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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>BSCL2-Related Neurologic Disorders / Seipinopathy - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="GeneReviews® [Internet]">
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<meta name="citation_title" content="BSCL2-Related Neurologic Disorders / Seipinopathy">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2018/05/24">
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<meta name="citation_author" content="Daisuke Ito">
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<meta name="citation_pmid" content="20301484">
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<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1307/">
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<meta name="citation_keywords" content="Spastic Paraplegia 17">
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<meta name="citation_keywords" content="Silver Syndrome">
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<meta name="citation_keywords" content="Distal Hereditary Motor Neuropathy Type V (dHMN-V)">
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<meta name="citation_keywords" content="Variants of Charcot-Marie-Tooth Disease Type 2">
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<meta name="citation_keywords" content="Seipin">
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<meta name="citation_keywords" content="BSCL2">
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<meta name="citation_keywords" content="BSCL2-Related Neurologic Disorders/Seipinopathy">
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<meta name="DC.Title" content="BSCL2-Related Neurologic Disorders / Seipinopathy">
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<meta name="DC.Publisher" content="University of Washington, Seattle">
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<meta name="DC.Contributor" content="Daisuke Ito">
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<meta name="DC.Date" content="2018/05/24">
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<meta name="description" content="The spectrum of BSCL2-related neurologic disorders includes Silver syndrome and variants of Charcot-Marie-Tooth neuropathy type 2, distal hereditary motor neuropathy (dHMN) type V, and spastic paraplegia 17. Features of these disorders include onset of symptoms ranging from the first to the seventh decade, slow disease progression, upper motor neuron involvement (gait disturbance with pyramidal signs ranging from mild to severe spasticity with hyperreflexia in the lower limbs and variable extensor plantar responses), lower motor neuron involvement (amyotrophy of the peroneal muscles and small muscles of the hand), and pes cavus and other foot deformities. Disease severity is variable among and within families.">
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<meta name="og:description" content="The spectrum of BSCL2-related neurologic disorders includes Silver syndrome and variants of Charcot-Marie-Tooth neuropathy type 2, distal hereditary motor neuropathy (dHMN) type V, and spastic paraplegia 17. Features of these disorders include onset of symptoms ranging from the first to the seventh decade, slow disease progression, upper motor neuron involvement (gait disturbance with pyramidal signs ranging from mild to severe spasticity with hyperreflexia in the lower limbs and variable extensor plantar responses), lower motor neuron involvement (amyotrophy of the peroneal muscles and small muscles of the hand), and pes cavus and other foot deformities. Disease severity is variable among and within families.">
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yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK1307_"><span class="title" itemprop="name"><i>BSCL2</i>-Related Neurologic Disorders / Seipinopathy</span></h1><p class="contribs">Ito D.</p><p class="fm-aai"><a href="#_NBK1307_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 17 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="spg17.Summary" itemprop="description"><h2 id="_spg17_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>The spectrum of <i>BSCL2</i>-related neurologic disorders includes Silver syndrome and variants of Charcot-Marie-Tooth neuropathy type 2, distal hereditary motor neuropathy (dHMN) type V, and spastic paraplegia 17. Features of these disorders include onset of symptoms ranging from the first to the seventh decade, slow disease progression, upper motor neuron involvement (gait disturbance with pyramidal signs ranging from mild to severe spasticity with hyperreflexia in the lower limbs and variable extensor plantar responses), lower motor neuron involvement (amyotrophy of the peroneal muscles and small muscles of the hand), and <i>pes cavus</i> and other foot deformities. Disease severity is variable among and within families.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of a <i>BSCL2</i>-related neurologic disorder is established in a proband with characteristic clinical and electrophysiologic features and identification of a heterozygous <i>BSCL2</i> pathogenic variant on molecular genetic testing.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Symptomatic treatment includes physiotherapy, orthopedic shoes, and calipers to stabilize gait. Foot deformities may be corrected with surgery.</p><p><i>Prevention of secondary complications:</i> Early regular physiotherapy may prevent contractures.</p><p><i>Surveillance</i>: Annual evaluation of gait, strength, muscular atrophy, and deep tendon reflexes by a neurologist.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>BSCL2</i>-related neurologic disorders are inherited in an autosomal dominant manner. Each child of an individual with a <i>BSCL2</i>-related neurologic disorder has a 50% chance of inheriting the pathogenic variant. Penetrance is incomplete, with more than 20% of individuals with the pathogenic variant showing no clinical abnormalities or only minor clinical signs. Prenatal testing for a pregnancy at increased risk is possible in families in which the pathogenic variant is known; however, requests for prenatal testing for adult-onset disorders are not common.</p></div></div><div id="spg17.GeneReview_Scope"><h2 id="_spg17_GeneReview_Scope_"><i>GeneReview</i> Scope</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figspg17Tc"><a href="/books/NBK1307/table/spg17.Tc/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobspg17Tc"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="spg17.Tc"><a href="/books/NBK1307/table/spg17.Tc/?report=objectonly" target="object" rid-ob="figobspg17Tc">Table</a></h4><p class="float-caption no_bottom_margin">Distal hereditary motor neuropathy type V (dHMN-V) Silver syndrome</p></div></div></div><div id="spg17.Diagnosis"><h2 id="_spg17_Diagnosis_">Diagnosis</h2><p>The phenotypic spectrum of <i>BSCL2</i>-related neurologic disorders includes Silver syndrome and variants of Charcot-Marie-Tooth disease type 2, distal hereditary motor neuropathy (dHMN) type V, and spastic paraplegia 17.</p><div id="spg17.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>BSCL2</i>-related neurologic disorders <b>should be suspected</b> in individuals with the following clinical and electrophysiologic features.</p><p>
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<b>Clinical features</b>
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</p><ul><li class="half_rhythm"><div>Onset of symptoms from the first to seventh decade (range: age 6-66 years; mean: age 19 years)</div></li><li class="half_rhythm"><div>Slow disease progression</div></li><li class="half_rhythm"><div>Upper motor neuron involvement: gait disturbance with pyramidal signs ranging from mild to severe spasticity with hyperreflexia in the lower limbs and variable extensor plantar responses</div></li><li class="half_rhythm"><div>Lower motor neuron involvement: amyotrophy (wasting) of the peroneal muscles and the small muscles of the hand (particularly the thenar and 1st dorsal interosseus muscles) that is frequently unilateral</div></li><li class="half_rhythm"><div>Paresthesia, sensory loss, and sphincter disturbances usually absent</div></li><li class="half_rhythm"><div><i>Pes cavus</i> and other foot deformities</div></li></ul><p>
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<b>Electrophysiologic features</b>
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</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Reduced compound motor action potentials (CMAP)</b> in the lower limbs indicate primarily axonal nerve damage. Marked chronodispersion of the CMAP is found.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Motor nerve conduction velocities (MNCV)</b> are sometimes in the demyelinating range (<37 m/sec) pointing to additional demyelination of the peripheral nerves. Partial conduction blocks may occur.</div><div class="half_rhythm">Note: In the upper limbs, changes of the MNCV and CMAP are more frequently seen in the median nerve than in the ulnar nerve.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Median and sural sensory nerve conduction velocities (SNCV)</b> do not show significant changes, but reduction of the sensory nerve action potentials (SNAP) in individuals with advanced disease strongly suggests that <i>BSCL2</i> pathogenic variants also lead to axonal damage of the sensory nerves.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Electromyography</b> usually reveals chronic neurogenic disturbance with high potential amplitudes [<a class="bibr" href="#spg17.REF.auergrumbach.2000.1612" rid="spg17.REF.auergrumbach.2000.1612">Auer-Grumbach et al 2000</a>].</div></li></ul></div><div id="spg17.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of <i>BSCL2</i>-related neurologic disorders <b>is established</b> in a proband with the above <a href="#spg17.Suggestive_Findings">Suggestive Findings</a> and a heterozygous pathogenic (or likely pathogenic) variant in <i>BSCL2</i> identified by molecular genetic testing (see <a href="/books/NBK1307/table/spg17.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobspg17Tmoleculargenetictestingusedi">Table 1</a>).</p><p>Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [<a class="bibr" href="#spg17.REF.richards.2015.405" rid="spg17.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous <i>BSCL2</i> variant of uncertain significance does not establish or rule out the diagnosis</p><p>Molecular genetic testing approaches can include a combination of <b>gene-targeted testing</b> (single-gene testing, multigene panel) and <b>comprehensive</b>
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<b>genomic testing</b> (exome sequencing, genome sequencing) depending on the phenotype.</p><p>Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of <i>BSCL2</i>-related neurologic disorders is broad, individuals with the distinctive findings described in <a href="#spg17.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#spg17.Option_1">Option 1</a>), whereas those in whom the diagnosis of <i>BSCL2</i>-related neurologic disorders has not been considered are more likely to be diagnosed using genomic testing (see <a href="#spg17.Option_2">Option 2</a>).</p><div id="spg17.Option_1"><h4>Option 1</h4><p>When the phenotypic and laboratory findings suggest the diagnosis of <i>BSCL2</i>-related neurologic disorders, molecular genetic testing approaches can include <b>single-gene testing</b> or use of a <b>multigene panel</b>:</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-gene testing.</b> Sequence analysis of <i>BSCL2</i> detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.</div><div class="half_rhythm">Note: All reported pathogenic variants (<a href="/books/NBK1307/table/spg17.T.bscl2_variants_discussed_in_this/?report=objectonly" target="object" rid-ob="figobspg17Tbscl2variantsdiscussedinthis">p.Asn88Ser</a>, <a href="/books/NBK1307/table/spg17.T.bscl2_variants_discussed_in_this/?report=objectonly" target="object" rid-ob="figobspg17Tbscl2variantsdiscussedinthis">p.Ser90Leu</a>, and <a href="/books/NBK1307/table/spg17.T.bscl2_variants_discussed_in_this/?report=objectonly" target="object" rid-ob="figobspg17Tbscl2variantsdiscussedinthis">p.Ser90Trp</a>) reside in exon 3; therefore, <b>targeted analysis</b> can be performed first by sequence analysis of <i>BSCL2</i> exon 3.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A multigene panel</b> that includes <i>BSCL2</i> and other genes of interest (see <a href="#spg17.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene 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 exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, 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/?report=reader#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels_FAQs">here</a>.</div></li></ul></div><div id="spg17.Option_2"><h4>Option 2</h4><p>When the diagnosis of <i>BSCL2</i>-related neurologic disorders is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.</p><p>For an introduction to comprehensive genomic testing click <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figspg17Tmoleculargenetictestingusedi"><a href="/books/NBK1307/table/spg17.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobspg17Tmoleculargenetictestingusedi"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="spg17.T.molecular_genetic_testing_used_i"><a href="/books/NBK1307/table/spg17.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobspg17Tmoleculargenetictestingusedi">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in <i>BSCL2</i>-Related Neurologic Disorders / Seipinopathy </p></div></div></div></div></div><div id="spg17.Clinical_Characteristics"><h2 id="_spg17_Clinical_Characteristics_">Clinical Characteristics</h2><div id="spg17.Clinical_Description"><h3>Clinical Description</h3><p><i>BSCL2</i>-related neurologic disorders affect both the lower and upper motor neurons. Detailed clinical and electrophysiologic studies in 90 individuals with the <a href="/books/NBK1307/table/spg17.T.bscl2_variants_discussed_in_this/?report=objectonly" target="object" rid-ob="figobspg17Tbscl2variantsdiscussedinthis">p.Asn88Ser</a> pathogenic variant showed incomplete penetrance, clinical intrafamilial variability with several phenotypic subtypes being reported (even within the same family), and broad variation in disease severity, suggesting a subdivision into the following six main phenotypes (<b>subtypes 1-6</b>), all of which can be seen in the same family [<a class="bibr" href="#spg17.REF.auergrumbach.2005.415" rid="spg17.REF.auergrumbach.2005.415">Auer-Grumbach et al 2005</a>].</p><p><b>Subtype 1.</b> No signs or symptoms. No clinical or electrophysiologic abnormalities are present.</p><p><b>Subtype 2.</b> Clinical signs but no symptoms. Suggestive clinical signs include foot deformity, mild asymmetric thenar wasting, brisk lower-limb deep-tendon reflexes (DTRs), and/or electrophysiologic abnormalities.</p><p><b>Subtype 3.</b> Distal hereditary motor neuropathy (dHMN) type V phenotype. Symptoms are exclusively or predominantly symmetric or unilateral muscle weakness and wasting in the small muscles of the hand. Gait disturbances may occur later. Muscle tone is normal; tendon reflexes may be preserved or slightly brisk.</p><p><b>Subtype 4.</b> Silver syndrome phenotype [<a class="bibr" href="#spg17.REF.silver.1966.69" rid="spg17.REF.silver.1966.69">Silver 1966</a>]. Findings are mild-to-severe symmetric or unilateral amyotrophy of the small muscles of the hand, variable spasticity of the lower limbs, and other signs of pyramidal tract disturbance (very brisk tendon reflexes and/or extensor plantar responses and/or increased muscle tone).</p><p><b>Subtype 5.</b> Charcot-Marie-Tooth neuropathy type 2 (spinal CMT) phenotype. Findings are distal muscle weakness and wasting of the lower limbs and, to a lesser degree, of the upper limbs. Muscle tone is normal and tendon reflexes are usually preserved or slightly brisk. Depending on the absence or presence of clinical and electrophysiologic sensory abnormalities, affected individuals may show spinal CMT syndrome or hereditary motor and sensory neuropathy (HMSN) type II.</p><p><b>Subtype 6.</b> Hereditary spastic paraplegia (HSP) phenotype. Findings include: absence of weakness or wasting of the small hand muscles; and presence of spastic paraparesis in the lower limbs manifesting as EITHER of the following:</p><ul><li class="half_rhythm"><div>Pure hereditary spastic paraparesis (pHSP) when no additional clinical or electrophysiologic features (except foot deformity) are present</div></li><li class="half_rhythm"><div>Complicated hereditary spastic paraparesis (cHSP) when spasticity is accompanied by amyotrophy of the distal muscles of the legs and/or pathologic nerve conduction velocities. This latter group may also be diagnosed as hereditary motor and sensory neuropathy (HMSN) type V.</div></li></ul><p><b>Onset.</b> Most affected individuals develop symptoms in the second decade of life, but some first notice symptoms as late as the seventh decade. Only a few persons have signs before age ten years. In some individuals with mild disease, the age at onset cannot be determined as they are not aware of being affected.</p><p><b>Tendon reflexes</b> are normal in the upper extremities. Patellar and Achilles tendon reflexes are rarely absent or diminished. Most individuals have preserved or even brisk reflexes, which correspond to increased muscle tone.</p><p>Affected individuals often present with other signs of pyramidal tract involvement such as extensor plantar responses. Individuals with spasticity in the lower limbs often complain of leg stiffness and muscle cramps.</p><p><b>Hand muscle involvement</b> is a major feature. Weakness that is often more evident in one hand than the other and wasting of the thenar and first dorsal interosseus muscles often result in a characteristic adduction position of the thumb and difficulty with handwriting. In advanced stages of the disease, camptodactyly (fixed flexion deformity of the fingers) can be a significant finding in some, but not all, affected individuals. The predilection for these two muscle groups and the left-right asymmetry (which does not correlate with handedness in the affected individual) remain unexplained.</p><p><b>Gait.</b> Mild-to-severe gait abnormalities are often observed and result from EITHER or BOTH of the following:</p><ul><li class="half_rhythm"><div>Wasting and weakness of the distal muscles of the lower limbs leading to a steppage gait</div></li><li class="half_rhythm"><div>Stiffness and spasticity</div></li></ul><p><b>Foot deformity</b> is present in the majority of individuals and may vary from mild to severe <i>pes cavus</i>, congenital <i>pes planus</i>, hammertoes, or clubfeet.</p><p><b>Prognosis.</b> Disease progression is slow. People with this disorder have a generally normal life expectancy.</p><p><b>Histopathology.</b> Sural nerve biopsy shows mild loss of myelinated fibers and fiber regeneration [<a class="bibr" href="#spg17.REF.chen.2009.543" rid="spg17.REF.chen.2009.543">Chen et al 2009</a>, <a class="bibr" href="#spg17.REF.luigetti.2010.448" rid="spg17.REF.luigetti.2010.448">Luigetti et al 2010</a>]. The diameter histogram shows a reduction in small fibers (diameter <10 μm).</p></div><div id="spg17.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>Individuals with the <i>BSCL2</i> pathogenic missense variant <a href="/books/NBK1307/table/spg17.T.bscl2_variants_discussed_in_this/?report=objectonly" target="object" rid-ob="figobspg17Tbscl2variantsdiscussedinthis">p.Asn88Ser</a> (in which the amino acid asparagine required for N-glycosylation is exchanged) usually remain ambulatory and active up to old age. In many individuals, the phenotype is dominated by subtypes 2, 3, or 5 [<a class="bibr" href="#spg17.REF.auergrumbach.2000.1612" rid="spg17.REF.auergrumbach.2000.1612">Auer-Grumbach et al 2000</a>].</p><p>Individuals with the <i>BSCL2</i> pathogenic variant <a href="/books/NBK1307/table/spg17.T.bscl2_variants_discussed_in_this/?report=objectonly" target="object" rid-ob="figobspg17Tbscl2variantsdiscussedinthis">p.Ser90Leu</a> exhibit more severe phenotypes (subtypes 4 and 6). Some of these individuals may become wheelchair bound during the second decade [<a class="bibr" href="#spg17.REF.irobi.2004.2124" rid="spg17.REF.irobi.2004.2124">Irobi et al 2004</a>].</p><p>Pathogenic variant <a href="/books/NBK1307/table/spg17.T.bscl2_variants_discussed_in_this/?report=objectonly" target="object" rid-ob="figobspg17Tbscl2variantsdiscussedinthis">p.Ser90Trp</a>, which disrupts the N-glycosylation motif, was identified in affected individuals from a Korean family with autosomal dominant CMT type 2. These individuals had predominant hand involvement, pyramidal signs, and sensory loss. Notably, the majority of individuals (73%) complained of sensory loss, in which vibration sense was prominently impaired [<a class="bibr" href="#spg17.REF.choi.2013.35" rid="spg17.REF.choi.2013.35">Choi et al 2013</a>].</p><p>A variant of unknown significance (<a href="/books/NBK1307/table/spg17.T.bscl2_variants_discussed_in_this/?report=objectonly" target="object" rid-ob="figobspg17Tbscl2variantsdiscussedinthis">p.Arg96His</a>) that is not in the N-glycosylation motif was identified in an individual with sporadic dHMN from a Taiwanese cohort. In vitro studies demonstrated that this variant results in the aggregation tendency of seipin protein, but does not induce endoplasmic reticulum stress, which is characteristically provoked by both <a href="/books/NBK1307/table/spg17.T.bscl2_variants_discussed_in_this/?report=objectonly" target="object" rid-ob="figobspg17Tbscl2variantsdiscussedinthis">p.Asn88Ser</a> and <a href="/books/NBK1307/table/spg17.T.bscl2_variants_discussed_in_this/?report=objectonly" target="object" rid-ob="figobspg17Tbscl2variantsdiscussedinthis">p.Ser90Leu</a> pathogenic variants [<a class="bibr" href="#spg17.REF.hsiao.2016.e0147677" rid="spg17.REF.hsiao.2016.e0147677">Hsiao et al 2016</a>].</p><p>Note: (1) Pathogenic null variants in <i>BSCL2</i> are associated with autosomal recessive <a href="/books/n/gene/bscl/?report=reader">Berardinelli-Seip congenital lipodystrophy</a> (see <a href="#spg17.Genetically_Related_Allelic_Disord">Genetically Related Disorders</a>). (2) Exon 7 skipping due to pathogenic variant c.985C>T results in an early-onset progressive encephalopathy (see <a href="#spg17.Genetically_Related_Allelic_Disord">Genetically Related Disorders</a>).</p></div><div id="spg17.Penetrance"><h3>Penetrance</h3><p>Reduced penetrance for <i>BSCL2</i>-related neurologic disorders has been shown by <a class="bibr" href="#spg17.REF.patel.2001.209" rid="spg17.REF.patel.2001.209">Patel et al [2001]</a> and <a class="bibr" href="#spg17.REF.windpassinger.2003.99" rid="spg17.REF.windpassinger.2003.99">Windpassinger et al [2003]</a>. A detailed genotype-phenotype correlation study in 90 individuals with the <a href="/books/NBK1307/table/spg17.T.bscl2_variants_discussed_in_this/?report=objectonly" target="object" rid-ob="figobspg17Tbscl2variantsdiscussedinthis">p.Asn88Ser</a> pathogenic variant demonstrated that 24.4% of individuals with the variant remained asymptomatic (subtype 1) or were only subclinically affected (subtype 2) [<a class="bibr" href="#spg17.REF.auergrumbach.2005.415" rid="spg17.REF.auergrumbach.2005.415">Auer-Grumbach et al 2005</a>].</p></div><div id="spg17.Nomenclature"><h3>Nomenclature</h3><p>Silver syndrome was first described in 1966 in two British families [<a class="bibr" href="#spg17.REF.silver.1966.69" rid="spg17.REF.silver.1966.69">Silver 1966</a>].</p></div><div id="spg17.Prevalence"><h3>Prevalence</h3><p>The prevalence of <i>BSCL2</i>-related neurologic disorders / seipinopathy is unknown. To date, approximately 30 families worldwide with <i>BSCL2</i> pathogenic variants <a href="/books/NBK1307/table/spg17.T.bscl2_variants_discussed_in_this/?report=objectonly" target="object" rid-ob="figobspg17Tbscl2variantsdiscussedinthis">p.Asn88Ser</a> and <a href="/books/NBK1307/table/spg17.T.bscl2_variants_discussed_in_this/?report=objectonly" target="object" rid-ob="figobspg17Tbscl2variantsdiscussedinthis">p.Ser90Leu</a> have been identified and described [<a class="bibr" href="#spg17.REF.ito.2009.8" rid="spg17.REF.ito.2009.8">Ito & Suzuki 2009</a>]. <a class="bibr" href="#spg17.REF.dierick.2008.1217" rid="spg17.REF.dierick.2008.1217">Dierick et al [2008]</a> carried out genetic analyses in a cohort of 112 individuals with a clinical diagnosis of dHMN and found that pathogenic variants in <i>BSCL2</i> are one of the most common causes of dHMN (7%) (see <a href="#spg17.Differential_Diagnosis">Differential Diagnosis</a>).</p></div></div><div id="spg17.Genetically_Related_Allelic_Disord"><h2 id="_spg17_Genetically_Related_Allelic_Disord_">Genetically Related (Allelic) Disorders</h2><p>In addition to <i>BSCL2</i>-related neurologic disorders, the other phenotype associated with pathogenic variants in <i>BSCL2</i> is <a href="/books/n/gene/bscl/?report=reader">Berardinelli-Seip congenital lipodystrophy type 2</a>. Berardinelli-Seip congenital lipodystrophy (BSCL) type 1 and type 2, which are inherited in an autosomal recessive manner, are characterized by lipoatrophy affecting the trunk, limbs, and face; acromegaloid features; hepatomegaly; elevated serum concentration of triglycerides; and insulin resistance. Hypertrophic cardiomyopathy occurs in 20%-25% of affected individuals and is a significant cause of morbidity and mortality. Notably, abnormality of motor neurons has not been reported in Berardinelli-Seip congenital lipodystrophy type 2.</p><p>Exon 7 skipping in <i>BSCL2</i> due to the c.985C>T pathogenic variant results in an aberrant isoform of seipin. This pathogenic variant is lethal in both homozygosity and compound heterozygosity with a <i>BSCL</i> type 2 pathogenic variant, resulting in an early-onset progressive encephalopathy (OMIM <a href="https://omim.org/entry/615924" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615924</a>).</p></div><div id="spg17.Differential_Diagnosis"><h2 id="_spg17_Differential_Diagnosis_">Differential Diagnosis</h2><p><b>Hereditary disorders to consider in the differential diagnosis for subtypes of <i>BSCL2</i>-related neurologic disorder.</b> Other types of axonal neuropathies (see <a href="/books/n/gene/cmt/?report=reader">Charcot-Marie-Tooth Hereditary Neuropathy Overview</a>), variants of <a href="/books/n/gene/als-overview/?report=reader">amyotrophic lateral sclerosis</a> (ALS), or <a href="/books/n/gene/hsp/?report=reader">hereditary spastic paraplegia </a>may mimic <i>BSCL2</i>-related neurologic disorder subtypes:</p><ul><li class="half_rhythm"><div><b>Subtype 3.</b>
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<a href="/books/n/gene/cmt2d/?report=reader"><i>GARS1</i>-associated axonal neuropathy</a> caused by pathogenic variants in <i>GARS1</i> and inherited in an autosomal dominant manner</div></li><li class="half_rhythm"><div>
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<b>Subtype 4</b>
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</div><ul><li class="half_rhythm"><div>ALS4 (juvenile-onset motor neuron disease) caused by pathogenic variants in <i>SETX</i> and inherited in an autosomal dominant manner (See <a href="/books/n/gene/als-overview/?report=reader">ALS Overview</a>.)</div></li><li class="half_rhythm"><div>SPG3A, caused by pathogenic variants in <i>ATL1</i> and typically inherited in an autosomal dominant manner</div></li></ul></li><li class="half_rhythm"><div>
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<b>Subtype 5</b>
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</div><ul><li class="half_rhythm"><div>Charcot-Marie-Tooth neuropathy type 2 (See <a href="/books/n/gene/cmt/?report=reader">CMT Overview</a>.)</div></li><li class="half_rhythm"><div>Spinal CMT (dHMN II) caused by pathogenic variants in <i>HSPB8</i> and inherited in an autosomal dominant manner</div></li><li class="half_rhythm"><div>ALS4 (juvenile-onset motor neuron disease) caused by pathogenic variants in <i>SETX</i> and inherited in an autosomal dominant manner (See <a href="/books/n/gene/als-overview/?report=reader">ALS Overview</a>.)</div></li></ul></li><li class="half_rhythm"><div><b>Subtype 6.</b> Genes responsible for pure and complicated autosomal dominant hereditary spastic paraplegia (see <a href="/books/n/gene/hsp/?report=reader">Hereditary Spastic Paraplegia Overview</a>) and hereditary motor and sensory neuropathy type V (OMIM <a href="https://omim.org/entry/600361" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">600361</a>)</div></li></ul><p>
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<b>Acquired disorders to consider in the differential diagnosis of <i>BSCL2</i>-related neurologic disorder</b>
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</p><ul><li class="half_rhythm"><div>Acquired motor neuron disorders (e.g., multifocal motor neuropathy, amyotrophic lateral sclerosis)</div></li><li class="half_rhythm"><div>Entrapment syndromes of the upper extremities (e.g., carpal tunnel syndrome, compression of ulnar nerve)</div></li></ul></div><div id="spg17.Management"><h2 id="_spg17_Management_">Management</h2><div id="spg17.Evaluations_Following_Initial_Diag"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with <i>BSCL2</i>-related neurologic disorders, 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>Physical examination to determine extent of weakness and atrophy, <i>pes cavus</i>, gait stability, and deep tendon reflex</div></li><li class="half_rhythm"><div>EMG with NCV</div></li><li class="half_rhythm"><div>Complete family history</div></li><li class="half_rhythm"><div>Consultation with a clinical geneticist and/or genetic counselor</div></li></ul></div><div id="spg17.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Treatment remains symptomatic and affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, clinical geneticists, and physical and occupational therapists.</p><p>Physiotherapy is appropriate.</p><p>Orthopedic treatment includes orthopedic shoes and calipers (polypropylene devices that fit between the thighs and hold the legs and hips in a balanced position for standing, used in conjunction with crutches or a walker) to stabilize gait. Foot deformities are corrected surgically.</p></div><div id="spg17.Prevention_of_Secondary_Complicati"><h3>Prevention of Secondary Complications</h3><p>Early regular physiotherapy can prevent contractures to a certain extent.</p></div><div id="spg17.Surveillance"><h3>Surveillance</h3><p>Annual neurologic evaluation of gait, strength, muscular atrophy, and deep tendon reflexes by a neurologist is appropriate.</p></div><div id="spg17.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#spg17.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="spg17.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="spg17.Genetic_Counseling"><h2 id="_spg17_Genetic_Counseling_">Genetic Counseling</h2><p>
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<i>Genetic counseling is the process of providing individuals and families with
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information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
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make informed medical and personal decisions. The following section deals with genetic
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risk assessment and the use of family history and genetic testing to clarify genetic
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status for family members; it is not meant to address all personal, cultural, or
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ethical issues that may arise or to substitute for consultation with a genetics
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professional</i>. —ED.</p><div id="spg17.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>BSCL2</i>-related neurologic disorders / seipinopathy are inherited in an autosomal dominant manner.</p></div><div id="spg17.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>Most individuals diagnosed with a <i>BSCL2</i>-related neurologic disorder have an affected parent.</div></li><li class="half_rhythm"><div>A proband with a <i>BSCL2</i>-related neurologic disorder may have the disorder as the result of a <i>de novo</i> pathogenic variant. The proportion of cases caused by <i>de novo</i> pathogenic variants is unknown.</div></li><li class="half_rhythm"><div>Molecular genetic testing is recommended for the parents of a proband with an apparent <i>de novo</i> pathogenic variant; evaluation may also include detailed clinical and electrophysiologic studies.</div></li><li class="half_rhythm"><div>The family history of some individuals diagnosed with a <i>BSCL2</i>-related neurologic disorder may appear to be negative because of reduced penetrance, failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. (Note: <i>BSCL2</i>-related neurologic disorders are characterized by clinical intrafamilial variability; several phenotypic subtypes may occur even within the same family.)</div></li><li class="half_rhythm"><div>If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.</div></li></ul><p><b>Sibs of a proband.</b> The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:</p><ul><li class="half_rhythm"><div>If a parent is affected/known to have the <i>BSCL2</i> pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. However, penetrance is incomplete and approximately 24% of individuals with pathogenic variants are asymptomatic.</div></li><li class="half_rhythm"><div>If the <i>BSCL2</i> pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [<a class="bibr" href="#spg17.REF.rahbari.2016.126" rid="spg17.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>BSCL2</i> pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for a <i>BSCL2</i>-related neurologic disorder because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.</div></li></ul><p><b>Offspring of a proband.</b> Each child of an individual with a <i>BSCL2</i>-related neurologic disorder has a 50% chance of inheriting the pathogenic variant. However, penetrance is incomplete and approximately 24% of individuals with pathogenic variants are asymptomatic.</p><p><b>Other family members.</b> The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or has a pathogenic variant, the parent's family members are at risk.</p></div><div id="spg17.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p><b>Considerations in families with an apparent <i>de novo</i> pathogenic variant.</b> When neither parent of a proband with an autosomal dominant 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 alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.</p><p>
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<b>Family planning</b>
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</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer genetic counseling (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="spg17.Prenatal_Testing_and_Preimplantati"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers in North America would consider use of prenatal testing to be personal decision, discussion of these issues may be helpful. In Europe and other parts of the world, prenatal testing may be discouraged if treatment is not available.</p></div></div><div id="spg17.Resources"><h2 id="_spg17_Resources_">Resources</h2><p>
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<i>GeneReviews staff has selected the following disease-specific and/or umbrella
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support organizations and/or registries for the benefit of individuals with this disorder
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and their families. GeneReviews is not responsible for the information provided by other
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organizations. For information on selection criteria, click <a href="/books/n/gene/app4/?report=reader">here</a>.</i></p>
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<ul><li class="half_rhythm"><div>
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<b>National Institute of Neurological Disorders and Stroke (NINDS)</b>
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</div><div>
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<a href="https://www.ninds.nih.gov/Disorders/All-Disorders/Hereditary-Spastic-Paraplegia-Information-Page" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Hereditary Spastic Paraplegia</a>
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</div></li><li class="half_rhythm"><div>
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<b>National Library of Medicine Genetics Home Reference</b>
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</div><div>
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<a href="https://ghr.nlm.nih.gov/condition/distalhereditarymotorneuropathytypev" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Distal hereditary motor neuropathy, type V</a>
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</div></li><li class="half_rhythm"><div>
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<b>Spastic Paraplegia Foundation, Inc.</b>
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</div><div><b>Phone:</b> 877-773-4483</div><div><b>Email:</b> information@sp-foundation.org</div><div>
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<a href="http://sp-foundation.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">sp-foundation.org</a>
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</div></li></ul>
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</div><div id="spg17.Molecular_Genetics"><h2 id="_spg17_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 class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figspg17molgenTA"><a href="/books/NBK1307/table/spg17.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobspg17molgenTA"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="spg17.molgen.TA"><a href="/books/NBK1307/table/spg17.molgen.TA/?report=objectonly" target="object" rid-ob="figobspg17molgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">BSCL2-Related Neurologic Disorders / Seipinopathy: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figspg17molgenTB"><a href="/books/NBK1307/table/spg17.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobspg17molgenTB"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="spg17.molgen.TB"><a href="/books/NBK1307/table/spg17.molgen.TB/?report=objectonly" target="object" rid-ob="figobspg17molgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for BSCL2-Related Neurologic Disorders / Seipinopathy (View All in OMIM) </p></div></div><p><b>Gene structure.</b>
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<i>BSCL2</i> has 11 exons spanning approximately 17 kb of genomic DNA. For a detailed summary of gene and protein information, see <a href="/books/NBK1307/?report=reader#spg17.molgen.TA">Table A</a>, <b>Gene</b>.</p><p><b>Pathogenic variants.</b> To date, three pathogenic missense variants have been detected in individuals with <i>BSCL2</i>-related neurologic disorders (see <a href="/books/NBK1307/table/spg17.T.bscl2_variants_discussed_in_this/?report=objectonly" target="object" rid-ob="figobspg17Tbscl2variantsdiscussedinthis">Table 2</a>). In addition, a variant of uncertain significance, <a href="/books/NBK1307/table/spg17.T.bscl2_variants_discussed_in_this/?report=objectonly" target="object" rid-ob="figobspg17Tbscl2variantsdiscussedinthis">p.Arg96His</a>, was reported in one Taiwanese individual with distal hereditary motor neuropathy.</p><p>Note: Exon 7 skipping due to pathogenic variant c.985C>T results in an autosomal recessive early-onset progressive encephalopathy (OMIM <a href="https://omim.org/entry/615924" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615924</a>). Other reported pathogenic variants, which include loss-of-function variants, lead to <a href="/books/n/gene/bscl/?report=reader">Berardinelli-Seip congenital lipodystrophy</a>, also an autosomal recessive disorder.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figspg17Tbscl2variantsdiscussedinthis"><a href="/books/NBK1307/table/spg17.T.bscl2_variants_discussed_in_this/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobspg17Tbscl2variantsdiscussedinthis"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="spg17.T.bscl2_variants_discussed_in_this"><a href="/books/NBK1307/table/spg17.T.bscl2_variants_discussed_in_this/?report=objectonly" target="object" rid-ob="figobspg17Tbscl2variantsdiscussedinthis">Table 2. </a></h4><p class="float-caption no_bottom_margin"><i>BSCL2</i> Variants Discussed in This <i>GeneReview</i> </p></div></div><p><b>Normal gene product.</b> The function of seipin, a 398-amino acid residue integral membrane protein of the endoplasmic reticulum (ER), is regulation of adipocyte differentiation and lipid droplet formation [<a class="bibr" href="#spg17.REF.fei.2011.204" rid="spg17.REF.fei.2011.204">Fei et al 2011</a>].</p><p><b>Abnormal gene product.</b> The p.Asn88Ser and p.Ser90Leu pathogenic variants disrupt the N-glycosylation motif and appear to result in proteins that are improperly folded. Furthermore, mutated proteins abnormally accumulate in the ER and eventually lead to cell death [<a class="bibr" href="#spg17.REF.ito.2007.237" rid="spg17.REF.ito.2007.237">Ito & Suzuki 2007</a>]. The p.Asn88Ser seipin transgenic mice develop a progressive spastic motor deficit and neurogenic muscular atrophy, recapitulating the phenotype of individuals with seipinopathy [<a class="bibr" href="#spg17.REF.yagi.2011.3831" rid="spg17.REF.yagi.2011.3831">Yagi et al 2011</a>].</p></div><div id="spg17.Chapter_Notes"><h2 id="_spg17_Chapter_Notes_">Chapter Notes</h2><div id="spg17.Author_History"><h3>Author History</h3><p>Michaela Auer-Grumbach, MD; Medical University Graz (2005-2009)<br />Daisuke Ito, MD, PhD (2009-present)<br />Klaus Wagner, MD, PhD; Medical University Graz (2005-2009)</p></div><div id="spg17.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>24 May 2018 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>7 June 2012 (cd) Revision: targeted mutation analysis no longer offered clinically</div></li><li class="half_rhythm"><div>15 September 2011 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>3 September 2009 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>6 December 2005 (me) Review posted live</div></li><li class="half_rhythm"><div>2 February 2005 (kw) Original submission</div></li></ul></div></div><div id="spg17.References"><h2 id="_spg17_References_">References</h2><div id="spg17.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="spg17.REF.auergrumbach.2000.1612">Auer-Grumbach M, Loscher WN, Wagner K, Petek E, Korner E, Offenbacher H, Hartung HP. Phenotypic and genotypic heterogeneity in hereditary motor neuronopathy type V: a clinical, electrophysiological and genetic study. <span><span class="ref-journal">Brain. </span>2000;<span class="ref-vol">123</span>:1612–23.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10908191" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10908191</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="spg17.REF.auergrumbach.2005.415">Auer-Grumbach M, Schlotter-Weigel B, Lochmuller H, Strobl-Wildemann G, Auer-Grumbach P, Fischer R, Offenbacher H, Zwick EB, Robl T, Hartl G, Hartung HP, Wagner K, Windpassinger C. Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation. <span><span class="ref-journal">Ann Neurol. </span>2005;<span class="ref-vol">57</span>:415–24.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15732094" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15732094</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="spg17.REF.chen.2009.543">Chen B, Zheng R, Luan X, Zhang W, Wang Z, Yuan Y. Clinical and pathological study of distal motor neuropathy with N88S mutation in BSCL2. <span><span class="ref-journal">Neuropathology. </span>2009;<span class="ref-vol">29</span>:543–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19323790" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19323790</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="spg17.REF.choi.2013.35">Choi BO, Park MH, Chung KW, Woo HM, Koo H, Chung HK, Choi KG, Park KD, Lee HJ, Hyun YS, Koo SK. Clinical and histopathological study of Charcot-Marie-Tooth neuropathy with a novel S90W mutation in BSCL2. <span><span class="ref-journal">Neurogenetics. </span>2013;<span class="ref-vol">14</span>:35–42.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23142943" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23142943</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="spg17.REF.dierick.2008.1217">Dierick I, Baets J, Irobi J, Jacobs A, De Vriendt E, Deconinck T, Merlini L, Van den Bergh P, Rasic VM, Robberecht W, Fischer D, Morales RJ, Mitrovic Z, Seeman P, Mazanec R, Kochanski A, Jordanova A, Auer-Grumbach M, Helderman-van den Enden AT, Wokke JH, Nelis E, De Jonghe P, Timmerman V. Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study. <span><span class="ref-journal">Brain. </span>2008;<span class="ref-vol">131</span>:1217–27.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18325928" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18325928</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="spg17.REF.fei.2011.204">Fei W, Du X, Yang H. Seipin, adipogenesis and lipid droplets. <span><span class="ref-journal">Trends Endocrinol Metab. </span>2011;<span class="ref-vol">22</span>:204–10.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21497513" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21497513</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="spg17.REF.hsiao.2016.e0147677">Hsiao CT, Tsai PC, Lin CC, Liu YT, Huang YH, Liao YC, Huang HW, Lin KP, Soong BW, Lee YC. Clinical and molecular characterization of BSCL2 mutations in a Taiwanese cohort with hereditary neuropathy. <span><span class="ref-journal">PLoS One. </span>2016;<span class="ref-vol">11</span>:e0147677. </span> [<a href="/pmc/articles/PMC4729478/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4729478</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26815532" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26815532</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="spg17.REF.irobi.2004.2124">Irobi J, Van den Bergh P, Merlini L, Verellen C, Van Maldergem L, Dierick I, Verpoorten N, Jordanova A, Windpassinger C, De Vriendt E, Van Gerwen V, Auer-Grumbach M, Wagner K, Timmerman V, De Jonghe P. The phenotype of motor neuropathies associated with BSCL2 mutations is broader than Silver syndrome and distal HMN type V. <span><span class="ref-journal">Brain. </span>2004;<span class="ref-vol">127</span>:2124–30.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15242882" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15242882</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="spg17.REF.ito.2007.237">Ito D, Suzuki N. Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases. <span><span class="ref-journal">Ann Neurol. </span>2007;<span class="ref-vol">61</span>:237–50.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17387721" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17387721</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="spg17.REF.ito.2009.8">Ito D, Suzuki N. Seipinopathy: a novel endoplasmic reticulum stress-associated disease. <span><span class="ref-journal">Brain. </span>2009;<span class="ref-vol">132</span>:8–15.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18790819" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18790819</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="spg17.REF.luigetti.2010.448">Luigetti M, Fabrizi GM, Madia F, Ferrarini M, Conte A, Delgrande A, Tonali PA, Sabatelli M. Seipin S90L mutation in an Italian family with CMT2/dHMN and pyramidal signs. <span><span class="ref-journal">Muscle Nerve. </span>2010;<span class="ref-vol">42</span>:448–51.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20806400" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20806400</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="spg17.REF.patel.2001.209">Patel H, Hart PE, Warner TT, Houlston RS, Patton MA, Jeffery S, Crosby AH. The Silver syndrome variant of hereditary spastic paraplegia maps to chromosome 11q12-q14, with evidence for genetic heterogeneity within this subtype. <span><span class="ref-journal">Am J Hum Genet. </span>2001;<span class="ref-vol">69</span>:209–15.</span> [<a href="/pmc/articles/PMC1226036/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1226036</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11389484" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11389484</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="spg17.REF.rahbari.2016.126">Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. <span><span class="ref-journal">Nat Genet. </span>2016;<span class="ref-vol">48</span>:126–33.</span> [<a href="/pmc/articles/PMC4731925/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4731925</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26656846" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26656846</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="spg17.REF.richards.2015.405">Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. <span><span class="ref-journal">Genet Med. </span>2015;<span class="ref-vol">17</span>:405–24.</span> [<a href="/pmc/articles/PMC4544753/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4544753</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25741868" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25741868</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="spg17.REF.silver.1966.69">Silver JR. Familial spastic paraplegia with amyotrophy of the hands. <span><span class="ref-journal">Ann Hum Genet. </span>1966;<span class="ref-vol">30</span>:69–75.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/5964029" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 5964029</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="spg17.REF.windpassinger.2003.99">Windpassinger C, Wagner K, Petek E, Fischer R, Auer-Grumbach M. Refinement of the Silver syndrome locus on chromosome 11q12-q14 in four families and exclusion of eight candidate genes. <span><span class="ref-journal">Hum Genet. </span>2003;<span class="ref-vol">114</span>:99–109.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/13680364" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 13680364</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="spg17.REF.yagi.2011.3831">Yagi T, Ito D, Nihei Y, Ishihara T, Suzuki N. N88S seipin mutant transgenic mice develop features of seipinopathy/BSCL2-related motor neuron disease via endoplasmic reticulum stress. <span><span class="ref-journal">Hum Mol Genet. </span>2011;<span class="ref-vol">20</span>:3831–40.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21750110" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21750110</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK1307_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Daisuke Ito</span>, MD, PhD<div class="affiliation small">Department of Neurology
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School of Medicine
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Keio University
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Tokyo, Japan<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="pj.en.ten-os.9kj@oti-d" class="oemail">pj.en.ten-os.9kj@oti-d</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">December 6, 2005</span>; Last Update: <span itemprop="dateModified">May 24, 2018</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
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a registered trademark of the University of Washington, Seattle. All rights
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reserved.<p class="small">GeneReviews® chapters are owned by the University of Washington. Permission is
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hereby granted to reproduce, distribute, and translate copies of content materials for
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Washington) are included with each copy; (ii) a link to the original material is provided
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whenever the material is published elsewhere on the Web; and (iii) reproducers,
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use.</p><p class="small">For more information, see the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
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Disclaimer</a>.</p><p class="small">For questions regarding permissions or whether a specified use is allowed,
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contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div></div><h3>Publisher</h3><p><a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>, Seattle (WA)</p><h3>NLM Citation</h3><p>Ito D. BSCL2-Related Neurologic Disorders / Seipinopathy. 2005 Dec 6 [Updated 2018 May 24]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/gene/brca1/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gene/bachmann-bupp/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobspg17Tc"><div id="spg17.Tc" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1307/table/spg17.Tc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__spg17.Tc_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_spg17.Tc_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><i>BSCL2</i>-Related Neurologic Disorders / Seipinopathy: Included Phenotypes <sup>1</sup></th></tr></thead><tbody><tr><td headers="hd_h_spg17.Tc_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><ul><li class="half_rhythm"><div>Distal hereditary motor neuropathy type V (dHMN-V)</div></li><li class="half_rhythm"><div>Silver syndrome</div></li><li class="half_rhythm"><div>Variants of Charcot-Marie-Tooth disease type 2</div></li><li class="half_rhythm"><div>Spastic paraplegia 17</div></li></ul>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="spg17.TF.c.1"><p class="no_margin">For other genetic causes of these phenotypes see <a href="#spg17.Differential_Diagnosis">Differential Diagnosis</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobspg17Tmoleculargenetictestingusedi"><div id="spg17.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 <i>BSCL2</i>-Related Neurologic Disorders / Seipinopathy</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1307/table/spg17.T.molecular_genetic_testing_used_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__spg17.T.molecular_genetic_testing_used_i_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_spg17.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_spg17.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_spg17.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 Probands with a Pathogenic Variant <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_spg17.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>BSCL2</i>
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</td><td headers="hd_h_spg17.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_spg17.T.molecular_genetic_testing_used_i_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_spg17.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 deletion/duplication analysis <sup>5</sup></td><td headers="hd_h_spg17.T.molecular_genetic_testing_used_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown; none reported</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="spg17.TF.1.1"><p class="no_margin">See <a href="/books/NBK1307/?report=reader#spg17.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="spg17.TF.1.2"><p class="no_margin">See <a href="#spg17.Molecular_Genetics">Molecular Genetics</a> for information on allelic variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="spg17.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="spg17.TF.1.4"><p class="no_margin">Because this disorder is defined by the presence of a causative pathogenic variant in <i>BSCL2</i>, the variant detection rate is expected to be 100%; the rate would be less if any deletions/duplications were found to cause the disorder.</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="spg17.TF.1.5"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobspg17molgenTA"><div id="spg17.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>BSCL2-Related Neurologic Disorders / Seipinopathy: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1307/table/spg17.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__spg17.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_spg17.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_spg17.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_spg17.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_spg17.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_spg17.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_spg17.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_spg17.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/26580" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>BSCL2</i>
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</a>
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</td><td headers="hd_b_spg17.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=26580" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">11q12<wbr style="display:inline-block"></wbr>​.3</a>
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</td><td headers="hd_b_spg17.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.uniprot.org/uniprot/Q96G97" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Seipin</a>
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</td><td headers="hd_b_spg17.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://databases.lovd.nl/shared/genes/BSCL2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">BSCL2 database</a>
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</td><td headers="hd_b_spg17.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=BSCL2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">BSCL2</a>
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</td><td headers="hd_b_spg17.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=BSCL2[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">BSCL2</a>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="spg17.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
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<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
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chromosome locus from
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<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
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protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
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For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
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<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobspg17molgenTB"><div id="spg17.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for BSCL2-Related Neurologic Disorders / Seipinopathy (<a href="/omim/270685,600794,606158,615924" 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/NBK1307/table/spg17.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__spg17.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/270685" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">270685</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SPASTIC PARAPLEGIA 17, AUTOSOMAL DOMINANT; SPG17</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/600794" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">600794</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 5; HMND5</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/606158" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">606158</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">BSCL2 GENE; BSCL2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/615924" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">615924</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ENCEPHALOPATHY, PROGRESSIVE, WITH OR WITHOUT LIPODYSTROPHY; PELD</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobspg17Tbscl2variantsdiscussedinthis"><div id="spg17.T.bscl2_variants_discussed_in_this" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p><i>BSCL2</i> Variants Discussed in This <i>GeneReview</i></p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1307/table/spg17.T.bscl2_variants_discussed_in_this/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__spg17.T.bscl2_variants_discussed_in_this_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_spg17.T.bscl2_variants_discussed_in_this_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_spg17.T.bscl2_variants_discussed_in_this_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_spg17.T.bscl2_variants_discussed_in_this_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_spg17.T.bscl2_variants_discussed_in_this_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.263A>G</td><td headers="hd_h_spg17.T.bscl2_variants_discussed_in_this_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Asn88Ser</td><td headers="hd_h_spg17.T.bscl2_variants_discussed_in_this_1_1_1_3" rowspan="4" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_032667" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_032667<wbr style="display:inline-block"></wbr>​.6</a>
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<br />
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<a href="https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_116056.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_116056<wbr style="display:inline-block"></wbr>​.3</a>
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</td></tr><tr><td headers="hd_h_spg17.T.bscl2_variants_discussed_in_this_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.269C>T</td><td headers="hd_h_spg17.T.bscl2_variants_discussed_in_this_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ser90Leu</td></tr><tr><td headers="hd_h_spg17.T.bscl2_variants_discussed_in_this_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.269C>G</td><td headers="hd_h_spg17.T.bscl2_variants_discussed_in_this_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ser90Trp</td></tr><tr><td headers="hd_h_spg17.T.bscl2_variants_discussed_in_this_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.287G>A</td><td headers="hd_h_spg17.T.bscl2_variants_discussed_in_this_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg96His</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><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></dl><dl class="bkr_refwrap"><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/?report=reader">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script></div></div>
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