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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="SPTLC1-Related Hereditary Sensory Neuropathy" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2021/12/02" /><meta name="citation_author" content="Garth A Nicholson" /><meta name="citation_pmid" content="20301564" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1390/" /><meta name="citation_keywords" content="Hereditary Sensory and Autonomic Neuropathy Type IA" /><meta name="citation_keywords" content="Hereditary Sensory Neuropathy Type IA" /><meta name="citation_keywords" content="HSAN1A" /><meta name="citation_keywords" content="HSN1A" /><meta name="citation_keywords" content="Hereditary Sensory and Autonomic Neuropathy Type IA" /><meta name="citation_keywords" content="Hereditary Sensory Neuropathy Type IA" /><meta name="citation_keywords" content="HSAN1A" /><meta name="citation_keywords" content="HSN1A" /><meta name="citation_keywords" content="Serine palmitoyltransferase 1" /><meta name="citation_keywords" content="SPTLC1" /><meta name="citation_keywords" content="SPTLC1-Related Hereditary Sensory Neuropathy" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="SPTLC1-Related Hereditary Sensory Neuropathy" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Garth A Nicholson" /><meta name="DC.Date" content="2021/12/02" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK1390/" /><meta name="description" content="SPTLC1-related hereditary sensory neuropathy (HSN) is an axonal form of hereditary motor and sensory neuropathy distinguished by prominent early sensory loss and later positive sensory phenomena including dysesthesia and characteristic "lightning" or "shooting" pains. Loss of sensation can lead to painless injuries, which, if unrecognized, result in slow wound healing and subsequent osteomyelitis requiring distal amputations. Motor involvement is present in all advanced cases and can be severe. After age 20 years, the distal wasting and weakness may involve proximal muscles, possibly leading to wheelchair dependency by the seventh or eighth decade. Sensorineural hearing loss is variable." /><meta name="og:title" content="SPTLC1-Related Hereditary Sensory Neuropathy" /><meta name="og:type" content="book" /><meta name="og:description" content="SPTLC1-related hereditary sensory neuropathy (HSN) is an axonal form of hereditary motor and sensory neuropathy distinguished by prominent early sensory loss and later positive sensory phenomena including dysesthesia and characteristic "lightning" or "shooting" pains. Loss of sensation can lead to painless injuries, which, if unrecognized, result in slow wound healing and subsequent osteomyelitis requiring distal amputations. Motor involvement is present in all advanced cases and can be severe. After age 20 years, the distal wasting and weakness may involve proximal muscles, possibly leading to wheelchair dependency by the seventh or eighth decade. 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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="#__NBK1390_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK1390_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/sptbn4/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/stac3-dis/" 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="_NBK1390_"><span class="title" itemprop="name"><i>SPTLC1</i>-Related Hereditary Sensory Neuropathy</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: Hereditary Sensory and Autonomic Neuropathy Type IA, Hereditary Sensory Neuropathy Type IA, HSAN1A, HSN1A</div><p class="contrib-group"><span itemprop="author">Garth A Nicholson</span>, MBBS, PhD.</p><a data-jig="ncbitoggler" href="#__NBK1390_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK1390_ai__"><div class="contrib half_rhythm"><span itemprop="author">Garth A Nicholson</span>, MBBS, PhD<div class="affiliation small">Department of Medicine
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University of Sydney
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Hereditary Neuropathies Clinic and Molecular Medicine Laboratory
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Concord Hospital
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Sydney, Australia<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ua.ude.yendys@noslohcin.htrag" class="oemail">ua.ude.yendys@noslohcin.htrag</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">September 23, 2002</span>; Last Revision: <span itemprop="dateModified">December 2, 2021</span>.</p><p><em>Estimated reading time: 17 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="hsn1.Summary" itemprop="description"><h2 id="_hsn1_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><i>SPTLC1</i>-related hereditary sensory neuropathy (HSN) is an axonal form of hereditary motor and sensory neuropathy distinguished by prominent early sensory loss and later positive sensory phenomena including dysesthesia and characteristic "lightning" or "shooting" pains. Loss of sensation can lead to painless injuries, which, if unrecognized, result in slow wound healing and subsequent osteomyelitis requiring distal amputations. Motor involvement is present in all advanced cases and can be severe. After age 20 years, the distal wasting and weakness may involve proximal muscles, possibly leading to wheelchair dependency by the seventh or eighth decade. Sensorineural hearing loss is variable.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of <i>SPTLC1</i>-related HSN is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with characteristic clinical features and identification of a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>SPTLC1</i> on <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>: Clean and protect wounds on neuropathic limbs; surgical treatment similar to that for leprosy; ankle/foot orthotics for foot drop; arthrodesis for Charcot joints; pregabalin, carbamazepine, gabapentin, or amitriptyline, or a combination of anti-seizure medication and an antidepressant drug for shooting pains.</p><p><i>Prevention of secondary complications</i>: Routine care by a diabetic foot care specialist to prevent/treat calluses and foot ulcers; education about good skin care and burn prevention (e.g., to hands when cooking).</p><p><i>Surveillance</i>: At least daily inspection of feet for injuries or sources of wear.</p><p><i>Agents/circumstances to avoid</i>: Opiates as <i>SPTLC1</i>-related HSN is a chronic disorder.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>SPTLC1</i>-related HSN is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner. Most probands have an affected parent. Offspring of an affected individual have a 50% chance of inheriting the <i>SPTLC1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been identified in the family.</p></div></div><div id="hsn1.Diagnosis"><h2 id="_hsn1_Diagnosis_">Diagnosis</h2><div id="hsn1.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>SPTLC1</i>-related hereditary sensory neuropathy (HSN) <b>should be suspected</b> in individuals with the following clinical findings and family history:</p><ul><li class="half_rhythm"><div>Initial sensory neuropathy that then becomes a motor and sensory axonal neuropathy</div></li><li class="half_rhythm"><div>Painless injuries in the feet and hands with skin ulceration, Charcot joints, sometimes amputations</div></li><li class="half_rhythm"><div>Distal muscle weakness that spreads proximally producing limb girdle weakness in advanced stages</div></li><li class="half_rhythm"><div>At some stage, occurrence of typical sharp shooting "lightning" pains lasting seconds to minutes</div></li><li class="half_rhythm"><div>Sensorineural hearing loss (variably present)</div></li><li class="half_rhythm"><div>Family history consistent with <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> inheritance</div></li></ul></div><div id="hsn1.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of <i>SPTLC1</i>-related HSN <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with the above <a href="#hsn1.Suggestive_Findings">Suggestive Findings</a> and a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>SPTLC1</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK1390/table/hsn1.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobhsn1Tmoleculargenetictestingusedin">Table 1</a>).</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> (single-gene testing, <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 that the clinician 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 <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of <i>SPTLC1</i>-related HSN is broad, individuals with the distinctive findings described in <a href="#hsn1.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#hsn1.Option_1">Option 1</a>), whereas those with a phenotype indistinguishable from many other inherited disorders with sensory neuropathy are more likely to be diagnosed using genomic testing (see <a href="#hsn1.Option_2">Option 2</a>).</p><div id="hsn1.Option_1"><h4>Option 1</h4><p>When the phenotypic and laboratory findings suggest the diagnosis of <i>SPTLC1</i>-related HSN, <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> approaches can include <b>single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing</b> or use of a <b><a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b>:</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing.</b> Sequence analysis of <i>SPTLC1</i> detects 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. Note: To date <a class="def" href="/books/n/gene/glossary/def-item/gain-of-function/">gain-of-function</a> pathogenic variants located in exons 5 and 6 have been reported (see <a href="#hsn1.Molecular_Genetics">Molecular Genetics</a>). No duplications or deletions have been found or are expected given the disease mechanism.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes <i>SPTLC1</i> and other genes of interest (see <a href="#hsn1.Differential_Diagnosis">Differential Diagnosis</a>) may be considered 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></ul></div><div id="hsn1.Option_2"><h4>Option 2</h4><p>When the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> is indistinguishable from many other inherited disorders characterized by sensory neuropathy, <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (which does not require the clinician to determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>[s] are likely involved) is the best option. <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><div id="hsn1.T.molecular_genetic_testing_used_in" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>SPTLC1</i>-Related Hereditary Sensory Neuropathy</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1390/table/hsn1.T.molecular_genetic_testing_used_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__hsn1.T.molecular_genetic_testing_used_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_hsn1.T.molecular_genetic_testing_used_in_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_hsn1.T.molecular_genetic_testing_used_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_hsn1.T.molecular_genetic_testing_used_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with a Pathogenic Variant <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_hsn1.T.molecular_genetic_testing_used_in_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>SPTLC1</i>
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</td><td headers="hd_h_hsn1.T.molecular_genetic_testing_used_in_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_hsn1.T.molecular_genetic_testing_used_in_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_hsn1.T.molecular_genetic_testing_used_in_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_hsn1.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None reported <sup>6</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="hsn1.TF.1.1"><p class="no_margin">See <a href="/books/NBK1390/#hsn1.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="hsn1.TF.1.2"><p class="no_margin">See <a href="#hsn1.Molecular_Genetics">Molecular Genetics</a> for information on allelic variants detected in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>.</p></div></dd><dt>3. </dt><dd><div id="hsn1.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, <a class="def" href="/books/n/gene/glossary/def-item/likely-benign/">likely benign</a>, of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>, or pathogenic. Variants may include small intragenic deletions/insertions and <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications are not detected. For issues to consider in interpretation of <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>4. </dt><dd><div id="hsn1.TF.1.4"><p class="no_margin">Includes pathogenic variants in <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 5 and exon 6 [<a class="bk_pop" href="#hsn1.REF.bejaoui.2001.261">Bejaoui et al 2001</a>; <a class="bk_pop" href="#hsn1.REF.dawkins.2001.309">Dawkins et al 2001</a>; <a class="bk_pop" href="#hsn1.REF.houlden.2006.411">Houlden et al 2006</a>; Author, personal communication]; see <a href="#hsn1.Molecular_Genetics">Molecular Genetics</a>.</p></div></dd><dt>5. </dt><dd><div id="hsn1.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 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><dt>6. </dt><dd><div id="hsn1.TF.1.6"><p class="no_margin">No duplications or deletions have been found or are expected as the disease mechanism involves a <a class="def" href="/books/n/gene/glossary/def-item/gain-of-function/">gain-of-function</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> of the active site of the enzyme (see <a href="#hsn1.Molecular_Genetics">Molecular Genetics</a>).</p></div></dd></dl></div></div></div></div></div></div><div id="hsn1.Clinical_Characteristics"><h2 id="_hsn1_Clinical_Characteristics_">Clinical Characteristics</h2><div id="hsn1.Clinical_Description"><h3>Clinical Description</h3><p><i>SPTLC1</i>-related hereditary sensory neuropathy (HSN) is usually first noticed when painless injuries appear. Onset ranges from the teens to the sixth decade. Later, positive sensory phenomena occur (numbness, paresthesia, burning, and shooting pains). Shooting pains may be a distinctive but variable feature of <i>SPTLC1</i>-related HSN.</p><p>If the sensory loss is unheeded, chronic ulcerations of the extremities may lead to osteomyelitis and require amputations. Neuropathic joints are common.</p><p>Weakness commences in the distal lower limbs, followed by the distal upper limbs and in severe cases, proximal upper- and lower-limb girdle muscles. Distal muscle weakness and wasting are present in all advanced cases. The weakness of ankle flexors produces a floppy, flipper-like foot rather than <i>pes cavus</i>.</p><p>A few instances of early severe motor involvement have been reported [<a class="bk_pop" href="#hsn1.REF.houlden.2006.411">Houlden et al 2006</a>].</p><p>Older affected individuals may require a wheelchair for mobility.</p><p>Retained and even brisk proximal reflexes in some affected individuals may indicate some upper motor neuron involvement. Corticospinal degeneration was not observed on an autopsy of an individual with <i>SPTLC1</i>-related HSN, but data are limited.</p><p>Sensorineural hearing loss is variable. When present, its onset is in middle to late adulthood.</p><p>Rarely, pupillary abnormalities termed "tonic pupils" or pseudo-Argyll-Robertson pupils (i.e., those not associated with syphilis) are present.</p><p>Visceral autonomic features are rare [Nicholson, unpublished data], with abdominal pain, diarrhea, and weight loss reported in some individuals in one family only [<a class="bk_pop" href="#hsn1.REF.houlden.2006.411">Houlden et al 2006</a>].</p><p><b>Electrophysiology</b> is initially normal and is not useful for early detection [Author, personal observation].</p><ul><li class="half_rhythm"><div>Sensory nerve action potentials are reduced only late in the disease.</div></li><li class="half_rhythm"><div>Motor nerve conduction velocities are normal until motor action potential amplitudes become reduced.</div></li><li class="half_rhythm"><div>Motor nerve conduction velocities are mildly slowed and motor action potentials are reduced in advanced cases.</div></li></ul><p><b>Sural nerve biopsy</b> shows axonal degeneration with loss of both small and large fibers. These findings are nonspecific and not diagnostic.</p><p><b>Neuropathology.</b> The disease process affects the axons and cell bodies of dorsal root ganglia neurons and motor neurons in the anterior horns of the spinal cord. Studies show a distal axonal degeneration with loss of unmyelinated, small myelinated, and large myelinated fibers with decreasing severity in that order, proceeding to ganglion cell loss [<a class="bk_pop" href="#hsn1.REF.houlden.2006.411">Houlden et al 2006</a>, <a class="bk_pop" href="#hsn1.REF.auergrumbach.2013.893">Auer-Grumbach 2013</a>]. See review in <a class="bk_pop" href="#hsn1.REF.thomas.1993.157">Thomas [1993]</a>.</p></div><div id="hsn1.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p><i>SPTLC1</i> pathogenic variants at Ser331, including p.Ser331Phe [<a class="bk_pop" href="#hsn1.REF.suh.2014.481">Suh et al 2014</a>] and p.Ser331Tyr [<a class="bk_pop" href="#hsn1.REF.rotthier.2009.2699">Rotthier et al 2009</a>, <a class="bk_pop" href="#hsn1.REF.auergrumbach.2013.893">Auer-Grumbach 2013</a>], are associated with severe childhood-onset motor and sensory neuropathy (generally without skin ulceration as in classic HSAN1A). Affected individuals have muscle atrophy (which may include atrophy of the tongue), hypotonia, growth deficiency, intellectual disability (in some individuals), cataracts, and laryngeal involvement. Disease is caused by accumulation of toxic sphingolipids [<a class="bk_pop" href="#hsn1.REF.auergrumbach.2013.893">Auer-Grumbach 2013</a>]. The general absence of skin ulceration in these severe childhood-onset neuropathies may be explained by slow accumulation of toxic sphingolipids. (One individual, described by <a class="bk_pop" href="#hsn1.REF.suh.2014.481">Suh et al [2014]</a>, was reported to have skin ulceration.)</p><p>An individual with <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> p.Ser331Tyr was included in a description of <i>SPTLC1</i>-related juvenile ALS by <a class="bk_pop" href="#hsn1.REF.johnson.2021.1236">Johnson et al [2021]</a>. The described syndrome was caused by toxic sphingolipids and sensory involvement was demonstrated; thus, it was most likely a severe early-onset form of HSN.</p></div><div id="hsn1.Penetrance"><h3>Penetrance</h3><p>Variable <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> has been observed [<a class="bk_pop" href="#hsn1.REF.houlden.2006.411">Houlden et al 2006</a>].</p></div><div id="hsn1.Nomenclature"><h3>Nomenclature</h3><p>The term "hereditary sensory neuropathy" (HSN) was first used by <a class="bk_pop" href="#hsn1.REF.hicks.1922.319">Hicks [1922]</a> to describe a family with associated spontaneous shooting pains and deafness. The family was later reported as having a form of peroneal muscular atrophy.</p><p>Motor involvement was also noted in other families in southern England and described by Ellison in his University of Edinburgh MD thesis, and later by <a class="bk_pop" href="#hsn1.REF.campbell.1964.67">Campbell & Hoffman [1964]</a>. The Australian families with an <i>SPTLC1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> described by <a class="bk_pop" href="#hsn1.REF.dawkins.2001.309">Dawkins et al [2001]</a> have no visceral autonomic signs or symptoms and share a common ancestor with the southern English families described by Ellison and reported by <a class="bk_pop" href="#hsn1.REF.campbell.1964.67">Campbell & Hoffman [1964]</a> as having HSN. Therefore, the term "HSN" was used in the review by <a class="bk_pop" href="#hsn1.REF.thomas.1993.157">Thomas [1993]</a>, and the disorder is also listed in OMIM as HSN1A. Although individuals with HSN1 rarely have visceral autonomic signs, this disorder is still classified as a hereditary sensory and autonomic neuropathy (HSAN1A).</p><p>Even so, the terms "HSN" and "HSAN" are not ideal, as the disorder is both a sensory and a <i>motor</i> neuropathy. Therefore, strictly, it is a form of Charcot-Marie-Tooth neuropathy. The <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> is that of a slowly progressive length-dependent adult-onset axonal form of <a href="/books/n/gene/cmt/">Charcot-Marie-Tooth neuropathy</a> (CMT type II, and hereditary motor and sensory neuropathy, HMSN II) but with prominent loss of pain fibers.</p><p>The term "HSN1" designates <i>dominantly</i> inherited forms of hereditary sensory neuropathy. HSAN types 2 to 6 are recessively inherited forms of sensory and autonomic neuropathies.</p></div><div id="hsn1.Prevalence"><h3>Prevalence</h3><p>HSN affects 25 of 600 families (4.2%) with CMT studied by the author. Of these families with HSN, 25% have <i>SPTLC1</i>-related HSN (1% of all families with CMT).</p><p>If the overall incidence of motor and sensory neuropathies is 30:100,000, the prevalence of HSN is on the order of 2:1,000,000. HSN1A may be underestimated because diagnosis previously depended erroneously on finding pure sensory involvement, shooting pains, and/or skin damage or ulcers.</p></div></div><div id="hsn1.Genetically_Related_Allelic_Disorde"><h2 id="_hsn1_Genetically_Related_Allelic_Disorde_">Genetically Related (Allelic) Disorders</h2><p><b><i>SPTLC1</i>-related juvenile-onset amyotrophic lateral sclerosis (ALS).</b> Several (typically <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a>) <i>SPTLC1</i> pathogenic variants have been reported in individuals with juvenile ALS [<a class="bk_pop" href="#hsn1.REF.mohassel.2021.1197">Mohassel et al 2021</a>]. <i>SPTLC1</i>-related ALS is a severe childhood-onset motor neuropathy with bulbar and upper motor neuron signs. (The transmitting parent in one multiplex family had a later-onset motor and sensory neuropathy.) These ALS-associated <i>SPTLC1</i> pathogenic variants upregulate sphingolipid production ‒ unlike other pathogenic variants in <i>SPTLC1</i>, which alter substrate specificity leading to production of poorly metabolized toxic sphingolipids.</p></div><div id="hsn1.Differential_Diagnosis"><h2 id="_hsn1_Differential_Diagnosis_">Differential Diagnosis</h2><p>Dominant forms of hereditary sensory neuropathy (HSN) are genetically heterogeneous:</p><ul><li class="half_rhythm"><div>HSAN1B (OMIM <a href="https://omim.org/entry/608088" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">608088</a>), a dominantly inherited sensory neuropathy without foot ulcers but with cough and gastroesophageal reflux disease, maps to <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> 3p24-p22.</div></li><li class="half_rhythm"><div>HSAN1C (OMIM <a href="https://omim.org/entry/613640" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">613640</a>) is caused by pathogenic variants in <i>SPTLC2</i>. The neuropathy is phenotypically similar to <i>SPTLC1</i>-related HSN.</div></li><li class="half_rhythm"><div>HSN1D (OMIM <a href="https://omim.org/entry/613708" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">613708</a>) is caused by pathogenic variants in <i>ATL1</i>.</div></li><li class="half_rhythm"><div>HSN1E (<a href="/books/n/gene/dnmt1-ddsn/">hereditary sensory neuropathy with dementia and hearing loss</a>), a late-onset mild sensory neuropathy associated with ataxia and deafness, is caused by pathogenic variants in <i>DNMT1.</i></div></li></ul><p>Disorders with similar phenotypes are two forms of <a href="/books/n/gene/cmt/">CMT2</a>:</p><ul><li class="half_rhythm"><div>CMT2B, a motor and sensory neuropathy with severe sensory loss and foot ulcers but no shooting pains. CMT2B is caused by pathogenic variants in <i>RAB7.</i></div></li><li class="half_rhythm"><div>CMT2I/J. The <i>MPZ</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> p.Thr124Met is associated with a <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> almost identical to HSAN1A, with severe sensory loss, shooting pains, and occasional pseudo-Argyl-Robertson pupils but no ulcerations.</div></li></ul><p>Painful diabetic neuropathy may have a similar <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> but usually lacks a family history of neuropathy.</p><p>See <a href="https://omim.org/phenotypicSeries/PS162400" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Hereditary Sensory and Autonomic Neuropathy: OMIM Phenotypic Series</a> to view genes associated with this <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> in OMIM.</p></div><div id="hsn1.Management"><h2 id="_hsn1_Management_">Management</h2><div id="hsn1.Evaluations_Following_Initial_Diagn"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with <i>SPTLC1</i>-related hereditary sensory neuropathy (HSN), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:</p><ul><li class="half_rhythm"><div>Examination of the skin of the feet, ankles, and hands</div></li><li class="half_rhythm"><div>Examination of joints for evidence of Charcot joints</div></li><li class="half_rhythm"><div>Strength assessment</div></li><li class="half_rhythm"><div>Examination for loss of sweating and compensatory patchy hyperhidrosis</div></li><li class="half_rhythm"><div>Consultation with a clinical geneticist and/or genetic counselor</div></li></ul></div><div id="hsn1.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Wounds on neuropathic limbs heal if they are clean and protected and the limb is rested. Principles of treatment are the same as for leprosy surgery; see <a class="bk_pop" href="#hsn1.REF.warren.1999">Warren & Nade [1999]</a>.</p><p>Foot drop can be treated with ankle/foot orthotics, but these need sleeving with stockings or some form of second skin to prevent skin abrasion.</p><p>Charcot joints may require arthrodesis.</p><p>Shooting pains are difficult to treat and only partial relief can be obtained with carbamazepine, gabapentin, or amitriptyline, or a combination of anti-seizure and antidepressant medication. Opiates are contraindicated as <i>SPTLC1-</i>related HSN is a chronic disorder.</p></div><div id="hsn1.Prevention_of_Secondary_Complicatio"><h3>Prevention of Secondary Complications</h3><p>Foot ulcers are frequently caused by breakdown of callus. Therefore, it is important to prevent callus formation by removing sources of pressure and to treat existing callus by softening the skin. Routine foot care by a diabetic clinic or by a podiatrist instructed to treat as for a diabetic foot is recommended.</p><p>Burns can be prevented by using gloves as needed (e.g., during cooking).</p><p>A diabetic education clinic is an excellent source of advice regarding skin care.</p></div><div id="hsn1.Surveillance"><h3>Surveillance</h3><p>Feet should be inspected at least daily for injuries or sources of wear.</p></div><div id="hsn1.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Opiates are contraindicated as this is a chronic disorder.</p></div><div id="hsn1.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#hsn1.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="hsn1.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p><a class="bk_pop" href="#hsn1.REF.penno.2010.11178">Penno et al [2010]</a> found that <i>SPTLC1</i> pathogenic variants associated with HSN result in decreased specificity of the active site of the enzyme, allowing alanine and glycine into the active site and producing neurotoxic sphingoid bases. The finding suggests that <i>SPTLC1-</i>related HSN is caused by these toxic products and opens an avenue for possible (at present, experimental) therapeutic approaches. Addition of serine to the diet of an HSN1A animal model and to 14 humans with <i>SPTLC1-</i>related HSN was effective in reducing plasma levels of the toxic deoxysphingolipids [<a class="bk_pop" href="#hsn1.REF.garofalo.2011.4735">Garofalo et al 2011</a>].</p><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.</p></div></div><div id="hsn1.Genetic_Counseling"><h2 id="_hsn1_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="hsn1.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>SPTLC1-</i>related hereditary sensory neuropathy (HSN) is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner.</p></div><div id="hsn1.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>Most individuals diagnosed with <i>SPTLC1-</i>related HSN have an affected parent.</div></li><li class="half_rhythm"><div>Some individuals diagnosed with <i>SPTLC1-</i>related HSN may have the disorder as the result of a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a>
|
||
<i>SPTLC1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>. One apparently <i>de novo</i> variant, reported as pathogenic [<a class="bk_pop" href="#hsn1.REF.verhoeven.2004.1001">Verhoeven et al 2004</a>], is now thought to be non-pathogenic [<a class="bk_pop" href="#hsn1.REF.hornemann.2009.135">Hornemann et al 2009</a>]; the proportion of <i>SPTLC1-</i>related HSN 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/pathogenic-variant/">pathogenic variant</a> found in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> cannot be detected in the leukocyte DNA of either parent, possible explanations include a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> pathogenic variant in the proband or <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a> in a parent. Although no instances of germline mosaicism have been reported, it remains a possibility.</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> with an apparent <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>. Note: Recommendations for evaluation of the parents also include clinical examination and electrophysiologic testing; however, diagnostic clinical and electrophysiologic findings have not been reported to emerge after age 30 years.</div></li><li class="half_rhythm"><div>The family history of some individuals diagnosed with <i>SPTLC1-</i>related HSN may appear to be negative because of failure to recognize the disorder in family members, reduced <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a>, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. 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 been performed on the parents of 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 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> is affected and/or is known to have the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the proband, the risk to each sib of inheriting the pathogenic variant is 50%; sibs who inherit the pathogenic variant may or may not be affected as reduced <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> has been observed.</div></li><li class="half_rhythm"><div>If the <i>SPTLC1</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 <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a> [<a class="bk_pop" href="#hsn1.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>SPTLC1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> but are clinically unaffected, the risk to the sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for <i>SPTLC1-</i>related HSN because of the possibility of reduced <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> in a parent or the theoretic possibility of parental <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a>.</div></li><li class="half_rhythm"><div>Note: Because diagnostic clinical and electrophysiologic findings have not been reported to emerge after age 30 years, sibs who are asymptomatic at age 30 years are no longer considered to be at increased risk for <i>SPTLC1-</i>related HSN.</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 HSN1A has a 50% chance of inheriting the <i>SPTLC1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p><p><b>Other family members.</b> The risk to other family members depends on the status of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents: if a parent is affected, his or her family members are at risk.</p></div><div id="hsn1.Related_Genetic_Counseling_Issues"><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>SPTLC1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> has been identified in an affected family member.</div></li><li class="half_rhythm"><div>Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> prior to testing.</div></li></ul><p>
|
||
<b>Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals age <18 years)</b>
|
||
</p><ul><li class="half_rhythm"><div>For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.</div></li><li class="half_rhythm"><div>For more information, see the National Society of Genetic Counselors <a href="https://www.nsgc.org/Policy-Research-and-Publications/Position-Statements/Position-Statements/Post/genetic-testing-of-minors-for-adult-onset-conditions" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">position statement</a> on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics <a href="https://pediatrics.aappublications.org/content/131/3/620.full.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">policy statement</a>: ethical and policy issues in genetic testing and screening of children.</div></li></ul><p>In a family with an established diagnosis of HSN1A it is appropriate to consider testing of symptomatic individuals regardless of age.</p><p><b>Considerations in families with an apparent <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</b> When neither parent of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely <i>de novo</i>. However, non-medical explanations including <a class="def" href="/books/n/gene/glossary/def-item/alternate-paternity/">alternate paternity</a> or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.</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="hsn1.Prenatal_Testing_and_Preimplantatio"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>SPTLC1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> has been identified in an affected family member, <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for a pregnancy at increased risk and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p><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>, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. 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="hsn1.Resources"><h2 id="_hsn1_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>MedlinePlus</b>
|
||
</div><div>
|
||
<a href="https://medlineplus.gov/genetics/condition/hereditary-sensory-neuropathy-type-ia/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Hereditary sensory neuropathy type 1A</a>
|
||
</div></li></ul>
|
||
</div><div id="hsn1.Molecular_Genetics"><h2 id="_hsn1_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="hsn1.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>SPTLC1-Related Hereditary Sensory Neuropathy: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1390/table/hsn1.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__hsn1.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_hsn1.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_hsn1.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_hsn1.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_hsn1.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_hsn1.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_hsn1.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_hsn1.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/10558" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>SPTLC1</i>
|
||
</a>
|
||
</td><td headers="hd_b_hsn1.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=10558" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">9q22<wbr style="display:inline-block"></wbr>.31</a>
|
||
</td><td headers="hd_b_hsn1.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/O15269" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Serine palmitoyltransferase 1</a>
|
||
</td><td headers="hd_b_hsn1.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://databases.lovd.nl/shared/genes/SPTLC1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SPTLC1 @ LOVD</a>
|
||
</td><td headers="hd_b_hsn1.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=SPTLC1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SPTLC1</a>
|
||
</td><td headers="hd_b_hsn1.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=SPTLC1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SPTLC1</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="hsn1.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="hsn1.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for SPTLC1-Related Hereditary Sensory Neuropathy (<a href="/omim/162400,605712" 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/NBK1390/table/hsn1.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__hsn1.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/162400" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">162400</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IA; HSAN1A</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/605712" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">605712</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SERINE PALMITOYLTRANSFERASE, LONG-CHAIN BASE SUBUNIT 1; SPTLC1</td></tr></tbody></table></div></div><p><b>Gene structure.</b> The <i>SPTLC1</i> reference sequence <a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_006415.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_006415.3</a> is the longest transcript variant and has 15 exons. Alternatively spliced variants encoding different <a class="def" href="/books/n/gene/glossary/def-item/isoforms/">isoforms</a> have been identified. For a detailed summary of <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> and protein information, see <a href="/books/NBK1390/#hsn1.molgen.TA">Table A</a>, <b>Gene</b>.</p><p><b>Pathogenic variants.</b> The following three pathogenic variants result in significant amino acid changes likely to have functional or structural effects:</p><ul><li class="half_rhythm"><div>The most common <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, p.Cys133Trp in <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 5, was found in English and Canadian families and in US and Australian families of English origin [<a class="bk_pop" href="#hsn1.REF.bejaoui.2001.261">Bejaoui et al 2001</a>, <a class="bk_pop" href="#hsn1.REF.dawkins.2001.309">Dawkins et al 2001</a>].</div></li><li class="half_rhythm"><div>A <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> affecting the same codon, p.Cys133Tyr, was described in two families of Austrian and German origin [<a class="bk_pop" href="#hsn1.REF.bejaoui.2001.261">Bejaoui et al 2001</a>, <a class="bk_pop" href="#hsn1.REF.dawkins.2001.309">Dawkins et al 2001</a>].</div></li><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> p.Val144Asp in <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 6 was found in two Australian families of English and Scottish origins [<a class="bk_pop" href="#hsn1.REF.dawkins.2001.309">Dawkins et al 2001</a>].</div></li></ul><div id="hsn1.T.sptlc1_pathogenic_variants_discus" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p><i>SPTLC1</i> Pathogenic Variants Discussed in This <i>GeneReview</i></p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1390/table/hsn1.T.sptlc1_pathogenic_variants_discus/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__hsn1.T.sptlc1_pathogenic_variants_discus_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_hsn1.T.sptlc1_pathogenic_variants_discus_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_hsn1.T.sptlc1_pathogenic_variants_discus_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_hsn1.T.sptlc1_pathogenic_variants_discus_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th></tr></thead><tbody><tr><td headers="hd_h_hsn1.T.sptlc1_pathogenic_variants_discus_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.399T>G</td><td headers="hd_h_hsn1.T.sptlc1_pathogenic_variants_discus_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Cys133Trp</td><td headers="hd_h_hsn1.T.sptlc1_pathogenic_variants_discus_1_1_1_3" rowspan="5" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_006415.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_006415<wbr style="display:inline-block"></wbr>.2</a>
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<a href="https://www.ncbi.nlm.nih.gov/protein/NP_006406.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_006406<wbr style="display:inline-block"></wbr>.1</a>
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</td></tr><tr><td headers="hd_h_hsn1.T.sptlc1_pathogenic_variants_discus_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.398G>A</td><td headers="hd_h_hsn1.T.sptlc1_pathogenic_variants_discus_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Cys133Tyr</td></tr><tr><td headers="hd_h_hsn1.T.sptlc1_pathogenic_variants_discus_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.431T>A</td><td headers="hd_h_hsn1.T.sptlc1_pathogenic_variants_discus_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Val144Asp</td></tr><tr><td headers="hd_h_hsn1.T.sptlc1_pathogenic_variants_discus_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.992C>A</td><td headers="hd_h_hsn1.T.sptlc1_pathogenic_variants_discus_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ser331Tyr <sup>1</sup></td></tr><tr><td headers="hd_h_hsn1.T.sptlc1_pathogenic_variants_discus_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.992C>T</td><td headers="hd_h_hsn1.T.sptlc1_pathogenic_variants_discus_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ser331Phe <sup>1</sup></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 author. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>.hgvs.org</a>). See <a href="/books/n/gene/app3/">Quick Reference</a> for an explanation of nomenclature.</p></div></dd><dt>1. </dt><dd><div id="hsn1.TF.2.1"><p class="no_margin">See <a href="#hsn1.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>.</p></div></dd></dl></div></div></div><p><b>Variant of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>.</b> A p.Gly387Ala (<a href="https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?type=rs&rs=rs119482084" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs119482084</a>; OMIM <a href="https://omim.org/entry/605712" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">605712</a>) variant was identified in two sisters of Belgian origin [<a class="bk_pop" href="#hsn1.REF.verhoeven.2004.1001">Verhoeven et al 2004</a>]; their parents were not available for testing. Since this change has been observed in the general population and in the <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> state in a parent of an affected person [<a class="bk_pop" href="#hsn1.REF.hornemann.2009.135">Hornemann et al 2009</a>], it is unlikely to be pathogenic.</p><p><b>Normal <a class="def" href="/books/n/gene/glossary/def-item/gene-product/">gene product</a>.</b> The serine palmitoyltransferase light chain 1 has 473 amino acids.</p><p><b>Abnormal <a class="def" href="/books/n/gene/glossary/def-item/gene-product/">gene product</a>.</b> Pathogenic variants in the active sites of the <i>SPTLC1</i> result in a gain of function by altering substrate specificity allowing alanine and glycine to be incorporated into new toxic sphingolipids which cannot be degraded, leading to the accumulation of the toxic lipids 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine. Raised levels of toxic deoxy-sphingoid bases (DSBs) 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine have been reported in plasma of individuals with <i>SPTLC1-</i>related HSN [<a class="bk_pop" href="#hsn1.REF.penno.2010.11178">Penno et al 2010</a>].</p><p>Expression of the mutated <a class="def" href="/books/n/gene/glossary/def-item/gene-product/">gene product</a> has not been investigated.</p><p>Overexpression of the <a class="def" href="/books/n/gene/glossary/def-item/wild_type/">wild type</a> <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> in a mouse model of HSN1A has reversed the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> [<a class="bk_pop" href="#hsn1.REF.eichler.2009.14646">Eichler et al 2009</a>]. This finding opens the prospect of possible treatments aimed at reducing the levels of these metabolites.</p></div><div id="hsn1.Chapter_Notes"><h2 id="_hsn1_Chapter_Notes_">Chapter Notes</h2><div id="hsn1.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>2 December 2021 (aa) Revision: additions to Genetically Related Disorders and Genotype-Phenotype Correlations [<a class="bk_pop" href="#hsn1.REF.johnson.2021.1236">Johnson et al 2021</a>, <a class="bk_pop" href="#hsn1.REF.mohassel.2021.1197">Mohassel et al 2021</a>]</div></li><li class="half_rhythm"><div>21 November 2018 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>10 September 2015 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>7 March 2013 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>3 May 2012 (gn) Revision: edits to Therapies Under Investigation</div></li><li class="half_rhythm"><div>15 March 2012 (cd) Revision: <a class="def" href="/books/n/gene/glossary/def-item/targeted-mutation-analysis/">targeted mutation analysis</a> no longer listed as available clinically in the GeneTests™ Laboratory Directory</div></li><li class="half_rhythm"><div>22 September 2011 (cd) Revision: addition to Differential Diagnosis; change in disease nomenclature (HSN1 → HSN1A)</div></li><li class="half_rhythm"><div>20 July 2010 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>2 October 2007 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>11 March 2005 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>28 September 2004 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>21 May 2004 (gn) Revision: <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> available</div></li><li class="half_rhythm"><div>23 September 2002 (me) Review posted live</div></li><li class="half_rhythm"><div>21 March 2002 (gn) Original submission</div></li></ul></div></div><div id="hsn1.References"><h2 id="_hsn1_References_">References</h2><div id="hsn1.Published_Guidelines__Consensus_Sta"><h3>Published Guidelines / Consensus Statements</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="hsn1.REF1">Committee on Bioethics; Committee on Genetics, and American College of Medical Genetics and Genomics: Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available <a href="https://pediatrics.aappublications.org/content/131/3/620.full.pdf" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">online</a>. 2013. Accessed 11-30-21.</div></li><li class="half_rhythm"><div class="bk_ref" id="hsn1.REF2">National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available <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=cite-ref&targetsite=external&targetcat=link&targettype=uri">online</a>. 2018. Accessed 11-30-21.</div></li></ul></div><div id="hsn1.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="hsn1.REF.auergrumbach.2013.893">Auer-Grumbach M. Hereditary sensory and autonomic neuropathies. <span><span class="ref-journal">Handb Clin Neurol. </span>2013;<span class="ref-vol">115</span>:893–906.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23931820" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23931820</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hsn1.REF.bejaoui.2001.261">Bejaoui K, Wu C, Scheffler MD, Haan G, Ashby P, Wu L, de Jong P, Brown RH Jr. SPTLC1 is mutated in hereditary sensory neuropathy, type 1. <span><span class="ref-journal">Nat Genet. </span>2001;<span class="ref-vol">27</span>:261–2.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11242106" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11242106</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hsn1.REF.campbell.1964.67">Campbell AM, Hoffman HL. Sensory radicular neuropathy associated with muscle wasting in two cases. <span><span class="ref-journal">Brain. </span>1964;<span class="ref-vol">87</span>:67–74.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14152213" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14152213</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hsn1.REF.dawkins.2001.309">Dawkins JL, Hulme DJ, Brahmbhatt SB, Auer-Grumbach M, Nicholson GA. Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. <span><span class="ref-journal">Nat Genet. </span>2001;<span class="ref-vol">27</span>:309–12.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11242114" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11242114</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hsn1.REF.eichler.2009.14646">Eichler FS, Hornemann T, McCampbell A, Kuljis D, Penno A, Vardeh D, Tamrazian E, Garofalo K, Lee HJ, Kini L, Selig M, Frosch M, Gable K, von Eckardstein A, Woolf CJ, Guan G, Harmon JM, Dunn TM, Brown RH Jr. Overexpression of the wild-type SPT1 subunit lowers desoxysphingolipid levels and rescues the phenotype of HSAN1. <span><span class="ref-journal">J Neurosci. </span>2009;<span class="ref-vol">29</span>:14646–51.</span> [<a href="/pmc/articles/PMC3849752/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3849752</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19923297" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19923297</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hsn1.REF.garofalo.2011.4735">Garofalo K, Penno A, Schmidt BP, Lee HJ, Frosch MP, von Eckardstein A, Brown RH, Hornemann T, Eichler FS. Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. <span><span class="ref-journal">J Clin Invest. </span>2011;<span class="ref-vol">121</span>:4735–45.</span> [<a href="/pmc/articles/PMC3225995/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3225995</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22045570" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22045570</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hsn1.REF.hicks.1922.319">Hicks EP. Hereditary perforating ulcer of the foot. <span><span class="ref-journal">Lancet. </span>1922;<span class="ref-vol">1</span>:319–21.</span></div></li><li class="half_rhythm"><div class="bk_ref" id="hsn1.REF.hornemann.2009.135">Hornemann T, Penno A, Richard S, Nicholson G, van Dijk FS, Rotthier A, Timmerman V, von Eckardstein A. A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated. <span><span class="ref-journal">Neurogenetics. </span>2009;<span class="ref-vol">10</span>:135–43.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19132419" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19132419</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hsn1.REF.houlden.2006.411">Houlden H, King R, Blake J, Groves M, Love S, Woodward C, Hammans S, Nicoll J, Lennox G, O'Donovan DG, Gabriel C, Thomas PK, Reilly MM. Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I). <span><span class="ref-journal">Brain. </span>2006;<span class="ref-vol">129</span>:411–25.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16364956" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16364956</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hsn1.REF.johnson.2021.1236">Johnson JO, Chia R, Miller DE, Li R, Kumaran R, Abramzon Y, Alahmady N, Renton AE, Topp SD, Gibbs JR, Cookson MR, Sabir MS, Dalgard CL, Troakes C, Jones AR, Shatunov A, Iacoangeli A, Al Khleifat A, Ticozzi N, Silani V, Gellera C, Blair IP, Dobson-Stone C, Kwok JB, Bonkowski ES, Palvadeau R, Tienari PJ, Morrison KE, Shaw PJ, Al-Chalabi A, Brown RH Jr, Calvo A, Mora G, Al-Saif H, Gotkine M, Leigh F, Chang IJ, Perlman SJ, Glass I, Scott AI, Shaw CE, Basak AN, Landers JE, Chiò A, Crawford TO, Smith BN, Traynor BJ, et al. Association of variants in the SPTLC1 gene with juvenile amyotrophic lateral sclerosis. <span><span class="ref-journal">JAMA Neurol. </span>2021;<span class="ref-vol">78</span>:1236–48.</span> [<a href="/pmc/articles/PMC8406220/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8406220</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/34459874" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34459874</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hsn1.REF.mohassel.2021.1197">Mohassel P, Donkervoort S, Lone MA, Nalls M, Gable K, Gupta SD, Foley AR, Hu Y, Saute JAM, Moreira AL, Kok F, Introna A, Logroscino G, Grunseich C, Nickolls AR, Pourshafie N, Neuhaus SB, Saade D, Gangfuß A, Kölbel H, Piccus Z, Le Pichon CE, Fiorillo C, Ly CV, Töpf A, Brady L, Specht S, Zidell A, Pedro H, Mittelmann E, Thomas FP, Chao KR, Konersman CG, Cho MT, Brandt T, Straub V, Connolly AM, Schara U, Roos A, Tarnopolsky M, Höke A, Brown RH, Lee CH, Hornemann T, Dunn TM, Bönnemann CG. Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis. <span><span class="ref-journal">Nat Med. </span>2021;<span class="ref-vol">27</span>:1197–204.</span> [<a href="/pmc/articles/PMC9309980/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9309980</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/34059824" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34059824</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hsn1.REF.penno.2010.11178">Penno A, Reilly MM, Houlden H, Laurá M, Rentsch K, Niederkofler V, Stoeckli ET, Nicholson G, Eichler F, Brown RH Jr, von Eckardstein A, Hornemann T. Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. <span><span class="ref-journal">J Biol Chem. </span>2010;<span class="ref-vol">285</span>:11178–87.</span> [<a href="/pmc/articles/PMC2856995/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2856995</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20097765" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20097765</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hsn1.REF.rahbari.2016.126">Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR. UK10K Consortium, Hurles ME. Timing, rates and spectra of human germline mutation. <span><span class="ref-journal">Nat Genet. </span>2016;<span class="ref-vol">48</span>:126–33.</span> [<a href="/pmc/articles/PMC4731925/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4731925</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26656846" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26656846</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hsn1.REF.rotthier.2009.2699">Rotthier A, Baets J, De Vriendt E, Jacobs A, Auer-Grumbach M, Lévy N, Bonello-Palot N, Kilic SS, Weis J, Nascimento A, Swinkels M, Kruyt MC, Jordanova A, De Jonghe P, Timmerman V. Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype correlation. <span><span class="ref-journal">Brain. </span>2009;<span class="ref-vol">132</span>:2699–711.</span> [<a href="/pmc/articles/PMC2759337/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2759337</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19651702" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19651702</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hsn1.REF.suh.2014.481">Suh BC, Hong YB, Nakhro K, Nam SH, Chung KW, Choi BO. Early onset severe hereditary sensory and autonomic neuropathy type 1 with S331F SPTLC1 mutation. <span><span class="ref-journal">Mol Med Rep. </span>2014;<span class="ref-vol">9</span>:481–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24247255" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24247255</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hsn1.REF.thomas.1993.157">Thomas PK. Hereditary sensory neuropathies. <span><span class="ref-journal">Brain Pathol. </span>1993;<span class="ref-vol">3</span>:157–63.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8293177" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8293177</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hsn1.REF.verhoeven.2004.1001">Verhoeven K, Coen K, De Vriendt E, Jacobs A, Van Gerwen V, Smouts I, Pou-Serradell A, Martin JJ, Timmerman V, De Jonghe P. SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type I. <span><span class="ref-journal">Neurology. </span>2004;<span class="ref-vol">62</span>:1001–2.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15037712" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15037712</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hsn1.REF.warren.1999">Warren G, Nade S. <em>The Care of Neuropathic Limbs: A Practical Manual.</em> London and New York: Parthenon Publishing; 1999.</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
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