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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="Spinocerebellar Ataxia with Axonal Neuropathy Type 1" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2022/06/30" /><meta name="citation_author" content="Mustafa AM Salih" /><meta name="citation_author" content="Hiroshi Takashima" /><meta name="citation_author" content="Cornelius F Boerkoel" /><meta name="citation_pmid" content="20301284" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1105/" /><meta name="citation_keywords" content="SCAN1, TDP1-Related Spinocerebellar Ataxia with Axonal Neuropathy" /><meta name="citation_keywords" content="SCAN1" /><meta name="citation_keywords" content="TDP1-Related Spinocerebellar Ataxia with Axonal Neuropathy" /><meta name="citation_keywords" content="Tyrosyl-DNA phosphodiesterase 1" /><meta name="citation_keywords" content="TDP1" /><meta name="citation_keywords" content="Spinocerebellar Ataxia with Axonal Neuropathy Type 1" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Spinocerebellar Ataxia with Axonal Neuropathy Type 1" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Mustafa AM Salih" /><meta name="DC.Contributor" content="Hiroshi Takashima" /><meta name="DC.Contributor" content="Cornelius F Boerkoel" /><meta name="DC.Date" content="2022/06/30" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK1105/" /><meta name="description" content="Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1) is characterized by late-childhood-onset slowly progressive cerebellar ataxia and distal sensorimotor axonal neuropathy. Gaze nystagmus and dysarthria usually develop after the onset of ataxic gait. As the disease advances, pain and touch sensation in the hands and feet become impaired; vibration sense is lost in hands and lower thighs. Individuals with advanced disease develop a steppage gait and pes cavus and eventually become wheelchair dependent. Cognitive dysfunction – present in some – manifests as mild intellectual disability and poor executive function. To date only seven affected individuals have been described from three apparently unrelated consanguineous families (one from Saudi Arabia and two from Oman); therefore, it is likely that the full phenotypic spectrum of this disorder is not yet known." /><meta name="og:title" content="Spinocerebellar Ataxia with Axonal Neuropathy Type 1" /><meta name="og:type" content="book" /><meta name="og:description" content="Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1) is characterized by late-childhood-onset slowly progressive cerebellar ataxia and distal sensorimotor axonal neuropathy. Gaze nystagmus and dysarthria usually develop after the onset of ataxic gait. As the disease advances, pain and touch sensation in the hands and feet become impaired; vibration sense is lost in hands and lower thighs. Individuals with advanced disease develop a steppage gait and pes cavus and eventually become wheelchair dependent. Cognitive dysfunction – present in some – manifests as mild intellectual disability and poor executive function. 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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="#__NBK1105_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK1105_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/sca38/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/spondylocostal-d/" 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="_NBK1105_"><span class="title" itemprop="name">Spinocerebellar Ataxia with Axonal Neuropathy Type 1</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonym: SCAN1, <i>TDP1</i>-Related Spinocerebellar Ataxia with Axonal Neuropathy</div><p class="contrib-group"><span itemprop="author">Mustafa AM Salih</span>, MD, Dr Med Sci, FRCPCH, <span itemprop="author">Hiroshi Takashima</span>, MD, PhD, and <span itemprop="author">Cornelius F Boerkoel</span>, MD, PhD.</p><a data-jig="ncbitoggler" href="#__NBK1105_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK1105_ai__"><div class="contrib half_rhythm"><span itemprop="author">Mustafa AM Salih</span>, MD, Dr Med Sci, FRCPCH<div class="affiliation small">Division of Pediatric Neurology<br />College of Medicine<br />King Saud University<br />Riyadh, Saudi Arabia<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="moc.oohay@50hilas_afatsum" class="oemail">moc.oohay@50hilas_afatsum</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Hiroshi Takashima</span>, MD, PhD<div class="affiliation small">Department of Neurology and Geriatrics<br />Kagoshima University Graduate School of Medical and Dental Sciences<br />Kagoshima, Japan<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="pj.ca.u-amihsogak.mfuk.3m@ihsoriht" class="oemail">pj.ca.u-amihsogak.mfuk.3m@ihsoriht</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Cornelius F Boerkoel</span>, MD, PhD<div class="affiliation small">Provincial Medical Genetics Program<br />Child and Family Research Institute<br />Department of Medical Genetics<br />University of British Columbia<br />Vancouver, Canada<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ac.cbu.egnahcretni@leokreob" class="oemail">ac.cbu.egnahcretni@leokreob</a><span style="unicode-bidi: bidi-override; direction: ltr;">; </span><a href="mailto:dev@null" data-email="ac.cbu@leokreob.suilenroc" class="oemail">ac.cbu@leokreob.suilenroc</a><div></div></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">October 22, 2007</span>; Last Update: <span itemprop="dateModified">June 30, 2022</span>.</p><p><em>Estimated reading time: 15 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="scan1.Summary" itemprop="description"><h2 id="_scan1_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1) is characterized by late-childhood-onset slowly progressive cerebellar ataxia and distal sensorimotor axonal neuropathy. Gaze nystagmus and dysarthria usually develop after the onset of ataxic gait. As the disease advances, pain and touch sensation in the hands and feet become impaired; vibration sense is lost in hands and lower thighs. Individuals with advanced disease develop a steppage gait and pes cavus and eventually become wheelchair dependent. Cognitive dysfunction – present in some – manifests as mild intellectual disability and poor executive function. To date only seven affected individuals have been described from three apparently unrelated <a class="def" href="/books/n/gene/glossary/def-item/consanguineous/">consanguineous</a> families (one from Saudi Arabia and two from Oman); therefore, it is likely that the full phenotypic spectrum of this disorder is not yet known.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of SCAN1 is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with suggestive findings and <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variants in <i>TDP1</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations</i>: Supportive care provided by specialists in neurology, rehabilitation medicine, occupational therapy, physical therapy, speech-language pathology, and clinical genetics.</p><p><i>Surveillance</i>: Routine follow up as determined by treating specialists to monitor the response to supportive care and to assess for changes in existing manifestations and/or emergence of new manifestations.</p><p><i>Agents/circumstances to avoid</i>: Because <i>TDP1</i> codes for a DNA repair enzyme, genotoxic anti-cancer drugs such as camptothecins (e.g., irinotecan and topotecan) and bleomycin are likely to be extremely harmful and possibly fatal; exposure to radiation is also likely to be extremely harmful and possibly fatal.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>SCAN1 is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner. If both parents are known to be <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a <i>TDP1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, and a 25% chance of inheriting neither of the <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> pathogenic variants. Once the <i>TDP1</i> pathogenic variants have been identified in an affected family member, <a class="def" href="/books/n/gene/glossary/def-item/carrier-testing/">carrier testing</a> for at-risk relatives and 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="scan1.Diagnosis"><h2 id="_scan1_Diagnosis_">Diagnosis</h2><p>No consensus clinical diagnostic criteria for spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1) have been published.</p><div id="scan1.Suggestive_Findings"><h3>Suggestive Findings</h3><p>SCAN1 is suspected in individuals with the following clinical findings, electrophysiologic studies, laboratory findings, brain imaging, and family history [<a class="bk_pop" href="#scan1.REF.takashima.2002.267">Takashima et al 2002</a>, <a class="bk_pop" href="#scan1.REF.scott.2019.139">Scott et al 2019</a>].</p><p>
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<b>Clinical findings</b>
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</p><ul><li class="half_rhythm"><div>Slowly progressive disorder beginning in late childhood to early adulthood (ages 13-27 years)</div></li><li class="half_rhythm"><div>Cerebellar ataxia manifesting initially as gait ataxia and subsequently as dysarthria</div></li><li class="half_rhythm"><div>Distal sensorimotor neuropathy manifesting initially as areflexia and subsequently as weakness and loss of sensation</div></li><li class="half_rhythm"><div>Cognitive dysfunction in some, manifesting as mild intellectual disability and poor executive function</div></li><li class="half_rhythm"><div>Absence of:</div><ul><li class="half_rhythm"><div>Oculomotor apraxia</div></li><li class="half_rhythm"><div>Extraneurologic findings</div></li></ul></li></ul><p><b>Nerve conduction studies / electromyogram findings</b> are consistent with distal axonal neuropathy.</p><p><b>Laboratory findings.</b> Mildly decreased serum albumin, hypercholesterolemia, and elevated serum alpha fetoprotein support the diagnosis of SCAN1.</p><p><b>Brain MRI</b> shows cerebellar atrophy especially of the vermis.</p><p><b>Family history</b> is consistent with <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> inheritance (e.g., affected sibs and/or parental <a class="def" href="/books/n/gene/glossary/def-item/consanguinity/">consanguinity</a>). Absence of a known family history does not preclude the diagnosis.</p></div><div id="scan1.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of SCAN1 <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with suggestive findings and <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variants in <i>TDP1</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK1105/table/scan1.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobscan1Tmoleculargenetictestingusedi">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="#scan1.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include likely pathogenic variants. (2) Identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>TDP1</i> variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> (or identification of one known <i>TDP1</i> pathogenic variant and one <i>TDP1</i> variant of uncertain significance) does not establish or rule out the diagnosis.</p><p>Because the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of SCAN1 is indistinguishable from many other inherited disorders with ataxia, recommended <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> approaches include use of a <b><a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> or <b>comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b>.</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>An ataxia</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes <i>TDP1</i> and other genes of interest (see <a href="#scan1.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> and pathogenic variants in genes that do not explain the underlying <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>. Note: (1) The genes included in the panel and the diagnostic <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> of the testing used for each <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused <a class="def" href="/books/n/gene/glossary/def-item/exome/">exome</a> analysis that includes genes specified by the clinician. (4) Methods used in a panel may include <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>, <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>, and/or other non-sequencing-based tests.</div><div class="half_rhythm">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>.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> does not require the clinician to determine which genes are 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.</div><div class="half_rhythm">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>.</div></li></ul><div id="scan1.T.molecular_genetic_testing_used_i" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Spinocerebellar Ataxia with Axonal Neuropathy Type 1</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1105/table/scan1.T.molecular_genetic_testing_used_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__scan1.T.molecular_genetic_testing_used_i_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_scan1.T.molecular_genetic_testing_used_i_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_scan1.T.molecular_genetic_testing_used_i_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_scan1.T.molecular_genetic_testing_used_i_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Identified by Method</th></tr></thead><tbody><tr><td headers="hd_h_scan1.T.molecular_genetic_testing_used_i_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>TDP1</i>
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</td><td headers="hd_h_scan1.T.molecular_genetic_testing_used_i_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_scan1.T.molecular_genetic_testing_used_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">All variants reported to date <sup>4</sup></td></tr><tr><td headers="hd_h_scan1.T.molecular_genetic_testing_used_i_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_scan1.T.molecular_genetic_testing_used_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None reported to date <sup>4</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="scan1.TF.1.1"><p class="no_margin">See <a href="/books/NBK1105/#scan1.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="scan1.TF.1.2"><p class="no_margin">See <a href="#scan1.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="scan1.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, <a class="def" href="/books/n/gene/glossary/def-item/likely-benign/">likely benign</a>, of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>, or pathogenic. Variants may include <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 and small intragenic deletions/insertions; 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="scan1.TF.1.4"><p class="no_margin"><a class="bk_pop" href="#scan1.REF.takashima.2002.267">Takashima et al [2002]</a>, <a class="bk_pop" href="#scan1.REF.scott.2019.139">Scott et al [2019]</a>, and data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bk_pop" href="#scan1.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd><dt>5. </dt><dd><div id="scan1.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 id="scan1.Clinical_Characteristics"><h2 id="_scan1_Clinical_Characteristics_">Clinical Characteristics</h2><div id="scan1.Clinical_Description"><h3>Clinical Description</h3><p>Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1) is characterized by progressive ataxia, cerebellar atrophy, and distal sensorimotor axonal neuropathy based on findings in three persons in a <a class="def" href="/books/n/gene/glossary/def-item/consanguineous/">consanguineous</a> family from Saudi Arabia [<a class="bk_pop" href="#scan1.REF.takashima.2002.267">Takashima et al 2002</a>] and four affected individuals from two apparently unrelated consanguineous families from Oman [<a class="bk_pop" href="#scan1.REF.scott.2019.139">Scott et al 2019</a>]. The following description of the phenotypic features associated with this condition is based on these two reports.</p><p><b>Cerebellar ataxia.</b> Ataxic gait appears in the second decade of life between ages 13 and 15 years. The ataxia progresses slowly, initially manifesting as mild incoordination of the upper limbs and lower limbs and then progressing to inability to walk.</p><p>Horizontal gaze-evoked nystagmus and mild dysarthria usually develop after the onset of ataxic gait.</p><p><b>Neuropathy.</b> Weakness initially develops in the hands and feet with preserved strength of the more proximal upper and lower leg muscles. Progression of the weakness is accompanied by atrophy of the muscles of the fingers and feet, fasciculations, and mild weakness.</p><p>Deep tendon reflexes are lost in the third decade of life.</p><p>Sensory function is initially preserved. As the disease advances, pain, cold, and touch sensations become severely impaired in the hands and lower thigh. Vibration sense disappears in the hands and legs.</p><p>In the advanced stages of the disease, affected persons develop a steppage gait and pes cavus.</p><p>Dysphagia develops with progression of the cerebellar ataxia.</p><p><b>Cognitive function.</b> Mildly impaired intellectual capacity has been observed [<a class="bk_pop" href="#scan1.REF.scott.2019.139">Scott et al 2019</a>].</p><p><b>Other.</b> One individual developed adult-onset epilepsy (grand mal) [<a class="bk_pop" href="#scan1.REF.takashima.2002.267">Takashima et al 2002</a>].</p></div><div id="scan1.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> are known as the data available are too limited [<a class="bk_pop" href="#scan1.REF.takashima.2002.267">Takashima et al 2002</a>, <a class="bk_pop" href="#scan1.REF.scott.2019.139">Scott et al 2019</a>].</p></div><div id="scan1.Nomenclature"><h3>Nomenclature</h3><p>SCAN1 may also be referred to as "<i>TDP1</i>-related spinocerebellar ataxia with axonal neuropathy" based on the dyadic naming approach proposed by <a class="bk_pop" href="#scan1.REF.biesecker.2021.8">Biesecker et al [2021]</a> to delineate mendelian genetic disorders.</p></div><div id="scan1.Prevalence"><h3>Prevalence</h3><p>Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1) is very rare.</p><p>To date, one extended family from Saudi Arabia with nine affected individuals [<a class="bk_pop" href="#scan1.REF.takashima.2002.267">Takashima et al 2002</a>] and two apparently unrelated families from Oman [<a class="bk_pop" href="#scan1.REF.scott.2019.139">Scott et al 2019</a>] have been reported with the same variant, <a href="/books/NBK1105/table/scan1.T.notable_tdp1_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobscan1Tnotabletdp1pathogenicvariants">c.1478A>G; p.His493Arg</a>. A shared <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> haplotype identified in the probands from the Omani families suggests a founder haplotype [<a class="bk_pop" href="#scan1.REF.scott.2019.139">Scott et al 2019</a>]. Although haplotype studies were not performed on the Saudi Arabian family, it may share ancestral origin with the Omani individuals.</p></div></div><div id="scan1.Genetically_Related_Allelic_Disord"><h2 id="_scan1_Genetically_Related_Allelic_Disord_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> pathogenic variants in <i>TDP1</i>.</p></div><div id="scan1.Differential_Diagnosis"><h2 id="_scan1_Differential_Diagnosis_">Differential Diagnosis</h2><div id="scan1.T.genes_of_interest_in_the_differe" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Genes of Interest in the Differential Diagnosis of Spinocerebellar Ataxia with Axonal Neuropathy Type 1</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1105/table/scan1.T.genes_of_interest_in_the_differe/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__scan1.T.genes_of_interest_in_the_differe_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Phenotype</th></tr></thead><tbody><tr><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ABHD12</i>
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</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Polyneuropathy, hearing loss, ataxia, RP, & cataract (OMIM <a href="https://omim.org/entry/612674" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">612674</a>)</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pes cavus; Achilles tendon contractures; RP; ataxic &/or spastic gait; progressive sensorimotor peripheral neuropathy</td></tr><tr><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>APTX</i>
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</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ataxia w/oculomotor apraxia type 1 (AOA1) (OMIM <a href="https://omim.org/entry/208920" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">208920</a>)</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Early-onset cerebellar ataxia; axonal neuropathy; oculomotor apraxia; chorea or dystonia; ↓ serum concentration of albumin & ↑ total cholesterol. AOA1 can be distinguished from SCAN1 by presence of oculomotor apraxia (80% of persons w/AOA1), but this sign is not obvious in the early stages of disease.</td></tr><tr><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>ATM</i>
|
||
</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/ataxia-telangiectas/">Ataxia-telangiectasia</a>
|
||
</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Telangiectasia; ataxia; cerebellar degeneration</td></tr><tr><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>COA7</i>
|
||
</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Spinocerebellar ataxia w/axonal neuropathy 3 (OMIM <a href="https://omim.org/entry/618387" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">618387</a>)</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Childhood onset; axonal motor & sensory neuropathy; cerebellar ataxia cerebellum atrophy on MRI. Clinically similar to SCAN1.</td></tr><tr><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>CYP27A1</i>
|
||
</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/ctx/">Cerebrotendinous xanthomatosis</a>
|
||
</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Symmetric distal sensory loss & weakness; cerebellar ataxia; upper motor signs; enlarged tendons</td></tr><tr><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>ERCC4</i>
|
||
</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>ERCC4</i>-related <a href="/books/n/gene/xp/">xeroderma pigmentosum</a></td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Freckle-like lesions, xerosis, & poikiloderma on sun-exposed skin; ocular abnormalities; in 25% of affected persons, progressive neurologic abnormalities</td></tr><tr><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>ERCC6</i>
|
||
</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>ERCC6</i>-related <a href="/books/n/gene/cockayne/">Cockayne syndrome</a></td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ID; demyelinating neuropathy; retinopathy; <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> cataracts; joint contractures; prominent nasal bridge; sensorineural hearing loss; severe motor dysfunction</td></tr><tr><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>FXN</i>
|
||
</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/friedreich/">Friedreich ataxia</a> (FRDA)</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Slowly progressive ataxia; depressed tendon reflexes; dysarthria; muscle weakness; lower-limb spasticity; optic nerve atrophy; scoliosis; bladder dysfunction; loss of position & vibration senses; onset age usually <25 yrs</td></tr><tr><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>MRE11</i>
|
||
</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ataxia-telangiectasia-like disorder (OMIM <a href="https://omim.org/entry/604391" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">604391</a>)</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Similar to ataxia-telangiectasia; cerebellar degeneration; normal intellect</td></tr><tr><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>PHYH</i>
|
||
</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>PHYH</i>-related <a href="/books/n/gene/refsum/">Refsum disease</a></td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Childhood to adult onset; night blindness; demyelinating neuropathy; anosmia; ataxia; RP</td></tr><tr><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>PNKP</i>
|
||
</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ataxia w/oculomotor apraxia type 4 (OMIM <a href="https://omim.org/entry/616267" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">616267</a>)</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Childhood onset; dystonia; ataxia; oculomotor apraxia; cognitive impairment</td></tr><tr><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>POLG</i>
|
||
</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>POLG</i>-related ataxia neuropathy spectrum <sup>1</sup> (See <a href="/books/n/gene/alpers/"><i>POLG</i>-Related Disorders</a>.)</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adolescent to adult onset; sensory loss; ataxia; ophthalmoplegia</td></tr><tr><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SACS</i>
|
||
</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/arsacs/">ARSACS</a>
|
||
</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neuropathy; ataxia; spasticity; ID; prominent myelinated nerve fibers</td></tr><tr><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SETX</i>
|
||
</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/aoa2/">Ataxia w/oculomotor apraxia type 2</a> (AOA2)</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Early-onset cerebellar ataxia; axonal neuropathy; oculomotor apraxia; chorea or dystonia; ↑ serum alpha-fetoprotein (AFP) level</td></tr><tr><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SLC52A2</i>
|
||
</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>SLC52A2</i>-related <a href="/books/n/gene/riboflavin-tn/">riboflavin transporter deficiency</a></td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Progressive bulbar palsy; childhood-onset sensorineural deafness; childhood-onset neuronopathy that is more prominent as upper than lower extremity weakness; tongue fasciculations & weakness; respiratory failure; optic atrophy; ↓ visual acuity</td></tr><tr><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>TTPA</i>
|
||
</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/aved/">Ataxia w/vitamin E deficiency</a> (AVED)</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_scan1.T.genes_of_interest_in_the_differe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cerebellar ataxia; loss of proprioception; areflexia; markedly ↓ plasma vitamin E (alpha-tocopherol) levels. AVED can be treated by vitamin E supplementation.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Adapted from <a class="bk_pop" href="#scan1.REF.scott.2019.139">Scott et al [2019]</a></p></div></dd><dt></dt><dd><div><p class="no_margin">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>; RP = retinitis pigmentosa; SCAN1 = spinocerebellar ataxia with axonal neuropathy type 1</p></div></dd><dt>1. </dt><dd><div id="scan1.TF.2.1"><p class="no_margin">The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO).</p></div></dd></dl></div></div></div></div><div id="scan1.Management"><h2 id="_scan1_Management_">Management</h2><p>No clinical practice guidelines for spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1) have been published.</p><div id="scan1.Evaluations_Following_Initial_Diag"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with SCAN1, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:</p><ul><li class="half_rhythm"><div>Complete neurologic examination including use of the Scale for the Assessment and Rating of Ataxia (SARA) and assessment of muscle strength, reflexes, and sensation</div></li><li class="half_rhythm"><div>Assessment by specialists in rehabilitation medicine, occupational therapy, and physical therapy regarding gross motor skills, fine motor skills, and need for adaptive equipment such as prostheses, walking aids, and/or wheelchairs</div></li><li class="half_rhythm"><div>Assessment by a speech-language pathologist for evidence of dysarthria and need for ongoing speech-language therapy</div></li><li class="half_rhythm"><div>Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>, and implications of SCAN1 in order to facilitate medical and personal decision making</div></li></ul><p>To support the family of an individual diagnosed with SCAN1, review of the following options is recommended:</p><ul><li class="half_rhythm"><div>Use of community or online resources (e.g., <a href="https://www.p2pusa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parent to Parent</a>)</div></li><li class="half_rhythm"><div>Social work involvement for parental support</div></li><li class="half_rhythm"><div>Home nursing referral (if needed)</div></li><li class="half_rhythm"><div>Ethics consultation (clinical ethics services) to assess health care decisions in the context of the best interest of the child and the values and preferences of the family</div></li></ul></div><div id="scan1.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>There is no cure for SCAN1.</p><p>Supportive care is provided by specialists in neurology, rehabilitation medicine, occupational therapy, physical therapy, speech-language pathology, and clinical genetics.</p><p>Physical therapy may be helpful in maintaining a more active lifestyle.</p></div><div id="scan1.Surveillance"><h3>Surveillance</h3><p>Routine follow up as determined by treating specialists is recommended to monitor the response to supportive care and to assess for changes in existing manifestations and/or emergence of new manifestations.</p></div><div id="scan1.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Likely to be extremely harmful and possibly fatal:</p><ul><li class="half_rhythm"><div>Exposure to genotoxic anti-cancer drugs such as camptothecins (e.g., irinotecan and topotecan) and bleomycin [<a class="bk_pop" href="#scan1.REF.hirano.2007.4732">Hirano et al 2007</a>]</div></li><li class="half_rhythm"><div>Exposure to radiation [<a class="bk_pop" href="#scan1.REF.elkhamisy.2007.1485">El-Khamisy et al 2007</a>]</div></li></ul></div><div id="scan1.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#scan1.Related_Genetic_Counseling_Issues">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="scan1.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="scan1.Genetic_Counseling"><h2 id="_scan1_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="scan1.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1) is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner.</p></div><div id="scan1.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>The parents of an affected child are presumed to be <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a <i>TDP1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</div></li><li class="half_rhythm"><div>Molecular genetic testing is recommended for the parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> to confirm that both parents are <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a <i>TDP1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> and to allow reliable <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> assessment.</div></li><li class="half_rhythm"><div>If a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> occurred as a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> event in the proband or as a <a class="def" href="/books/n/gene/glossary/def-item/postzygotic/">postzygotic</a> <i>de novo</i> event in a mosaic parent [<a class="bk_pop" href="#scan1.REF.j_nsson.2017.519">Jónsson et al 2017</a>]. If the proband appears to have <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:</div><ul><li class="half_rhythm"><div>A single- or multiexon <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> that was not detected by <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> and that resulted in the artifactual appearance of homozygosity;</div></li><li class="half_rhythm"><div>Uniparental isodisomy for the parental <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> with the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> that resulted in homozygosity for the pathogenic variant in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</div></li></ul></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p>
|
||
<b>Sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>If both parents are known to be <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a <i>TDP1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, and a 25% chance of inheriting neither of the <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> pathogenic variants.</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p>
|
||
<b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>Unless an affected individual's reproductive partner also has SCAN1 or is a <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, offspring will be obligate heterozygotes (carriers) for a <i>TDP1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</div></li><li class="half_rhythm"><div>The offspring of an individual with SCAN1 and an individual who is <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a <i>TDP1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> have a 50% chance of having SCAN1. This is a consideration in populations with a <a class="def" href="/books/n/gene/glossary/def-item/founder-variant/">founder variant</a> (see <a href="#scan1.Prevalence">Prevalence</a>) or with a high rate of <a class="def" href="/books/n/gene/glossary/def-item/consanguinity/">consanguinity</a>.</div></li></ul><p><b>Other family members of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> Each sib of the proband's parents is at a 50% risk of being a <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> of a <i>TDP1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p></div><div id="scan1.Carrier_Detection"><h3>Carrier Detection</h3><p>Carrier testing for at-risk relatives requires prior identification of the <i>TDP1</i> pathogenic variants in the family.</p></div><div id="scan1.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><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, are carriers, or at risk of being carriers.</div></li><li class="half_rhythm"><div>Carrier testing for reproductive partners of known carriers should be considered, particularly if <a class="def" href="/books/n/gene/glossary/def-item/consanguinity/">consanguinity</a> is likely.</div></li></ul></div><div id="scan1.Prenatal_Testing_and_Preimplantati"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>TDP1</i> pathogenic variants have been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> for a pregnancy at increased risk 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="scan1.Resources"><h2 id="_scan1_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>Ataxia UK</b>
|
||
</div><div>United Kingdom</div><div><b>Phone:</b> 0800 995 6037; +44 (0) 20 7582 1444 (from abroad)</div><div><b>Email:</b> help@ataxia.org.uk</div><div>
|
||
<a href="https://www.ataxia.org.uk" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ataxia.org.uk</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>euro-ATAXIA (European Federation of Hereditary Ataxias)</b>
|
||
</div><div>United Kingdom</div><div><b>Email:</b> ageorgousis@ataxia.org.uk</div><div>
|
||
<a href="https://www.euroataxia.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">euroataxia.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Hereditary Neuropathy Foundation</b>
|
||
</div><div><b>Phone:</b> 855-435-7268 (toll-free); 212-722-8396</div><div><b>Fax:</b> 917-591-2758</div><div><b>Email:</b> info@hnf-cure.org</div><div>
|
||
<a href="http://www.hnf-cure.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.hnf-cure.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>National Ataxia Foundation</b>
|
||
</div><div><b>Phone:</b> 763-553-0020</div><div><b>Email:</b> naf@ataxia.org</div><div>
|
||
<a href="https://www.ataxia.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ataxia.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>CoRDS Registry</b>
|
||
</div><div>Sanford Research</div><div><b>Phone:</b> 605-312-6300</div><div>
|
||
<a href="https://research.sanfordhealth.org/rare-disease-registry" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CoRDS Registry</a>
|
||
</div></li></ul>
|
||
</div><div id="scan1.Molecular_Genetics"><h2 id="_scan1_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="scan1.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Spinocerebellar Ataxia with Axonal Neuropathy, Autosomal Recessive: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1105/table/scan1.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__scan1.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_scan1.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_scan1.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_scan1.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_scan1.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_scan1.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_scan1.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_scan1.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/55775" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>TDP1</i>
|
||
</a>
|
||
</td><td headers="hd_b_scan1.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=55775" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">14q32<wbr style="display:inline-block"></wbr>.11</a>
|
||
</td><td headers="hd_b_scan1.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/Q9NUW8" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Tyrosyl-DNA phosphodiesterase 1</a>
|
||
</td><td headers="hd_b_scan1.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://databases.lovd.nl/shared/genes/TDP1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">TDP1 database</a>
|
||
</td><td headers="hd_b_scan1.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=TDP1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">TDP1</a>
|
||
</td><td headers="hd_b_scan1.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=TDP1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">TDP1</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="scan1.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="scan1.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Spinocerebellar Ataxia with Axonal Neuropathy, Autosomal Recessive (<a href="/omim/607198,607250" 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/NBK1105/table/scan1.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__scan1.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/607198" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">607198</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TYROSYL-DNA PHOSPHODIESTERASE 1; TDP1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/607250" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">607250</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 1; SCAN1</td></tr></tbody></table></div></div><div id="scan1.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>TDP1</i> encodes the nuclear protein tyrosyl-DNA phosphodiesterase 1 (TDP1), an enzyme that is a member of phospholipase D superfamily and participates in DNA damage repair by unblocking complexes of trapped topoisomerase 1 and DNA through cleavage of a diester bond. Phosphorylated TDP1 interacts with DNA ligase III alpha, a component of the single strand break repair machinery [<a class="bk_pop" href="#scan1.REF.elkhamisy.2005.108">El-Khamisy et al 2005</a>, <a class="bk_pop" href="#scan1.REF.das.2009.3667">Das et al 2009</a>, <a class="bk_pop" href="#scan1.REF.chiang.2010.588">Chiang et al 2010</a>].</p><p>TDP1 contains two HKD motifs that comprise the active site of this enzyme and catalyze phosphoryl transfer reactions [<a class="bk_pop" href="#scan1.REF.interthal.2001.12009">Interthal et al 2001</a>].</p><p>Protein modeling showed that the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> <a href="/books/NBK1105/table/scan1.T.notable_tdp1_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobscan1Tnotabletdp1pathogenicvariants">p.His493Arg</a> disrupts the symmetric structure of the active center of the enzyme [<a class="bk_pop" href="#scan1.REF.takashima.2002.267">Takashima et al 2002</a>]. The mutated TDP1 protein, which has decreased enzyme activity [<a class="bk_pop" href="#scan1.REF.elkhamisy.2005.108">El-Khamisy et al 2005</a>, <a class="bk_pop" href="#scan1.REF.interthal.2005b.2224">Interthal et al 2005b</a>, <a class="bk_pop" href="#scan1.REF.zhou.2005.289">Zhou et al 2005</a>, <a class="bk_pop" href="#scan1.REF.elkhamisy.2007.1260">El-Khamisy & Caldecott 2007</a>], is also less efficient at repairing topo1-DNA complexes [<a class="bk_pop" href="#scan1.REF.interthal.2005b.2224">Interthal et al 2005b</a>, <a class="bk_pop" href="#scan1.REF.miao.2006.1489">Miao et al 2006</a>].</p><p>In the absence of <a class="def" href="/books/n/gene/glossary/def-item/wild_type/">wild type</a> <i>TDP1</i> for DNA repair, the <a href="/books/NBK1105/table/scan1.T.notable_tdp1_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobscan1Tnotabletdp1pathogenicvariants">p.His493Arg</a> TDP1 variant becomes covalently trapped in the normally transient TDP1-DNA intermediate state causing a DNA break [<a class="bk_pop" href="#scan1.REF.interthal.2005a.36518">Interthal et al 2005a</a>, <a class="bk_pop" href="#scan1.REF.hirano.2007.4732">Hirano et al 2007</a>]. TDP1 also participates in maintenance of the mitochondrial genome and mitochondrial function. Mitochondrial dysfunction likely contributes to the pathophysiology of SCAN1 [<a class="bk_pop" href="#scan1.REF.fam.2018.4304">Fam et al 2018</a>, <a class="bk_pop" href="#scan1.REF.huang.2019.3015">Huang & Pommier 2019</a>]. Identification of additional disease-causing variants could improve understanding of the mechanism for disease causation.</p><p><b>Mechanism of disease causation.</b> Functional studies suggest a recessive neomorphic (<a class="def" href="/books/n/gene/glossary/def-item/gain-of-function/">gain-of-function</a>) mechanism for the <a href="/books/NBK1105/table/scan1.T.notable_tdp1_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobscan1Tnotabletdp1pathogenicvariants">c.1478A>G; p.His493Arg</a> variant.</p><div id="scan1.T.notable_tdp1_pathogenic_variants" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Notable <i>TDP1</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1105/table/scan1.T.notable_tdp1_pathogenic_variants/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__scan1.T.notable_tdp1_pathogenic_variants_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_scan1.T.notable_tdp1_pathogenic_variants_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_scan1.T.notable_tdp1_pathogenic_variants_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide<br />Change</th><th id="hd_h_scan1.T.notable_tdp1_pathogenic_variants_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted<br />Protein Change</th><th id="hd_h_scan1.T.notable_tdp1_pathogenic_variants_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_scan1.T.notable_tdp1_pathogenic_variants_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_018319.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_018319<wbr style="display:inline-block"></wbr>.4</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_060789.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_060789<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td><td headers="hd_h_scan1.T.notable_tdp1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1478A>G</td><td headers="hd_h_scan1.T.notable_tdp1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.His493Arg</td><td headers="hd_h_scan1.T.notable_tdp1_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Founder variant reported in 2 apparently unrelated Omani families [<a class="bk_pop" href="#scan1.REF.scott.2019.139">Scott et al 2019</a>]; also reported in an unrelated Saudi Arabian family [<a class="bk_pop" href="#scan1.REF.takashima.2002.267">Takashima et al 2002</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="scan1.Chapter_Notes"><h2 id="_scan1_Chapter_Notes_">Chapter Notes</h2><div id="scan1.Author_History"><h3>Author History</h3><p>Cornelius Boerkoel, MD, PhD (2007-present)<br />Hok Khim Fam, BSc; University of British Columbia (2012-2022)<br />Ryuki Hirano, MD, PhD; Kagoshima University (2007-2012)<br />Mustafa AM Salih, MD, Dr Med Sci, FRCPCH (2007-present)<br />Hiroshi Takashima, MD, PhD (2007-present)</p></div><div id="scan1.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>30 June 2022 (bp) Comprehensive update posted live</div></li><li class="half_rhythm"><div>26 April 2012 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>22 October 2007 (me) Review posted live</div></li><li class="half_rhythm"><div>26 September 2007 (cfb) Original submission</div></li></ul></div></div><div id="scan1.References"><h2 id="_scan1_References_">References</h2><div id="scan1.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="scan1.REF.biesecker.2021.8">Biesecker
|
||
LG, Adam
|
||
MP, Alkuraya
|
||
FS, Amemiya
|
||
AR, Bamshad
|
||
MJ, Beck
|
||
AE, Bennett
|
||
JT, Bird
|
||
LM, Carey
|
||
JC, Chung
|
||
B, Clark
|
||
RD, Cox
|
||
TC, Curry
|
||
C, Dinulos
|
||
MBP, Dobyns
|
||
WB, Giampietro
|
||
PF, Girisha
|
||
KM, Glass
|
||
IA, Graham
|
||
JM
|
||
Jr, Gripp
|
||
KW, Haldeman-Englert
|
||
CR, Hall
|
||
BD, Innes
|
||
AM, Kalish
|
||
JM, Keppler-Noreuil
|
||
KM, Kosaki
|
||
K, Kozel
|
||
BA, Mirzaa
|
||
GM, Mulvihill
|
||
JJ, Nowaczyk
|
||
MJM, Pagon
|
||
RA, Retterer
|
||
K, Rope
|
||
AF, Sanchez-Lara
|
||
PA, Seaver
|
||
LH, Shieh
|
||
JT, Slavotinek
|
||
AM, Sobering
|
||
AK, Stevens
|
||
CA, Stevenson
|
||
DA, Tan
|
||
TY, Tan
|
||
WH, Tsai
|
||
AC, Weaver
|
||
DD, Williams
|
||
MS, Zackai
|
||
E, Zarate
|
||
YA. A dyadic approach to the delineation of diagnostic entities in clinical genomics.
|
||
Am J Hum Genet.
|
||
2021;108:8–15.
|
||
[<a href="/pmc/articles/PMC7820621/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7820621</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/33417889" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33417889</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="scan1.REF.chiang.2010.588">Chiang
|
||
SC, Carroll
|
||
J, El-Khamisy
|
||
SF. TDP1 serine 81 promotes interaction with DNA ligase IIIalpha and facilitates cell survival following DNA damage.
|
||
Cell Cycle.
|
||
2010;9:588–95.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/20009512" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20009512</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="scan1.REF.das.2009.3667">Das
|
||
BB, Antony
|
||
S, Gupta
|
||
S, Dexheimer
|
||
TS, Redon
|
||
CE, Garfield
|
||
S, Shiloh
|
||
Y, Pommier
|
||
Y. Optimal function of the DNA repair enzyme TDP1 requires its phosphorylation by ATM and/or DNA-PK.
|
||
EMBO J.
|
||
2009;28:3667–80.
|
||
[<a href="/pmc/articles/PMC2790489/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2790489</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19851285" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19851285</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="scan1.REF.elkhamisy.2007.1260">El-Khamisy
|
||
SF, Caldecott
|
||
KW. DNA single-strand break repair and spinocerebellar ataxia with axonal neuropathy-1.
|
||
Neuroscience.
|
||
2007;145:1260–6.
|
||
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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=medgen&DbFrom=books&Cmd=Link&LinkName=books_medgen&IdsFromResult=1490766" ref="log$=recordlinks">MedGen</a><div class="brieflinkpop offscreen_noflow">Related information in MedGen</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=omim&DbFrom=books&Cmd=Link&LinkName=books_omim&IdsFromResult=1490766" ref="log$=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=1490766" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=1490766" ref="log$=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=1490766" ref="log$=recordlinks">Gene</a><div class="brieflinkpop offscreen_noflow">Locus Links</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301790" ref="ordinalpos=1&linkpos=1&log$=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> Ataxia-Telangiectasia.</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> Ataxia-Telangiectasia.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Veenhuis S, van Os N, Weemaes C, Kamsteeg EJ, Willemsen M. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301656" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Adenosine Deaminase Deficiency.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Adenosine Deaminase Deficiency.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Hershfield M, Tarrant T. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301294" ref="ordinalpos=1&linkpos=3&log$=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> ATP1A3-Related Disorder.</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> ATP1A3-Related Disorder.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Brashear A, Sweadner KJ, Haq I, Napoli E, Ozelius 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/20301458" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Friedreich Ataxia.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Friedreich Ataxia.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Bidichandani SI, Delatycki MB, Napierala M, Duquette A. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/37824696" ref="ordinalpos=1&linkpos=5&log$=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> WARS2 Deficiency.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> WARS2 Deficiency.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Mroczek M, Busra A, Houlden H, Efthymiou S, Nagy 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></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=20301284" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=20301284" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="recent_activity" id="Shutter"></a></div><div class="portlet_content"><div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" id="HTDisplay" class=""><div class="action"><a href="javascript:historyDisplayState('ClearHT')">Clear</a><a href="javascript:historyDisplayState('HTOff')" class="HTOn">Turn Off</a><a href="javascript:historyDisplayState('HTOn')" class="HTOff">Turn On</a></div><ul id="activity"><li class="ra_rcd ralinkpopper 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