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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="VPS35-Related Parkinson Disease" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2023/03/23" /><meta name="citation_author" content="Jaroslaw Dulski" /><meta name="citation_author" content="Owen A Ross" /><meta name="citation_author" content="Zbigniew K Wszolek" /><meta name="citation_pmid" content="28796472" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK447258/" /><meta name="citation_keywords" content="PARK17" /><meta name="citation_keywords" content="PARK-VPS35" /><meta name="citation_keywords" content="PARK17" /><meta name="citation_keywords" content="PARK-VPS35" /><meta name="citation_keywords" content="Vacuolar protein sorting-associated protein 35" /><meta name="citation_keywords" content="VPS35" /><meta name="citation_keywords" content="VPS35-Related Parkinson Disease" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="VPS35-Related Parkinson Disease" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Jaroslaw Dulski" /><meta name="DC.Contributor" content="Owen A Ross" /><meta name="DC.Contributor" content="Zbigniew K Wszolek" /><meta name="DC.Date" content="2023/03/23" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK447258/" /><meta name="description" content="VPS35-related Parkinson disease (PARK-VPS35) is indistinguishable from Parkinson disease of unknown cause representing a simplex case (also referred to as "sporadic" Parkinson disease). PARK-VPS35 is characterized by typical parkinsonism (resting tremor, bradykinesia, rigidity, disturbance of postural reflexes) presenting on average a decade earlier than in individuals with simplex Parkinson disease of unknown cause. Median age of onset is approximately 50 years, with a range of onset spanning the third to eighth decade of life. PARK-VPS35 subtypes can include tremor dominant, akinetic rigid, gait difficulty, or mixed. Asymmetric presentation is typical. The disease course is usually milder than that of simplex Parkinson disease of unknown cause, with a decreased incidence of atypical signs. Dyskinesia and motor fluctuations may occur. Neuropsychiatric manifestations (depression and schizophrenia), learning difficulties, mild cognitive impairment, and dementia have been reported, albeit with lower occurrence than in simplex Parkinson disease of unknown cause. Additional findings include impaired sense of smell and autonomic manifestations including orthostasis and constipation." /><meta name="og:title" content="VPS35-Related Parkinson Disease" /><meta name="og:type" content="book" /><meta name="og:description" content="VPS35-related Parkinson disease (PARK-VPS35) is indistinguishable from Parkinson disease of unknown cause representing a simplex case (also referred to as "sporadic" Parkinson disease). PARK-VPS35 is characterized by typical parkinsonism (resting tremor, bradykinesia, rigidity, disturbance of postural reflexes) presenting on average a decade earlier than in individuals with simplex Parkinson disease of unknown cause. Median age of onset is approximately 50 years, with a range of onset spanning the third to eighth decade of life. PARK-VPS35 subtypes can include tremor dominant, akinetic rigid, gait difficulty, or mixed. Asymmetric presentation is typical. The disease course is usually milder than that of simplex Parkinson disease of unknown cause, with a decreased incidence of atypical signs. Dyskinesia and motor fluctuations may occur. Neuropsychiatric manifestations (depression and schizophrenia), learning difficulties, mild cognitive impairment, and dementia have been reported, albeit with lower occurrence than in simplex Parkinson disease of unknown cause. 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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="#__NBK447258_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK447258_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/vps13d-md/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/porphyria-var/" 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="_NBK447258_"><span class="title" itemprop="name"><i>VPS35</i>-Related Parkinson Disease</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: PARK17, PARK-<i>VPS35</i></div><p class="contrib-group"><span itemprop="author">Jaroslaw Dulski</span>, MD, PhD, <span itemprop="author">Owen A Ross</span>, PhD, and <span itemprop="author">Zbigniew K Wszolek</span>, MD.</p><a data-jig="ncbitoggler" href="#__NBK447258_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK447258_ai__"><div class="contrib half_rhythm"><span itemprop="author">Jaroslaw Dulski</span>, MD, PhD<div class="affiliation small">Department of Neurology<br />Mayo Clinic<br />Jacksonville, Florida</div><div class="affiliation small">Division of Neurological and Psychiatric Nursing<br />Faculty of Health Sciences<br />Medical University of Gdansk<br />Gdansk, Poland</div><div class="affiliation small">Neurology Department<br />St Adalbert Hospital<br />Copernicus PL Ltd<br />Gdansk, Poland<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.oyam@walsoraj.ikslud" class="oemail">ude.oyam@walsoraj.ikslud</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Owen A Ross</span>, PhD<div class="affiliation small">Departments of Neuroscience and Clinical Genomics<br />Mayo Clinic<br />Jacksonville, Florida<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.oyam@newo.ssor" class="oemail">ude.oyam@newo.ssor</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Zbigniew K Wszolek</span>, MD<div class="affiliation small">Department of Neurology<br />Mayo Clinic<br />Jacksonville, Florida<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.oyam@weingibz.kelozsw" class="oemail">ude.oyam@weingibz.kelozsw</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">August 10, 2017</span>; Last Update: <span itemprop="dateModified">March 23, 2023</span>.</p><p><em>Estimated reading time: 32 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="vps35-pd.Summary" itemprop="description"><h2 id="_vps35-pd_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><i>VPS35</i>-related Parkinson disease (PARK<i>-VPS35</i>) is indistinguishable from Parkinson disease of unknown cause representing a <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> case (also referred to as "<a class="def" href="/books/n/gene/glossary/def-item/sporadic/">sporadic</a>" Parkinson disease). PARK-<i>VPS35</i> is characterized by typical parkinsonism (resting tremor, bradykinesia, rigidity, disturbance of postural reflexes) presenting on average a decade earlier than in individuals with simplex Parkinson disease of unknown cause. Median age of onset is approximately 50 years, with a range of onset spanning the third to eighth decade of life. PARK-<i>VPS35</i> subtypes can include tremor dominant, akinetic rigid, gait difficulty, or mixed. Asymmetric presentation is typical. The disease course is usually milder than that of simplex Parkinson disease of unknown cause, with a decreased incidence of atypical signs. Dyskinesia and motor fluctuations may occur. Neuropsychiatric manifestations (depression and schizophrenia), learning difficulties, mild cognitive impairment, and dementia have been reported, albeit with lower occurrence than in simplex Parkinson disease of unknown cause. Additional findings include impaired sense of smell and autonomic manifestations including orthostasis and constipation.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of PARK-<i>VPS35</i> is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with parkinsonism (bradykinesia with rigidity and/or resting tremor) and a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <i>VPS35</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> 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> To date, treatment of PARK<i>-VPS35</i> does not differ from that of <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> Parkinson disease of unknown cause. Drugs to treat motor manifestations include levodopa, in combination with a peripheral dopa decarboxylase inhibitor (carbidopa, benserazide), dopamine agonists, inhibitors of catechol-O-methyltransferase or monoamine oxidase-B, anticholinergics, and amantadine. Most individuals respond well to levodopa and other dopaminergic medications. Individuals benefit from physical, occupational, and speech therapies. Due to the lower risk of atypical signs, neuropsychiatric disturbances, and dementia, individuals with PARK-<i>VPS35</i> seem to be good candidates for treatment with dopamine agonists. In addition, in those with dyskinesia and motor fluctuations, subthalamic deep brain stimulation and apomorphine intermittent injections or continuous therapy with an infusion pump should be considered. Peak-dose dyskinesia may be ameliorated with amantadine and dopaminergic treatment reduction (if tolerated). Low-dose clozapine, quetiapine, or pimavanserin and reduction of dopaminergic therapy can decrease delusions and hallucinations. Standard treatments for depression; consider droxidopa for orthostasis; symptomatic treatment for constipation.</p><p><i>Surveillance:</i> Neurologic evaluations to assess tremor, bradykinesia, rigidity, gait, neuropsychiatric symptoms, cognition, and treatment efficacy every six to 12 months or as needed; neuropsychiatric and cognitive assessments as needed; assess for symptoms of orthostasis, measure blood pressure, and assess for constipation at each visit; echocardiogram as needed in those treated with ergot-derived dopamine agonists; assess family and social work needs at each visit.</p><p><i>Agents/circumstances to avoid:</i> Drugs that may induce or exacerbate parkinsonism include but are not limited to neuroleptics, antidepressants, calcium channel blockers, valproate, lithium, and amiodarone. Ergot-derived dopaminergic drugs should be discontinued if fibrotic heart-valve changes are identified.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>PARK<i>-VPS35</i> is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner. About 90% of individuals diagnosed with PARK<i>-VPS35</i> have positive family history of Parkinson disease. Each child of an individual with PARK<i>-VPS35</i> has a 50% chance of inheriting the <i>VPS35</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>. Once the <i>VPS35</i> pathogenic variant 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> are possible.</p></div></div><div id="vps35-pd.Diagnosis"><h2 id="_vps35-pd_Diagnosis_">Diagnosis</h2><div id="vps35-pd.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>VPS35</i>-related Parkinson disease (PARK-<i>VPS35</i>) <b>should be considered</b> in individuals with the following clinical, imaging, and family history findings.</p><p><b>Clinical findings.</b> The clinical manifestations of PARK-<i>VPS35</i> are similar to those of Parkinson disease of unknown cause representing a <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> case (also referred to as "<a class="def" href="/books/n/gene/glossary/def-item/sporadic/">sporadic</a>" Parkinson disease; see <a href="#vps35-pd.Nomenclature">Nomenclature</a>). However, onset for PARK-<i>VPS35</i> is on average a decade earlier, progression is slower, and there is a lower risk of atypical signs, neuropsychiatric disturbances, and dementia. The cardinal sign of PARK-<i>VPS35</i> is parkinsonism, defined as:</p><ul><li class="half_rhythm"><div>Bradykinesia (slowness of movement AND decrement in amplitude or speed) in combination with at least one of the following:</div><ul><li class="half_rhythm"><div>Resting tremor (rhythmic tremor usually of the hands and forearms when relaxed, which disappears with active limb movement)</div></li><li class="half_rhythm"><div>Rigidity (increased muscle tone resulting in resistance to passive movement)</div></li></ul></li></ul><p>Additional clinical findings of PARK<i>-VPS35</i>:</p><ul><li class="half_rhythm"><div>Adult onset</div></li><li class="half_rhythm"><div>Typically unilateral onset</div></li><li class="half_rhythm"><div>Slow disease progression</div></li><li class="half_rhythm"><div>Good response to levodopa therapy</div></li></ul><p><b>Imaging findings.</b> Normal brain MRI</p><p><b>Family history</b> is consistent with <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.</p></div><div id="vps35-pd.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of PARK-<i>VPS35</i>
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<b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with parkinsonism (bradykinesia with rigidity and/or resting tremor) and a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <i>VPS35</i> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variant identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK447258/table/vps35-pd.T.molecular_genetic_testing_use/?report=objectonly" target="object" rid-ob="figobvps35pdTmoleculargenetictestinguse">Table 1</a>).</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "<a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>" and "<a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a> variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [<a class="bk_pop" href="#vps35-pd.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> 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>VPS35</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>Molecular genetic testing approaches can include a combination of <b><a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted testing</b> (<a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a>) and <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (<a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a>, <a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a>) depending on the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>.</p><p>Gene-targeted testing requires the clinician to determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>(s) are likely involved, whereas <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing does not. Because the phenotypes of inherited Parkinson disease are largely indistinguishable, most individuals with PARK<i>-VPS35</i> are diagnosed by the following <a href="#vps35-pd.Recommended_Testing">recommended testing</a> or <a href="#vps35-pd.Testing_to_Consider">testing to consider</a>.</p><div id="vps35-pd.Recommended_Testing"><h4>Recommended Testing</h4><p><b>A multigene Parkinson disease panel</b> including <i>VPS35</i> and other genes of interest (see <a href="/books/NBK447258/table/vps35-pd.T.genes_associated_with_earlyon/?report=objectonly" target="object" rid-ob="figobvps35pdTgenesassociatedwithearlyon">Table 3a</a> in <a href="#vps35-pd.Differential_Diagnosis">Differential Diagnosis</a>) is recommended. 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>; thus, clinicians need to determine which <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</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>. Given the rarity of PARK-<i>VPS35</i>, some panels for Parkinson disease may not include this gene.</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="vps35-pd.Testing_to_Consider"><h4>Testing to Consider</h4><p><b>Comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> does not require the clinician to determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> is likely involved. <b>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.</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><p>Note: Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing (<a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> of <i>VPS35</i>) is typically not recommended because the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> overlaps with that of other inherited forms of Parkinson disease.</p><div id="vps35-pd.T.molecular_genetic_testing_use" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>VPS35</i>-Related Parkinson Disease</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK447258/table/vps35-pd.T.molecular_genetic_testing_use/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vps35-pd.T.molecular_genetic_testing_use_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vps35-pd.T.molecular_genetic_testing_use_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_vps35-pd.T.molecular_genetic_testing_use_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_vps35-pd.T.molecular_genetic_testing_use_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_vps35-pd.T.molecular_genetic_testing_use_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>VPS35</i>
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</td><td headers="hd_h_vps35-pd.T.molecular_genetic_testing_use_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_vps35-pd.T.molecular_genetic_testing_use_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100% <sup>4</sup></td></tr><tr><td headers="hd_h_vps35-pd.T.molecular_genetic_testing_use_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_vps35-pd.T.molecular_genetic_testing_use_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None reported <sup>4</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="vps35-pd.TF.1.1"><p class="no_margin">See <a href="/books/NBK447258/#vps35-pd.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="vps35-pd.TF.1.2"><p class="no_margin">See <a href="#vps35-pd.Molecular_Genetics">Molecular Genetics</a> for information on 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="vps35-pd.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 detected 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="vps35-pd.TF.1.4"><p class="no_margin"><a class="bk_pop" href="#vps35-pd.REF.vilari_og_ell.2011.162">Vilariño-Güell et al [2011]</a>, <a class="bk_pop" href="#vps35-pd.REF.zimprich.2011.168">Zimprich et al [2011]</a>, <a class="bk_pop" href="#vps35-pd.REF.ando.2012.1413">Ando et al [2012]</a>, <a class="bk_pop" href="#vps35-pd.REF.kumar.2012.1360">Kumar et al [2012]</a>, <a class="bk_pop" href="#vps35-pd.REF.lesage.2012.1449">Lesage et al [2012]</a>, <a class="bk_pop" href="#vps35-pd.REF.sharma.2012.721">Sharma et al [2012]</a>, <a class="bk_pop" href="#vps35-pd.REF.sheerin.2012.838.e1">Sheerin et al [2012]</a>, and data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bk_pop" href="#vps35-pd.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd><dt>5. </dt><dd><div id="vps35-pd.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.</p></div></dd></dl></div></div></div></div></div></div><div id="vps35-pd.Clinical_Characteristics"><h2 id="_vps35-pd_Clinical_Characteristics_">Clinical Characteristics</h2><div id="vps35-pd.Clinical_Description"><h3>Clinical Description</h3><p><i>VPS35</i>-related Parkinson disease (PARK-<i>VPS35</i>) is indistinguishable from Parkinson disease of unknown cause representing a <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> case (also referred to as "<a class="def" href="/books/n/gene/glossary/def-item/sporadic/">sporadic</a>" Parkinson disease; see <a href="#vps35-pd.Nomenclature">Nomenclature</a>). PARK<i>-VPS35</i> is characterized by cardinal manifestations of typical parkinsonism (resting tremor, bradykinesia, rigidity, disturbance of postural reflexes). Similar to simplex Parkinson disease of unknown cause, non-motor symptoms also occur; however, neuropsychiatric disturbances and dementia are less common. Atypical features are also of lower frequency compared to simplex Parkinson disease of unknown cause. Disturbances of postural reflexes, autonomic manifestations, and sleep disorders occur at a similar rate to simplex Parkinson disease of unknown cause. PARK<i>-VPS35</i> manifestations may be variable among affected individuals within the same family. To date, approximately 150 individuals with PARK-<i>VPS35</i> have been identified [<a class="bk_pop" href="#vps35-pd.REF.vilari_og_ell.2011.162">Vilariño-Güell et al 2011</a>; <a class="bk_pop" href="#vps35-pd.REF.zimprich.2011.168">Zimprich et al 2011</a>; <a class="bk_pop" href="#vps35-pd.REF.ando.2012.1413">Ando et al 2012</a>; <a class="bk_pop" href="#vps35-pd.REF.kumar.2012.1360">Kumar et al 2012</a>; <a class="bk_pop" href="#vps35-pd.REF.lesage.2012.1449">Lesage et al 2012</a>; <a class="bk_pop" href="#vps35-pd.REF.sharma.2012.721">Sharma et al 2012</a>; <a class="bk_pop" href="#vps35-pd.REF.sheerin.2012.838.e1">Sheerin et al 2012</a>; <a class="bk_pop" href="#vps35-pd.REF.trinh.2018.1857">Trinh et al 2018</a>; <a class="bk_pop" href="#vps35-pd.REF.dulski.2022.1023574">Dulski et al 2022</a>; <a class="bk_pop" href="#vps35-pd.REF.vollstedt.2023.286">Vollstedt et al 2023</a>; Dulski et al, unpublished data].</p><div id="vps35-pd.T.select_features_of_vps35relat" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Select Features of <i>VPS35</i>-Related Parkinson Disease</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK447258/table/vps35-pd.T.select_features_of_vps35relat/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vps35-pd.T.select_features_of_vps35relat_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of Persons w/Feature <sup>1</sup></th><th id="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Resting tremor</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">98%</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Bradykinesia</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">96%</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rigidity</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">95%</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disturbance of postural reflexes</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">67%</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neuropsychiatric manifestations</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">68%</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cognitive issues</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">42%</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Learning difficulties, mild cognitive impairment, dementia</td></tr><tr><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Good response to levodopa</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">80%</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Motor fluctuations</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">85%</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dyskinesia</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">80%</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dystonia</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">32%</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Autonomic manifestations</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">75%</td><td headers="hd_h_vps35-pd.T.select_features_of_vps35relat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="vps35-pd.TF.2.1"><p class="no_margin">
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<a class="bk_pop" href="#vps35-pd.REF.trinh.2018.1857">Trinh et al [2018]</a>
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</p></div></dd></dl></div></div></div><p><b>Age of onset.</b> Median age of onset was 52 years (interquartile range [IQR]: 45-61) in a group of 67 affected individuals [<a class="bk_pop" href="#vps35-pd.REF.trinh.2018.1857">Trinh et al 2018</a>], and 48 years (IQR: 44-56) in a group of 23 affected individuals [<a class="bk_pop" href="#vps35-pd.REF.vollstedt.2023.286">Vollstedt et al 2023</a>].</p><p><b>Parkinson subtype.</b> The motor manifestations do not differ from <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> Parkinson disease of unknown cause. Affected individuals may manifest tremor dominant, akinetic rigid, gait difficulty, and mixed subtypes [<a class="bk_pop" href="#vps35-pd.REF.dulski.2022.1023574">Dulski et al 2022</a>].</p><p>
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<b>Course of disease</b>
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</p><ul><li class="half_rhythm"><div>Presentation is asymmetric.</div></li><li class="half_rhythm"><div>The disease course is usually milder than that of <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> Parkinson disease of unknown cause.</div></li><li class="half_rhythm"><div>Dyskinesia and motor fluctuations may occur.</div></li><li class="half_rhythm"><div>Atypical signs are very rare. To date, atypical features were observed in only one individual, who developed classic manifestations of Parkinson disease in his early 70s, followed by bulbar symptoms, gait apraxia, falls, supranuclear gaze palsy, apraxia of eyelid opening, and dysexecutive syndrome. However, this individual also had a <i>FBXO7</i> variant, and the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> could have been due to <a class="def" href="/books/n/gene/glossary/def-item/double-heterozygosity/">double heterozygosity</a> for <i>VPS35</i> and <i>FBXO7</i> variants. A cousin of the affected individual also had the <i>VPS35</i> variant and presented with classic late-onset Parkinson disease [<a class="bk_pop" href="#vps35-pd.REF.bartonikova.2016.e5398">Bartonikova et al 2016</a>, <a class="bk_pop" href="#vps35-pd.REF.men__kov_.2019.171">Menšíková et al 2019</a>].</div></li></ul><p>
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<b>Neuropsychiatric manifestations</b>
|
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</p><ul><li class="half_rhythm"><div>Depression was observed in up to 70% of individuals [<a class="bk_pop" href="#vps35-pd.REF.trinh.2018.1857">Trinh et al 2018</a>].</div></li><li class="half_rhythm"><div>Psychotic symptoms occurred in up to 25% of individuals [<a class="bk_pop" href="#vps35-pd.REF.trinh.2018.1857">Trinh et al 2018</a>].</div></li><li class="half_rhythm"><div>Anxiety is rare [<a class="bk_pop" href="#vps35-pd.REF.trinh.2018.1857">Trinh et al 2018</a>].</div></li></ul><p><b>Cognitive issues.</b> Impairment of cognition ranges from mild to dementia and occurs in up to 45% of individuals.</p><p>
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<b>Other findings</b>
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</p><ul><li class="half_rhythm"><div>Impaired sense of smell was reported in most individuals. However, the reported number of affected individuals is small, and further investigation is required [<a class="bk_pop" href="#vps35-pd.REF.zimprich.2011.168">Zimprich et al 2011</a>, <a class="bk_pop" href="#vps35-pd.REF.sheerin.2012.838.e1">Sheerin et al 2012</a>, <a class="bk_pop" href="#vps35-pd.REF.struhal.2014.755">Struhal et al 2014</a>, <a class="bk_pop" href="#vps35-pd.REF.trinh.2018.1857">Trinh et al 2018</a>, <a class="bk_pop" href="#vps35-pd.REF.vollstedt.2023.286">Vollstedt et al 2023</a>].</div></li><li class="half_rhythm"><div>Autonomic manifestations including orthostasis and gastrointestinal symptoms (constipation) affect up to 75% of individuals [<a class="bk_pop" href="#vps35-pd.REF.trinh.2018.1857">Trinh et al 2018</a>].</div></li></ul><p><b>Functional imaging studies</b> show presynaptic dopaminergic dysfunction, which is apparently indistinguishable from findings in other individuals with Parkinson disease.</p><p>Single photon emission computed tomography (SPECT) of cerebral blood flow was normal in one individual [<a class="bk_pop" href="#vps35-pd.REF.ando.2012.1413">Ando et al 2012</a>, <a class="bk_pop" href="#vps35-pd.REF.vollstedt.2023.286">Vollstedt et al 2023</a>].</p><p><sup>18</sup>F-fluorodopa positron emission tomography (PET) showed asymmetrically reduced striatal <sup>18</sup>F-fluorodopa uptake with a posterior predominance [<a class="bk_pop" href="#vps35-pd.REF.wider.2008.465">Wider et al 2008</a>].</p><p>[<sup>123</sup>I]-FP-CIT SPECT showed asymmetric tracer uptake [<a class="bk_pop" href="#vps35-pd.REF.zimprich.2011.168">Zimprich et al 2011</a>].</p><p><b>Transcranial sonography.</b> In one individual with Parkinson disease that started with resting tremor on the left side, transcranial sonography performed after a disease course of about 15 years showed normal echogenicity of the left substantia nigra, whereas the bone window was insufficient to allow visualization on the right side [<a class="bk_pop" href="#vps35-pd.REF.kumar.2012.1360">Kumar et al 2012</a>].</p></div><div id="vps35-pd.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>No <a class="def" href="/books/n/gene/glossary/def-item/genotype-phenotype-correlations/">genotype-phenotype correlations</a> have been identified [<a class="bk_pop" href="#vps35-pd.REF.dulski.2022.1023574">Dulski et al 2022</a>].</p></div><div id="vps35-pd.Penetrance"><h3>Penetrance</h3><p>To date, data is too limited to allow quantification of <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a>.</p></div><div id="vps35-pd.Nomenclature"><h3>Nomenclature</h3><p>Based on the International Parkinson and Movement Disorder Society Task Force for the Nomenclature of Genetic Movement Disorders, the recommended name for Parkinson disease caused by <i>VPS35</i> pathogenic variants is "PARK-<i>VPS35</i>" [<a class="bk_pop" href="#vps35-pd.REF.lange.2022.905">Lange et al 2022</a>].</p><p>"Idiopathic Parkinson disease" and "<a class="def" href="/books/n/gene/glossary/def-item/sporadic/">sporadic</a> Parkinson disease" are terms used in the Parkinson disease medical literature to describe Parkinson disease of unknown cause diagnosed in an individual with a negative family history. Because future advances in the understanding of genetic risk factors are likely to identify genetic causes /risk factors for some Parkinson disease currently considered "<a class="def" href="/books/n/gene/glossary/def-item/idiopathic/">idiopathic</a>" or "sporadic," these terms are generally not used in this <i>GeneReview</i>. Instead, the term "Parkinson disease of unknown cause representing a <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> case" is preferred because "simplex case" refers specifically to an individual with no family history of Parkinson disease without implying presence or absence of a genetic factor or a specific <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a>.</p></div><div id="vps35-pd.Prevalence"><h3>Prevalence</h3><p>PARK-<i>VPS35</i> is exceedingly rare, and to date only 150 affected individuals have been reported worldwide [<a class="bk_pop" href="#vps35-pd.REF.vilari_og_ell.2011.162">Vilariño-Güell et al 2011</a>, <a class="bk_pop" href="#vps35-pd.REF.zimprich.2011.168">Zimprich et al 2011</a>, <a class="bk_pop" href="#vps35-pd.REF.ando.2012.1413">Ando et al 2012</a>, <a class="bk_pop" href="#vps35-pd.REF.kumar.2012.1360">Kumar et al 2012</a>, <a class="bk_pop" href="#vps35-pd.REF.lesage.2012.1449">Lesage et al 2012</a>, <a class="bk_pop" href="#vps35-pd.REF.sharma.2012.721">Sharma et al 2012</a>, <a class="bk_pop" href="#vps35-pd.REF.sheerin.2012.838.e1">Sheerin et al 2012</a>, <a class="bk_pop" href="#vps35-pd.REF.trinh.2018.1857">Trinh et al 2018</a>, <a class="bk_pop" href="#vps35-pd.REF.vollstedt.2023.286">Vollstedt et al 2023</a>].</p><p>The largest study to date included 67 individuals with PARK-<i>VPS35</i>. Of these individuals, 45% were White, 35% were Asian, and 20% were <a class="def" href="/books/n/gene/glossary/def-item/ashkenazi-jewish/">Ashkenazi Jewish</a>; more than half of the affected individuals were from Western Europe [<a class="bk_pop" href="#vps35-pd.REF.trinh.2018.1857">Trinh et al 2018</a>]. In a smaller study that included 26 individuals, all were White, and most were of Western European ancestry [<a class="bk_pop" href="#vps35-pd.REF.vollstedt.2023.286">Vollstedt et al 2023</a>].</p><p>The prevalence of PARK<i>-VPS35</i> among persons with <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> Parkinson disease is less than 1% [<a class="bk_pop" href="#vps35-pd.REF.dulski.2022.1023574">Dulski et al 2022</a>].</p></div></div><div id="vps35-pd.Genetically_Related_Allelic_Dis"><h2 id="_vps35-pd_Genetically_Related_Allelic_Dis_">Genetically Related (Allelic) Disorders</h2><p>A <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> <i>VPS35</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> p.Leu625Pro was reported in an individual with early-onset Alzheimer disease [<a class="bk_pop" href="#vps35-pd.REF.roveletlecrux.2015.1046">Rovelet-Lecrux et al 2015</a>].</p><p>In another study <i>VPS35</i> variant p.Arg499His was identified in two of 1,118 individuals with dementia with Lewy bodies [<a class="bk_pop" href="#vps35-pd.REF.orme.2020.5">Orme et al 2020</a>]. All individuals were of northern European ethnicity. Although the prevalence of p.Arg499His in the general population is less than 0.004% (see <a href="https://gnomad.broadinstitute.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">gnomAD</a>), identification of this variant in individuals with dementia with Lewy bodies was most likely coincidental [<a class="bk_pop" href="#vps35-pd.REF.orme.2020.5">Orme et al 2020</a>].</p></div><div id="vps35-pd.Differential_Diagnosis"><h2 id="_vps35-pd_Differential_Diagnosis_">Differential Diagnosis</h2><p>The differential diagnosis of PARK-<i>VPS35</i> includes other types of hereditary adult-onset Parkinson disease (see <a href="/books/NBK447258/table/vps35-pd.T.genes_associated_with_earlyon/?report=objectonly" target="object" rid-ob="figobvps35pdTgenesassociatedwithearlyon">Table 3a</a>) and <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> Parkinson disease of unknown cause (referred to as <a class="def" href="/books/n/gene/glossary/def-item/sporadic/">sporadic</a> or <a class="def" href="/books/n/gene/glossary/def-item/idiopathic/">idiopathic</a> Parkinson disease in the literature; see <a href="#vps35-pd.Nomenclature">Nomenclature</a>).</p><p>Apart from a younger age at onset and typically slower progression, the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of PARK-<i>VPS35</i> is clinically indistinguishable from that of <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> Parkinson disease of unknown cause (average onset is age 60 years). Thus, the differential diagnosis of PARK-<i>VPS35</i> is the same as it is for Parkinson disease in general (see <a href="/books/n/gene/parkinson-overview/">Parkinson Disease Overview</a>). In addition, an extensive list of differential diagnoses of <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> parkinsonism can be found in <a class="bk_pop" href="#vps35-pd.REF.dulski.2022.1023574">Dulski et al [2022]</a> and Dulski et al [unpublished data].</p><div id="vps35-pd.T.genes_associated_with_earlyon" class="table"><h3><span class="label">Table 3a. </span></h3><div class="caption"><p>Genes Associated with Early-Onset Adult Parkinson Disease (Age 20-50 Years) and Late-Onset Adult Parkinson Disease (Age >50 Years)</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK447258/table/vps35-pd.T.genes_associated_with_earlyon/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vps35-pd.T.genes_associated_with_earlyon_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vps35-pd.T.genes_associated_with_earlyon_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_vps35-pd.T.genes_associated_with_earlyon_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PD Designation <sup>2</sup></th><th id="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of Adult PD</th><th id="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comments</th></tr></thead><tbody><tr><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>GBA1</i> (<i>GBA</i>) <sup>3</sup></td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PARK-<i>GBA</i> (OMIM <a href="https://omim.org/entry/606463" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">606463</a>)</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3%-7%<br />(20% in AJ ancestry)</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Onset age may be <50 yrs.</div></li><li class="half_rhythm"><div>Higher likelihood of cognitive impairment & atypical motor findings</div></li><li class="half_rhythm"><div>Faster progression</div></li><li class="half_rhythm"><div>Assoc w/dementia w/Lewy bodies</div></li><li class="half_rhythm"><div>Variable <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> dependent on age, variant, & ethnicity</div></li><li class="half_rhythm"><div>Consider if family history of <a href="/books/n/gene/gaucher/">Gaucher disease.</a></div></li></ul>
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</td></tr><tr><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>LRRK2</i>
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</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PARK-<i>LRRK2</i><br />(See <a href="/books/n/gene/lrrk2/"><i>LRRK2</i> PD</a>.)</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1%-2%<br />(13%-30% in AJ ancestry; 41% in African Berber ancestry)</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Classic manifestations w/less non-motor involvement</div></li><li class="half_rhythm"><div>Variable <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> dependent on age, variant, & ethnicity</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>PARK7</i><br />(<i>DJ1</i>)</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PARK-<i>DJ1</i> (OMIM <a href="https://omim.org/entry/606324" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">606324</a>)</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Phenotype similar to PARK-<i>Parkin</i></div></li><li class="half_rhythm"><div>ID &/or seizures occasionally</div></li><li class="half_rhythm"><div>Risk to heterozygotes unknown</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>PINK1</i>
|
||
</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PARK-<i>PINK1</i><br />(See <a href="/books/n/gene/pink1-pd/"><i>PINK1</i> Type of Young-Onset PD</a>.)</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare<br />(3.7% of early-onset adult PD)</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Phenotype similar to PARK-<i>Parkin</i></div></li><li class="half_rhythm"><div>Non-motor manifestations (incl psychiatric features) more common</div></li><li class="half_rhythm"><div>Heterozygotes may have ↑ PD risk.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>PRKN</i>
|
||
</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PARK-<i>Parkin</i><br />(See <a href="/books/n/gene/jpd/">Parkin Type of Early-Onset PD</a>.)</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1%<br />(4.6%-10.5% of early-onset adult PD)</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Slow progression</div></li><li class="half_rhythm"><div>Can have lower-limb dystonia, dyskinesias, hyperreflexia</div></li><li class="half_rhythm"><div>Mild non-motor manifestations</div></li><li class="half_rhythm"><div>Heterozygotes may have ↑ PD risk.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SNCA</i>
|
||
</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PARK-<i>SNCA</i> (OMIM <a href="https://omim.org/entry/168601" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">168601</a>, <a href="https://omim.org/entry/605543" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">605543</a>)</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Onset age may be <50 yrs.</div></li><li class="half_rhythm"><div>Cognitive & psychiatric features more likely</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>VPS13C</i>
|
||
</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PARK-<i>VPS13C</i> (OMIM <a href="https://omim.org/entry/616840" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">616840</a>)</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare</td><td headers="hd_h_vps35-pd.T.genes_associated_with_earlyon_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Early-onset PD w/very rapid progression</div></li><li class="half_rhythm"><div>Truncating variants cause severe disease.</div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Based on <a class="bk_pop" href="#vps35-pd.REF.dulski.2022.1023574">Dulski et al [2022]</a>, Dulski et al [unpublished data]</p></div></dd><dt></dt><dd><div><p class="no_margin">AD = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a>; AJ = <a class="def" href="/books/n/gene/glossary/def-item/ashkenazi-jewish/">Ashkenazi Jewish</a>; AR = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a>; ID = intellectual disability; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; PD = Parkinson disease</p></div></dd><dt>1. </dt><dd><div id="vps35-pd.TF.3a.1"><p class="no_margin">Genes are listed in alphabetic order.</p></div></dd><dt>2. </dt><dd><div id="vps35-pd.TF.3a.2"><p class="no_margin">Nomenclature based on <a class="bk_pop" href="#vps35-pd.REF.lange.2022.905">Lange et al [2022]</a></p></div></dd><dt>3. </dt><dd><div id="vps35-pd.TF.3a.3"><p class="no_margin">There is some disagreement among researchers as to whether <i>GBA1</i> should be classified as a monogenic disorder or, alternatively, a risk factor – due to its low age-related <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> (see <a href="/books/n/gene/parkinson-overview/">Parkinson Disease Overview</a>).</p></div></dd></dl></div></div></div><p><b>Suspected genetic risk factors for Parkinson disease.</b>
|
||
<a href="/books/NBK447258/table/vps35-pd.T.suspected_genetic_risk_factor/?report=objectonly" target="object" rid-ob="figobvps35pdTsuspectedgeneticriskfactor">Table 3b</a> lists genetic loci reported in a small number of individuals. Additional studies are needed to confirm and clarify the role of variants in these genes in Parkinson disease causation.</p><div id="vps35-pd.T.suspected_genetic_risk_factor" class="table"><h3><span class="label">Table 3b. </span></h3><div class="caption"><p>Suspected Genetic Risk Factors for Parkinson Disease</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK447258/table/vps35-pd.T.suspected_genetic_risk_factor/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vps35-pd.T.suspected_genetic_risk_factor_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PD Designation <sup>1</sup></th><th id="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of Adult PD</th><th id="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comments</th></tr></thead><tbody><tr><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>ARSA</i>
|
||
</td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PARK-<i>ARSA</i></td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Very rare</td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Juvenile-, early-, or late-onset PD</div></li><li class="half_rhythm"><div>Tremor-dominant parkinsonism</div></li><li class="half_rhythm"><div>Slow progression</div></li><li class="half_rhythm"><div>Good response to levodopa</div></li><li class="half_rhythm"><div>Mild cognitive impairment</div></li><li class="half_rhythm"><div>Autonomic dysfunction</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>CHCHD2</i>
|
||
</td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PARK-<i>CHCHD2</i></td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Very rare</td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Early or late onset</div></li><li class="half_rhythm"><div>Frequent depression</div></li><li class="half_rhythm"><div>Dementia uncommon</div></li><li class="half_rhythm"><div>Good response to levodopa</div></li><li class="half_rhythm"><div>Persons of Asian descent</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>LRP10</i>
|
||
</td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PARK-<i>LRP10</i></td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Very rare</td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Late-onset PD</div></li><li class="half_rhythm"><div>High prevalence of dementia, which may be a first sign</div></li><li class="half_rhythm"><div>Good response to levodopa</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>PSAP</i>
|
||
</td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PARK-<i>PSAP</i></td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Very rare</td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Early- or late-onset PD</div></li><li class="half_rhythm"><div>Motor fluctuations</div></li><li class="half_rhythm"><div>Dyskinesia</div></li><li class="half_rhythm"><div>Good response to levodopa</div></li><li class="half_rhythm"><div>Persons of Japanese descent</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>RIC3</i>
|
||
</td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PARK-<i>RIC3</i></td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Very rare</td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Early- or late-onset PD</div></li><li class="half_rhythm"><div>Dystonia</div></li><li class="half_rhythm"><div>Restless legs syndrome</div></li><li class="half_rhythm"><div>REM sleep behavior disorder</div></li><li class="half_rhythm"><div>Psychosis</div></li><li class="half_rhythm"><div>Persons of South Indian descent</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>TMEM230</i> <sup>2</sup></td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PARK-<i>TMEM230</i></td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Very rare</td><td headers="hd_h_vps35-pd.T.suspected_genetic_risk_factor_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Late-onset PD</div></li><li class="half_rhythm"><div>Slow progression</div></li><li class="half_rhythm"><div>Good response to levodopa</div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Based on <a class="bk_pop" href="#vps35-pd.REF.dulski.2022.1023574">Dulski et al [2022]</a>, Dulski et al [unpublished data]</p></div></dd><dt>1. </dt><dd><div id="vps35-pd.TF.3b.1"><p class="no_margin">Nomenclature based on <a class="bk_pop" href="#vps35-pd.REF.lange.2022.905">Lange et al [2022]</a></p></div></dd></dl></div></div></div><p>2. In a large family with multiple affected family members, hereditary Parkinson disease was attributed to a variant in <i>DNAJC13</i> [<a class="bk_pop" href="#vps35-pd.REF.vilari_og_ell.2014.1794">Vilariño-Güell et al 2014</a>]. In a subsequent study of the same family, Parkinson disease was reattributed to a variant in <i>TMEM230</i> [<a class="bk_pop" href="#vps35-pd.REF.deng.2016.733">Deng et al 2016</a>] (see OMIM <a href="https://omim.org/entry/616361" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">616361</a>).</p></div><div id="vps35-pd.Management"><h2 id="_vps35-pd_Management_">Management</h2><div id="vps35-pd.Evaluations_Following_Initial_D"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with PARK-<i>VPS35</i>, the evaluations summarized in <a href="/books/NBK447258/table/vps35-pd.T.recommended_evaluations_follo/?report=objectonly" target="object" rid-ob="figobvps35pdTrecommendedevaluationsfollo">Table 4</a> (if not performed as part of the evaluation that led to diagnosis) are recommended.</p><div id="vps35-pd.T.recommended_evaluations_follo" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with <i>VPS35</i>-Related Parkinson Disease</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK447258/table/vps35-pd.T.recommended_evaluations_follo/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vps35-pd.T.recommended_evaluations_follo_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurologic</b>
|
||
</td><td headers="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic eval</td><td headers="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In particular, assessment of movement disorder(s)</td></tr><tr><td headers="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Physical medicine & rehab / PT & OT eval</td><td headers="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl assessment of:
|
||
<ul><li class="half_rhythm"><div>Gross motor & fine motor skills</div></li><li class="half_rhythm"><div>Mobility, ADL, & need for adaptive devices</div></li><li class="half_rhythm"><div>Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Psychiatric</b>
|
||
</td><td headers="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neuropsychiatric eval</td><td headers="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for psychiatric manifestations (e.g., mood disorders, hallucinations, delusions, anxiety, sleep disorders)</td></tr><tr><td headers="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cognition</b>
|
||
</td><td headers="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cognitive assessment</td><td headers="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Autonomic dysfunction</b>
|
||
</td><td headers="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Assess for symptoms of orthostasis & measure supine & standing BP & pulse.</div></li><li class="half_rhythm"><div>Assess for constipation.</div></li></ul>
|
||
</td><td headers="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Genetic counseling</b>
|
||
</td><td headers="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected persons & their families re nature, MOI, & implications of PARK<i>-VPS35</i> to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family support</b>
|
||
<br />
|
||
<b>& resources</b>
|
||
</td><td headers="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess need for:
|
||
<ul><li class="half_rhythm"><div>Community or <a href="#vps35-pd.Resources">online resources</a>;</div></li><li class="half_rhythm"><div>Social work support;</div></li><li class="half_rhythm"><div>Home nursing referral.</div></li></ul>
|
||
</td><td headers="hd_h_vps35-pd.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ADL = activities of daily living; BP = blood pressure; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; OT = occupational therapy; PT = physical therapy; PARK<i>-VPS35</i> = <i>VPS35</i>-related Parkinson disease</p></div></dd><dt>1. </dt><dd><div id="vps35-pd.TF.4.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="vps35-pd.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>To date, the treatment of individuals with PARK-<i>VPS35</i> does not differ from that of <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> Parkinson disease of unknown cause (also referred to as "<a class="def" href="/books/n/gene/glossary/def-item/sporadic/">sporadic</a> Parkinson disease"; see <a href="#vps35-pd.Nomenclature">Nomenclature</a>). The following is a brief summary of recommended treatment for Parkinson disease, based on extensive existing guidelines and recommendations for pharmacotherapy of motor and non-motor manifestations of Parkinson disease as well as neurosurgical interventions for motor findings [<a class="bk_pop" href="#vps35-pd.REF.zesiewicz.2010.924">Zesiewicz et al 2010</a>, <a class="bk_pop" href="#vps35-pd.REF.oertel.a">Oertel et al 2011a</a>, <a class="bk_pop" href="#vps35-pd.REF.oertel.b">Oertel et al 2011b</a>, <a class="bk_pop" href="#vps35-pd.REF.seppi.2011.s42">Seppi et al 2011</a>, <a class="bk_pop" href="#vps35-pd.REF.ferreira.2013.5">Ferreira et al 2013</a>, <a class="bk_pop" href="#vps35-pd.REF.odin.2015.1133">Odin et al 2015</a>, <a class="bk_pop" href="#vps35-pd.REF.trenkwalder.2015.1023">Trenkwalder et al 2015</a>].</p><div id="vps35-pd.T.treatment_of_manifestations_i" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with <i>VPS35</i>-Related Parkinson Disease</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK447258/table/vps35-pd.T.treatment_of_manifestations_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vps35-pd.T.treatment_of_manifestations_i_lrgtbl__"><table><thead><tr><th id="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurologic</b>
|
||
</td><td headers="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Levodopa in combination w/peripheral dopa decarboxylase inhibitor (carbidopa, benserazide):
|
||
<dl class="temp-labeled-list"><dt>1.</dt><dd><p class="no_top_margin">Immediate-release (IR) tablets</p></dd><dt>2.</dt><dd><p class="no_top_margin">Disintegrating tablets</p></dd><dt>3.</dt><dd><p class="no_top_margin">Controlled-release (CR) tablets</p></dd><dt>4.</dt><dd><p class="no_top_margin">Extended-release (ER) capsules</p></dd><dt>5.</dt><dd><p class="no_top_margin">Inhalation powder</p></dd><dt>6.</dt><dd><p class="no_top_margin">Enteral suspension (pump)</p></dd></dl>
|
||
Dopamine agonists
|
||
<dl class="temp-labeled-list"><dt>1.</dt><dd><p class="no_top_margin">IR & CR tablets</p></dd><dt>2.</dt><dd><p class="no_top_margin">Subcutaneous injections & infusion pump (apomorphine)</p></dd><dt>3.</dt><dd><p class="no_top_margin">Transdermal patch (rotigotine)</p></dd></dl>
|
||
Other drugs used in combination w/levodopa & dopamine agonists: inhibitors of catechol-O-methyltransferase or monoamine oxidase-B, anticholinergics, & amantadine.</td><td headers="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>A good levodopa response was seen in nearly all persons w/PARK<i>-VPS35</i>.</div></li><li class="half_rhythm"><div>Since there is low risk of neuropsychiatric symptoms in PARK-<i>VPS35</i>, treatment w/dopamine agonist should be considered.</div></li><li class="half_rhythm"><div>To ↓ or delay side effects (e.g., dyskinesias, hallucinations, impulse control disorder) of levodopa & dopaminergic medication, doses should not exceed levels required for satisfactory clinical response.</div></li><li class="half_rhythm"><div>In younger persons, treatment w/dopamine agonists should be given preference.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>PT &/or OT to improve &/or maintain gross motor & fine motor skills.</div></li><li class="half_rhythm"><div>Speech therapy</div></li></ul>
|
||
</td><td headers="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Dyskinesias</b>
|
||
</td><td headers="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment options:
|
||
<ul><li class="half_rhythm"><div>Reduction of levodopa dose</div></li><li class="half_rhythm"><div>Use of dopamine receptor agonists</div></li><li class="half_rhythm"><div>Deep brain stimulation</div></li><li class="half_rhythm"><div>Continuous application of levodopa or apomorphine</div></li></ul>
|
||
</td><td headers="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Deep brain stimulation & apomorphine pump may be considered for persons who develop motor fluctuations & disabling dyskinesia.</td></tr><tr><td headers="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neuropsychiatric manifestations</b>
|
||
</td><td headers="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Atypical neuroleptic agents such as low-dose clozapine, quetiepine, or pimavanserin & reduction of dopaminergic therapy can ↓ delusions & hallucinations.</div></li><li class="half_rhythm"><div>Standard treatments for depression</div></li></ul>
|
||
</td><td headers="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Dementia</b>
|
||
</td><td headers="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment w/cholinesterase inhibitor (rivastigmine) should be considered.</td><td headers="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Orthostasis</b>
|
||
</td><td headers="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider treatment w/droxidopa, midodrine, fludrocortisone.</td><td headers="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Constipation</b>
|
||
</td><td headers="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Symptomatic treatment</td><td headers="hd_h_vps35-pd.T.treatment_of_manifestations_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div></div></div><div id="vps35-pd.Surveillance"><h3>Surveillance</h3><p>To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in <a href="/books/NBK447258/table/vps35-pd.T.recommended_surveillance_for/?report=objectonly" target="object" rid-ob="figobvps35pdTrecommendedsurveillancefor">Table 6</a> are recommended.</p><div id="vps35-pd.T.recommended_surveillance_for" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with <i>VPS35</i>-Related Parkinson Disease</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK447258/table/vps35-pd.T.recommended_surveillance_for/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vps35-pd.T.recommended_surveillance_for_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vps35-pd.T.recommended_surveillance_for_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_vps35-pd.T.recommended_surveillance_for_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_vps35-pd.T.recommended_surveillance_for_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_vps35-pd.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurologic</b>
|
||
</td><td headers="hd_h_vps35-pd.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic eval to assess motor & non-motor symptoms & treatment effects</td><td headers="hd_h_vps35-pd.T.recommended_surveillance_for_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 6-12 mos or as needed</td></tr><tr><td headers="hd_h_vps35-pd.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Psychiatric</b>
|
||
</td><td headers="hd_h_vps35-pd.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neuropsychiatric eval</td><td headers="hd_h_vps35-pd.T.recommended_surveillance_for_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In those w/mood disorder or psychotic symptoms, or as needed</td></tr><tr><td headers="hd_h_vps35-pd.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cognition</b>
|
||
</td><td headers="hd_h_vps35-pd.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cognitive assessment</td><td headers="hd_h_vps35-pd.T.recommended_surveillance_for_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In those w/cognitive impairments or neuropsychiatric symptoms (psychosis), or as needed</td></tr><tr><td headers="hd_h_vps35-pd.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Autonomic dysfunction</b>
|
||
</td><td headers="hd_h_vps35-pd.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Assess for symptoms of orthostasis & measure supine & standing BP & pulse.</div></li><li class="half_rhythm"><div>Assess for constipation.</div></li></ul>
|
||
</td><td headers="hd_h_vps35-pd.T.recommended_surveillance_for_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_vps35-pd.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cardiac manifestations <sup>1</sup></b>
|
||
</td><td headers="hd_h_vps35-pd.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Echocardiogram to assess for fibrotic heart-valve changes</td><td headers="hd_h_vps35-pd.T.recommended_surveillance_for_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As needed in those treated w/ergot-derived dopaminergic drugs</td></tr><tr><td headers="hd_h_vps35-pd.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family support</b>
|
||
<br />
|
||
<b>& resources</b>
|
||
</td><td headers="hd_h_vps35-pd.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess need for:
|
||
<ul><li class="half_rhythm"><div>Community or <a href="#vps35-pd.Resources">online resources</a>;</div></li><li class="half_rhythm"><div>Social work support;</div></li><li class="half_rhythm"><div>Home nursing referral.</div></li></ul>
|
||
</td><td headers="hd_h_vps35-pd.T.recommended_surveillance_for_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">BP = blood pressure</p></div></dd><dt>1. </dt><dd><div id="vps35-pd.TF.6.1"><p class="no_margin">Caused by ergot-derived dopamine agonists</p></div></dd></dl></div></div></div></div><div id="vps35-pd.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Neuroleptic drugs may increase the severity of parkinsonism in individuals with PARK<i>-VPS35</i> (as in Parkinson disease in general). In general, atypical neuroleptics are less likely to exacerbate parkinsonism than typical neuroleptics; in particular clozapine, quetiapine, or pimavanserin are considered well tolerated and effective in Parkinson disease. Other drugs that may induce or exacerbate parkinsonism include but are not limited to antidepressants, calcium channel blockers, valproate, lithium, and amiodarone [<a class="bk_pop" href="#vps35-pd.REF.bondonguitton.2011.2226">Bondon-Guitton et al 2011</a>, <a class="bk_pop" href="#vps35-pd.REF.bohlega.2013.215">Bohlega & Al-Foghom 2013</a>].</p><p>Ergot-derived dopaminergic drugs should be discontinued if fibrotic heart-valve changes are identified [<a class="bk_pop" href="#vps35-pd.REF.antonini.2007.826">Antonini & Poewe 2007</a>].</p></div><div id="vps35-pd.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#vps35-pd.Related_Genetic_Counseling_Issu">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="vps35-pd.Pregnancy_Management"><h3>Pregnancy Management</h3><p>Reports addressing pregnancy management in women with PARK-<i>VPS35</i> are not available.</p><p>The effect of Parkinson disease of any cause on pregnancy has not been well characterized, since pregnancy is uncommon in women with Parkinson disease. In general, half of affected individuals experience improvement or no change in manifestations during pregnancy, whereas half experience worsening manifestations [<a class="bk_pop" href="#vps35-pd.REF.seier.2017.11">Seier & Hiller 2017</a>]. Monotherapy with levodopa seems to be the best treatment option for pregnant individuals, both in terms of safety and efficacy [<a class="bk_pop" href="#vps35-pd.REF.seier.2017.11">Seier & Hiller 2017</a>].</p><p>No long-term outcome data exist for children born to mothers with Parkinson disease.</p><ul><li class="half_rhythm"><div>Levodopa has not been linked with a higher risk of spontaneous abortions, teratogenicity, or birth complications [<a class="bk_pop" href="#vps35-pd.REF.seier.2017.11">Seier & Hiller 2017</a>].</div></li><li class="half_rhythm"><div>There is insufficient evidence to determine the safety of dopamine agonists, selegiline, and rasagiline in affected individuals during pregnancy [<a class="bk_pop" href="#vps35-pd.REF.seier.2017.11">Seier & Hiller 2017</a>].</div></li><li class="half_rhythm"><div>Anticholinergics were associated with minor birth defects, but no other complications [<a class="bk_pop" href="#vps35-pd.REF.seier.2017.11">Seier & Hiller 2017</a>].</div></li><li class="half_rhythm"><div>Amantadine should be avoided during pregnancy due to teratogenicity [<a class="bk_pop" href="#vps35-pd.REF.seier.2017.11">Seier & Hiller 2017</a>].</div></li></ul><p>Discussion of the risks and benefits of using a given medication during pregnancy should ideally take place prior to conception. See <a href="https://www.mothertobaby.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MotherToBaby</a> for further information on medication use during pregnancy.</p></div><div id="vps35-pd.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 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="vps35-pd.Genetic_Counseling"><h2 id="_vps35-pd_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="vps35-pd.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>VPS35</i>-related Parkinson disease (PARK<i>-VPS35</i>) is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner.</p></div><div id="vps35-pd.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>About 90% of individuals diagnosed with PARK<i>-VPS35</i> have a positive family history of Parkinson disease. Of note, PARK<i>-VPS35</i> manifestations may be variable among affected individuals within the same family.</div></li><li class="half_rhythm"><div>About 10% of individuals with PARK<i>-VPS35</i> represent <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> cases (i.e., a single occurrence in a family). However, the parents of these individuals have not been evaluated sufficiently to determine if the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> occurred <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a><i>;</i> therefore, the proportion of PARK<i>-VPS35</i> caused by a <i>de novo</i> pathogenic variant is unknown.</div></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> appears to be the only affected family member, <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> is recommended for the parents of the proband to evaluate their genetic status and inform <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> assessment.</div></li><li class="half_rhythm"><div>If the <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> is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:</div><ul><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has a <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>The <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> inherited a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> from a parent with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> (or somatic and germline) <a class="def" href="/books/n/gene/glossary/def-item/mosaicism/">mosaicism</a>. Note: Testing of parental leukocyte DNA may not detect all instances of <a class="def" href="/books/n/gene/glossary/def-item/somatic-mosaicism/">somatic mosaicism</a> and will not detect a pathogenic variant that is present in the germ cells only.</div></li></ul></li><li class="half_rhythm"><div>The family history of some individuals diagnosed with PARK<i>-VPS35</i> may appear to be negative because of failure to recognize the disorder in family members, age-related or reduced <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> of the disease in a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> parent, or early death of the parent before the onset of disease manifestations. 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> has demonstrated that neither parent is heterozygous for the <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>.</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 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> has the <i>VPS35</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, the risk to the sibs of inheriting the pathogenic variant is 50%.</div><ul><li class="half_rhythm"><div>To date, data are too limited to allow quantification of <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a>; the likelihood that a sib who inherits a <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> <i>VPS35</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> will develop manifestations of PARK<i>-VPS35</i> is not known.</div></li><li class="half_rhythm"><div>The manifestations of PARK<i>-VPS35</i> may be variable among affected family members with the same <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</div></li></ul></li><li class="half_rhythm"><div>If the <i>VPS35</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, 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="#vps35-pd.REF.rahbari.2016.126">Rahbari et al 2016</a>].</div></li><li class="half_rhythm"><div>If the parents have not been tested for the <i>VPS35</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> but are clinically unaffected, sibs are still presumed to be at increased risk for PARK<i>-VPS35</i> because of the possibility of age-related or reduced <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> in a parent and 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 PARK<i>-VPS35</i> has a 50% chance of inheriting the <i>VPS35</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 genetic status of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents: if a parent has the <i>VPS35</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, the parent's family members may be at risk.</p></div><div id="vps35-pd.Related_Genetic_Counseling_Issu"><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>VPS35</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> has been identified in an affected family member. The utility of predictive testing for a known <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> <i>VPS35</i> pathogenic variant may be of limited clinical use because current data are too limited to allow quantification of <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> (i.e., the likelihood that an asymptomatic individual found to be <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a familial <i>VPS35</i> pathogenic variant will develop PARK<i>-VPS35</i> is not known).</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 found to be <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a>) 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><li class="half_rhythm"><div>Predictive testing may facilitate participation in research to better understand PARK<i>-VPS35</i> and, in the long term, contribute to the discovery of biomarkers and therapy.</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>Note: It is appropriate to consider testing symptomatic individuals regardless of age in a family with an established diagnosis of PARK<i>-VPS35</i>.</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.</div></li></ul></div><div id="vps35-pd.Prenatal_Testing_and_Preimplant"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>VPS35</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> 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="vps35-pd.Resources"><h2 id="_vps35-pd_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>Parkinson’s UK</b>
|
||
</div><div>United Kingdom</div><div><b>Phone:</b> 020 7931 8080</div><div><b>Email:</b> hello@parkinsons.org.uk</div><div>
|
||
<a href="https://www.parkinsons.org.uk/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.parkinsons.org.uk</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>American Parkinson Disease Association (APDA)</b>
|
||
</div><div><b>Phone:</b> 800-223-2732</div><div><b>Email:</b> apda@apdaparkinson.org</div><div>
|
||
<a href="http://www.apdaparkinson.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">apdaparkinson.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Fox Trial Finder</b>
|
||
</div><div>
|
||
<a href="https://www.michaeljfox.org/trial-finder" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">michaeljfox.org/trial-finder</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>MedlinePlus</b>
|
||
</div><div>
|
||
<a href="https://medlineplus.gov/genetics/condition/parkinson-disease/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parkinson disease</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Michael J. Fox Foundation for Parkinson's Research</b>
|
||
</div><div><b>Phone:</b> 212-509-0995</div><div><b>Email:</b> info@michaeljfox.org</div><div>
|
||
<a href="http://www.michaeljfox.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">michaeljfox.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>National Institute of Neurological Disorders and Stroke (NINDS)</b>
|
||
</div><div>
|
||
<a href="https://www.ninds.nih.gov/Disorders/All-Disorders/Parkinsons-Disease-Information-Page" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parkinson's Disease</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Parkinson's Foundation</b>
|
||
</div><div><b>Phone:</b> 800-473-4636</div><div><b>Email:</b> Helpline@Parkinson.org</div><div>
|
||
<a href="http://www.parkinson.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">parkinson.org</a>
|
||
</div></li></ul>
|
||
</div><div id="vps35-pd.Molecular_Genetics"><h2 id="_vps35-pd_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="vps35-pd.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>VPS35-Related Parkinson Disease: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK447258/table/vps35-pd.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vps35-pd.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_vps35-pd.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_vps35-pd.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_vps35-pd.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_vps35-pd.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_vps35-pd.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_vps35-pd.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/55737" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>VPS35</i>
|
||
</a>
|
||
</td><td headers="hd_b_vps35-pd.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=55737" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">16q11<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td><td headers="hd_b_vps35-pd.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/Q96QK1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Vacuolar protein sorting-associated protein 35</a>
|
||
</td><td headers="hd_b_vps35-pd.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=VPS35" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">VPS35</a>
|
||
</td><td headers="hd_b_vps35-pd.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=VPS35[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">VPS35</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="vps35-pd.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="vps35-pd.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for VPS35-Related Parkinson Disease (<a href="/omim/601501,614203" 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/NBK447258/table/vps35-pd.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vps35-pd.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/601501" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">601501</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">VPS35 RETROMER COMPLEX COMPONENT; VPS35</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/614203" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">614203</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PARKINSON DISEASE 17; PARK17</td></tr></tbody></table></div></div><div id="vps35-pd.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>VPS35</i> encodes vacuolar protein sorting-associated protein 35 (VPS35), which is part of the retromer, an evolutionarily conserved complex that associates with the cytosolic face of endosomes. The retromer is involved in the retrograde transport of transmembrane cargo (receptors, including dopamine receptors, transporters, adhesion molecules, and other proteins) from endosomes to the trans-Golgi network and to the plasma membrane; its cargo proteins are either recycled or degraded [<a class="bk_pop" href="#vps35-pd.REF.williams.2022.105768">Williams et al 2022</a>].</p><p>The retromer comprises two assembling subunits: one consists of a trimeric complex of VPS35, VPS26, and VPS29 proteins and is also termed a cargo-selective complex, and the other consists of a sortin nexin dimer (SNX). VPS35 forms a horseshoe-shaped alpha-helical solenoid predicted to contain 33 helices [<a class="bk_pop" href="#vps35-pd.REF.lucas.2016.1623">Lucas et al 2016</a>]. It functions as the central platform for binding to other retromer proteins. VPS35 also mediates the association with the WASH complex, which includes FAM21. FAM21 binds to VPS35 through its extended unstructured "tail" <a class="def" href="/books/n/gene/glossary/def-item/domain/">domain</a>, thereby allowing WASH-dependent retromer-mediated sorting of proteins (reviewed in <a class="bk_pop" href="#vps35-pd.REF.burd.2014.6">Burd & Cullen [2014]</a>).</p><p><i>VPS35</i> pathogenic variants have been shown to:</p><ul><li class="half_rhythm"><div>Increase the activation of the LRRK2 kinase, thus exerting similar effects as <i>LRRK2</i> pathogenic variants [<a class="bk_pop" href="#vps35-pd.REF.mir.2018.1861">Mir et al 2018</a>, <a class="bk_pop" href="#vps35-pd.REF.williams.2022.105768">Williams et al 2022</a>];</div></li><li class="half_rhythm"><div>Affect VPS35 binding to FAM21 of the WASH complex, resulting in impairment of recruitment of the WASH complex to endosomes, retromer-mediated sorting of proteins, and autophagy [<a class="bk_pop" href="#vps35-pd.REF.follett.2014.230">Follett et al 2014</a>, <a class="bk_pop" href="#vps35-pd.REF.mcgough.2014.1670">McGough et al 2014</a>, <a class="bk_pop" href="#vps35-pd.REF.zavodszky.2014a.3828">Zavodszky et al 2014a</a>, <a class="bk_pop" href="#vps35-pd.REF.zavodszky.2014b.2155">Zavodszky et al 2014b</a>, <a class="bk_pop" href="#vps35-pd.REF.williams.2022.105768">Williams et al 2022</a>];</div></li><li class="half_rhythm"><div>Redistribute endosomes to a perinuclear localization [<a class="bk_pop" href="#vps35-pd.REF.follett.2014.230">Follett et al 2014</a>];</div></li><li class="half_rhythm"><div>Enlarge endosomes [<a class="bk_pop" href="#vps35-pd.REF.follett.2014.230">Follett et al 2014</a>];</div></li><li class="half_rhythm"><div>Lead to lysosomal dysfunction through abnormal sorting of cathepsin D [<a class="bk_pop" href="#vps35-pd.REF.follett.2014.230">Follett et al 2014</a>, <a class="bk_pop" href="#vps35-pd.REF.williams.2022.105768">Williams et al 2022</a>];</div></li><li class="half_rhythm"><div>Impair VPS35 interaction with dopamine receptor D1 (DRD1), causing dysregulation of DRD1 trafficking and impairment of DRD1-mediated dopamine signaling [<a class="bk_pop" href="#vps35-pd.REF.wang.2016.22">Wang et al 2016</a>];</div></li><li class="half_rhythm"><div>Damage dopaminergic pathways, including loss of dopaminergic neurons and axonal degeneration [<a class="bk_pop" href="#vps35-pd.REF.williams.2022.105768">Williams et al 2022</a>];</div></li><li class="half_rhythm"><div>Lead to lysosomal dysfunction through abnormal sorting of cathepsin D [<a class="bk_pop" href="#vps35-pd.REF.williams.2022.105768">Williams et al 2022</a>];</div></li><li class="half_rhythm"><div>Cause mitochondrial dysfunction [<a class="bk_pop" href="#vps35-pd.REF.williams.2022.105768">Williams et al 2022</a>];</div></li><li class="half_rhythm"><div>Induce tau pathology and accumulation of total alpha-synuclein in animal models [<a class="bk_pop" href="#vps35-pd.REF.williams.2022.105768">Williams et al 2022</a>].</div></li></ul><p><b>Mechanism of disease causation.</b> Gain of function or partial loss of function; the exact mechanism remains to be elucidated [<a class="bk_pop" href="#vps35-pd.REF.williams.2022.105768">Williams et al 2022</a>].</p><div id="vps35-pd.T.notable_vps35_pathogenic_vari" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Notable <i>VPS35</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK447258/table/vps35-pd.T.notable_vps35_pathogenic_vari/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vps35-pd.T.notable_vps35_pathogenic_vari_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vps35-pd.T.notable_vps35_pathogenic_vari_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_vps35-pd.T.notable_vps35_pathogenic_vari_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_vps35-pd.T.notable_vps35_pathogenic_vari_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_vps35-pd.T.notable_vps35_pathogenic_vari_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_vps35-pd.T.notable_vps35_pathogenic_vari_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_018206.6" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_018206<wbr style="display:inline-block"></wbr>.6</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_060676.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_060676<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td><td headers="hd_h_vps35-pd.T.notable_vps35_pathogenic_vari_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1858G>A</td><td headers="hd_h_vps35-pd.T.notable_vps35_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Asp620Asn</td><td headers="hd_h_vps35-pd.T.notable_vps35_pathogenic_vari_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Common variant found on several haplotypes; suspected mutational <a class="def" href="/books/n/gene/glossary/def-item/hot-spot/">hot spot</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></dl></div></div></div></div></div><div id="vps35-pd.Chapter_Notes"><h2 id="_vps35-pd_Chapter_Notes_">Chapter Notes</h2><div id="vps35-pd.Author_Notes"><h3>Author Notes</h3><p><b>Jaroslaw Dulski, MD, PhD,</b> is Visiting Research Fellow at the Department of Neurology, Mayo Clinic, Florida. He is a board-certified neurologist and an assistant professor at the Medical University of Gdansk and St Adalbert Hospital in Gdansk, Poland. Since the beginning of his professional and scientific career, he has been interested in the genetics of Parkinson disease. In 2020 he received an award from the Chancellor of the Medical University of Gdansk for an outstanding PhD dissertation. In 2021, he received the Joseph Babinski Award from the Polish Neurological Society for the best original publication in the years from 2017-2021. He has received scholarships from the European Academy of Neurology, the Polish National Agency for Academic Exchange, the Polish Neurological Society, the Medical University of Gdansk, and the Haworth Family Professorship in Neurodegenerative Diseases Fund. Email: <a href="mailto:dev@null" data-email="ude.oyam@walsoraj.ikslud" class="oemail">ude.oyam@walsoraj.ikslud</a>; <a href="mailto:dev@null" data-email="lp.ude.demug@ikslud.walsoraj" class="oemail">lp.ude.demug@ikslud.walsoraj</a></p><p><a href="https://www.mayo.edu/research/faculty/ross-owen-a-ph-d/bio-00093014" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri"><b>Owen A Ross, PhD,</b></a> obtained his PhD in the genetics of aging from the University of Ulster and Queens University Belfast in Ireland. In 2010, Dr Ross started his independent lab at the Department of Neuroscience at the Mayo Clinic College of Medicine in Jacksonville, Florida. He now pursues the role of <i>LRRK2</i>, <i>VPS35</i>, and other genes in Parkinson disease. He received an honorable mention for the Moore Award in clinicopathology research for his work on <i>LRRK2</i> variant p.Gly2019Ser with Professor Dennis W Dickson. Dr Ross has published over 350 articles in the fields of aging and neurodegeneration and is presently an associate professor of neuroscience at the Mayo Clinic College of Medicine. He also served on the editorial board of <i>Parkinsonism and Related Disorders</i>, <i>PloS ONE</i>, and <i>American Journal of Neurodegenerative Disease</i>. His research is supported by several active grants from the National Institutes of Health, among other foundations. His primary research interests are in the genetics of neurodegeneration, specifically in Parkinson disease and related movement disorders. Email: <a href="mailto:dev@null" data-email="ude.oyam@newo.ssor" class="oemail">ude.oyam@newo.ssor</a></p><p><a href="https://www.mayo.edu/research/faculty/wszolek-zbigniew-k-m-d/bio-00078164" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri"><b>Zbigniew Wszolek, MD,</b></a> is a consultant in the Department of Neurology at Mayo Clinic in Jacksonville, Florida, and the Haworth Family Professor in Neurodegenerative Diseases. Dr Wszolek has contributed to discoveries related to the genetic basis of Parkinson disease and parkinsonism-related disorders. He has amassed vast clinical information about family pedigrees. Dr Wszolek has published more than 600 journal articles, reviews, editorials, and chapters, and 740 abstracts and letters. He is co-editor-in-chief of the <i>Polish Journal of Neurology and Neurosurgery</i>, and former co-editor-in chief of <i>Parkinsonism and Related Disorders</i>. He is a founding officer of the International Association of Parkinsonism and Related Disorders. Email: <a href="mailto:dev@null" data-email="ude.oyam@weingibz.kelozsw" class="oemail">ude.oyam@weingibz.kelozsw</a></p><p>Dr Zbigniew Wszolek (<a href="mailto:dev@null" data-email="ude.oyam@weingibz.kelozsw" class="oemail">ude.oyam@weingibz.kelozsw</a>) and Dr Jaroslaw Dulski (<a href="mailto:dev@null" data-email="ude.oyam@walsoraj.ikslud" class="oemail">ude.oyam@walsoraj.ikslud</a>) are actively involved in clinical research regarding individuals with PARK-<i>VPS35</i>. They would be happy to communicate with persons who have any questions regarding the diagnosis of PARK-<i>VPS35</i> or other considerations.</p><p>Contact Dr Zbigniew Wszolek (<a href="mailto:dev@null" data-email="ude.oyam@weingibz.kelozsw" class="oemail">ude.oyam@weingibz.kelozsw</a>) to inquire about the review of <i>VPS35</i> variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>.</p></div><div id="vps35-pd.Acknowledgments"><h3>Acknowledgments</h3><p>The authors would like to thank the patients and their families for participating in research and their contributions to the field.</p><p>JD is partially supported by the Polish National Agency for Academic Exchange (BPN/WAL/2022/1/00007/U/00001), and the Haworth Family Professorship in Neurodegenerative Diseases Fund.</p><p>OAR is supported by NIH (RF1 NS085070; U01 NS100620; R01 AG056366; U19 AG071754), DOD (W81XWH-17-1-0249), The Michael J Fox Foundation, American Brain Foundation, and the Mayo Clinic LBD Center without Walls (U54-NS110435). Mayo Clinic is an American Parkinson Disease Association (APDA) Mayo Clinic Information and Referral Center, an APDA Center for Advanced Research, and a Lewy Body Dementia Association (LBDA) Research Center of Excellence.</p><p>ZKW is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, gifts from the Donald G and Jodi P Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases Fund, and The Albertson Parkinson's Research Foundation. He serves as PI or co-PI on Biohaven Pharmaceuticals, Inc (BHV4157-206), Neuraly, Inc (NLY01-PD-1), and Vigil Neuroscience, Inc (VGL101-01.002, VGL101-01.201, PET tracer development protocol, and Csf1r biomarker and repository project) grants. He serves as co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for the Vigil Neuroscience, Inc.</p></div><div id="vps35-pd.Author_History"><h3>Author History</h3><p>Angela Deutschländer, MD; Mayo Clinic (2017-2023)<br />Jaroslaw Dulski, MD, PhD (2023-present)<br />Owen A Ross, PhD (2017-present)<br />Zbigniew K Wszolek, MD (2017-present)</p></div><div id="vps35-pd.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>23 March 2023 (sw) Comprehensive updated posted live</div></li><li class="half_rhythm"><div>10 August 2017 (bp) Review posted live</div></li><li class="half_rhythm"><div>15 December 2016 (ad) Original submission</div></li></ul></div></div><div id="vps35-pd.References"><h2 id="_vps35-pd_References_">References</h2><div id="vps35-pd.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="vps35-pd.REF.ando.2012.1413">Ando
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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/NBK447258/?report=reader">PubReader</a></li><li><a href="/books/NBK447258/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK447258" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK447258" style="display:none" title="Cite this Page"><div class="bk_tt">Dulski J, Ross OA, Wszolek ZK. VPS35-Related Parkinson Disease. 2017 Aug 10 [Updated 2023 Mar 23]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></div></div></li><li><a href="/books/NBK447258/pdf/Bookshelf_NBK447258.pdf">PDF version of this page</a> (571K)</li><li><a href="#" class="toggle-glossary-link" title="Enable/disable links to the glossary">Disable Glossary Links</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this GeneReview</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" 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="#vps35-pd.Summary" ref="log$=inpage&link_id=inpage">Summary</a></li><li><a href="#vps35-pd.Diagnosis" ref="log$=inpage&link_id=inpage">Diagnosis</a></li><li><a href="#vps35-pd.Clinical_Characteristics" ref="log$=inpage&link_id=inpage">Clinical Characteristics</a></li><li><a href="#vps35-pd.Genetically_Related_Allelic_Dis" ref="log$=inpage&link_id=inpage">Genetically Related (Allelic) Disorders</a></li><li><a href="#vps35-pd.Differential_Diagnosis" ref="log$=inpage&link_id=inpage">Differential Diagnosis</a></li><li><a href="#vps35-pd.Management" ref="log$=inpage&link_id=inpage">Management</a></li><li><a href="#vps35-pd.Genetic_Counseling" ref="log$=inpage&link_id=inpage">Genetic Counseling</a></li><li><a href="#vps35-pd.Resources" ref="log$=inpage&link_id=inpage">Resources</a></li><li><a href="#vps35-pd.Molecular_Genetics" ref="log$=inpage&link_id=inpage">Molecular Genetics</a></li><li><a href="#vps35-pd.Chapter_Notes" ref="log$=inpage&link_id=inpage">Chapter Notes</a></li><li><a href="#vps35-pd.References" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Bulk Download</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" 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="https://ftp.ncbi.nlm.nih.gov/pub/litarch/ca/84/" ref="pagearea=source-links&targetsite=external&targetcat=link&targettype=uri">Bulk download GeneReviews data from FTP</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>GeneReviews Links</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" 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/n/gene/advanced/"><i>GeneReviews</i> Advanced Search</a></li><li><a href="/books/n/gene/glossary/"><i>GeneReviews</i> Glossary</a></li><li><a href="/books/n/gene/resource_mats/">Resource Materials</a> <span class="bk_hlight1">NEW FEATURE</span></li><li><a href="/books/n/gene/updates/">New in <i>GeneReviews</i></a></li><li><a href="/books/n/gene/authors/">Author List</a></li><li><a href="/books/n/gene/prospective_authors/">For Current/Prospective Authors</a></li><li><a href="/books/n/gene/GRpersonnel/"><i>GeneReviews</i> Personnel</a></li><li><a href="/books/n/gene/howto_linkin/">Download/Link to <i>GeneReviews</i></a></li><li><a href="/books/n/gene/contact_us/">Contact Us</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Tests in GTR by Gene</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" 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>
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<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=55737[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">VPS35</a>
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</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=omim&DbFrom=books&Cmd=Link&LinkName=books_omim&IdsFromResult=4433752" ref="log$=recordlinks">OMIM</a><div class="brieflinkpop offscreen_noflow">Related OMIM records</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=4433752" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=4433752" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=gene&DbFrom=books&Cmd=Link&LinkName=books_gene&IdsFromResult=4433752" ref="log$=recordlinks">Gene</a><div class="brieflinkpop offscreen_noflow">Locus Links</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301792" ref="ordinalpos=1&linkpos=1&log$=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> PINK1 Type of Young-Onset Parkinson Disease.</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> PINK1 Type of Young-Onset Parkinson Disease.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Lange LM, Klein C. </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/20301668" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Hemophilia B.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Hemophilia B.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Konkle BA, Nakaya Fletcher S. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/33983693" ref="ordinalpos=1&linkpos=3&log$=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> DNAJC6 Parkinson Disease.</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> DNAJC6 Parkinson Disease.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Kurian MA, Abela 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/20301510" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> FBN1-Related Marfan Syndrome.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> FBN1-Related Marfan Syndrome.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Dietz H. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/23409300" ref="ordinalpos=1&linkpos=5&log$=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> Variegate Porphyria.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" 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