All GeneReviews" href="/books/n/gene/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" alt="Cover of GeneReviews®" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>GeneReviews<sup>®</sup> [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK1371_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK1371_dtls__"><div>Adam MP, Feldman J, Mirzaa GM, et al., editors.</div><div>Seattle (WA): <a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>; 1993-2025.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/gene/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search GeneReviews" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search GeneReviews" submit="false" style="padding: 0.1em 0.4em;" /></div></form><div><ul class="inline_list"><li><a href="/books/n/gene/advanced/">GeneReviews Advanced Search</a></li><li style="margin-left:.5em"><a href="/books/n/gene/helpadvsearch/">Help</a></li></ul></div></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/grin2d-dee/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/drd/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK1371_"><span class="title" itemprop="name"><i>GRN</i> Frontotemporal Dementia</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonym: FTD-GRN</div><p class="contrib-group"><span itemprop="author">Ging-Yuek Robin Hsiung</span>, MD, MHSc, FRCPC and <span itemprop="author">Howard H Feldman</span>, MD, CM, FRCPC.</p><a data-jig="ncbitoggler" href="#__NBK1371_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK1371_ai__"><div class="contrib half_rhythm"><span itemprop="author">Ging-Yuek Robin Hsiung</span>, MD, MHSc, FRCPC<div class="affiliation small">Associate Professor, Division of Neurology<br />Faculty of Medicine<br />University of British Columbia and Providence Health Care<br />Vancouver, British Columbia, Canada<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ac.cbu.liam@gnuish" class="oemail">ac.cbu.liam@gnuish</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Howard H Feldman</span>, MD, CM, FRCPC<div class="affiliation small">Professor, Division of Neurology<br />Faculty of Medicine<br />University of British Columbia<br />Vancouver, British Columbia, Canada<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ac.cbu@namdlef.drawoh" class="oemail">ac.cbu@namdlef.drawoh</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">September 7, 2007</span>; Last Update: <span itemprop="dateModified">February 6, 2020</span>.</p><p><em>Estimated reading time: 31 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="ftd-grn.Summary" itemprop="description"><h2 id="_ftd-grn_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>The spectrum of <i>GRN</i> frontotemporal dementia (<i>GRN</i>-FTD) includes the behavioral variant (bvFTD), primary progressive aphasia (PPA; further subcategorized as progressive nonfluent aphasia [PNFA] and semantic dementia [SD]), and movement disorders with extrapyramidal features such as parkinsonism and corticobasal syndrome (CBS). A broad range of clinical features both within and between families is observed. The age of onset ranges from 35 to 87 years. Behavioral disturbances are the most common early feature, followed by progressive aphasia. Impairment in executive function manifests as loss of judgment and insight. In early stages, PPA often manifests as deficits in naming, word finding, or word comprehension. In late stages, affected individuals often become mute and lose their ability to communicate. Early findings of parkinsonism include rigidity, bradykinesia or akinesia (slowing or absence of movements), limb dystonia, apraxia (loss of ability to carry out learned purposeful movements), and disequilibrium. Late motor findings may include myoclonus, dysarthria, and dysphagia. Most affected individuals eventually lose the ability to walk. Disease duration is three to 12 years.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of <i>GRN</i>-FTD is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with suggestive findings and a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>GRN</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Behavioral manifestations such as apathy, impulsivity, and compulsiveness may respond to selective serotonin reuptake inhibitors. Roaming, delusions, and hallucinations may respond to antipsychotic medications. Reports have suggested potential benefits with certain pharmacotherapy on management of FTD; however, evidence from randomized controlled trials is limited. Small-scale studies have suggested that trazodone may be helpful for treating irritability, agitation, depression, and eating disorders; methylphenidate and dextro-amphetamine may help minimize risk-taking behavior. Cholinesterase inhibitors examined in clinical trials were generally well tolerated: galantamine was used to treat PPA with stabilization of symptoms; rivastigmine was used to treat behavioral manifestations and appeared to decrease caregiver burden. Two open-label studies of memantine, an NMDA partial agonist-antagonist, demonstrated some efficacy on frontal behavior in those with bvFTD and improvement in cognitive performance in those with PPA-PNFA.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>GRN</i>-FTD is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner. About 95% of individuals diagnosed with <i>GRN</i>-FTD have an affected parent. The proportion of affected individuals with a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a>
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<i>GRN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is unknown but is estimated to be 5% or fewer. Each child of an individual with <i>GRN</i>-FTD has a 50% chance of inheriting the pathogenic variant. Once a <i>GRN</i> pathogenic variant has been identified in an affected family member, <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for a pregnancy at increased risk and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p></div></div><div id="ftd-grn.Diagnosis"><h2 id="_ftd-grn_Diagnosis_">Diagnosis</h2><div id="ftd-grn.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>GRN</i> frontotemporal dementia (<i>GRN</i>-FTD) <b>should be suspected</b> in individuals with the following clinical presentations and neuroimaging findings.</p><div id="ftd-grn.Clinical_Presentations"><h4>Clinical Presentations</h4><p>Clinical presentations of <i>GRN</i>-FTD vary widely both among and within families and may resemble behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), atypical parkinsonism, or corticobasal syndrome.</p><p><b>Behavioral variant FTD</b> [<a class="bk_pop" href="#ftd-grn.REF.rascovsky.2011.2456">Rascovsky et al 2011</a>]</p><ul><li class="half_rhythm"><div>Early behavioral disinhibition (including one of the following):</div><ul><li class="half_rhythm"><div>Socially inappropriate behavior</div></li><li class="half_rhythm"><div>Loss of manners or decorum</div></li><li class="half_rhythm"><div>Impulsive, rash, or careless actions</div></li></ul></li><li class="half_rhythm"><div>Early apathy or inertia (one of the following):</div><ul><li class="half_rhythm"><div>Apathy</div></li><li class="half_rhythm"><div>Inertia</div></li></ul></li><li class="half_rhythm"><div>Early loss of sympathy or empathy (one of the following):</div><ul><li class="half_rhythm"><div>Diminished response to other people's needs and feelings</div></li><li class="half_rhythm"><div>Diminished social interest, interrelatedness, or personal warmth</div></li></ul></li><li class="half_rhythm"><div>Early perseverative, stereotyped, or compulsive/ritualistic behavior (one of the following):</div><ul><li class="half_rhythm"><div>Simple repetitive movements</div></li><li class="half_rhythm"><div>Complex, compulsive, or ritualistic behaviors</div></li><li class="half_rhythm"><div>Stereotypy of speech</div></li></ul></li><li class="half_rhythm"><div>Hyperorality and dietary changes (one of the following):</div><ul><li class="half_rhythm"><div>Altered food preferences</div></li><li class="half_rhythm"><div>Binge eating, increased consumption of alcohol or cigarettes</div></li><li class="half_rhythm"><div>Oral exploration or consumption of inedible objects</div></li></ul></li><li class="half_rhythm"><div>Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions (<b>all</b> of the following):</div><ul><li class="half_rhythm"><div>Deficits in executive tasks</div></li><li class="half_rhythm"><div>Relative sparing of episodic memory</div></li><li class="half_rhythm"><div>Relative sparing of visuospatial skills</div></li></ul></li></ul><p><b>Primary progressive aphasia (PPA).</b> PPA has been further classified into three subtypes [<a class="bk_pop" href="#ftd-grn.REF.gornotempini.2011.1006">Gorno-Tempini et al 2011</a>]:</p><ul><li class="half_rhythm"><div>Progressive nonfluent aphasia (PNFA, also known as nonfluent or agrammatic subtype of PPA)</div></li><li class="half_rhythm"><div>Semantic dementia (SD)</div></li><li class="half_rhythm"><div>Logopenic variant (logopenic PPA)</div><div>Note: To date, the logopenic variant has not been associated with <i>GRN</i>-FTD.</div></li></ul><p>The majority of the literature describes PNFA to be the predominant form of PPA in <i>GRN</i>-FTD, although there are a few reports of the SD <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> as well.</p><p>The currently proposed diagnostic algorithm for PNFA requires a two-step process. First, individuals must meet the criteria for PPA, and after the diagnosis of PPA is established, the main features of the speech and language abnormalities may be considered to subcategorize into each of the PPA variants.</p><p>The diagnostic criteria of PPA [<a class="bk_pop" href="#ftd-grn.REF.mesulam.2001.425">Mesulam 2001</a>]:</p><ul><li class="half_rhythm"><div>The most prominent clinical feature is difficulty with language.</div></li><li class="half_rhythm"><div>Language deficits are the principal cause of impaired daily living activities.</div></li><li class="half_rhythm"><div>Aphasia is the most prominent deficit at symptom onset and for the initial phases of the disease.</div></li></ul><p>Note: The pattern of deficits cannot be accounted for by other nondegenerative diseases of the nervous system, medical disorders, or psychiatric diagnoses.</p><p>
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<b>PPA subtypes</b>
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</p><ul><li class="half_rhythm"><div><b>Nonfluent variant of PPA (PPA-PNFA).</b> The diagnostic criteria of PPA-PNFA include clinical presentation of aphasia with [<a class="bk_pop" href="#ftd-grn.REF.gornotempini.2011.1006">Gorno-Tempini et al 2011</a>]:</div><ul><li class="half_rhythm"><div>At least one of the following core features:</div><ul><li class="half_rhythm"><div>Agrammatism in language production</div></li><li class="half_rhythm"><div>Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)</div></li></ul></li><li class="half_rhythm"><div>At least two of the three following supportive features:</div><ul><li class="half_rhythm"><div>Impaired comprehension of syntactically complex sentences</div></li><li class="half_rhythm"><div>Spared single-word comprehension</div></li><li class="half_rhythm"><div>Spared object knowledge</div></li></ul></li></ul></li><li class="half_rhythm"><div><b>Semantic variant of PPA (PPA-SD).</b> The diagnostic criteria of PPA-SD require the presence of both of the following core features:</div><ul><li class="half_rhythm"><div>Impaired confrontation naming</div></li><li class="half_rhythm"><div>Impaired single-word comprehension</div></li></ul><div>AND at least three of the following four additional diagnostic features:</div><ul><li class="half_rhythm"><div>Impaired object knowledge, particularly for low frequency or low-familiarity items</div></li><li class="half_rhythm"><div>Surface dyslexia or dysgraphia</div></li><li class="half_rhythm"><div>Spared repetition</div></li><li class="half_rhythm"><div>Spared speech production (grammar and motor speech)</div></li></ul></li></ul><p><b>Atypical parkinsonism.</b> Clinical features include the following:</p><ul><li class="half_rhythm"><div>Bradykinesia</div></li><li class="half_rhythm"><div>Rigidity</div></li><li class="half_rhythm"><div>Gait instability</div></li><li class="half_rhythm"><div>Resting tremor</div></li></ul><p><b>Corticobasal syndrome.</b> Clinical features include the following [<a class="bk_pop" href="#ftd-grn.REF.armstrong.2013.496">Armstrong et al 2013</a>]:</p><ul><li class="half_rhythm"><div>Progressive asymmetric rigidity</div></li><li class="half_rhythm"><div>Apraxia</div></li><li class="half_rhythm"><div>Alien-limb phenomenon</div></li><li class="half_rhythm"><div>Cortical sensory loss</div></li><li class="half_rhythm"><div>Focal dystonia</div></li><li class="half_rhythm"><div>Myoclonus</div></li><li class="half_rhythm"><div>Dementia</div></li></ul></div><div id="ftd-grn.Neuroimaging"><h4>Neuroimaging</h4><p><b>Computed tomography (CT) or magnetic resonance imaging (MRI)</b> may show focal, often asymmetric atrophy in the frontal, temporal, and/or parietal lobes [<a class="bk_pop" href="#ftd-grn.REF.rohrer.2011.542">Rohrer & Warren 2011</a>]. Volumetric studies comparing the rate of brain atrophy between <i>GRN</i>-FTD and <i>MAPT</i>-FTD showed that individuals with <i>GRN</i>-FTD have a higher rate of whole-brain atrophy (3.5% per year) than those with <i>MAPT</i>-related FTD [<a class="bk_pop" href="#ftd-grn.REF.whitwell.2011.393">Whitwell et al 2011</a>].</p><p><b>Single photon emission computed tomography (SPECT)</b> may reveal decreased perfusion in the frontal and temporal lobes [<a class="bk_pop" href="#ftd-grn.REF.pasquier.2003.s32">Pasquier et al 2003</a>]. There is also evidence of poor cerebral perfusion in both anterior parietal lobes, predominantly on the left hemisphere and on the right inferior parietal cortex [<a class="bk_pop" href="#ftd-grn.REF.le_ber.2008.732">Le Ber et al 2008</a>].</p><p><b>Positron emission tomography (PET)</b> may demonstrate decreased glucose metabolism in the frontal and temporal regions in the presymptomatic stage prior to structural changes [<a class="bk_pop" href="#ftd-grn.REF.jacova.2013.1322">Jacova et al 2013</a>, <a class="bk_pop" href="#ftd-grn.REF.caroppo.2015.751">Caroppo et al 2015</a>].</p></div></div><div id="ftd-grn.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of <i>GRN</i> frontotemporal dementia (<i>GRN</i>-FTD) <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variant in <i>GRN</i> by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK1371/table/ftd-grn.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobftdgrnTmoleculargenetictestingused">Table 1</a>).</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "<a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a> variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [<a class="bk_pop" href="#ftd-grn.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <i>GRN</i> variant of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> does not establish or rule out the diagnosis.</p><p>Gene-targeted testing (<a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a>) requires that the clinician determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>(s) are likely involved, whereas comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing does not. Because the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of <i>GRN</i>-FTD is broad, individuals with the distinctive findings described in <a href="#ftd-grn.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#ftd-grn.Option_1">Option 1</a>), whereas those in whom the diagnosis of <i>GRN</i>-FTD has not been considered are more likely to be diagnosed using genomic testing (see <a href="#ftd-grn.Option_2">Option 2</a>).</p><div id="ftd-grn.Option_1"><h4>Option 1</h4><p><b>A frontotemporal dementia</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes <i>GRN</i> and other genes of interest (see <a href="#ftd-grn.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> and pathogenic variants in genes that do not explain the underlying <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>. Note: (1) The genes included in the panel and the diagnostic <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> of the testing used for each <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused <a class="def" href="/books/n/gene/glossary/def-item/exome/">exome</a> analysis that includes genes specified by the clinician. (4) Methods used in a panel may include <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>, <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>, and/or other non-sequencing-based tests. For <i>GRN</i>-FTD a multigene panel that also includes deletion/duplication analysis is recommended (see <a href="/books/NBK1371/table/ftd-grn.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobftdgrnTmoleculargenetictestingused">Table 1</a>).</p><p>For an introduction to multigene panels click <a href="/books/n/gene/app5/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</p></div><div id="ftd-grn.Option_2"><h4>Option 2</h4><p><b>Comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing. Exome sequencing</b> is most commonly used; <b><a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a></b> is also possible. If <a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a> is not diagnostic – and particularly when evidence supports <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> inheritance – <b><a class="def" href="/books/n/gene/glossary/def-item/exome-array/">exome array</a></b> (when clinically available) may be considered to detect (multi)<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications that cannot be detected by <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>.</p><p>For an introduction to comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div id="ftd-grn.T.molecular_genetic_testing_used" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>GRN</i> Frontotemporal Dementia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1371/table/ftd-grn.T.molecular_genetic_testing_used/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ftd-grn.T.molecular_genetic_testing_used_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ftd-grn.T.molecular_genetic_testing_used_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_ftd-grn.T.molecular_genetic_testing_used_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_ftd-grn.T.molecular_genetic_testing_used_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with a Pathogenic Variant <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_ftd-grn.T.molecular_genetic_testing_used_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>GRN</i>
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</td><td headers="hd_h_ftd-grn.T.molecular_genetic_testing_used_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_ftd-grn.T.molecular_genetic_testing_used_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~98.5% <sup>4</sup></td></tr><tr><td headers="hd_h_ftd-grn.T.molecular_genetic_testing_used_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> <sup>5</sup></td><td headers="hd_h_ftd-grn.T.molecular_genetic_testing_used_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~1.5% <sup>4, 6</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="ftd-grn.TF.1.1"><p class="no_margin">See <a href="/books/NBK1371/#ftd-grn.molgen.TA">Table A. Genes and Databases</a> for <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> and protein.</p></div></dd><dt>2. </dt><dd><div id="ftd-grn.TF.1.2"><p class="no_margin">See <a href="#ftd-grn.Molecular_Genetics">Molecular Genetics</a> for information on allelic variants detected in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>.</p></div></dd><dt>3. </dt><dd><div id="ftd-grn.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, <a class="def" href="/books/n/gene/glossary/def-item/likely-benign/">likely benign</a>, of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>, or pathogenic. Variants may include small intragenic deletions/insertions and <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications are not detected. For issues to consider in interpretation of <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>4. </dt><dd><div id="ftd-grn.TF.1.4"><p class="no_margin"><a class="bk_pop" href="#ftd-grn.REF.cruts.2006.920">Cruts et al [2006]</a>, <a class="bk_pop" href="#ftd-grn.REF.chenplotkin.2011.488">Chen-Plotkin et al [2011]</a>, <a class="bk_pop" href="#ftd-grn.REF.van_langenhove.2013.365">Van Langenhove et al [2013]</a>, <a class="bk_pop" href="#ftd-grn.REF.pottier.2018.548">Pottier et al [2018]</a>. Note: <a class="bk_pop" href="#ftd-grn.REF.pottier.2018.548">Pottier et al [2018]</a> identified 449 affected individuals with <i>GRN</i> disease-associated variants detected by sequence and <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> in the ascertainment step of a genome-wide association study (see <a class="bk_pop" href="#ftd-grn.REF.pottier.2018.548">Pottier et al [2018]</a>, Supplementary Table 2).</p></div></dd><dt>5. </dt><dd><div id="ftd-grn.TF.1.5"><p class="no_margin">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> detects intragenic deletions or duplications. Methods used may include a range of techniques such as <a class="def" href="/books/n/gene/glossary/def-item/quantitative-pcr/">quantitative PCR</a>, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted microarray designed to detect single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by <a class="bk_pop" href="#ftd-grn.REF.milan.2017.193.e9">Milan et al [2017]</a>) may not be detected by these methods.</p></div></dd><dt>6. </dt><dd><div id="ftd-grn.TF.1.6"><p class="no_margin"><a class="bk_pop" href="#ftd-grn.REF.gijselinck.2008.53">Gijselinck et al [2008]</a>, <a class="bk_pop" href="#ftd-grn.REF.pickeringbrown.2008.721">Pickering-Brown et al [2008]</a>, <a class="bk_pop" href="#ftd-grn.REF.roveletlecrux.2008.41">Rovelet-Lecrux et al [2008]</a>, <a class="bk_pop" href="#ftd-grn.REF.finch.2009.583">Finch et al [2009]</a>, <a class="bk_pop" href="#ftd-grn.REF.chenplotkin.2011.488">Chen-Plotkin et al [2011]</a>, <a class="bk_pop" href="#ftd-grn.REF.rohrer.2013.1411">Rohrer et al [2013]</a>, <a class="bk_pop" href="#ftd-grn.REF.van_langenhove.2013.365">Van Langenhove et al [2013]</a>, <a class="bk_pop" href="#ftd-grn.REF.clot.2014.95">Clot et al [2014]</a></p></div></dd></dl></div></div></div></div></div></div><div id="ftd-grn.Clinical_Characteristics"><h2 id="_ftd-grn_Clinical_Characteristics_">Clinical Characteristics</h2><div id="ftd-grn.Clinical_Description"><h3>Clinical Description</h3><p><i>GRN</i> frontotemporal dementia (<i>GRN</i>-FTD) generally affects the frontal and temporal cortex leading to behavioral changes, executive dysfunction, and language disturbances. In <i>GRN</i>-FTD, the parietal cortex and basal ganglia may be affected as well, resulting in parkinsonism, cortical basal syndrome, and memory impairment [<a class="bk_pop" href="#ftd-grn.REF.baker.2006.916">Baker et al 2006</a>, <a class="bk_pop" href="#ftd-grn.REF.masellis.2006.3115">Masellis et al 2006</a>, <a class="bk_pop" href="#ftd-grn.REF.mukherjee.2006.314">Mukherjee et al 2006</a>, <a class="bk_pop" href="#ftd-grn.REF.behrens.2007.1">Behrens et al 2007</a>, <a class="bk_pop" href="#ftd-grn.REF.josephs.2007.142">Josephs et al 2007</a>, <a class="bk_pop" href="#ftd-grn.REF.mesulam.2007.43">Mesulam et al 2007</a>, <a class="bk_pop" href="#ftd-grn.REF.spina.2007.820">Spina et al 2007</a>].</p><p><b>Age of onset.</b> The age of onset of <i>GRN</i>-FTD ranges from 35 to 87 years with a mean of 64.9 ± 11.3 years [<a class="bk_pop" href="#ftd-grn.REF.bruni.2007.140">Bruni et al 2007</a>, <a class="bk_pop" href="#ftd-grn.REF.le_ber.2007.846">Le Ber et al 2007</a>, <a class="bk_pop" href="#ftd-grn.REF.rademakers.2007.857">Rademakers et al 2007</a>, <a class="bk_pop" href="#ftd-grn.REF.chenplotkin.2011.488">Chen-Plotkin et al 2011</a>].</p><p>Comparison studies demonstrate that onset age in individuals with <i>GRN</i>-FTD does not differ significantly from that in individuals without an identified <i>GRN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> [<a class="bk_pop" href="#ftd-grn.REF.beck.2008.706">Beck et al 2008</a>, <a class="bk_pop" href="#ftd-grn.REF.pickeringbrown.2008.721">Pickering-Brown et al 2008</a>], while some studies suggested a younger onset age in those with <i>GRN</i>-FTD [<a class="bk_pop" href="#ftd-grn.REF.huey.2006.374">Huey et al 2006</a>, <a class="bk_pop" href="#ftd-grn.REF.davion.2007.1113">Davion et al 2007</a>].</p><p><b>Neurocognitive symptoms.</b> Neuropsychological testing may demonstrate early impairment on frontal lobe tasks or specific language dysfunction prior to the onset of frank dementia.</p><p>Behavioral disturbances are the most common early feature, followed by progressive aphasia [<a class="bk_pop" href="#ftd-grn.REF.gass.2006.2988">Gass et al 2006</a>, <a class="bk_pop" href="#ftd-grn.REF.josephs.2007.142">Josephs et al 2007</a>]. This is usually an insidious but profound change in personality and conduct, characterized by distractibility, loss of initiative, apathy, and loss of interest in their environment, often accompanied by neglect in personal hygiene and social disinhibition. Some affected individuals demonstrate impulsiveness or compulsiveness and may alter their eating habits with food fads and food craving.</p><p>With impairment in executive function, there is loss of judgment and insight, which may manifest early in the disease course as, for example, making poor financial decisions, quitting jobs abruptly, or becoming unduly forward or rude to strangers. Alternatively, persons with predominant apathy may lose all interest and initiative with usual activities, appear socially withdrawn, give up all previous hobbies and interests, and be unable to complete tasks due to lack of persistence. Early in the course of the illness, affected individuals may be misdiagnosed as having psychiatric conditions such as depression, mania, or psychosis because of the unusual and bizarre nature of their behavior. Psychometric testing may demonstrate impairment on frontal executive tasks including the Trail-Making Test, proverb interpretation, descriptions of similarities, categorical naming, and abstract pattern recognition (e.g., Wisconsin Card Sort Test).</p><p><b>Language deficits.</b> Primary progressive aphasia (PPA), particularly the progressive nonfluent aphasia (PNFA) variant, can be another presentation of <i>GRN</i>-FTD [<a class="bk_pop" href="#ftd-grn.REF.mesulam.2007.43">Mesulam et al 2007</a>]. In early stages, PPA-PNFA often manifests as deficits in naming, word finding, or word comprehension. Although behavioral manifestations tend to be more common than language deficits as the initial presentation of <i>GRN</i>-FTD, in one series 82% of affected individuals eventually developed language issues [<a class="bk_pop" href="#ftd-grn.REF.josephs.2007.142">Josephs et al 2007</a>, <a class="bk_pop" href="#ftd-grn.REF.caso.2012.759">Caso et al 2012</a>].</p><p>In contrast with PPA-PNFA, semantic dementia is characterized by impaired naming and comprehension, semantic paraphasias, and impaired recognition of familiar faces or objects. Although rare in <i>GRN</i>-FTD, pure semantic dementia (PPA-SD) has been described in a few studies [<a class="bk_pop" href="#ftd-grn.REF.whitwell.2007.371">Whitwell et al 2007</a>, <a class="bk_pop" href="#ftd-grn.REF.beck.2008.706">Beck et al 2008</a>]. In late stages, individuals with PPA-SD may develop impaired face recognition and behavioral changes including disinhibition and compulsion [<a class="bk_pop" href="#ftd-grn.REF.seeley.2005.1384">Seeley et al 2005</a>].</p><p>A number of studies have reported individuals with <i>GRN</i>-FTD who have presented with amnestic mild cognitive impairment, which may be mistaken for Alzheimer disease [<a class="bk_pop" href="#ftd-grn.REF.carecchio.2009.291">Carecchio et al 2009</a>, <a class="bk_pop" href="#ftd-grn.REF.kelley.2010.171">Kelley et al 2010</a>].</p><p><b>Movement disorders.</b> In several families with <i>GRN</i>-FTD, parkinsonism is prominent, and in some the initial clinical diagnosis was corticobasal syndrome [<a class="bk_pop" href="#ftd-grn.REF.gass.2006.2988">Gass et al 2006</a>, <a class="bk_pop" href="#ftd-grn.REF.masellis.2006.3115">Masellis et al 2006</a>, <a class="bk_pop" href="#ftd-grn.REF.benussi.2009.379">Benussi et al 2009</a>, <a class="bk_pop" href="#ftd-grn.REF.moreno.2009.1367">Moreno et al 2009</a>]. Early findings include rigidity, bradykinesia or akinesia (slowing or absence of movements), limb dystonia, apraxia (loss of ability to carry out learned purposeful movements), and disequilibrium. Late motor findings may include myoclonus, dysarthria, and dysphagia. Most affected individuals eventually lose the ability to walk.</p><p><b>Motor neuron disease.</b> Although the histopathologic findings of ubiquitin-positive inclusions were initially associated with motor neuron disease, it appears to occur only rarely (if at all) in <i>GRN</i>-FTD [<a class="bk_pop" href="#ftd-grn.REF.schymick.2007.754">Schymick et al 2007</a>].</p><p><b>Disease course.</b> The mean age at death is 65±8 years. Disease duration ranges from three to 12 years [<a class="bk_pop" href="#ftd-grn.REF.gass.2006.2988">Gass et al 2006</a>].</p><p><b>Neuropathology.</b> The neuropathology of <i>GRN</i>-FTD is characterized by the following [<a class="bk_pop" href="#ftd-grn.REF.mackenzie.2006.3081">Mackenzie et al 2006</a>, <a class="bk_pop" href="#ftd-grn.REF.mackenzie.2011.111">Mackenzie et al 2011</a>]:</p><ul><li class="half_rhythm"><div class="half_rhythm">Tau-negative alpha-synuclein-negative ubiquitin-positive "cat-eye" or lentiform-shaped neuronal intranuclear inclusions (NII), often found in the neocortex and striatum</div></li><li class="half_rhythm"><div class="half_rhythm">Superficial laminar spongiosis with ubiquitin-positive neurites and neuronal cytoplasmic inclusions (NCI) in the neocortex</div></li><li class="half_rhythm"><div class="half_rhythm">Granular appearance of the ubiquitin-immunoreactive (ub-ir) neurites in the striatum and the NCI in the hippocampus</div></li><li class="half_rhythm"><div class="half_rhythm">Phosphorylation of S409/410 of TDP-43 in pathologic inclusions [<a class="bk_pop" href="#ftd-grn.REF.neumann.2009.137">Neumann et al 2009</a>]</div><div class="half_rhythm">The major protein component of these ubiquitin inclusions is a TAR DNA-binding protein of 43 kd (TDP-43). TDP-43 is a nuclear factor involved in regulating transcription and alternative <a class="def" href="/books/n/gene/glossary/def-item/splicing/">splicing</a> [<a class="bk_pop" href="#ftd-grn.REF.arai.2006.602">Arai et al 2006</a>, <a class="bk_pop" href="#ftd-grn.REF.neumann.2006.130">Neumann et al 2006</a>]. It is mostly a nuclear protein, although recent studies have shown that it shuttles between the nucleus and cytoplasm in normal conditions [<a class="bk_pop" href="#ftd-grn.REF.ayala.2008.3778">Ayala et al 2008</a>]. While its physiologic function remains unclear, it has been demonstrated to bind to a large number of RNA targets with a preference for UG-rich <a class="def" href="/books/n/gene/glossary/def-item/intronic/">intronic</a> regions and is important in many vital cellular processes [<a class="bk_pop" href="#ftd-grn.REF.sendtner.2011.403">Sendtner 2011</a>].</div></li></ul><p>It is now recognized that pathologically, <i>GRN</i>-FTD is a major subtype of frontotemporal lobar degeneration (FTLD). The neuropathologic diagnostic criteria for FTLD have been updated based on current molecular understanding of the disease [<a class="bk_pop" href="#ftd-grn.REF.mackenzie.2011.111">Mackenzie et al 2011</a>].</p></div><div id="ftd-grn.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>No obvious correlations between age of onset, disease duration, or clinical <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> and specific <i>GRN</i> pathogenic variants have been identified. Clinical variability is high among individuals with the same <i>GRN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p></div><div id="ftd-grn.Penetrance"><h3>Penetrance</h3><p>Penetrance of <i>GRN</i>-FTD is about 90% by age 75 years, but apparent reduced <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> has also been observed on occasion [<a class="bk_pop" href="#ftd-grn.REF.cruts.2006.920">Cruts et al 2006</a>, <a class="bk_pop" href="#ftd-grn.REF.gass.2006.2988">Gass et al 2006</a>].</p><p>A study of the common <a href="/books/NBK1371/table/ftd-grn.T.notable_grn_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobftdgrnTnotablegrnpathogenicvariant">p.Arg493Ter</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> showed that 60% of individuals with this variant were affected by age 60 years, and more than 95% were affected by age 70 years [<a class="bk_pop" href="#ftd-grn.REF.rademakers.2007.857">Rademakers et al 2007</a>]. Age at onset of frontotemporal lobar degeneration (FTLD) was younger in individuals with a <i>GRN</i> pathogenic variant vs those without one (median: 58.0 vs 61.0 years), as was age at death (median: 65.5 vs 69.0 years) [<a class="bk_pop" href="#ftd-grn.REF.chenplotkin.2011.488">Chen-Plotkin et al 2011</a>].</p><p>In a large series in France, 3.2% of <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> cases (i.e., only one affected individual in a family) with FTD were found to have a <i>GRN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, suggesting possible <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> variant or incomplete <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> [<a class="bk_pop" href="#ftd-grn.REF.le_ber.2007.846">Le Ber et al 2007</a>].</p></div><div id="ftd-grn.Nomenclature"><h3>Nomenclature</h3><p>The term frontotemporal dementia (FTD) is used in this <i>GeneReview</i> to designate the clinical presentation of the dementing illness, while the term frontotemporal lobar degeneration (FTLD) is used to denote the pathologic diagnosis of the disease.</p><p>Note that <i>PGRN</i>, the earlier designation for the <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> <i>GRN,</i> may be used in the literature as well (e.g., <i>PGRN</i>-FTD).</p><p>Prior to the identification of <i>GRN</i> as the <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> in which a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is responsible for this form of FTD, a number of terms were used to describe this disorder.</p><ul><li class="half_rhythm"><div><b>FTDU-17.</b> Analogous to FTDP-17, the term "FTDU-17" has been used because the pathologic characteristics of this condition are associated with <b>ubiquitinated</b> inclusions and the genetic <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> was also located on <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> 17.</div></li><li class="half_rhythm"><div><b>HDDD1 and HDDD2.</b> Familial dementia in other kindreds with similar clinical presentations was descriptively named hereditary dysphasic disinhibition dementia (HDDD1 and HDDD2). It has now been shown that <i>GRN</i> pathogenic variants are also responsible for the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> in these families, and therefore these are now considered <i>GRN</i>-FTD [<a class="bk_pop" href="#ftd-grn.REF.mukherjee.2006.314">Mukherjee et al 2006</a>, <a class="bk_pop" href="#ftd-grn.REF.behrens.2007.1">Behrens et al 2007</a>].</div></li></ul></div><div id="ftd-grn.Prevalence"><h3>Prevalence</h3><p>Frontotemporal dementia (FTD) accounts for 5%-10% of all individuals with dementia and 10%-20% of individuals with dementia with onset before age 65 years [<a class="bk_pop" href="#ftd-grn.REF.bird.2003.s29">Bird et al 2003</a>].</p><p><i>GRN</i>-FTD represents about 5% of all FTD, and 20% of FTD in which the family history is positive.</p></div></div><div id="ftd-grn.Genetically_Related_Allelic_Diso"><h2 id="_ftd-grn_Genetically_Related_Allelic_Diso_">Genetically Related (Allelic) Disorders</h2><p>Individuals with <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>GRN</i> pathogenic variants and the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of neuronal ceroid lipofuscinosis, a lysosomal storage disease that is strikingly different from FTD, have been reported [<a class="bk_pop" href="#ftd-grn.REF.smith.2012.1102">Smith et al 2012</a>, <a class="bk_pop" href="#ftd-grn.REF.kamate.2019.542">Kamate et al 2019</a>]. This finding further highlights the role of GRN in lysosomal function and regulation (see <a href="#ftd-grn.Molecular_Genetics">Molecular Genetics</a>).</p></div><div id="ftd-grn.Differential_Diagnosis"><h2 id="_ftd-grn_Differential_Diagnosis_">Differential Diagnosis</h2><p>Neuroimaging can evaluate for other conditions that mimic frontotemporal dementia (FTD) (e.g., white matter diseases, frontotemporal focal lesions, frontal lobe tumors, and cerebrovascular disease).</p><p>The clinical manifestations of <i>GRN</i>-FTD significantly overlap with those of other conditions including FTD with or without parkinsonism associated with pathogenic variants in <a href="/books/n/gene/ftdp-17/"><i>MAPT</i></a>, <a href="/books/n/gene/parkinson-overview/">Parkinson disease</a>, <a href="/books/n/gene/alzheimer/">Alzheimer disease</a>, Pick disease (OMIM <a href="https://omim.org/entry/172700" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">172700</a>), other inherited FTD disorders, corticobasal degeneration, progressive supranuclear palsy, and Creutzfeldt-Jacob disease (OMIM <a href="https://omim.org/entry/123400" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">123400</a>). This clinical overlap makes it difficult to predict which family has a <i>GRN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> by clinical presentation alone.</p><p>Up to 50% of individuals with FTD have a positive family history of dementia, usually with <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> inheritance. <a href="/books/NBK1371/table/ftd-grn.T.genes_in_the_differential_diag/?report=objectonly" target="object" rid-ob="figobftdgrnTgenesinthedifferentialdiag">Table 2</a> below lists the most common genes associated with <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> FTD.</p><div id="ftd-grn.T.genes_in_the_differential_diag" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Genes in the Differential Diagnosis of <i>GRN</i> Frontotemporal Dementia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1371/table/ftd-grn.T.genes_in_the_differential_diag/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ftd-grn.T.genes_in_the_differential_diag_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_2" style="text-align:left;vertical-align:middle;">DiffDx<br />Disorder</th><th id="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3" colspan="4" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Clinical Features of DiffDx Disorder</th></tr><tr><th headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3" id="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Onset</th><th headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3" id="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disease<br />Duration</th><th headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3" id="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pathology</th><th headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3" id="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_1 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_2 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_1 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_2 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_4" colspan="6" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">
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<b>Most commonly involved genes</b>
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</td></tr><tr><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>C9orf72</i>
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</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/als-ftd/">ALS & FTD</a>
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</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mean: 54.3 yrs; range: 34-74 yrs</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mean: 5.3 yrs; range: 1-16 yrs</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">TDP-43 pathology is found in a wide neuroanatomic distribution, w/particular involvement in extramotor neocortex & hippocampus & in lower motor neurons</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May be misdiagnosed as bvFTD, PPA-PNFA, or ALS. <sup>1</sup> Heterogeneity in clinical presentation is common w/in families. Phenotypes tend to converge w/disease progression.</td></tr><tr><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MAPT</i>
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</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">FTDP-17 (See <a href="/books/n/gene/ftdp-17/"><i>MAPT</i>-Related Frontotemporal Dementia</a>.)</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Usually age 40-60 yrs; may occur earlier or later</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Usually 5-10 yrs; may be up to 20-30 yrs</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At autopsy, all persons w/FTDP-17 show tau-positive inclusion pathology, whereas all persons w/<i>GRN</i>-FTD show ub-ir neuronal intranuclear inclusions. <sup>2</sup></td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Presenile dementia affecting frontal & temporal cortex & some subcortical nuclei. Variable presentation; may present w/slowly progressive behavioral changes, language disturbances, &/or extrapyramidal signs; progresses over a few yrs to profound dementia w/mutism. 25%-40% of families w/AD FTD have mutation of <i>MAPT</i>.</td></tr><tr><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_1 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_2 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_1 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_2 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_4" colspan="6" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Less commonly involved genes</b>
|
||
</td></tr><tr><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>CHMP2B</i>
|
||
</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/ftd-chmp2b/"><i>CHMP2B</i>-FTD</a>
|
||
</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Typically in late 50s</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neuropathology assoc w/ubiquitin-positive but TDP-43- & FUS-negative inclusions</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Usually presents w/a frontal lobe syndrome, parkinsonism, dystonia, pyramidal signs. Myoclonus may occur later in disease course.</td></tr><tr><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>TARDBP</i>
|
||
</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/tardbp-als/"><i>TARDBP</i>-related ALS or ALS w/FTD</a>
|
||
</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">41-60 yrs</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2-4 yrs</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">TDP-43 inclusions in upper & lower motor neurons & cortex</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assoc w/~3% of <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> ALS & occasionally FTD w/ALS</td></tr><tr><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>VCP</i>
|
||
</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/ibmpfd/">Inclusion body myopathy w/Paget disease of bone & FTD</a> (IBMPFD)</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Muscle disease & PDB: age 42 yrs; FTD: age 55 yrs</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Numerous intranuclear & infrequent # of neuronal cytoplasmatic inclusions & dystrophic neuritis seen in neuropathology</td><td headers="hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_1_3 hd_h_ftd-grn.T.genes_in_the_differential_diag_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adult-onset proximal & distal muscle weakness (clinically LGMD <sup>3</sup>), early-onset PDB <sup>4</sup>, & FTD. Early-stage FTD: dysnomia, dyscalculia, comprehension deficits, paraphasic errors, & relative preservation of memory. Later stages: inability to speak, auditory comprehension deficits for even 1-step commands, alexia, & agraphia</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AD= <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a>; ALS = amyotrophic lateral sclerosis; DiffDx = differential diagnosis; FTD = frontotemporal dementia; bvFTD = behavioral variant FTD; FTDP = frontotemporal dementia with parkinsonism; FUS = fused in sarcoma; LGMD = limb-girdle muscular dystrophy; PNFA = progressive nonfluent aphasia; PDB = Paget disease of bone; PPA = primary progressive aphasia</p></div></dd><dt>1. </dt><dd><div id="ftd-grn.TF.2.1"><p class="no_margin">See <a href="/books/n/gene/als-overview/">Amyotrophic Lateral Sclerosis Overview</a>.</p></div></dd><dt>2. </dt><dd><div id="ftd-grn.TF.2.2"><p class="no_margin"><a class="bk_pop" href="#ftd-grn.REF.ghetti.2003">Ghetti et al [2003]</a>, <a class="bk_pop" href="#ftd-grn.REF.mackenzie.2007.49">Mackenzie [2007]</a></p></div></dd><dt>3. </dt><dd><div id="ftd-grn.TF.2.3"><p class="no_margin">Muscle weakness progresses to involve other limb & respiratory muscles; cardiac failure & cardiomyopathy have been observed in later stages of IBMPFD.</p></div></dd><dt>4. </dt><dd><div id="ftd-grn.TF.2.4"><p class="no_margin">Paget disease of bone (PDB) involves focal areas of increased bone turnover that typically lead to spine and/or hip pain and localized enlargement and deformity of the long bones.</p></div></dd></dl></div></div></div></div><div id="ftd-grn.Management"><h2 id="_ftd-grn_Management_">Management</h2><div id="ftd-grn.Evaluations_Following_Initial_Di"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with <i>GRN</i> frontotemporal dementia (<i>GRN</i>-FTD), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:</p><ul><li class="half_rhythm"><div>Detailed general, neurologic, and family history</div></li><li class="half_rhythm"><div>Physical examination</div></li><li class="half_rhythm"><div>Neurologic examination</div></li><li class="half_rhythm"><div>Cognitive examination. When clinical cognitive assessments are not informative enough, a neuropsychological assessment may be performed to provide a more comprehensive and objective view of a patient's cognitive function. Formal neuropsychological assessment requires comparison of the patient's raw score on a specific test to a large general population normative sample which is usually drawn from a population comparable to that of the person being examined. This allows for the patient's performance to be compared to a suitable control group, adjusted for age, sex, level of education, and/or ethnicity. While much more sensitive than bedside clinical cognitive examination, such assessment is resource intensive and time consuming.</div></li><li class="half_rhythm"><div>Discussion of capabilities for job and for driving</div></li><li class="half_rhythm"><div>Discussion of advanced care planning</div></li><li class="half_rhythm"><div>Consultation with a clinical geneticist and/or genetic counselor</div></li></ul></div><div id="ftd-grn.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>There is currently no known treatment for <i>GRN</i>-FTD or FTD in general. Psychosocial support is essential in the management of FTD and should include occupational therapy and environmental and physical interventions.</p><p>However, some behavioral manifestations such as apathy, impulsivity, and compulsiveness may respond to selective serotonin reuptake inhibitors. Behavioral changes and the loss of insight and judgment in individuals with <i>GRN</i>-FTD often present a considerable burden for caregivers. Information about the disease and psychological support for partners or other caregivers is essential. Caregiver support groups are valuable.</p><p>The behavioral and psychological manifestations should be treated as in other types of FTD. There is no consensus treatment guideline for <i>GRN</i>-FTD. In clinical practice those affected individuals who have very aggressive behavior have proven quite difficult to treat and have in some instances been treated with high doses of antipsychotics and/or antidepressants in order to relieve the physical aggressiveness. Administered antipsychotics should be reevaluated at short intervals with the purpose of discontinuation as soon as feasible.</p><p>Roaming, delusions, and hallucinations may respond to antipsychotic medications.</p><p>Although reports have suggested potential benefits with certain pharmacotherapy on management of FTD in general, evidence from randomized controlled trials is limited [<a class="bk_pop" href="#ftd-grn.REF.freedman.2007.s118">Freedman 2007</a>]. All of the following findings require confirmation with larger clinical trials:</p><ul><li class="half_rhythm"><div>One double-blind placebo-controlled crossover trial suggests that trazodone, a serotonergic agent, may be beneficial in treating the symptoms of irritability, agitation, depression, and eating disorders in FTD [<a class="bk_pop" href="#ftd-grn.REF.lebert.2004.355">Lebert et al 2004</a>].</div></li><li class="half_rhythm"><div>While an open-label study suggested some benefits on behavioral symptoms with paroxetine, a double-blind placebo-controlled trial of ten subjects found worsening of performance on paired associates learning, reversal learning, and delayed pattern recognition [<a class="bk_pop" href="#ftd-grn.REF.moretti.2003.13">Moretti et al 2003</a>, <a class="bk_pop" href="#ftd-grn.REF.deakin.2004.400">Deakin et al 2004</a>].</div></li><li class="half_rhythm"><div>A study of galantamine in bvFTD and primary progressive aphasia (PPA) found significant benefits in subjects with PPA but not in those with bvFTD [<a class="bk_pop" href="#ftd-grn.REF.kertesz.2005.s47">Kertesz et al 2005</a>]. A follow-up study of 36 individuals who were on galantamine therapy for 18 weeks revealed stabilization but not improvement on language scores in the PPA group [<a class="bk_pop" href="#ftd-grn.REF.kertesz.2008.178">Kertesz et al 2008</a>].</div></li><li class="half_rhythm"><div>A 12-month open-label rivastigmine trial showed improvement of behavioral symptoms and decreased caregiver burden in individuals with FTD; however, the treatment did not prevent cognitive decline [<a class="bk_pop" href="#ftd-grn.REF.moretti.2004.931">Moretti et al 2004</a>].</div></li><li class="half_rhythm"><div>A double-blind placebo-controlled crossover study of methylphenidate found attenuation of risk-taking behavior but worsening of spatial span [<a class="bk_pop" href="#ftd-grn.REF.rahman.2006.651">Rahman et al 2006</a>].</div></li><li class="half_rhythm"><div>A small clinical trial of dextroamphetamine treatment on eight individuals with bvFTD revealed improvement of behavioral symptoms [<a class="bk_pop" href="#ftd-grn.REF.huey.2008.1981">Huey et al 2008</a>].</div></li><li class="half_rhythm"><div>A few open-label studies of memantine, a partial NMDA agonist, demonstrated an improvement on the frontal battery inventory in individuals with bvFTD after a six-month trial, but a decline in other cognitive performance [<a class="bk_pop" href="#ftd-grn.REF.diehlschmid.2008.754">Diehl-Schmid et al 2008</a>]. Among the three subtypes of FTD, PPA-PNFA remained stable on cognitive and functional measurements when treated with memantine [<a class="bk_pop" href="#ftd-grn.REF.boxer.2009.211">Boxer et al 2009</a>]. A study using [<sup>18</sup>F]-fluorodeoxyglucose positron emission tomography (FDG-PET) as a surrogate outcome in individuals with semantic dementia found that cortical metabolic activity in salience network hubs was sustained when treated with memantine over a six-month period [<a class="bk_pop" href="#ftd-grn.REF.chow.2013.319">Chow et al 2013</a>]. While a meta-analysis suggest some benefit with memantine, the sample sizes were small and further studies with larger samples sizes are needed [<a class="bk_pop" href="#ftd-grn.REF.kishi.2015.2883">Kishi et al 2015</a>].</div></li></ul><p>Note: Donepezil treatment has been associated with exacerbation of disinhibition and compulsion symptoms [<a class="bk_pop" href="#ftd-grn.REF.mendez.2007.84">Mendez et al 2007</a>].</p></div><div id="ftd-grn.Surveillance"><h3>Surveillance</h3><p>Patients are often followed in a memory disorder clinic or a similar multidisciplinary clinic involving neurologic and psychiatric services and follow-up medical care.</p></div><div id="ftd-grn.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#ftd-grn.Related_Genetic_Counseling_Issue">Genetic Counseling</a> for issues related to testing of at-risk relatives for <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> purposes.</p></div><div id="ftd-grn.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="ftd-grn.Genetic_Counseling"><h2 id="_ftd-grn_Genetic_Counseling_">Genetic Counseling</h2><p>
|
||
<i>Genetic counseling is the process of providing individuals and families with
|
||
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
|
||
make informed medical and personal decisions. The following section deals with genetic
|
||
risk assessment and the use of family history and genetic testing to clarify genetic
|
||
status for family members; it is not meant to address all personal, cultural, or
|
||
ethical issues that may arise or to substitute for consultation with a genetics
|
||
professional</i>. —ED.</p><div id="ftd-grn.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>GRN</i> frontotemporal dementia (<i>GRN</i>-FTD) is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner.</p></div><div id="ftd-grn.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
|
||
<b>Parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div class="half_rhythm">Most (95%) individuals diagnosed with <i>GRN</i>-FTD have an affected parent [<a class="bk_pop" href="#ftd-grn.REF.gass.2006.2988">Gass et al 2006</a>].</div></li><li class="half_rhythm"><div class="half_rhythm">A <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with <i>GRN</i>-FTD may have the disorder as the result of a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a>
|
||
<i>GRN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>. The proportion of cases caused by a <i>de novo</i> pathogenic variant is unknown but is estimated at 5% or fewer.</div></li><li class="half_rhythm"><div class="half_rhythm">Recommendations for the evaluation of parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with an apparent <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a>
|
||
<i>GRN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> include a neurologic assessment and <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> for the <i>GRN</i> variant identified in the proband.</div></li><li class="half_rhythm"><div class="half_rhythm">If the <i>GRN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> found in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> cannot be detected in the leukocyte DNA of either parent, possible explanations include a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a>
|
||
<i>GRN</i> pathogenic variant in the proband or <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a> in a parent.* Though theoretically possible, no instances of a proband inheriting a pathogenic variant from a parent with germline mosaicism have been reported.</div><div class="half_rhythm">* Misattributed parentage can also be explored as an alternative explanation for an apparent <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</div></li><li class="half_rhythm"><div class="half_rhythm">The family history of some individuals diagnosed with <i>GRN</i>-FTD may appear to be negative because of a milder phenotypic presentation, early death of the parent before the onset of manifestations, or age-related/reduced <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a>. Therefore, an apparently negative family history cannot be confirmed unless <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> for the <i>GRN</i> variant identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has been performed on the parents of the proband.</div></li></ul><p><b>Sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:</p><ul><li class="half_rhythm"><div>If a parent of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is affected and/or is known to have the <i>GRN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the proband, the risk to the sibs is 50%. Intrafamilial variability in clinical presentation and age of onset is observed in <i>GRN</i>-FTD.</div></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> found in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> cannot be detected in the leukocyte DNA of either parent, the <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> to sibs is estimated to be 1% because of the theoretic possibility of parental <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a> [<a class="bk_pop" href="#ftd-grn.REF.rahbari.2016.126">Rahbari et al 2016</a>].</div></li><li class="half_rhythm"><div>If the clinically unaffected parents have not been tested for the <i>GRN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>, sibs are still presumed to be at increased risk for <i>GRN</i>-FTD because of the possibility of age-related/reduced <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> in a parent <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for the <i>GRN</i> pathogenic variant or the theoretic possibility of parental <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a>.</div></li></ul><p><b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> Each child of an individual with <i>GRN</i>-FTD has a 50% chance of inheriting the <i>GRN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p><p><b>Other family members.</b> The risk to other family members depends on the status of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents: if a parent has the <i>GRN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the proband, the parent's family members may also be at risk.</p></div><div id="ftd-grn.Related_Genetic_Counseling_Issue"><h3>Related Genetic Counseling Issues</h3><p>
|
||
<b>Predictive testing (i.e., testing of asymptomatic at-risk individuals)</b>
|
||
</p><ul><li class="half_rhythm"><div>Predictive testing for at-risk relatives is possible once the <i>GRN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> has been identified in an affected family member.</div></li><li class="half_rhythm"><div>Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> prior to testing.</div></li></ul><p>
|
||
<b>Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years)</b>
|
||
</p><ul><li class="half_rhythm"><div>For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.</div></li><li class="half_rhythm"><div>For more information, see the National Society of Genetic Counselors <a href="https://www.nsgc.org/Policy-Research-and-Publications/Position-Statements/Position-Statements/Post/genetic-testing-of-minors-for-adult-onset-conditions" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">position statement</a> on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics <a href="https://pediatrics.aappublications.org/content/131/3/620.full.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">policy statement</a>: ethical and policy issues in genetic testing and screening of children.</div></li></ul><p>In a family with an established diagnosis of <i>GRN</i>-FTD, it is appropriate to consider testing of symptomatic individuals regardless of age.</p><p>
|
||
<b>Family planning</b>
|
||
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/<a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected.</div></li></ul></div><div id="ftd-grn.Prenatal_Testing_and_Preimplanta"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>GRN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> has been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> for <i>GRN</i>-FTD are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a>. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="ftd-grn.Resources"><h2 id="_ftd-grn_Resources_">Resources</h2><p>
|
||
<i>GeneReviews staff has selected the following disease-specific and/or umbrella
|
||
support organizations and/or registries for the benefit of individuals with this disorder
|
||
and their families. GeneReviews is not responsible for the information provided by other
|
||
organizations. For information on selection criteria, click <a href="/books/n/gene/app4/">here</a>.</i></p>
|
||
<ul><li class="half_rhythm"><div>
|
||
<b>Association for Frontotemporal Degeneration (AFTD)</b>
|
||
</div><div><b>Phone:</b> 866-507-7222</div><div><b>Email:</b> info@theaftd.org</div><div>
|
||
<a href="http://www.theaftd.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.theaftd.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>FTD Talk</b>
|
||
</div><div>United Kingdom</div><div><b>Email:</b> j.rohrer@ucl.ac.uk</div><div>
|
||
<a href="https://www.ftdtalk.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.ftdtalk.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>National Institute of Neurological Disorders and Stroke (NINDS)</b>
|
||
</div><div>PO Box 5801</div><div>Bethesda MD 20824</div><div><b>Phone:</b> 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)</div><div>
|
||
<a href="https://www.ninds.nih.gov/Disorders/All-Disorders/Frontotemporal-Dementia-Information-Page" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Frontotemporal Dementia Information Page</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Rare Dementia Support </b>
|
||
</div><div>United Kingdom</div><div><b>Email:</b> contact@raredementiasupport.org</div><div>
|
||
<a href="https://www.raredementiasupport.org/familial-frontotemporal-dementia/fftd-at-risk/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.raredementiasupport.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration - Registry</b>
|
||
</div><div>
|
||
<a href="https://www.allftd.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.allftd.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>FTD Disorders Registry</b>
|
||
</div><div>
|
||
<a href="https://ftdregistry.org/?utm_campaign=website-launch&utm_medium=referral&utm_source=theaftd.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FTD Disorders Registry</a>
|
||
</div></li></ul>
|
||
</div><div id="ftd-grn.Molecular_Genetics"><h2 id="_ftd-grn_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div id="ftd-grn.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>GRN Frontotemporal Dementia: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1371/table/ftd-grn.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ftd-grn.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_ftd-grn.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_ftd-grn.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_ftd-grn.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_ftd-grn.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_ftd-grn.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_ftd-grn.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_ftd-grn.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/2896" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>GRN</i>
|
||
</a>
|
||
</td><td headers="hd_b_ftd-grn.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=2896" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">17q21<wbr style="display:inline-block"></wbr>.31</a>
|
||
</td><td headers="hd_b_ftd-grn.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/P28799" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Progranulin</a>
|
||
</td><td headers="hd_b_ftd-grn.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.ucl.ac.uk/ncl/cln11grn.shtml" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Neuronal Ceroid Lipofuscinoses; NCL Mutations (GRN)</a>
|
||
<br />
|
||
<a href="http://databases.lovd.nl/shared/genes/GRN" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GRN database</a>
|
||
</td><td headers="hd_b_ftd-grn.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=GRN" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GRN</a>
|
||
</td><td headers="hd_b_ftd-grn.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=GRN[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GRN</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="ftd-grn.TFA.1"><p class="no_margin">Data are compiled from the following standard references: <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> from
|
||
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
||
<a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> from
|
||
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
||
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
||
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
||
<a href="/books/n/gene/app1/">here</a>.</p></div></dd></dl></div></div></div><div id="ftd-grn.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for GRN Frontotemporal Dementia (<a href="/omim/138945,607485" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1371/table/ftd-grn.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ftd-grn.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/138945" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">138945</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GRANULIN PRECURSOR; GRN</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/607485" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">607485</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">FRONTOTEMPORAL DEMENTIA 2; FTD2</td></tr></tbody></table></div></div><div id="ftd-grn.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p>The granulins are a family of cysteine-rich polypeptides, some of which have growth-modulating activity. All four known human granulin-like peptides are produced from a single precursor, progranulin. <i>GRN</i> encodes progranulin, a glycoprotein with a highly conserved 12-cysteine backbone consensus sequence that is repeated seven times [<a class="bk_pop" href="#ftd-grn.REF.bateman.1998.145">Bateman & Bennett 1998</a>, <a class="bk_pop" href="#ftd-grn.REF.cruts.2006.920">Cruts et al 2006</a>]. Each tandem granulin repeat is encoded by two nonequivalent exons, a configuration unique to the granulins that would permit the formation of hybrid granulin-like proteins by alternate <a class="def" href="/books/n/gene/glossary/def-item/splicing/">splicing</a>.</p><p>Progranulin, also known as PC-cell-derived growth factor, proepithelin, granulin-epithelin, or acrogranin, is a high-molecular-weight secreted mitogen. Progranulin <a class="def" href="/books/n/gene/glossary/def-item/mrna/">mRNA</a> is widely expressed in rapidly cycling epithelial cells, in the immune system, and in neurons such as cerebellar Purkinje cells, suggesting an important function in these tissues. Progranulin is involved in multiple physiologic processes such as cellular proliferation and survival as well as tissue repair, and pathologic processes including tumorigenesis [<a class="bk_pop" href="#ftd-grn.REF.he.2003.600">He & Bateman 2003</a>].</p><p>Full-length progranulin has trophic and anti-inflammatory activity, while the cleaved granulin peptides promote inflammatory activity. In the periphery, progranulin is involved in wound healing responses and modulates inflammatory events. In the central nervous system, progranulin is expressed by neurons and microglia [<a class="bk_pop" href="#ftd-grn.REF.eriksen.2008.287">Eriksen & Mackenzie 2008</a>].</p><p>There is growing evidence that <i>GRN</i> is involved in lysosomal function, and impairment in lysosomal trafficking and lysosomal glucocerebrosidase activities may exacerbate the pathology of frontotemporal lobar degeneration [<a class="bk_pop" href="#ftd-grn.REF.tanaka.2014.78">Tanaka et al 2014</a>, <a class="bk_pop" href="#ftd-grn.REF.zhou.2017.15277">Zhou et al 2017</a>, <a class="bk_pop" href="#ftd-grn.REF.zhou.2019.e0212382">Zhou et al 2019</a>, <a class="bk_pop" href="#ftd-grn.REF.valdez.2020.716">Valdez et al 2020</a>]. There is also evidence that progranulin and granulin peptides have trophic and neuroprotective effects [<a class="bk_pop" href="#ftd-grn.REF.townley.2018.118">Townley et al 2018</a>].</p><p><b>Mechanism of disease causation.</b>
|
||
<i>GRN-</i>FTD occurs through a <a class="def" href="/books/n/gene/glossary/def-item/loss-of-function/">loss-of-function</a> mechanism as evidenced by the majority of pathogenic variants being <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, frameshift, and splice-site variants [<a class="bk_pop" href="#ftd-grn.REF.baker.2006.916">Baker et al 2006</a>, <a class="bk_pop" href="#ftd-grn.REF.cruts.2006.920">Cruts et al 2006</a>, <a class="bk_pop" href="#ftd-grn.REF.gass.2006.2988">Gass et al 2006</a>, <a class="bk_pop" href="#ftd-grn.REF.van_der_zee.2007.416">van der Zee et al 2007</a>].</p><p>Deletion of the progranulin <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> can also lead to the same clinical presentation of <i>GRN</i>-FTD as a result of <a class="def" href="/books/n/gene/glossary/def-item/haploinsufficiency/">haploinsufficiency</a> [<a class="bk_pop" href="#ftd-grn.REF.gijselinck.2008.53">Gijselinck et al 2008</a>].</p><div id="ftd-grn.T.notable_grn_pathogenic_variant" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Notable <i>GRN</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1371/table/ftd-grn.T.notable_grn_pathogenic_variant/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ftd-grn.T.notable_grn_pathogenic_variant_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ftd-grn.T.notable_grn_pathogenic_variant_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_ftd-grn.T.notable_grn_pathogenic_variant_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA<br />Nucleotide<br />Change<br />(Alias <sup>1</sup>)</th><th id="hd_h_ftd-grn.T.notable_grn_pathogenic_variant_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted<br />Protein<br />Change</th><th id="hd_h_ftd-grn.T.notable_grn_pathogenic_variant_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_ftd-grn.T.notable_grn_pathogenic_variant_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_002087" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM<wbr style="display:inline-block"></wbr>_002087</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_002078" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP<wbr style="display:inline-block"></wbr>_002078</a>
|
||
</td><td headers="hd_h_ftd-grn.T.notable_grn_pathogenic_variant_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1477C>T<br />(g.3240C>T)</td><td headers="hd_h_ftd-grn.T.notable_grn_pathogenic_variant_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg493Ter</td><td headers="hd_h_ftd-grn.T.notable_grn_pathogenic_variant_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Most frequently found <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a></div></li><li class="half_rhythm"><div>60% of individuals w/this variant were affected by age 60 yrs; >95% by age 70 yrs [<a class="bk_pop" href="#ftd-grn.REF.rademakers.2007.857">Rademakers et al 2007</a>].</div></li><li class="half_rhythm"><div>Haplotype analyses suggest a <a class="def" href="/books/n/gene/glossary/def-item/founder-effect/">founder effect</a> [<a class="bk_pop" href="#ftd-grn.REF.gass.2006.2988">Gass et al 2006</a>, <a class="bk_pop" href="#ftd-grn.REF.bronner.2007.369">Bronner et al 2007</a>, <a class="bk_pop" href="#ftd-grn.REF.van_der_zee.2007.416">van der Zee et al 2007</a>].</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_ftd-grn.T.notable_grn_pathogenic_variant_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.26C>A</td><td headers="hd_h_ftd-grn.T.notable_grn_pathogenic_variant_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ala9Asp</td><td headers="hd_h_ftd-grn.T.notable_grn_pathogenic_variant_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>2nd most commonly reported <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a></div></li><li class="half_rhythm"><div>Only 25% reported to have a family history, suggesting possible ↓ <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> or <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> occurrence [<a class="bk_pop" href="#ftd-grn.REF.chenplotkin.2011.488">Chen-Plotkin et al 2011</a>].</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_ftd-grn.T.notable_grn_pathogenic_variant_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_002087" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM<wbr style="display:inline-block"></wbr>_002087</a>
|
||
</td><td headers="hd_h_ftd-grn.T.notable_grn_pathogenic_variant_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.-8+5G>C<br />(IVS0+5G>C)</td><td headers="hd_h_ftd-grn.T.notable_grn_pathogenic_variant_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">--</td><td headers="hd_h_ftd-grn.T.notable_grn_pathogenic_variant_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Founder variant in an extended Belgian <a class="def" href="/books/n/gene/glossary/def-item/pedigree/">pedigree</a> [<a class="bk_pop" href="#ftd-grn.REF.cruts.2006.920">Cruts et al 2006</a>]</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>.hgvs.org</a>). See <a href="/books/n/gene/app3/">Quick Reference</a> for an explanation of nomenclature.</p></div></dd><dt>1. </dt><dd><div id="ftd-grn.TF.3.1"><p class="no_margin">Variant designation that does not conform to current naming conventions</p></div></dd></dl></div></div></div></div></div><div id="ftd-grn.Chapter_Notes"><h2 id="_ftd-grn_Chapter_Notes_">Chapter Notes</h2><div id="ftd-grn.Acknowledgments"><h3>Acknowledgments</h3><p>The authors gratefully acknowledge the funding received from the Canadian Institutes of Health Research operating grant #74580 and #179009 in support of their research on FTD as well as the collaborations of the investigators of the UBC FTD research team including Drs I Mackenzie, B Hallam, C Jacova, E Dwosh, and AD Sadovnick. Dr GYR Hsiung is supported by a CIHR Clinical Genetics Investigatorship.</p></div><div id="ftd-grn.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>6 February 2020 (bp) Comprehensive update posted live</div></li><li class="half_rhythm"><div>14 March 2013 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>7 September 2007 (me) Review posted live</div></li><li class="half_rhythm"><div>1 June 2007 (gyrh) Original submission</div></li></ul></div></div><div id="ftd-grn.References"><h2 id="_ftd-grn_References_">References</h2><div id="ftd-grn.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.arai.2006.602">Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. <span><span class="ref-journal">Biochem Biophys Res Commun. </span>2006;<span class="ref-vol">351</span>:602–11.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17084815" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17084815</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.armstrong.2013.496">Armstrong MJ, Litvan I, Lang AE, Bak TH, Bhatia KP, Borroni B, et al. Criteria for the diagnosis of corticobasal degeneration. <span><span class="ref-journal">Neurology. </span>2013;<span class="ref-vol">80</span>:496–503.</span> [<a href="/pmc/articles/PMC3590050/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3590050</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23359374" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23359374</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.ayala.2008.3778">Ayala YM, Zago P, D'Ambrogio A, Xu YF, Petrucelli L, Buratti E, Baralle FE. Structural determinants of the cellular localization and shuttling of TDP-43. <span><span class="ref-journal">J Cell Sci. </span>2008;<span class="ref-vol">121</span>:3778–85.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18957508" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18957508</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.baker.2006.916">Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. <span><span class="ref-journal">Nature. </span>2006;<span class="ref-vol">442</span>:916–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16862116" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16862116</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.bateman.1998.145">Bateman A, Bennett HP. Granulins: the structure and function of an emerging family of growth factors. <span><span class="ref-journal">J Endocrinol. </span>1998;<span class="ref-vol">158</span>:145–51.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9771457" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9771457</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.beck.2008.706">Beck J, Rohrer JD, Campbell T, Isaacs A, Morrison KE, Goodall EF, Warrington EK, Stevens J, Revesz T, Holton J, Al-Sarraj S, King A, Scahill R, Warren JD, Fox NC, Rossor MN, Collinge J, Mead S. A distinct clinical, neuropsychological and radiological phenotype is associated with progranulin gene mutations in a large UK series. <span><span class="ref-journal">Brain. </span>2008;<span class="ref-vol">131</span>:706–20.</span> [<a href="/pmc/articles/PMC2577762/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2577762</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18234697" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18234697</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.behrens.2007.1">Behrens MI, Mukherjee O, Tu PH, Liscic RM, Grinberg LT, Carter D, Paulsmeyer K, Taylor-Reinwald L, Gitcho M, Norton JB, Chakraverty S, Goate AM, Morris JC, Cairns NJ. Neuropathologic heterogeneity in HDDD1: a familial frontotemporal lobar degeneration with ubiquitin-positive inclusions and progranulin mutation. <span><span class="ref-journal">Alzheimer Dis Assoc Disord. </span>2007;<span class="ref-vol">21</span>:1–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17334266" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17334266</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.benussi.2009.379">Benussi L, Ghidoni R, Pegoiani E, Moretti DV, Zanetti O, Binetti G. Progranulin Leu271LeufsX10 is one of the most common FTLD and CBS associated mutations worldwide. <span><span class="ref-journal">Neurobiol Dis. </span>2009;<span class="ref-vol">33</span>:379–85.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19101631" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19101631</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.bird.2003.s29">Bird T, Knopman D, VanSwieten J, Rosso S, Feldman H, Tanabe H, Graff-Raford N, Geschwind D, Verpillat P, Hutton M. Epidemiology and genetics of frontotemporal dementia/Pick's disease. <span><span class="ref-journal">Ann Neurol. </span>2003;<span class="ref-vol">54</span> Suppl 5:S29–31.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12833366" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12833366</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.boxer.2009.211">Boxer AL, Lipton AM, Womack K, Merrilees J, Neuhaus J, Pavlic D, Gandhi A, Red D, Martin-Cook K, Svetlik D, Miller BL. An open-label study of memantine treatment in 3 subtypes of frontotemporal lobar degeneration. <span><span class="ref-journal">Alzheimer Dis Assoc Disord. </span>2009;<span class="ref-vol">23</span>:211–7.</span> [<a href="/pmc/articles/PMC2760056/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2760056</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19812461" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19812461</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.bronner.2007.369">Bronner IF, Rizzu P, Seelaar H, van Mil SE, Anar B, Azmani A, Kaat LD, Rosso S, Heutink P, van Swieten JC. Progranulin mutations in Dutch familial frontotemporal lobar degeneration. <span><span class="ref-journal">Eur J Hum Genet. </span>2007;<span class="ref-vol">15</span>:369–74.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17228326" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17228326</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.bruni.2007.140">Bruni AC, Momeni P, Bernardi L, Tomaino C, Frangipane F, Elder J, Kawarai T, Sato C, Pradella S, Wakutani Y, Anfossi M, Gallo M, Geracitano S, Costanzo A, Smirne N, Curcio SA, Mirabelli M, Puccio G, Colao R, Maletta RG, Kertesz A, St George-Hyslop P, Hardy J, Rogaeva E. Heterogeneity within a large kindred with frontotemporal dementia: a novel progranulin mutation. <span><span class="ref-journal">Neurology. </span>2007;<span class="ref-vol">69</span>:140–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17620546" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17620546</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.carecchio.2009.291">Carecchio M, Fenoglio C, De Riz M, Guidi I, Comi C, Cortini F, Venturelli E, Restelli I, Cantoni C, Bresolin N, Monaco F, Scarpini E, Galimberti D. Progranulin plasma levels as potential biomarker for the identification of GRN deletion carriers. A case with atypical onset as clinical amnestic mild cognitive impairment converted to Alzheimer's disease. <span><span class="ref-journal">J Neurol Sci. </span>2009;<span class="ref-vol">287</span>:291–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19683260" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19683260</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.caroppo.2015.751">Caroppo P, Habert MO, Durrleman S, Funkiewiez A, Perlbarg V, Hahn V, Bertin H, Gaubert M, Routier A, Hannequin D, Deramecourt V, Pasquier F, Rivaud-Pechoux S, Vercelletto M, Edouart G, Valabregue R, Lejeune P, Didic M, Corvol JC, Benali H, Lehericy S, Dubois B, Colliot O, Brice A, Le Ber I, et al. Lateral temporal lobe: an early imaging marker of the presymptomatic GRN disease? <span><span class="ref-journal">J Alzheimers Dis. </span>2015;<span class="ref-vol">47</span>:751–9.</span> [<a href="/pmc/articles/PMC4923734/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4923734</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26401709" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26401709</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.caso.2012.759">Caso F, Villa C, Fenoglio C, Santangelo R, Agosta F, Coppi E, Falautano M, Comi G, Filippi M, Scarpini E, Magnani G, Galimberti D. The progranulin (GRN) Cys157LysfsX97 mutation is associated with nonfluent variant of primary progressive aphasia clinical phenotype. <span><span class="ref-journal">J Alzheimers Dis. </span>2012;<span class="ref-vol">28</span>:759–63.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22072213" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22072213</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.chenplotkin.2011.488">Chen-Plotkin AS, Martinez-Lage M, Sleiman PM, Hu W, Greene R, Wood EM, Bing S, Grossman M, Schellenberg GD, Hatanpaa KJ, Weiner MF, White CL 3rd, Brooks WS, Halliday GM, Kril JJ, Gearing M, Beach TG, Graff-Radford NR, Dickson DW, Rademakers R, Boeve BF, Pickering-Brown SM, Snowden J, van Swieten JC, Heutink P, Seelaar H, Murrell JR, Ghetti B, Spina S, Grafman J, Kaye JA, Woltjer RL, Mesulam M, Bigio E, Lladó A, Miller BL, Alzualde A, Moreno F, Rohrer JD, Mackenzie IR, Feldman HH, Hamilton RL, Cruts M, Engelborghs S, De Deyn PP, Van Broeckhoven C, Bird TD, Cairns NJ, Goate A, Frosch MP, Riederer PF, Bogdanovic N, Lee VM, Trojanowski JQ, Van Deerlin VM. Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration. <span><span class="ref-journal">Arch Neurol. </span>2011;<span class="ref-vol">68</span>:488–97.</span> [<a href="/pmc/articles/PMC3160280/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3160280</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21482928" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21482928</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.chow.2013.319">Chow TW, Fam D, Graff-Guerrero A, Verhoeff NP, Tang-Wai DF, Masellis M, Black SE, Wilson AA, Houle S, Pollock BG. Fluorodeoxyglucose positron emission tomography in semantic dementia after 6 months of memantine: an open-label pilot study. <span><span class="ref-journal">Int J Geriatr Psychiatry. </span>2013;<span class="ref-vol">28</span>:319–25.</span> [<a href="/pmc/articles/PMC3467357/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3467357</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22674572" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22674572</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.clot.2014.95">Clot F, Rovelet-Lecrux A, Lamari F, Noël S, Keren B, Camuzat A, Michon A, Jornea L, Laudier B, de Septenville A, Caroppo P, Campion D, Cazeneuve C, Brice A, LeGuern E, Le Ber I, et al. Partial deletions of the GRN gene are a cause of frontotemporal lobar degeneration. <span><span class="ref-journal">Neurogenetics. </span>2014;<span class="ref-vol">15</span>:95–100.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24469240" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24469240</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.cruts.2006.920">Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ, van Duijn C, Peeters K, Sciot R, Santens P, De Pooter T, Mattheijssens M, Van den Broeck M, Cuijt I, Vennekens K, De Deyn PP, Kumar-Singh S, Van Broeckhoven C. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. <span><span class="ref-journal">Nature. </span>2006;<span class="ref-vol">442</span>:920–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16862115" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16862115</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.davion.2007.1113">Davion S, Johnson N, Weintraub S, Mesulam MM, Engberg A, Mishra M, Baker M, Adamson J, Hutton M, Rademakers R, Bigio EH. Clinicopathologic correlation in PGRN mutations. <span><span class="ref-journal">Neurology. </span>2007;<span class="ref-vol">69</span>:1113–21.</span> [<a href="/pmc/articles/PMC3545400/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3545400</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17522386" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17522386</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.deakin.2004.400">Deakin JB, Rahman S, Nestor PJ, Hodges JR, Sahakian BJ. Paroxetine does not improve symptoms and impairs cognition in frontotemporal dementia: a double-blind randomized controlled trial. <span><span class="ref-journal">Psychopharmacology (Berl). </span>2004;<span class="ref-vol">172</span>:400–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14666399" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14666399</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.diehlschmid.2008.754">Diehl-Schmid J, Forstl H, Perneczky R, Pohl C, Kurz A. A 6-month, open-label study of memantine in patients with frontotemporal dementia. <span><span class="ref-journal">Int J Geriatr Psychiatry. </span>2008;<span class="ref-vol">23</span>:754–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18213609" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18213609</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.eriksen.2008.287">Eriksen JL, Mackenzie IR. Progranulin: normal function and role in neurodegeneration. <span><span class="ref-journal">J Neurochem. </span>2008;<span class="ref-vol">104</span>:287–97.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17953663" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17953663</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.finch.2009.583">Finch N, Baker M, Crook R, Swanson K, Kuntz K, Surtees R, Bisceglio G, Rovelet-Lecrux A, Boeve B, Petersen RC, Dickson DW, Younkin SG, Deramecourt V, Crook J, Graff-Radford NR, Rademakers R. Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members. <span><span class="ref-journal">Brain. </span>2009;<span class="ref-vol">132</span>:583–91.</span> [<a href="/pmc/articles/PMC2664450/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2664450</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19158106" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19158106</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.freedman.2007.s118">Freedman M. Frontotemporal dementia: recommendations for therapeutic studies, designs, and approaches. <span><span class="ref-journal">Can J Neurol Sci. </span>2007;<span class="ref-vol">34</span> Suppl 1:S118–24.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17469694" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17469694</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.gass.2006.2988">Gass J, Cannon A, Mackenzie IR, Boeve B, Baker M, Adamson J, Crook R, Melquist S, Kuntz K, Petersen R, Josephs K, Pickering-Brown SM, Graff-Radford N, Uitti R, Dickson D, Wszolek Z, Gonzalez J, Beach TG, Bigio E, Johnson N, Weintraub S, Mesulam M, White CL 3rd, Woodruff B, Caselli R, Hsiung GY, Feldman H, Knopman D, Hutton M, Rademakers R. Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. <span><span class="ref-journal">Hum Mol Genet. </span>2006;<span class="ref-vol">15</span>:2988–3001.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16950801" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16950801</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.ghetti.2003">Ghetti B, Hutton M, Wszolek Z. Frontotemporal dementia and parkinsonism linked to chromosome 17 associated with Tau gene mutations (FTDP-17T). In: Dickson DW, ed. <em>Neurodegeneration: the Molecular Pathology of Dementia and Movement Disorders.</em> Basel, Switzerland: ISN Neuropath Press; 2003:86-102.</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.gijselinck.2008.53">Gijselinck I, van der Zee J, Engelborghs S, Goossens D, Peeters K, Mattheijssens M, Corsmit E, Del-Favero J, De Deyn PP, Van Broeckhoven C, Cruts M. Progranulin locus deletion in frontotemporal dementia. <span><span class="ref-journal">Hum Mutat. </span>2008;<span class="ref-vol">29</span>:53–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18157829" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18157829</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.gornotempini.2011.1006">Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa SF, Ogar JM, Rohrer JD, Black S, Boeve BF, Manes F, Dronkers NF, Vandenberghe R, Rascovsky K, Patterson K, Miller BL, Knopman DS, Hodges JR, Mesulam MM, Grossman M. Classification of primary progressive aphasia and its variants. <span><span class="ref-journal">Neurology. </span>2011;<span class="ref-vol">76</span>:1006–14.</span> [<a href="/pmc/articles/PMC3059138/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3059138</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21325651" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21325651</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.he.2003.600">He Z, Bateman A. Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis. <span><span class="ref-journal">J Mol Med. </span>2003;<span class="ref-vol">81</span>:600–12.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12928786" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12928786</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.huey.2008.1981">Huey ED, Garcia C, Wassermann EM, Tierney MC, Grafman J. Stimulant treatment of frontotemporal dementia in 8 patients. <span><span class="ref-journal">J Clin Psychiatry. </span>2008;<span class="ref-vol">69</span>:1981–2.</span> [<a href="/pmc/articles/PMC4489562/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4489562</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19203481" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19203481</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.huey.2006.374">Huey ED, Grafman J, Wassermann EM, Pietrini P, Tierney MC, Ghetti B, Spina S, Baker M, Hutton M, Elder JW, Berger SL, Heflin KA, Hardy J, Momeni P. Characteristics of frontotemporal dementia patients with a progranulin mutation. <span><span class="ref-journal">Ann Neurol. </span>2006;<span class="ref-vol">60</span>:374–80.</span> [<a href="/pmc/articles/PMC2987739/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2987739</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16983677" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16983677</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.jacova.2013.1322">Jacova C, Hsiung GY, Tawankanjanachot I, Dinelle K, McCormick S, Gonzalez M, et al. Anterior brain glucose hypometabolism predates dementia in progranulin mutation carriers. <span><span class="ref-journal">Neurology. </span>2013;<span class="ref-vol">81</span>:1322–31.</span> [<a href="/pmc/articles/PMC3806924/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3806924</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24005336" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24005336</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.josephs.2007.142">Josephs KA, Ahmed Z, Katsuse O, Parisi JF, Boeve BF, Knopman DS, Petersen RC, Davies P, Duara R, Graff-Radford NR, Uitti RJ, Rademakers R, Adamson J, Baker M, Hutton ML, Dickson DW. Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions with progranulin gene (PGRN) mutations. <span><span class="ref-journal">J Neuropathol Exp Neurol. </span>2007;<span class="ref-vol">66</span>:142–51.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17278999" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17278999</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.kamate.2019.542">Kamate M, Detroja M, Hattiholi V. Neuronal ceroid lipofuscinosis type-11 in an adolescent. <span><span class="ref-journal">Brain Dev. </span>2019;<span class="ref-vol">41</span>:542–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30922528" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30922528</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.kelley.2010.171">Kelley BJ, Haidar W, Boeve BF, Baker M, Shiung M, Knopman DS, Rademakers R, Hutton M, Adamson J, Kuntz KM, Dickson DW, Parisi JE, Smith GE, Petersen RC. Alzheimer disease-like phenotype associated with the c.154delA mutation in progranulin. <span><span class="ref-journal">Arch Neurol. </span>2010;<span class="ref-vol">67</span>:171–7.</span> [<a href="/pmc/articles/PMC2902004/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2902004</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20142525" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20142525</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.kertesz.2005.s47">Kertesz A, Blair M, Davidson W, Light M, Morlog D, Brashear R. A Pilot study of the safety and efficacy of galantamine for Pick complex/frontotemporal dementia (FTD). <span><span class="ref-journal">Ann Neurol. </span>2005;<span class="ref-vol">58</span>:S47.</span></div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.kertesz.2008.178">Kertesz A, Morlog D, Light M, Blair M, Davidson W, Jesso S, Brashear R. Galantamine in frontotemporal dementia and primary progressive aphasia. <span><span class="ref-journal">Dement Geriatr Cogn Disord. </span>2008;<span class="ref-vol">25</span>:178–85.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18196898" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18196898</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.kishi.2015.2883">Kishi T, Matsunaga S, Iwata N. Memantine for the treatment of frontotemporal dementia: a meta-analysis. <span><span class="ref-journal">Neuropsychiatr Dis Treat. </span>2015;<span class="ref-vol">11</span>:2883–5.</span> [<a href="/pmc/articles/PMC4648602/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4648602</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26648724" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26648724</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.le_ber.2008.732">Le Ber I, Camuzat A, Hannequin D, Pasquier F, Guedj E, Rovelet-Lecrux A, Hahn-Barma V, van der Zee J, Clot F, Bakchine S, Puel M, Ghanim M, Lacomblez L, Mikol J, Deramecourt V, Lejeune P, de la Sayette V, Belliard S, Vercelletto M, Meyrignac C, Van Broeckhoven C, Lambert JC, Verpillat P, Campion D, Habert MO, Dubois B, Brice A. French research network on FTD/FTD-MND. Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study. <span><span class="ref-journal">Brain. </span>2008;<span class="ref-vol">131</span>:732–46.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18245784" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18245784</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.le_ber.2007.846">Le Ber I, van der Zee J, Hannequin D, Gijselinck I, Campion D, Puel M, Laquerriere A, De Pooter T, Camuzat A, Van den Broeck M, Dubois B, Sellal F, Lacomblez L, Vercelletto M, Thomas-Anterion C, Michel BF, Golfier V, Didic M, Salachas F, Duyckaerts C, Cruts M, Verpillat P, Van Broeckhoven C, Brice A. Progranulin null mutations in both sporadic and familial frontotemporal dementia. <span><span class="ref-journal">Hum Mutat. </span>2007;<span class="ref-vol">28</span>:846–55.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17436289" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17436289</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.lebert.2004.355">Lebert F, Stekke W, Hasenbroekx C, Pasquier F. Frontotemporal dementia: a randomised, controlled trial with trazodone. <span><span class="ref-journal">Dement Geriatr Cogn Disord. </span>2004;<span class="ref-vol">17</span>:355–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15178953" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15178953</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.mackenzie.2007.49">Mackenzie IR. The neuropathology and clinical phenotype of FTD with progranulin mutations. <span><span class="ref-journal">Acta Neuropathol (Berl). </span>2007;<span class="ref-vol">114</span>:49–54.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17458552" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17458552</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.mackenzie.2006.3081">Mackenzie IR, Baker M, Pickering-Brown S, Hsiung GY, Lindholm C, Dwosh E, Gass J, Cannon A, Rademakers R, Hutton M, Feldman HH. The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. <span><span class="ref-journal">Brain. </span>2006;<span class="ref-vol">129</span>:3081–90.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17071926" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17071926</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.mackenzie.2011.111">Mackenzie IR, Neumann M, Baborie A, Sampathu DM, Du Plessis D, Jaros E, Perry RH, Trojanowski JQ, Mann DM, Lee VM. A harmonized classification system for FTLD-TDP pathology. <span><span class="ref-journal">Acta Neuropathol. </span>2011;<span class="ref-vol">122</span>:111–3.</span> [<a href="/pmc/articles/PMC3285143/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3285143</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21644037" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21644037</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.masellis.2006.3115">Masellis M, Momeni P, Meschino W, Heffner R Jr, Elder J, Sato C, Liang Y, St George-Hyslop P, Hardy J, Bilbao J, Black S, Rogaeva E. Novel splicing mutation in the progranulin gene causing familial corticobasal syndrome. <span><span class="ref-journal">Brain. </span>2006;<span class="ref-vol">129</span>:3115–23.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17030534" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17030534</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.mendez.2007.84">Mendez MF, Shapira JS, McMurtray A, Licht E. Preliminary findings: behavioral worsening on donepezil in patients with frontotemporal dementia. <span><span class="ref-journal">Am J Geriatr Psychiatry. </span>2007;<span class="ref-vol">15</span>:84–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17194818" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17194818</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.mesulam.2007.43">Mesulam M, Johnson N, Krefft TA, Gass JM, Cannon AD, Adamson JL, Bigio EH, Weintraub S, Dickson DW, Hutton ML, Graff-Radford NR. Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families. <span><span class="ref-journal">Arch Neurol. </span>2007;<span class="ref-vol">64</span>:43–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17210807" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17210807</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.mesulam.2001.425">Mesulam MM. Primary progressive aphasia. <span><span class="ref-journal">Ann Neurol. </span>2001;<span class="ref-vol">49</span>:425–32.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11310619" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11310619</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.milan.2017.193.e9">Milan G, Napoletano S, Pappatà S, et al. GRN deletion in familial frontotemporal dementia showing association with clinical variability in 3 familial cases. <span><span class="ref-journal">Neurobiol Aging. </span>2017;<span class="ref-vol">53</span>:193.e9–193.e16.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28153380" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28153380</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.moreno.2009.1367">Moreno F, Indakoetxea B, Barandiaran M, Alzualde A, Gabilondo A, Estanga A, Ruiz J, Ruibal M, Bergareche A, Martí-Massó JF, López de Munain A. "Frontotemporoparietal" dementia: clinical phenotype associated with the c.709-1G>A PGRN mutation. <span><span class="ref-journal">Neurology. </span>2009;<span class="ref-vol">73</span>:1367–74.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19858458" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19858458</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.moretti.2004.931">Moretti R, Torre P, Antonello RM, Cattaruzza T, Cazzato G, Bava A. Rivastigmine in frontotemporal dementia: an open-label study. <span><span class="ref-journal">Drugs Aging. </span>2004;<span class="ref-vol">21</span>:931–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15554751" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15554751</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.moretti.2003.13">Moretti R, Torre P, Antonello RM, Cazzato G, Bava A. Frontotemporal dementia: paroxetine as a possible treatment of behavior symptoms. A randomized, controlled, open 14-month study. <span><span class="ref-journal">Eur Neurol. </span>2003;<span class="ref-vol">49</span>:13–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12464713" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12464713</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.mukherjee.2006.314">Mukherjee O, Pastor P, Cairns NJ, Chakraverty S, Kauwe JS, Shears S, Behrens MI, Budde J, Hinrichs AL, Norton J, Levitch D, Taylor-Reinwald L, Gitcho M, Tu PH, Tenenholz Grinberg L, Liscic RM, Armendariz J, Morris JC, Goate AM. HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin. <span><span class="ref-journal">Ann Neurol. </span>2006;<span class="ref-vol">60</span>:314–22.</span> [<a href="/pmc/articles/PMC2803024/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2803024</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16983685" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16983685</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.neumann.2009.137">Neumann M, Kwong LK, Lee EB, Kremmer E, Flatley A, Xu Y, Forman MS, Troost D, Kretzschmar HA, Trojanowski JQ, Lee VM. Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies. <span><span class="ref-journal">Acta Neuropathol. </span>2009;<span class="ref-vol">117</span>:137–49.</span> [<a href="/pmc/articles/PMC2693625/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2693625</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19125255" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19125255</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.neumann.2006.130">Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. <span><span class="ref-journal">Science. </span>2006;<span class="ref-vol">314</span>:130–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17023659" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17023659</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.pasquier.2003.s32">Pasquier F, Fukui T, Sarazin M, Pijnenburg Y, Diehl J, Grundman M, Miller BL. Laboratory investigations and treatment in frontotemporal dementia. <span><span class="ref-journal">Ann Neurol. </span>2003;<span class="ref-vol">54</span> Suppl 5:S32–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12833367" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12833367</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.pickeringbrown.2008.721">Pickering-Brown SM, Rollinson S, Du Plessis D, Morrison KE, Varma A, Richardson AM, Neary D, Snowden JS, Mann DM. Frequency and clinical characteristics of progranulin mutation carriers in the Manchester frontotemporal lobar degeneration cohort: comparison with patients with MAPT and no known mutations. <span><span class="ref-journal">Brain. </span>2008;<span class="ref-vol">131</span>:721–31.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18192287" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18192287</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.pottier.2018.548">Pottier C, Zhou X, Perkerson RB 3rd, Baker M, Jenkins GD, Serie DJ, Ghidoni R, Benussi L, Binetti G, López de Munain A, Zulaica M, Moreno F, Le Ber I, Pasquier F, Hannequin D, Sánchez-Valle R, Antonell A, Lladó A, Parsons TM, Finch NA, Finger EC, Lippa CF, Huey ED, Neumann M, Heutink P, Synofzik M, Wilke C, Rissman RA, Slawek J, Sitek E, Johannsen P, Nielsen JE, Ren Y, van Blitterswijk M, DeJesus-Hernandez M, Christopher E, Murray ME, Bieniek KF, Evers BM, Ferrari C, Rollinson S, Richardson A, Scarpini E, Fumagalli GG, Padovani A, Hardy J, Momeni P, Ferrari R, Frangipane F, Maletta R, Anfossi M, Gallo M, Petrucelli L, Suh E, Lopez OL, Wong TH, van Rooij JGJ, Seelaar H, Mead S, Caselli RJ, Reiman EM, Noel Sabbagh M, Kjolby M, Nykjaer A, Karydas AM, Boxer AL, Grinberg LT, Grafman J, Spina S, Oblak A, Mesulam MM, Weintraub S, Geula C, Hodges JR, Piguet O, Brooks WS, Irwin DJ, Trojanowski JQ, Lee EB, Josephs KA, Parisi JE, Ertekin-Taner N, Knopman DS, Nacmias B, Piaceri I, Bagnoli S, Sorbi S, Gearing M, Glass J, Beach TG, Black SE, Masellis M, Rogaeva E, Vonsattel JP, Honig LS, Kofler J, Bruni AC, Snowden J, Mann D, Pickering-Brown S, Diehl-Schmid J, Winkelmann J, Galimberti D, Graff C, Öijerstedt L, Troakes C, Al-Sarraj S, Cruchaga C, Cairns NJ, Rohrer JD, Halliday GM, Kwok JB, van Swieten JC, White CL 3rd, Ghetti B, Murell JR, Mackenzie IRA, Hsiung GR, Borroni B, Rossi G, Tagliavini F, Wszolek ZK, Petersen RC, Bigio EH, Grossman M, Van Deerlin VM, Seeley WW, Miller BL, Graff-Radford NR, Boeve BF, Dickson DW, Biernacka JM, Rademakers R. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study. <span><span class="ref-journal">Lancet Neurol. </span>2018;<span class="ref-vol">17</span>:548–58.</span> [<a href="/pmc/articles/PMC6237181/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6237181</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29724592" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29724592</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.rademakers.2007.857">Rademakers R, Baker M, Gass J, Adamson J, Huey ED, Momeni P, Spina S, Coppola G, Karydas AM, Stewart H, Johnson N, Hsiung GY, Kelley B, Kuntz K, Steinbart E, Wood EM, Yu CE, Josephs K, Sorenson E, Womack KB, Weintraub S, Pickering-Brown SM, Schofield PR, Brooks WS, Van Deerlin VM, Snowden J, Clark CM, Kertesz A, Boylan K, Ghetti B, Neary D, Schellenberg GD, Beach TG, Mesulam M, Mann D, Grafman J, Mackenzie IR, Feldman H, Bird T, Petersen R, Knopman D, Boeve B, Geschwind DH, Miller B, Wszolek Z, Lippa C, Bigio EH, Dickson D, Graff-Radford N, Hutton M. Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C-->T (Arg493X) mutation: an international initiative. <span><span class="ref-journal">Lancet Neurol. </span>2007;<span class="ref-vol">6</span>:857–68.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17826340" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17826340</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.rahbari.2016.126">Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. <span><span class="ref-journal">Nat Genet. </span>2016;<span class="ref-vol">48</span>:126–33.</span> [<a href="/pmc/articles/PMC4731925/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4731925</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26656846" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26656846</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.rahman.2006.651">Rahman S, Robbins TW, Hodges JR, Mehta MA, Nestor PJ, Clark L, Sahakian BJ. Methylphenidate ('Ritalin') can ameliorate abnormal risk-taking behavior in the frontal variant of frontotemporal dementia. <span><span class="ref-journal">Neuropsychopharmacology. </span>2006;<span class="ref-vol">31</span>:651–8.</span> [<a href="/pmc/articles/PMC1852060/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1852060</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16160709" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16160709</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.rascovsky.2011.2456">Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, van Swieten JC, Seelaar H, Dopper EG, Onyike CU, Hillis AE, Josephs KA, Boeve BF, Kertesz A, Seeley WW, Rankin KP, Johnson JK, Gorno-Tempini ML, Rosen H, Prioleau-Latham CE, Lee A, Kipps CM, Lillo P, Piguet O, Rohrer JD, Rossor MN, Warren JD, Fox NC, Galasko D, Salmon DP, Black SE, Mesulam M, Weintraub S, Dickerson BC, Diehl-Schmid J, Pasquier F, Deramecourt V, Lebert F, Pijnenburg Y, Chow TW, Manes F, Grafman J, Cappa SF, Freedman M, Grossman M, Miller BL. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. <span><span class="ref-journal">Brain. </span>2011;<span class="ref-vol">134</span>:2456–77.</span> [<a href="/pmc/articles/PMC3170532/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3170532</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21810890" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21810890</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.richards.2015.405">Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. <span><span class="ref-journal">Genet Med. </span>2015;<span class="ref-vol">17</span>:405–24.</span> [<a href="/pmc/articles/PMC4544753/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4544753</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25741868" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25741868</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.rohrer.2013.1411">Rohrer JD, Beck J, Plagnol V, Gordon E, Lashley T, Revesz T, Janssen JC, Fox NC, Warren JD, Rossor MN, Mead S, Schott JM. Exome sequencing reveals a novel partial deletion in the progranulin gene causing primary progressive aphasia. <span><span class="ref-journal">J Neurol Neurosurg Psychiatry. </span>2013;<span class="ref-vol">84</span>:1411–2.</span> [<a href="/pmc/articles/PMC3905627/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3905627</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23904625" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23904625</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.rohrer.2011.542">Rohrer JD, Warren JD. Phenotypic signatures of genetic frontotemporal dementia. <span><span class="ref-journal">Curr Opin Neurol. </span>2011;<span class="ref-vol">24</span>:542–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21986680" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21986680</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.roveletlecrux.2008.41">Rovelet-Lecrux A, Deramecourt V, Legallic S, Maurage CA, Le Ber I, Brice A, Lambert JC, Frébourg T, Hannequin D, Pasquier F, Campion D. Deletion of the progranulin gene in patients with frontotemporal lobar degeneration or Parkinson disease. <span><span class="ref-journal">Neurobiol Dis. </span>2008;<span class="ref-vol">31</span>:41–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18479928" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18479928</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.schymick.2007.754">Schymick JC, Yang Y, Andersen PM, Vonsattel JP, Greenway M, Momeni P, Elder J, Chio A, Restagno G, Robberecht W, Dahlberg C, Mukherjee O, Goate A, Graff-Radford N, Caselli RJ, Hutton M, Gass J, Cannon A, Rademakers R, Singleton AB, Hardiman O, Rothstein J, Hardy J, Traynor BJ. Progranulin mutations and amyotrophic lateral sclerosis or amyotrophic lateral sclerosis-frontotemporal dementia phenotypes. <span><span class="ref-journal">J Neurol Neurosurg Psychiatry. </span>2007;<span class="ref-vol">78</span>:754–6.</span> [<a href="/pmc/articles/PMC2117704/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2117704</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17371905" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17371905</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.seeley.2005.1384">Seeley WW, Bauer AM, Miller BL, Gorno-Tempini ML, Kramer JH, Weiner M, Rosen HJ. The natural history of temporal variant frontotemporal dementia. <span><span class="ref-journal">Neurology. </span>2005;<span class="ref-vol">64</span>:1384–90.</span> [<a href="/pmc/articles/PMC2376750/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2376750</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/15851728" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15851728</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.sendtner.2011.403">Sendtner M. TDP-43: multiple targets, multiple disease mechanisms? <span><span class="ref-journal">Nat Neurosci. </span>2011;<span class="ref-vol">14</span>:403–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21445063" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21445063</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.smith.2012.1102">Smith KR, Damiano J, Franceschetti S, Carpenter S, Canafoglia L, Morbin M, et al. Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. <span><span class="ref-journal">Am J Hum Genet. </span>2012;<span class="ref-vol">90</span>:1102–7.</span> [<a href="/pmc/articles/PMC3370276/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3370276</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22608501" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22608501</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.spina.2007.820">Spina S, Murrell JR, Huey ED, Wassermann EM, Pietrini P, Baraibar MA, Barbeito AG, Troncoso JC, Vidal R, Ghetti B, Grafman J. Clinicopathologic features of frontotemporal dementia with progranulin sequence variation. <span><span class="ref-journal">Neurology. </span>2007;<span class="ref-vol">68</span>:820–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17202431" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17202431</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.tanaka.2014.78">Tanaka Y, Chambers JK, Matsuwaki T, Yamanouchi K, Nishihara M. Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice. <span><span class="ref-journal">Acta neuropathologica communications. </span>2014;<span class="ref-vol">2</span>:78.</span> [<a href="/pmc/articles/PMC4149276/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4149276</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25022663" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25022663</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.townley.2018.118">Townley RA, Boeve BF, Benarroch EE. Progranulin: functions and neurologic correlations. <span><span class="ref-journal">Neurology. </span>2018;<span class="ref-vol">90</span>:118–25.</span> [<a href="/pmc/articles/PMC5772162/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5772162</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29263224" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29263224</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.valdez.2020.716">Valdez C, Ysselstein D, Young TJ, Zheng J, Krainc D. Progranulin mutations result in impaired processing of prosaposin and reduced glucocerebrosidase activity. <span><span class="ref-journal">Hum Mol Genet. </span>2020;<span class="ref-vol">29</span>:716–26.</span> [<a href="/pmc/articles/PMC7104673/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7104673</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31600775" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31600775</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.van_der_zee.2007.416">van der Zee J, Le Ber I, Maurer-Stroh S, Engelborghs S, Gijselinck I, Camuzat A, Brouwers N, Vandenberghe R, Sleegers K, Hannequin D, Dermaut B, Schymkowitz J, Campion D, Santens P, Martin JJ, Lacomblez L, De Pooter T, Peeters K, Mattheijssens M, Vercelletto M, Van den Broeck M, Cruts M, De Deyn PP, Rousseau F, Brice A, Van Broeckhoven C. Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia. <span><span class="ref-journal">Hum Mutat. </span>2007;<span class="ref-vol">28</span>:416.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17345602" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17345602</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.van_langenhove.2013.365">Van Langenhove T, van der Zee J, Gijselinck I, Engelborghs S, Vandenberghe R, Vandenbulcke M, De Bleecker J, Sieben A, Versijpt J, Ivanoiu A, Deryck O, Willems C, Dillen L, Philtjens S, Maes G, Bäumer V, Van Den Broeck M, Mattheijssens M, Peeters K, Martin JJ, Michotte A, Santens P, De Jonghe P, Cras P, De Deyn PP, Cruts M, Van Broeckhoven C. Distinct clinical characteristics of C9orf72 expansion carriers compared with GRN, MAPT, and nonmutation carriers in a Flanders-Belgian FTLD cohort. <span><span class="ref-journal">JAMA Neurol. </span>2013;<span class="ref-vol">70</span>:365–73.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23338682" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23338682</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.whitwell.2007.371">Whitwell JL, Jack CR Jr, Baker M, Rademakers R, Adamson J, Boeve BF, Knopman DS, Parisi JF, Petersen RC, Dickson DW, Hutton ML, Josephs KA. Voxel-based morphometry in frontotemporal lobar degeneration with ubiquitin-positive inclusions with and without progranulin mutations. <span><span class="ref-journal">Arch Neurol. </span>2007;<span class="ref-vol">64</span>:371–6.</span> [<a href="/pmc/articles/PMC2752412/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2752412</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17353379" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17353379</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.whitwell.2011.393">Whitwell JL, Weigand SD, Gunter JL, Boeve BF, Rademakers R, Baker M, Knopman DS, Wszolek ZK, Petersen RC, Jack CR Jr, Josephs KA. Trajectories of brain and hippocampal atrophy in FTD with mutations in MAPT or GRN. <span><span class="ref-journal">Neurology. </span>2011;<span class="ref-vol">77</span>:393–8.</span> [<a href="/pmc/articles/PMC3140800/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3140800</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21753165" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21753165</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.zhou.2019.e0212382">Zhou X, Paushter DH, Pagan MD, Kim D, Nunez Santos M, Lieberman RL, Overkleeft HS, Sun Y, Smolka MB, Hu F. Progranulin deficiency leads to reduced glucocerebrosidase activity. <span><span class="ref-journal">PLoS One. </span>2019;<span class="ref-vol">14</span>:e0212382. </span> [<a href="/pmc/articles/PMC6619604/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6619604</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31291241" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31291241</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ftd-grn.REF.zhou.2017.15277">Zhou X, Sun L, Bracko O, Choi JW, Jia Y, Nana AL, Brady OA, Hernandez JCC, Nishimura N, Seeley WW, Hu F. Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations. <span><span class="ref-journal">Nat Commun. </span>2017;<span class="ref-vol">8</span>:15277.</span> [<a href="/pmc/articles/PMC5477518/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5477518</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28541286" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28541286</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK1371/?report=reader">PubReader</a></li><li><a href="/books/NBK1371/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK1371" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK1371" style="display:none" title="Cite this Page"><div class="bk_tt">Hsiung GYR, Feldman HH. GRN Frontotemporal Dementia. 2007 Sep 7 [Updated 2020 Feb 6]. 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id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301678" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> MAPT-Related Frontotemporal Dementia.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> MAPT-Related Frontotemporal Dementia.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Rohrer J, Ryan B, Ahmed R. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301377" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Phelan-McDermid Syndrome-SHANK3 Related.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Phelan-McDermid Syndrome-SHANK3 Related.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Phelan K, Rogers RC, Boccuto L. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301601" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Neuronal Ceroid-Lipofuscinoses – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Neuronal Ceroid-Lipofuscinoses – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Mole SE, Williams RE. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301656" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Adenosine Deaminase Deficiency.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Adenosine Deaminase Deficiency.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Hershfield M, Tarrant T. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301510" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> FBN1-Related Marfan Syndrome.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> FBN1-Related Marfan Syndrome.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Dietz H. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=20301545" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=20301545" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="recent_activity" id="Shutter"></a></div><div class="portlet_content"><div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" id="HTDisplay" class=""><div class="action"><a href="javascript:historyDisplayState('ClearHT')">Clear</a><a href="javascript:historyDisplayState('HTOff')" class="HTOn">Turn Off</a><a href="javascript:historyDisplayState('HTOn')" class="HTOff">Turn On</a></div><ul id="activity"><li class="ra_rcd ralinkpopper 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