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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Alexander Disease - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_title" content="Alexander Disease">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2020/11/12">
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<meta name="citation_author" content="Siddharth Srivastava">
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<meta name="citation_author" content="Amy Waldman">
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<meta name="citation_author" content="Sakkubai Naidu">
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<meta name="citation_keywords" content="Glial fibrillary acidic protein">
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<meta name="DC.Contributor" content="Siddharth Srivastava">
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<meta name="DC.Contributor" content="Sakkubai Naidu">
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id="jr-pm-right" class="hidden"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 40 800" preserveAspectRatio="none"><text font-stretch="ultra-condensed" x="800" y="-15" text-anchor="end" transform="rotate(90)" font-size="18" letter-spacing=".1em">Next Page</text></svg></nav><nav id="jr-fip" class="hidden"><nav id="jr-fip-term-p"><input type="search" placeholder="search this page" id="jr-fip-term" autocorrect="off" autocomplete="off" /><a id="jr-fip-mg" class="wsprkl btn" title="Find"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 550 600" preserveAspectRatio="none"><path fill="none" stroke="#000" stroke-width="36" stroke-linecap="round" style="fill:#FFF" d="m320,350a153,153 0 1,0-2,2l170,170m-91-117 110,110-26,26-110-110"></path></svg></a><a id="jr-fip-done" class="wsprkl btn" title="Dismiss find">✘</a></nav><nav id="jr-fip-info-p"><a id="jr-fip-prev" class="wsprkl btn" title="Jump to previuos match">◀</a><button id="jr-fip-matches">no matches 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="_NBK1172_"><span class="title" itemprop="name">Alexander Disease</span></h1><p class="contribs">Srivastava S, Waldman A, Naidu S.</p><p class="fm-aai"><a href="#_NBK1172_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 32 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="alexander.Summary" itemprop="description"><h2 id="_alexander_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Alexander disease, a progressive disorder of cerebral white matter caused by a heterozygous <i>GFAP</i> pathogenic variant, comprises a continuous clinical spectrum most recognizable in infants and children and a range of nonspecific neurologic manifestations in adults. This chapter discusses the spectrum of Alexander disease as four forms: neonatal, infantile, juvenile, and adult.</p><p>The <b>neonatal form</b> begins in the first 30 days after birth with neurologic findings (e.g., hypotonia, hyperexcitability, myoclonus) and/or gastrointestinal manifestations (e.g., gastroesophageal reflux, vomiting, failure to thrive), followed by severe developmental delay and regression, seizures, megalencephaly, and typically death within two years.</p><p>The <b>infantile form</b> is characterized by variable developmental issues: initially some have delayed or plateauing of acquisition of new skills, followed in some by a loss of gross and fine motor skills and language during in the first decade or in others a slow disease course that spans decades. Seizures, often triggered by illness, may be less frequent/severe than in the neonatal form.</p><p>The <b>juvenile form</b> typically presents in childhood or adolescence with clinical and imaging features that overlap with the other forms. Manifestations in early childhood are milder than those in the infantile form (e.g., mild language delay may be the only developmental abnormality or, with language acquisition, hypophonia or nasal speech may alter the voice, often prior to appearance of other neurologic features). Vomiting and failure to thrive as well as scoliosis and autonomic dysfunction are common.</p><p>The <b>adult form</b> is typically characterized by bulbar or pseudobulbar findings (palatal myoclonus, dysphagia, dysphonia, dysarthria or slurred speech), motor/gait abnormalities with pyramidal tract signs (spasticity, hyperreflexia, positive Babinski sign), or cerebellar abnormalities (ataxia, nystagmus, or dysmetria). Others may have hemiparesis or hemiplegia with a relapsing/remitting course or slowly progressive quadriparesis or quadriplegia. Other neurologic features can include sleep apnea, diplopia or disorders of extraocular motility, and autonomic dysfunction.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of Alexander disease is established in a proband with suggestive clinical and neuroimaging findings and a heterozygous pathogenic variant in <i>GFAP</i> identified by molecular genetic testing.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Treatment is supportive and focuses on management by multidisciplinary specialists to manage general care, feeding, and nutrition; anti-seizure medication; physical and occupational therapy; speech and language therapy; and appropriate educational services.</p><p><i>Surveillance:</i> Monitoring for progression of neurologic manifestations, developmental progress, and educational needs as well as need for services as they relate to physical therapy and occupational therapy, nutrition and safety of oral feeding, speech and language, gastrointestinal involvement, bladder function, evidence of autonomic dysfunction, pulmonary function, psychological/psychiatric manifestations, and sleep.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>Alexander disease is inherited in an autosomal dominant manner. To date, most reported individuals with molecularly confirmed Alexander disease have the disorder as the result of a <i>de novo</i>
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<i>GFAP</i> pathogenic variant; however, familial cases have been reported, including individuals with slowly progressive adult Alexander disease who have an affected parent. Individuals with Alexander disease with significant neurologic and cognitive impairment typically do not reproduce, whereas each child of an adult with slowly progressing Alexander disease has a 50% chance of inheriting the <i>GFAP</i> pathogenic variant. Once the <i>GFAP</i> pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for Alexander disease are possible.</p></div></div><div id="alexander.GeneReview_Scope"><h2 id="_alexander_GeneReview_Scope_"><i>GeneReview</i> Scope</h2><p>With the currently widespread use of advanced molecular genetic testing, it is apparent that heterozygous <i>GFAP</i> pathogenic variants cause a spectrum of features ranging from cerebral white matter disease manifesting most recognizably in infants and children to a range of nonspecific neurologic manifestations in adults. The scope of this <i>GeneReview</i> encompasses all individuals with a <i>GFAP</i> pathogenic variant (regardless of clinical findings that prompted molecular genetic testing), who should be evaluated for medically actionable manifestations across the entire phenotypic spectrum of Alexander disease.</p></div><div id="alexander.Diagnosis"><h2 id="_alexander_Diagnosis_">Diagnosis</h2><div id="alexander.Suggestive_Findings"><h3>Suggestive Findings</h3><p>Alexander disease <b>should be suspected</b> in individuals with the following age-related clinical and brain MRI findings.</p><div id="alexander.Clinical_Findings"><h4>Clinical Findings</h4><p>
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<b>Neonates</b>
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</p><ul><li class="half_rhythm"><div class="half_rhythm">Weak suck, feeding difficulties, hypotonia, and myoclonus</div></li><li class="half_rhythm"><div class="half_rhythm">Progressive psychomotor impairment or developmental regression</div></li><li class="half_rhythm"><div class="half_rhythm">Megalencephaly with frontal bossing</div><div class="half_rhythm">Note: Though the terms megalencephaly and macrocephaly are sometimes used interchangeably, macrocephaly refers to head circumference that is more than two standard deviations above the mean adjusting for age and sex, whereas megalencephaly refers to increased volume of brain parenchyma. Macrocephaly – which reflects the size of intracranial contents as well as bone and scalp – may result from megalencephaly but also other medical issues, such as hydrocephalus or thickening of the skull.</div></li><li class="half_rhythm"><div class="half_rhythm">Seizures</div></li><li class="half_rhythm"><div class="half_rhythm">Occasional hydrocephalus secondary to aqueductal stenosis</div></li><li class="half_rhythm"><div class="half_rhythm">CSF protein elevation [<a class="bibr" href="#alexander.REF.springer.2000.86" rid="alexander.REF.springer.2000.86">Springer et al 2000</a>]</div></li></ul><p>
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<b>Children</b>
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</p><ul><li class="half_rhythm"><div>Developmental delay (slow attainment of developmental milestones or failure to achieve later milestones)</div></li><li class="half_rhythm"><div>Seizures</div></li><li class="half_rhythm"><div>Megalencephaly</div></li><li class="half_rhythm"><div>Gradual loss of intellectual function</div></li><li class="half_rhythm"><div>Regression after mild head injury or seizure</div></li><li class="half_rhythm"><div>Dysarthria (in those children who attain speech)</div></li><li class="half_rhythm"><div>Failure to thrive</div></li></ul><p>
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<b>Juveniles</b>
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</p><ul><li class="half_rhythm"><div>Developmental delay</div></li><li class="half_rhythm"><div>Seizures</div></li><li class="half_rhythm"><div>Bulbar/pseudobulbar signs with nasal speech, dysphagia, dysphonia</div></li><li class="half_rhythm"><div>Failure to thrive</div></li><li class="half_rhythm"><div>Intractable vomiting</div></li><li class="half_rhythm"><div>Scoliosis</div></li><li class="half_rhythm"><div>Autonomic dysfunction</div></li></ul><p>
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<b>Adults</b>
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</p><ul><li class="half_rhythm"><div>Bulbar/pseudobulbar signs</div></li><li class="half_rhythm"><div>Pyramidal tract signs</div></li><li class="half_rhythm"><div>Cerebellar signs</div></li><li class="half_rhythm"><div>Dysautonomia</div></li><li class="half_rhythm"><div>Sleep disturbance</div></li><li class="half_rhythm"><div>Gait disturbance</div></li><li class="half_rhythm"><div>Hemiparesis/hemiplegia or quadriparesis/quadriplegia</div></li><li class="half_rhythm"><div>Diplopia or oculomotor abnormalities</div></li></ul></div><div id="alexander.Brain_MRI_Findings"><h4>Brain MRI Findings</h4><p>Based on a multi-institutional retrospective survey of MRI studies of 217 individuals with leukoencephalopathy [<a class="bibr" href="#alexander.REF.van_der_knaap.2001.541" rid="alexander.REF.van_der_knaap.2001.541">van der Knaap et al 2001</a>], it has been suggested that the presence of four of the five following criteria establishes an MRI-based diagnosis of Alexander disease, which can lead to targeted genetic testing:</p><ul><li class="half_rhythm"><div>Extensive cerebral white matter abnormalities with a frontal preponderance</div></li><li class="half_rhythm"><div>Periventricular rim of decreased signal intensity on T<sub>2</sub>-weighted images and elevated signal intensity on T<sub>1</sub>-weighted images</div></li><li class="half_rhythm"><div>Abnormalities of the basal ganglia and thalami that may include one or both of the following:</div><ul><li class="half_rhythm"><div>Swelling and increased signal intensity on T<sub>2</sub>-weighted images</div></li><li class="half_rhythm"><div>Atrophy and increased/decreased signal intensity on T<sub>2</sub>-weighted images</div></li></ul></li><li class="half_rhythm"><div>Brain stem abnormalities, particularly involving the medulla and midbrain</div></li><li class="half_rhythm"><div>Contrast enhancement of one or more of the following: ventricular lining, periventricular rim, frontal white matter, optic chiasm, fornix, basal ganglia, thalamus, dentate nucleus, and brain stem</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figalexanderTalexanderdiseasemrifeatur"><a href="/books/NBK1172/table/alexander.T.alexander_disease_mri_featur/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobalexanderTalexanderdiseasemrifeatur"><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="alexander.T.alexander_disease_mri_featur"><a href="/books/NBK1172/table/alexander.T.alexander_disease_mri_featur/?report=objectonly" target="object" rid-ob="figobalexanderTalexanderdiseasemrifeatur">Table 1. </a></h4><p class="float-caption no_bottom_margin">Alexander Disease: MRI Features by Age of Presentation </p></div></div><p>Prominent or distinguishing features within the <a class="bibr" href="#alexander.REF.van_der_knaap.2001.541" rid="alexander.REF.van_der_knaap.2001.541">van der Knaap et al [2001]</a> criteria by phenotype include the following.</p><p>
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<b>Neonatal form</b>
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</p><ul><li class="half_rhythm"><div>Severe white matter abnormalities with frontal predominance and extensive pathologic periventricular enhancement demonstrated on neuroradiologic contrast imaging</div></li><li class="half_rhythm"><div>Involvement of the basal ganglia and cerebellum</div></li></ul><p>
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<b>Infantile form</b>
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</p><ul><li class="half_rhythm"><div>Frontally predominant white matter T<sub>2</sub>-weighted hyperintensity, basal ganglia involvement, and a periventricular rim are present in most individuals.</div></li><li class="half_rhythm"><div>Brain stem abnormalities are less prominent than in other forms; typical findings may include symmetric signal abnormalities of the medulla.</div></li></ul><p>
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<b>Juvenile form</b>
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</p><ul><li class="half_rhythm"><div>Significant involvement of posterior fossa structures, such as focal brain stem lesions (mimicking tumor), or T<sub>2</sub>-weighted hyperintensities in the cerebellar white matter or hilus of the dentate nuclei [<a class="bibr" href="#alexander.REF.van_der_knaap.2005.327" rid="alexander.REF.van_der_knaap.2005.327">van der Knaap et al 2005</a>]</div></li><li class="half_rhythm"><div>T<sub>1</sub>-weighted post-contrast enhancement is frequently present in posterior fossa structures.</div></li><li class="half_rhythm"><div>Some individuals may lack other features described by <a class="bibr" href="#alexander.REF.van_der_knaap.2001.541" rid="alexander.REF.van_der_knaap.2001.541">van der Knaap et al [2001]</a>.</div></li><li class="half_rhythm"><div>Characteristic imaging features of this subgroup include symmetric or asymmetric lesions in the dorsal medulla that may enhance with gadolinium administration and are often initially diagnosed as tumors, especially in the absence of other imaging features of Alexander disease.</div></li><li class="half_rhythm"><div>The later onset and presence of prominent mass-like brain stem lesions and cerebellar abnormalities distinguish this phenotype from infantile cases. Such lesions account for the vomiting and cerebellar abnormalities seen in patients with this phenotype. While some individuals may have supratentorial and infratentorial abnormalities (an intermediate phenotype described by <a class="bibr" href="#alexander.REF.yoshida.2011.1998" rid="alexander.REF.yoshida.2011.1998">Yoshida et al [2011]</a>), the extensive frontal white matter involvement is not present in every individual with juvenile onset.</div></li></ul><p>
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<b>Adult form</b>
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</p><ul><li class="half_rhythm"><div>Abnormal signal intensity of the anterior portion of the medulla oblongata along with atrophy of the medulla and cervical spinal cord</div></li><li class="half_rhythm"><div>Signal abnormalities in the cerebellar white matter or hilus of the dentate nucleus [<a class="bibr" href="#alexander.REF.van_der_knaap.2005.327" rid="alexander.REF.van_der_knaap.2005.327">van der Knaap et al 2005</a>]</div></li><li class="half_rhythm"><div>Supratentorial white matter findings that may include [<a class="bibr" href="#alexander.REF.yoshida.2020.225" rid="alexander.REF.yoshida.2020.225">Yoshida et al 2020</a>]:</div><ul><li class="half_rhythm"><div>Mild-to-moderate cerebral involvement</div></li><li class="half_rhythm"><div>T<sub>2</sub>-weighted hyperintensities that are primarily localized around the anterior horn of the lateral ventricles</div></li><li class="half_rhythm"><div>Cyst formation in white matter around the anterior horn of the lateral ventricles</div></li><li class="half_rhythm"><div>Appearance of garland-like structures along the ventricular wall (ventricular garlands), reported to represent blood vessels with a high density of periventricular Rosenthal fibers [<a class="bibr" href="#alexander.REF.van_der_knaap.2006.494" rid="alexander.REF.van_der_knaap.2006.494">van der Knaap et al 2006</a>]</div></li></ul></li></ul></div></div><div id="alexander.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of Alexander disease <b>is established</b> in a proband with suggestive clinical and neuroimaging findings and a heterozygous pathogenic variant in <i>GFAP</i> identified by molecular genetic testing (see <a href="/books/NBK1172/table/alexander.T.molecular_genetic_testing_us/?report=objectonly" target="object" rid-ob="figobalexanderTmoleculargenetictestingus">Table 2</a>).</p><p>Note: Identification of a heterozygous <i>GFAP</i> variant of uncertain significance does not establish or rule out the diagnosis of Alexander disease.</p><p>Molecular genetic testing approaches can include a combination of <b>gene-targeted testing</b> (single-gene testing and multigene panel) and <b>comprehensive</b>
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<b>genomic testing</b> (exome sequencing, 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. Individuals with the distinctive findings described in <a href="#alexander.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#alexander.Option_1">Option 1</a>), whereas those in whom the diagnosis of Alexander disease has not been considered are more likely to be diagnosed using genomic testing (see <a href="#alexander.Option_2">Option 2</a>).</p><div id="alexander.Option_1"><h4>Option 1</h4><p><b>Single-gene testing.</b> Sequence analysis of <i>GFAP</i> is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.</p><p>Note: Alexander disease occurs through a gain-of-function mechanism (see <a href="#alexander.Molecular_Genetics">Molecular Genetics</a>) and, thus, intragenic deletion or duplication is a rare cause of disease; however, one in-frame exon deletion has been reported (see <a href="/books/NBK1172/table/alexander.T.molecular_genetic_testing_us/?report=objectonly" target="object" rid-ob="figobalexanderTmoleculargenetictestingus">Table 2</a>).</p><p><b>A leukodystrophy multigene panel</b> that includes <i>GFAP</i> and other genes of interest (see <a href="#alexander.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.</p><p>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>.</p></div><div id="alexander.Option_2"><h4>Option 2</h4><p><b>Comprehensive</b>
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<b>genomic testing</b> does not require the clinician to determine which gene is likely involved. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> 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="figalexanderTmoleculargenetictestingus"><a href="/books/NBK1172/table/alexander.T.molecular_genetic_testing_us/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobalexanderTmoleculargenetictestingus"><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="alexander.T.molecular_genetic_testing_us"><a href="/books/NBK1172/table/alexander.T.molecular_genetic_testing_us/?report=objectonly" target="object" rid-ob="figobalexanderTmoleculargenetictestingus">Table 2. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in Alexander Disease </p></div></div></div></div></div><div id="alexander.Clinical_Characteristics"><h2 id="_alexander_Clinical_Characteristics_">Clinical Characteristics</h2><div id="alexander.Clinical_Description"><h3>Clinical Description</h3><p>Alexander disease is a progressive disorder affecting cerebral white matter. It is most readily recognized in infants and children. Adults can also be affected, but manifestations and diagnosis may be under-recognized. Life expectancy is variable. Many individuals with Alexander disease present with nonspecific neurologic manifestations.</p><p>Previous classification recognized four forms: neonatal (sometimes considered a subset of the infantile form), infantile, juvenile, and adult. Based on a prior review of reports of <i>GFAP</i> variants, the infantile form of Alexander disease accounts for 42% (124/293) of reported individuals with an identifiable <i>GFAP</i> pathogenic variant; the juvenile form accounts for 22% (63/293); and the adult form accounts for 33% (96/293) (see <a href="/books/NBK1172/bin/alexander-table3.pdf">Table 3</a> [pdf]). Ten (3%) of the 293 individuals with an identifiable <i>GFAP</i> pathogenic variant were reported to be asymptomatic [<a class="bibr" href="#alexander.REF.stumpf.2003.1307" rid="alexander.REF.stumpf.2003.1307">Stumpf et al 2003</a>, <a class="bibr" href="#alexander.REF.shiihara.2004.125" rid="alexander.REF.shiihara.2004.125">Shiihara et al 2004</a>, <a class="bibr" href="#alexander.REF.yoshida.2011.1998" rid="alexander.REF.yoshida.2011.1998">Yoshida et al 2011</a>, <a class="bibr" href="#alexander.REF.messing.2012.208" rid="alexander.REF.messing.2012.208">Messing et al 2012</a>, <a class="bibr" href="#alexander.REF.wada.2013.161" rid="alexander.REF.wada.2013.161">Wada et al 2013</a>]. The current clinical status of these individuals is unknown.</p><p>Additional case series have suggested a two-group classification system (Type I and Type II) [<a class="bibr" href="#alexander.REF.prust.2011.1287" rid="alexander.REF.prust.2011.1287">Prust et al 2011</a>] or a three-group classification system (cerebral, bulbospinal, intermediate) [<a class="bibr" href="#alexander.REF.yoshida.2011.1998" rid="alexander.REF.yoshida.2011.1998">Yoshida et al 2011</a>].</p><p>See <a href="/books/NBK1172/table/alexander.T.alexander_disease_comparison/?report=objectonly" target="object" rid-ob="figobalexanderTalexanderdiseasecomparison">Table 4</a> for a comparison of select features seen in the different forms (based on age of onset).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figalexanderTalexanderdiseasecomparison"><a href="/books/NBK1172/table/alexander.T.alexander_disease_comparison/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobalexanderTalexanderdiseasecomparison"><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="alexander.T.alexander_disease_comparison"><a href="/books/NBK1172/table/alexander.T.alexander_disease_comparison/?report=objectonly" target="object" rid-ob="figobalexanderTalexanderdiseasecomparison">Table 4. </a></h4><p class="float-caption no_bottom_margin">Alexander Disease: Comparison of Forms by Select Features </p></div></div><p>The forms described in <a href="/books/NBK1172/table/alexander.T.alexander_disease_comparison/?report=objectonly" target="object" rid-ob="figobalexanderTalexanderdiseasecomparison">Table 4</a> and below likely represent a phenotypic continuum rather than distinct classifications. However, subgrouping is intended to help clinicians care for affected individuals and explain the disorder to them and/or their families.</p><p><b>Neonatal form.</b> Neurologic manifestations (e.g., hypotonia, hyperexcitability, myoclonus) and/or gastrointestinal manifestations (e.g., gastroesophageal reflux, vomiting, failure to thrive) begin within 30 days of birth [<a class="bibr" href="#alexander.REF.springer.2000.86" rid="alexander.REF.springer.2000.86">Springer et al 2000</a>]. Affected children fail to achieve early milestones, and if they do, may show developmental regression (though developmental regression may be difficult to identify at such an early age and may manifest only as loss of sucking reflex). Following these initial findings, seizures occur during the neonatal period or infancy. Seizures may be generalized, frequent, and/or intractable. Megalencephaly, with frontal bossing or over-proportional head growth compared to weight and length, occurs over the first several months of life. In this age group specifically, children should be monitored for hydrocephalus with raised intracranial pressure, primarily caused by aqueductal stenosis. Neurologic examination is notable for severe cognitive, language, and motor delay without prominent spasticity or ataxia. Rapid progression may occur, leading to severe disability or death, typically within two years.</p><p><b>Infantile form.</b> Affected children typically present with developmental delay or plateau (failure to gain additional skills). The acquisition of developmental milestones is variable. While some children learn to walk and speak in phrases or sentences, others do not achieve independent ambulation and demonstrate limited spoken language ability. Dysarthria is frequently present in individuals who achieve expressive language.</p><p>Most children are referred to neurology after an initial seizure, often leading to brain MRI that reveals characteristic features (see <a href="/books/NBK1172/table/alexander.T.alexander_disease_mri_featur/?report=objectonly" target="object" rid-ob="figobalexanderTalexanderdiseasemrifeatur">Table 1</a>) and recognition of the disorder. Seizures (often triggered by illness) may be less frequent/severe than in the neonatal form.</p><p>Frontal bossing and megalencephaly are not universally present. Macrocephaly is not always noted at the time of other neurologic manifestations (e.g., seizures, developmental delay) and may be detected through serial measurement of the head circumference many years after the initial neurologic manifestations and diagnosis.</p><p>While developmental regression may occur after a seizure or mild head trauma, some individuals can regain skills over time. Disease progression is also variable, with some individuals losing gross and fine motor as well as language skills in the first decade of life, while others follow a very slow disease course that spans decades.</p><p><b>Juvenile form.</b> Children may present with a combined or intermediate [<a class="bibr" href="#alexander.REF.yoshida.2011.1998" rid="alexander.REF.yoshida.2011.1998">Yoshida et al 2011</a>] phenotype with clinical and imaging features overlapping those of the other forms. Onset is usually in childhood or adolescence.</p><p>Compared to the infantile form, affected children have milder manifestations in early childhood. For example, mild language delay may be the only developmental abnormality or, with language acquisition, a change in voice (hypophonia or nasal speech) may develop, often prior to other neurologic features. Children and adolescents with this phenotype frequently have vomiting and failure to thrive as well as scoliosis and autonomic dysfunction.</p><p>Some individuals with Alexander disease present with vomiting as the only manifestation of bulbar dysfunction (i.e., dysphagia and dysphonia may not be present initially) [<a class="bibr" href="#alexander.REF.namekawa.2012.1389" rid="alexander.REF.namekawa.2012.1389">Namekawa et al 2012</a>]. Anorexia is frequently present as well, and affected individuals may be diagnosed with an eating disorder. Over time, individuals have failure to thrive (poor weight gain) and delayed physical growth (short stature). Progressive scoliosis occurs in some individuals.</p><p>It is possible that this phenotype represents a spectrum of disease with other presentations. Longitudinal evaluations of individuals with Alexander disease have deidentified those with isolated brain stem lesions whose symptoms spontaneously resolved and who subsequently developed medullary and cervical cord atrophy as noted in the adult phenotype [<a class="bibr" href="#alexander.REF.namekawa.2012.1389" rid="alexander.REF.namekawa.2012.1389">Namekawa et al 2012</a>].</p><p><b>Adult form.</b> Adults typically present with bulbar or motor manifestations reflecting the prominent infratentorial involvement in this form. Bulbar or pseudobulbar manifestations include palatal myoclonus, dysphagia, dysphonia, dysarthria, or slurred speech. Other individuals present with gait abnormalities and are noted to have pyramidal tract signs (spasticity, hyperreflexia, positive Babinski sign) or cerebellar abnormalities (ataxia, nystagmus, or dysmetria). While some individuals have hemiparesis or hemiplegia and may have a relapsing remitting course [<a class="bibr" href="#alexander.REF.ayaki.2010.1292" rid="alexander.REF.ayaki.2010.1292">Ayaki et al 2010</a>], others have a slowly progressive quadriparesis or quadriplegia. Other features include sleep apnea, diplopia or disorders of extraocular motility (impaired smooth pursuit, gaze-evoked horizontal nystagmus, slowed saccades, or ocular myoclonus) [<a class="bibr" href="#alexander.REF.martidis.1999.265" rid="alexander.REF.martidis.1999.265">Martidis et al 1999</a>], and autonomic dysfunction (incontinence, constipation, pollakiuria [urinary frequency], urinary retention, impotence, sweating abnormality, hypothermia, orthostatic hypotension) [<a class="bibr" href="#alexander.REF.spritzer.2013.333" rid="alexander.REF.spritzer.2013.333">Spritzer et al 2013</a>].</p><p><b>Variable expressivity</b> is most frequently observed in affected individuals within a family in which mildly affected parents and sibs of affected individuals have a <i>GFAP</i> pathogenic variant [<a class="bibr" href="#alexander.REF.messing.2018.693" rid="alexander.REF.messing.2018.693">Messing 2018</a>].</p><p>In contrast, in one family all three individuals with a <i>GFAP</i> pathogenic variant had mild manifestations: a boy age 16 months had macrocephaly; his mother (age 34 years) and sister (age 7 years) had normal physical and neurologic examinations, including head circumference. However, their brain MRIs showed abnormal signal intensities in the deep frontal white matter and caudate [<a class="bibr" href="#alexander.REF.shiihara.2004.125" rid="alexander.REF.shiihara.2004.125">Shiihara et al 2004</a>]. Clinical follow up has not been reported.</p><p><b>EEG.</b> Electroencephalographic studies are nonspecific. While some individuals may have a normal EEG, others may show slow waves over the frontal areas. Focal epileptiform discharges have been reported, and may be related to cortical abnormalities [<a class="bibr" href="#alexander.REF.gordon.2003.395" rid="alexander.REF.gordon.2003.395">Gordon 2003</a>], although generalized patterns have also occurred, likely due to thalamic involvement.</p><p><b>Histologic studies.</b> Prior to the definition of the molecular genetic basis of Alexander disease, the demonstration of enormous numbers of Rosenthal fibers on brain biopsy or at autopsy was the only method for definitive diagnosis. Rosenthal fibers are intracellular inclusion bodies composed of aggregates of glial fibrillary acidic protein, vimentin, αβ-crystallin, and heat shock protein 27 found exclusively in astrocytes. Rosenthal fibers increase in size and number during the course of the disease. Some individuals with mass-like lesions have been biopsied, and the presence of Rosenthal fibers has led to genetic confirmation of Alexander disease.</p></div><div id="alexander.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>A number of genotype-phenotype correlations have been observed for some recurrent variants, albeit with a limited number of affected individuals (see <a href="/books/NBK1172/bin/alexander-table3.pdf">Table 3</a> [pdf] for references and <a href="/books/NBK1172/table/alexander.T.notable_gfap_pathogenic_vari/?report=objectonly" target="object" rid-ob="figobalexanderTnotablegfappathogenicvari">Table 11</a>). It is possible that given the variable expressivity of the disorder, exceptions may occur.</p><ul><li class="half_rhythm"><div><b>Infantile form.</b> Recurrent pathogenic variants commonly (but not necessarily exclusively) observed in this form include: p.Met73Thr (c.218T>C), p.Leu76Phe (c.226C>T), p.Asn77Ser (c.230A>G), p.Arg79Cys (c.235C>T), p.Arg88Cys (c.262C>T), p.Leu97Pro (c.290T>C), p.Arg239Cys (c.715C>T), p.Arg239His (c.716G>A), p.Arg239Leu (c.716G>T), p.Arg239Pro (c.716G>C), p.Leu352Pro (c.1055T>C), p.Glu373Lys (c.1117G>A), p.Asp417MetfsTer15 (c.1249delG).</div></li><li class="half_rhythm"><div><b>Juvenile form.</b> Recurrent pathogenic variants commonly (but not necessarily exclusively) observed in this form include: p.Arg79Cys (c.235C>T), p.Arg88Cys (c.262C>T), p.Glu210Lys (c.628G>A), p.Leu235Pro (c.704T>C), p.Arg239Cys (c.715C>T), p.Arg416Trp (c.1246C>T).</div></li><li class="half_rhythm"><div><b>Adult form.</b> Recurrent pathogenic variants commonly (but not necessarily exclusively) observed in this form include: p.Arg66Gln (c.197G>A), p.Arg70Trp (208C>T), p.Arg70Gln (c.209G>A), p.Met74Thr (c.221T>C), p.Glu205Lys (c.613G>A), p.Arg258Cys (c.772C>T), p.Arg276Leu (c.827G>T), p.Leu359Pro (c.1076T>C), p.Ala364Thr (c.1090G>C), p.Ser393Ile (c.1178G>T), p.Arg416Trp (c.1246C>T).</div></li></ul></div><div id="alexander.Penetrance"><h3>Penetrance</h3><p>Penetrance appears to be nearly 100% in individuals with the infantile and juvenile forms [<a class="bibr" href="#alexander.REF.li.2002.259" rid="alexander.REF.li.2002.259">Li et al 2002</a>, <a class="bibr" href="#alexander.REF.messing.2003a.75" rid="alexander.REF.messing.2003a.75">Messing & Brenner 2003a</a>, <a class="bibr" href="#alexander.REF.messing.2018.693" rid="alexander.REF.messing.2018.693">Messing 2018</a>].</p><p>Reports of molecularly confirmed familial cases support the existence of asymptomatic adults with Alexander disease [<a class="bibr" href="#alexander.REF.stumpf.2003.1307" rid="alexander.REF.stumpf.2003.1307">Stumpf et al 2003</a>, <a class="bibr" href="#alexander.REF.shiihara.2004.125" rid="alexander.REF.shiihara.2004.125">Shiihara et al 2004</a>, <a class="bibr" href="#alexander.REF.messing.2012.208" rid="alexander.REF.messing.2012.208">Messing et al 2012</a>, <a class="bibr" href="#alexander.REF.wada.2013.161" rid="alexander.REF.wada.2013.161">Wada et al 2013</a>].</p></div><div id="alexander.Nomenclature"><h3>Nomenclature</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figalexanderTalexanderdiseasecomparison1"><a href="/books/NBK1172/table/alexander.T.alexander_disease_comparison_1/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figobalexanderTalexanderdiseasecomparison1"><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="alexander.T.alexander_disease_comparison_1"><a href="/books/NBK1172/table/alexander.T.alexander_disease_comparison_1/?report=objectonly" target="object" rid-ob="figobalexanderTalexanderdiseasecomparison1">Table 5. </a></h4><p class="float-caption no_bottom_margin">Alexander Disease: Comparison of Classification Systems </p></div></div></div><div id="alexander.Prevalence"><h3>Prevalence</h3><p>The prevalence of Alexander disease is not known, but hundreds of affected individuals with heterozygous <i>GFAP</i> pathogenic variants have been reported.</p><p>The only population-based prevalence estimate is one in 2.7 million [<a class="bibr" href="#alexander.REF.yoshida.2011.1998" rid="alexander.REF.yoshida.2011.1998">Yoshida et al 2011</a>].</p><p>The disorder is known to occur in diverse ethnic and racial groups [<a class="bibr" href="#alexander.REF.gorospe.2006.113" rid="alexander.REF.gorospe.2006.113">Gorospe & Maletkovic 2006</a>].</p></div></div><div id="alexander.Genetically_Related_Allelic_Di"><h2 id="_alexander_Genetically_Related_Allelic_Di_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with heterozygous germline pathogenic variants in <i>GFAP</i>.</p></div><div id="alexander.Differential_Diagnosis"><h2 id="_alexander_Differential_Diagnosis_">Differential Diagnosis</h2><p>Alexander disease is usually considered in the differential diagnosis of infants who present with megalencephaly, developmental delay, spasticity, and seizures, or in older individuals who have a preponderance of brain stem signs and spasticity with or without megalencephaly or seizures.</p><div id="alexander.Differential_Diagnosis_in_Neon"><h3>Differential Diagnosis in Neonates, Infants, and Juveniles</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figalexanderTgenesofinterestinthedif"><a href="/books/NBK1172/table/alexander.T.genes_of_interest_in_the_dif/?report=objectonly" target="object" title="Table 6. " class="img_link icnblk_img" rid-ob="figobalexanderTgenesofinterestinthedif"><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="alexander.T.genes_of_interest_in_the_dif"><a href="/books/NBK1172/table/alexander.T.genes_of_interest_in_the_dif/?report=objectonly" target="object" rid-ob="figobalexanderTgenesofinterestinthedif">Table 6. </a></h4><p class="float-caption no_bottom_margin">Genes of Interest in the Differential Diagnosis of the Neonatal, Infantile, and Juvenile Forms of Alexander Disease </p></div></div></div><div id="alexander.Differential_Diagnosis_in_Adul"><h3>Differential Diagnosis in Adults</h3><p><b>Multiple sclerosis (MS).</b> Similar to Alexander disease, MS is characterized by relapsing and remitting hemiparesis or hemiplegia, dysarthria, and ataxia. On MRI, MS is associated with mild frontal white matter involvement, periventricular rim, and brain stem or cervical cord signal abnormalities. Unlike Alexander disease, MS is not inherited in an autosomal dominant manner and, on MRI, MS is associated with generalized brain atrophy (rather than symmetric brain stem signal abnormalities with medullary and cord atrophy as in Alexander disease).</p><p>Hereditary disorders in the differential diagnosis of the adult form of Alexander disease are summarized in <a href="/books/NBK1172/table/alexander.T.genes_of_interest_in_the_dif_1/?report=objectonly" target="object" rid-ob="figobalexanderTgenesofinterestinthedif1">Table 7</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figalexanderTgenesofinterestinthedif1"><a href="/books/NBK1172/table/alexander.T.genes_of_interest_in_the_dif_1/?report=objectonly" target="object" title="Table 7. " class="img_link icnblk_img" rid-ob="figobalexanderTgenesofinterestinthedif1"><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="alexander.T.genes_of_interest_in_the_dif_1"><a href="/books/NBK1172/table/alexander.T.genes_of_interest_in_the_dif_1/?report=objectonly" target="object" rid-ob="figobalexanderTgenesofinterestinthedif1">Table 7. </a></h4><p class="float-caption no_bottom_margin">Genes of Interest in the Differential Diagnosis of the Adult Form of Alexander Disease </p></div></div></div></div><div id="alexander.Management"><h2 id="_alexander_Management_">Management</h2><p>No clinical practice guidelines for Alexander disease have been published.</p><div id="alexander.Evaluations_Following_Initial"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with Alexander disease, the evaluations summarized in <a href="/books/NBK1172/table/alexander.T.recommended_evaluations_foll/?report=objectonly" target="object" rid-ob="figobalexanderTrecommendedevaluationsfoll">Table 8</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figalexanderTrecommendedevaluationsfoll"><a href="/books/NBK1172/table/alexander.T.recommended_evaluations_foll/?report=objectonly" target="object" title="Table 8. " class="img_link icnblk_img" rid-ob="figobalexanderTrecommendedevaluationsfoll"><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="alexander.T.recommended_evaluations_foll"><a href="/books/NBK1172/table/alexander.T.recommended_evaluations_foll/?report=objectonly" target="object" rid-ob="figobalexanderTrecommendedevaluationsfoll">Table 8. </a></h4><p class="float-caption no_bottom_margin">Recommended Evaluations Following Initial Diagnosis in Individuals with Alexander Disease </p></div></div></div><div id="alexander.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>No specific therapy is currently available for Alexander disease; however, clinicians and families should routinely check <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> or other experts regarding potential experimental therapies [<a class="bibr" href="#alexander.REF.hagemann.2018.27" rid="alexander.REF.hagemann.2018.27">Hagemann et al 2018</a>].</p><p>Management is supportive and includes attention to general care, feeding and nutrition, anti-seizure medication (ASM) for seizure control, physical and occupational therapy, speech and language therapy, and appropriate educational services. The management by multidisciplinary specialists as outlined in <a href="/books/NBK1172/table/alexander.T.treatment_of_manifestations/?report=objectonly" target="object" rid-ob="figobalexanderTtreatmentofmanifestations">Table 9</a> is recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figalexanderTtreatmentofmanifestations"><a href="/books/NBK1172/table/alexander.T.treatment_of_manifestations/?report=objectonly" target="object" title="Table 9. " class="img_link icnblk_img" rid-ob="figobalexanderTtreatmentofmanifestations"><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="alexander.T.treatment_of_manifestations"><a href="/books/NBK1172/table/alexander.T.treatment_of_manifestations/?report=objectonly" target="object" rid-ob="figobalexanderTtreatmentofmanifestations">Table 9. </a></h4><p class="float-caption no_bottom_margin">Treatment of Manifestations in Individuals with Alexander Disease </p></div></div><div id="alexander.Developmental_Delay__Intellect"><h4>Developmental Delay / Intellectual Disability Management Issues</h4><p>The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.</p><p><b>Ages 0-3 years.</b> Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.</p><p><b>Ages 3-5 years.</b> In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.</p><p><b>All ages.</b> Consultation with specialists is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:</p><ul><li class="half_rhythm"><div>IEP services:</div><ul><li class="half_rhythm"><div>An IEP provides specially designed instruction and related services to children who qualify.</div></li><li class="half_rhythm"><div>IEP services will be reviewed annually to determine whether any changes are needed.</div></li><li class="half_rhythm"><div>Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.</div></li><li class="half_rhythm"><div>Hearing consultants should be a part of the child's IEP team to support access to academic material.</div></li><li class="half_rhythm"><div>PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.</div></li><li class="half_rhythm"><div>As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.</div></li></ul></li><li class="half_rhythm"><div>A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.</div></li><li class="half_rhythm"><div>Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.</div></li><li class="half_rhythm"><div>Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.</div></li></ul></div></div><div id="alexander.Surveillance"><h3>Surveillance</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figalexanderTrecommendedsurveillancefor"><a href="/books/NBK1172/table/alexander.T.recommended_surveillance_for/?report=objectonly" target="object" title="Table 10. " class="img_link icnblk_img" rid-ob="figobalexanderTrecommendedsurveillancefor"><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="alexander.T.recommended_surveillance_for"><a href="/books/NBK1172/table/alexander.T.recommended_surveillance_for/?report=objectonly" target="object" rid-ob="figobalexanderTrecommendedsurveillancefor">Table 10. </a></h4><p class="float-caption no_bottom_margin">Recommended Surveillance for Individuals with Alexander Disease </p></div></div></div><div id="alexander.Evaluation_of_Relatives_at_Ris"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#alexander.Related_Genetic_Counseling_Iss">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="alexander.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="alexander.Genetic_Counseling"><h2 id="_alexander_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="alexander.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Alexander disease is inherited in an autosomal dominant manner.</p></div><div id="alexander.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>To date, most reported individuals with molecularly confirmed Alexander disease have the disorder as the result of a <i>de novo</i>
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<i>GFAP</i> pathogenic variant, though familial cases have occurred [<a class="bibr" href="#alexander.REF.messing.2018.693" rid="alexander.REF.messing.2018.693">Messing 2018</a>].</div></li><li class="half_rhythm"><div>A study on unrelated individuals with Alexander disease revealed that the <i>GFAP</i> pathogenic variant was on the paternal chromosome in a majority of individuals (24/28), suggesting that most instances of <i>de novo</i> mutation occur during spermatogenesis rather than in the embryo [<a class="bibr" href="#alexander.REF.li.2006.137" rid="alexander.REF.li.2006.137">Li et al 2006</a>].</div></li><li class="half_rhythm"><div>Some individuals with slowly progressive adult Alexander disease have an affected parent [<a class="bibr" href="#alexander.REF.namekawa.2002.779" rid="alexander.REF.namekawa.2002.779">Namekawa et al 2002</a>, <a class="bibr" href="#alexander.REF.okamoto.2002.71" rid="alexander.REF.okamoto.2002.71">Okamoto et al 2002</a>, <a class="bibr" href="#alexander.REF.stumpf.2003.1307" rid="alexander.REF.stumpf.2003.1307">Stumpf et al 2003</a>, <a class="bibr" href="#alexander.REF.thyagarajan.2004.1244" rid="alexander.REF.thyagarajan.2004.1244">Thyagarajan et al 2004</a>, <a class="bibr" href="#alexander.REF.van_der_knaap.2006.494" rid="alexander.REF.van_der_knaap.2006.494">van der Knaap et al 2006</a>, <a class="bibr" href="#alexander.REF.messing.2012.208" rid="alexander.REF.messing.2012.208">Messing et al 2012</a>].</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 (i.e., a proband who appears to be the only affected family member).</div></li><li class="half_rhythm"><div>If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:</div><ul><li class="half_rhythm"><div class="half_rhythm">The proband has a <i>de novo</i> pathogenic variant. Note: A pathogenic variant is reported as "<i>de novo</i>" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed <i>de novo</i>" [<a class="bibr" href="#alexander.REF.richards.2015.405" rid="alexander.REF.richards.2015.405">Richards et al 2015</a>].</div></li><li class="half_rhythm"><div class="half_rhythm">The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. * Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. Sib recurrence of neuropathologically and molecularly proven Alexander disease in families in which the parents are neurologically intact suggest the possibility of germline mosaicism in one of the parents [<a class="bibr" href="#alexander.REF.messing.2012.208" rid="alexander.REF.messing.2012.208">Messing et al 2012</a>, <a class="bibr" href="#alexander.REF.messing.2018.693" rid="alexander.REF.messing.2018.693">Messing 2018</a>].</div><div class="half_rhythm">* An individual with somatic and germline mosaicism for a <i>GFAP</i> pathogenic variant may be mildly/minimally affected [<a class="bibr" href="#alexander.REF.flint.2012.1141" rid="alexander.REF.flint.2012.1141">Flint et al 2012</a>].</div></li></ul></li><li class="half_rhythm"><div>Some individuals with Alexander disease may appear to be the only affected family member because of failure to recognize the disorder in other family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced penetrance.</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 of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.</div></li><li class="half_rhythm"><div>Variable expressivity may occur in heterozygous family members (see <a href="#alexander.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a> and <a href="#alexander.Penetrance">Penetrance</a>).</div></li><li class="half_rhythm"><div>If the <i>GFAP</i> pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [<a class="bibr" href="#alexander.REF.messing.2018.693" rid="alexander.REF.messing.2018.693">Messing 2018</a>].</div></li><li class="half_rhythm"><div>If the parents have not been tested for the <i>GFAP</i> pathogenic variant but are clinically unaffected, the risk to the sibs of a proband with Alexander disease appears to be lower than 1:200 (i.e., <0.5%) because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.</div></li></ul><p>
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<b>Offspring of a proband</b>
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</p><ul><li class="half_rhythm"><div>Individuals with Alexander disease with significant neurologic and cognitive impairment typically do not reproduce.</div></li><li class="half_rhythm"><div>Each child of an adult with slowly progressing Alexander disease has a 50% chance of inheriting the <i>GFAP</i> pathogenic variant.</div></li></ul><p><b>Other family members.</b> The risk to other family members depends on the genetic status of the proband's parents: if a parent has the <i>GFAP</i> pathogenic variant, his or her family members may be at risk.</p></div><div id="alexander.Related_Genetic_Counseling_Iss"><h3>Related Genetic Counseling Issues</h3><p>
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<b>Predictive testing for Alexander disease (i.e., testing of asymptomatic at-risk individuals)</b>
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</p><ul><li class="half_rhythm"><div>Predictive testing for at-risk relatives is possible once the <i>GFAP</i> pathogenic variant 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 genetic counseling prior to testing.</div></li></ul><p>
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<b>Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years)</b>
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</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 Alexander disease, it is appropriate to consider testing of symptomatic individuals regardless of age.</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><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e. the causative pathogenic mechanism is unknown).</p></div><div id="alexander.Prenatal_Testing_and_Preimplan"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>GFAP</i> pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for Alexander disease are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. 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="alexander.Resources"><h2 id="_alexander_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>End Alexander Disease</b>
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</div><div>
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<a href="https://www.endaxd.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.endaxd.org</a>
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</div></li><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> MD </div><div>
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<a href="https://www.ninds.nih.gov/Disorders/All-Disorders/Alexander-Disease-Information-Page" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Alexander Disease Information Page</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/alexanderdisease" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Alexander disease</a>
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</div></li><li class="half_rhythm"><div>
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<b>Waisman Center for Alexander Disease</b>
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</div><div>University of Wisconsin-Madison</div><div>1500 Highland Avenue</div><div>Room 277</div><div>Madison WI 53705</div><div><b>Phone:</b> 608-263-5776</div><div><b>Fax:</b> 608-263-0529</div><div>
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<a href="http://www.waisman.wisc.edu/alexander/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.waisman.wisc.edu/alexander/index.html</a>
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</div></li><li class="half_rhythm"><div>
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<b>United Leukodystrophy Foundation</b>
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</div><div><b>Phone:</b> 815-748-0844</div><div><b>Email:</b> office@ulf.org</div><div>
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<a href="https://ulf.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ulf.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Myelin Disorders Bioregistry Project</b>
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</div><div><b>Phone:</b> 215-590-1719</div><div><b>Email:</b> sherbinio@chop.edu</div><div>
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<a href="https://www.chop.edu/research/myelin-disorders-biorepository-project" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Myelin Disorders Bioregistry Project</a>
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</div></li></ul>
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</div><div id="alexander.Molecular_Genetics"><h2 id="_alexander_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="figalexandermolgenTA"><a href="/books/NBK1172/table/alexander.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobalexandermolgenTA"><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="alexander.molgen.TA"><a href="/books/NBK1172/table/alexander.molgen.TA/?report=objectonly" target="object" rid-ob="figobalexandermolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">Alexander Disease: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figalexandermolgenTB"><a href="/books/NBK1172/table/alexander.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobalexandermolgenTB"><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="alexander.molgen.TB"><a href="/books/NBK1172/table/alexander.molgen.TB/?report=objectonly" target="object" rid-ob="figobalexandermolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for Alexander Disease (View All in OMIM) </p></div></div><div id="alexander.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>GFAP</i> encodes glial fibrillary acidic protein, the main intermediate filament protein expressed in mature astrocytes of the central nervous system. GFAP is a homotetramer, consisting of two dimers of paired alpha-helices and stabilized by a vast array of intermolecular interactions [<a class="bibr" href="#alexander.REF.kim.2018.2899" rid="alexander.REF.kim.2018.2899">Kim et al 2018</a>]. As a cytoskeletal protein providing structural stability, GFAP appears to be important in modulating the morphology and motility of astrocytes [<a class="bibr" href="#alexander.REF.eng.2000.1439" rid="alexander.REF.eng.2000.1439">Eng et al 2000</a>, <a class="bibr" href="#alexander.REF.messing.2003b.87" rid="alexander.REF.messing.2003b.87">Messing & Brenner 2003b</a>]; however, it may have other as-yet unknown functions.</p><p><b>Mechanism of disease causation.</b> Gain of function. The cellular mechanism causing the Alexander disease phenotype remains unresolved; however, abnormal protein oligomerization that alters either the oligomerization or the solubility of the protein has been proposed [<a class="bibr" href="#alexander.REF.hsiao.2005.2057" rid="alexander.REF.hsiao.2005.2057">Hsiao et al 2005</a>, <a class="bibr" href="#alexander.REF.der_perng.2006.197" rid="alexander.REF.der_perng.2006.197">Der Perng et al 2006</a>]. Proteins encoded by pathogenic variants in <i>GFAP</i> may interfere with the intermolecular interactions necessary to stabilize the protein, leading to increased protein aggregation [<a class="bibr" href="#alexander.REF.kim.2018.2899" rid="alexander.REF.kim.2018.2899">Kim et al 2018</a>, <a class="bibr" href="#alexander.REF.viedmapoyatos.2018.380" rid="alexander.REF.viedmapoyatos.2018.380">Viedma-Poyatos et al 2018</a>]. Expression of an abnormal protein may result in disturbance of the normal interaction between astrocytes and oligodendrocytes, resulting in hypomyelination or demyelination. See <a class="bibr" href="#alexander.REF.messing.2001.563" rid="alexander.REF.messing.2001.563">Messing et al [2001]</a>, <a class="bibr" href="#alexander.REF.gorospe.2006.113" rid="alexander.REF.gorospe.2006.113">Gorospe & Maletkovic [2006]</a>, and <a class="bibr" href="#alexander.REF.sosunov.2018.388" rid="alexander.REF.sosunov.2018.388">Sosunov et al [2018]</a>.</p><p>Consistent with a gain-of-function mechanism, the majority of disease-associated variants are missense or in-frame variants [<a class="bibr" href="#alexander.REF.li.2005.310" rid="alexander.REF.li.2005.310">Li et al 2005</a>, <a class="bibr" href="#alexander.REF.van_der_knaap.2006.494" rid="alexander.REF.van_der_knaap.2006.494">van der Knaap et al 2006</a>, <a class="bibr" href="#alexander.REF.murakami.2008.50" rid="alexander.REF.murakami.2008.50">Murakami et al 2008</a>, <a class="bibr" href="#alexander.REF.ayaki.2010.1292" rid="alexander.REF.ayaki.2010.1292">Ayaki et al 2010</a>, <a class="bibr" href="#alexander.REF.flint.2012.1141" rid="alexander.REF.flint.2012.1141">Flint et al 2012</a>, <a class="bibr" href="#alexander.REF.schmidt.2013.152" rid="alexander.REF.schmidt.2013.152">Schmidt et al 2013</a>].</p><p><b><i>GFAP</i>-specific laboratory technical considerations.</b> The most common pathogenic variants occur at three amino acid residues (p.Arg79, p.Arg88, and p.Arg239).</p><p>Most <i>GFAP</i> pathogenic variants have been reported on transcript <a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_002055.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_002055.4</a>; however, a heterozygous variant (p.Arg430His) presently only on the transcript <a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001131019.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_001131019.2</a> has been identified in multiple individuals [<a class="bibr" href="#alexander.REF.melchionda.2013.66" rid="alexander.REF.melchionda.2013.66">Melchionda et al 2013</a>, <a class="bibr" href="#alexander.REF.karp.2019.235" rid="alexander.REF.karp.2019.235">Karp et al 2019</a>, <a class="bibr" href="#alexander.REF.helman.2020.1131" rid="alexander.REF.helman.2020.1131">Helman et al 2020</a>] (see <a href="/books/NBK1172/table/alexander.T.notable_gfap_pathogenic_vari/?report=objectonly" target="object" rid-ob="figobalexanderTnotablegfappathogenicvari">Table 11</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figalexanderTnotablegfappathogenicvari"><a href="/books/NBK1172/table/alexander.T.notable_gfap_pathogenic_vari/?report=objectonly" target="object" title="Table 11. " class="img_link icnblk_img" rid-ob="figobalexanderTnotablegfappathogenicvari"><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="alexander.T.notable_gfap_pathogenic_vari"><a href="/books/NBK1172/table/alexander.T.notable_gfap_pathogenic_vari/?report=objectonly" target="object" rid-ob="figobalexanderTnotablegfappathogenicvari">Table 11. </a></h4><p class="float-caption no_bottom_margin">Notable <i>GFAP</i> Pathogenic Variants </p></div></div></div></div><div id="alexander.Chapter_Notes"><h2 id="_alexander_Chapter_Notes_">Chapter Notes</h2><div id="alexander.Author_Notes"><h3>Author Notes</h3><p>Website for Amy Waldman at the Children's Hospital of Philadelphia<br /><a href="https://www.chop.edu/doctors/waldman-amy" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.chop.edu/doctors/waldman-amy</a></p><p>Website for Siddharth Srivastava at Boston Children's Hospital<br /><a href="https://www.childrenshospital.org/directory/physicians/s/siddharth-srivastava" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.childrenshospital.org/directory/physicians/s/siddharth-srivastava</a></p><p>Clinical trial pertaining to outcome measures of Alexander disease at the Children's Hospital of Philadelphia<br /><a href="https://www.research.chop.edu/axd-outcomes" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.research.chop.edu/axd-outcomes</a></p></div><div id="alexander.Author_History"><h3>Author History</h3><p>J Rafael Gorospe, MD, PhD; NIH – National Center for Research Resource (2002-2015)<br />Sakkubai Naidu, MD (2015-present)<br />Siddharth Srivastava, MD (2015-present)<br />Amy Waldman, MD, MSCE (2020-present)</p></div><div id="alexander.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>12 November 2020 (bp) Comprehensive update posted live</div></li><li class="half_rhythm"><div>8 January 2015 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>22 April 2010 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>9 March 2007 (cd,jrg) Revision: sequence analysis of select exons and targeted mutation analysis no longer clinically available</div></li><li class="half_rhythm"><div>2 October 2006 (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>5 May 2003 (cd,jrg) Revision: molecular genetic testing clinically available</div></li><li class="half_rhythm"><div>15 November 2002 (me) Review posted live</div></li><li class="half_rhythm"><div>24 April 2002 (jrg) Original submission</div></li></ul></div></div><div id="alexander.References"><h2 id="_alexander_References_">References</h2><div id="alexander.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="alexander.REF.ayaki.2010.1292">Ayaki T, Shinohara M, Tatsumi S, Namekawa M, Yamamoto T. A case of sporadic adult Alexander disease presenting with acute onset, remission and relapse. <span><span class="ref-journal">J Neurol Neurosurg Psychiatry. </span>2010;<span class="ref-vol">81</span>:1292–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20562394" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20562394</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alexander.REF.de_beer.2014.2227">de Beer M, Engelen M, van Geel BM. Frequent occurrence of cerebral demyelination in adrenomyeloneuropathy. <span><span class="ref-journal">Neurology. </span>2014;<span class="ref-vol">83</span>:2227–31.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25378668" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25378668</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alexander.REF.der_perng.2006.197">Der Perng M, Su M, Wen SF, Li R, Gibbon T, Prescott AR, Brenner M, Quinlan RA. The Alexander disease-causing glial fibrillary acidic protein mutant, R416W, accumulates into Rosenthal fibers by a pathway that involves filament aggregation and the association of alpha B-crystallin and HSP27. <span><span class="ref-journal">Am J Hum Genet. </span>2006;<span class="ref-vol">79</span>:197–213.</span> [<a href="/pmc/articles/PMC1559481/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1559481</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16826512" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16826512</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alexander.REF.eng.2000.1439">Eng LF, Ghirnikar RS, Lee YL. Glial fibrillary acidic protein: GFAP-thirty-one years (1969-2000). <span><span class="ref-journal">Neurochem Res. </span>2000;<span class="ref-vol">25</span>:1439–51.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11059815" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11059815</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alexander.REF.flint.2012.1141">Flint D, Li R, Webster LS, Naidu S, Kolodny E, Percy A, van der Knaap M, Powers JM, Mantovani JF, Ekstein J, Goldman JE, Messing A, Brenner M. Splice site, frameshift, and chimeric GFAP mutations in Alexander disease. <span><span class="ref-journal">Hum Mutat. </span>2012;<span class="ref-vol">33</span>:1141–8.</span> [<a href="/pmc/articles/PMC3674965/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3674965</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22488673" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22488673</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alexander.REF.gordon.2003.395">Gordon N. Alexander disease. <span><span class="ref-journal">Eur J Paediatr Neurol. </span>2003;<span class="ref-vol">7</span>:395–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14623218" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14623218</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alexander.REF.gorospe.2006.113">Gorospe JR, Maletkovic J. Alexander disease and megalencephalic leukoencephalopathy with subcortical cysts: leukodystrophies arising from astrocyte dysfunction. <span><span class="ref-journal">Ment Retard Dev Disabil Res Rev. </span>2006;<span class="ref-vol">12</span>:113–22.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16807904" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16807904</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alexander.REF.green.2018.118">Green L, Berry IR, Childs AM, McCullagh H, Jose S, Warren D, Craven I, Camm N, Prescott K, van der Knaap MS, Sheridan E, Livingston JH. Whole exon deletion in the GFAP gene is a novel molecular mechanism causing Alexander disease. <span><span class="ref-journal">Neuropediatrics. </span>2018 Apr;<span class="ref-vol">49</span>:118–22.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/29253910" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29253910</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alexander.REF.hagemann.2018.27">Hagemann TL, Powers B, Mazur C, et al. Antisense suppression of glial fibrillary acidic protein as a treatment for Alexander disease. <span><span class="ref-journal">Ann Neurol. </span>2018;<span class="ref-vol">83</span>:27–39.</span> [<a href="/pmc/articles/PMC5876100/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5876100</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29226998" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29226998</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alexander.REF.helman.2020.1131">Helman G, Takanohashi A, Hagemann TL, Perng MD, Walkiewicz M, Woidill S, Sase S, Cross Z, Du Y, Zhao L, Waldman A, Haake BC, Fatemi A, Brenner M, Sherbini O, Messing A, Vanderver A, Simons C, Type II. Alexander disease caused by splicing errors and aberrant overexpression of an uncharacterized GFAP isoform. <span><span class="ref-journal">Hum Mutat. </span>2020;<span class="ref-vol">41</span>:1131–7.</span> [<a href="/pmc/articles/PMC7491703/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7491703</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32126152" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32126152</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alexander.REF.hsiao.2005.2057">Hsiao VC, Tian R, Long H, Der Perng M, Brenner M, Quinlan RA, Goldman JE. Alexander-disease mutation of GFAP causes filament disorganization and decreased solubility of GFAP. <span><span class="ref-journal">J Cell Sci. </span>2005;<span class="ref-vol">118</span>:2057–65.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15840648" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15840648</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alexander.REF.karp.2019.235">Karp N, Lee D, Shickh S, Jenkins ME. c. 1289G>A (p.Arg430His) variant in the epsilon isoform of the GFAP gene in a patient with adult onset Alexander disease. <span><span class="ref-journal">Eur J Med Genet. </span>2019;<span class="ref-vol">62</span>:235–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30048824" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30048824</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alexander.REF.kim.2018.2899">Kim B, Kim S, Jin MS. Crystal structure of the human glial fibrillary acidic protein 1B domain. <span><span class="ref-journal">Biochem Biophys Res Commun. </span>2018;<span class="ref-vol">503</span>:2899–905.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30126635" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30126635</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alexander.REF.li.2005.310">Li R, Johnson AB, Salomons G, Goldman JE, Naidu S, Quinlan R, Cree B, Ruyle SZ, Banwell B, D'Hooghe M, Siebert JR, Rolf CM, Cox H, Reddy A, Gutierrez-Solana LG, Collins A, Weller RO, Messing A, van der Knaap MS, Brenner M. Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease. <span><span class="ref-journal">Ann Neurol. </span>2005;<span class="ref-vol">57</span>:310–26.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15732097" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15732097</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alexander.REF.li.2006.137">Li R, Johnson AB, Salomons GS, van der Knaap MS, Rodriguez D, Boespflug-Tanguy O, Gorospe JR, Goldman JE, Messing A, Brenner M. Propensity for paternal inheritance of de novo mutations in Alexander disease. <span><span class="ref-journal">Hum Genet. </span>2006;<span class="ref-vol">119</span>:137–44.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16365765" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16365765</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alexander.REF.li.2002.259">Li R, Messing A, Goldman J, Brenner M. 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Dominantly-inherited adult-onset leukodystrophy with palatal tremor caused by a mutation in the glial fibrillary acidic protein gene. <span><span class="ref-journal">Mov Disord. </span>2004;<span class="ref-vol">19</span>:1244–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15390001" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15390001</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alexander.REF.van_der_knaap.2001.541">van der Knaap MS, Naidu S, Breiter SN, Blaser S, Stroink H, Springer S, Begeer JC, van Coster R, Barth PG, Thomas NH, Valk J, Powers JM. 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Characteristics of cerebral lesions in adult-onset Alexander disease. <span><span class="ref-journal">Neurol Sci. </span>2020;<span class="ref-vol">41</span>:225–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/31422506" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31422506</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK1172_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Siddharth Srivastava</span>, MD<div class="affiliation small">Department of Neurology
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Boston Children's Hospital
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Boston, Massachusetts<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.dravrah.snerdlihc@avatsavirs.htrahddis" class="oemail">ude.dravrah.snerdlihc@avatsavirs.htrahddis</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Amy Waldman</span>, MD, MSCE<div class="affiliation small">Division of Neurology, Children's Hospital of Philadelphia;
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Departments of Neurology and Pediatrics
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Perelman School of Medicine
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University of Pennsylvania
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Philadelphia, Pennsylvania<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.pohc.liame@namdlaw" class="oemail">ude.pohc.liame@namdlaw</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Sakkubai Naidu</span>, MD<div class="affiliation small">Kennedy Krieger Institute
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Pediatric Neurology and Pediatrics
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Johns Hopkins University Medical Institutions
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Baltimore, Maryland<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.regeirkydennek@udian" class="oemail">gro.regeirkydennek@udian</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">November 15, 2002</span>; Last Update: <span itemprop="dateModified">November 12, 2020</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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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>Srivastava S, Waldman A, Naidu S. Alexander Disease. 2002 Nov 15 [Updated 2020 Nov 12]. 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/alagille/?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/alkap/?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="figobalexanderTalexanderdiseasemrifeatur"><div id="alexander.T.alexander_disease_mri_featur" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Alexander Disease: MRI Features by Age of Presentation</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1172/table/alexander.T.alexander_disease_mri_featur/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alexander.T.alexander_disease_mri_featur_lrgtbl__"><table><thead><tr><th id="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th id="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neonatal</th><th id="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Infantile</th><th id="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Juvenile</th><th id="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adult</th></tr></thead><tbody><tr><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Periventricular rim</b>
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</td><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">+</td><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">+</td><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">+ or -</td><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">+ or -</td></tr><tr><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Basal ganglia or thalamus involvement</b>
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</td><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">+++</td><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">++</td><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">+ or -</td><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">+ or -</td></tr><tr><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Brain stem involvement</b>
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</td><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_2 hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_3" colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;">Symmetric signal abnormality of medulla</td><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mass-like brain stem lesions</td><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Medullary & cervical cord atrophy</td></tr><tr><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Contrast enhancing structures</b>
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</td><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequent in basal ganglia</td><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Variable</td><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequently present in posterior fossa structures</td><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">+ or -</td></tr><tr><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Other notes</b>
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</td><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_4 hd_h_alexander.T.alexander_disease_mri_featur_1_1_1_5" colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;">T<sub>2</sub>-weighted hyperintensities may be present in cerebellar white matter or hilus of dentate nuclei [<a class="bibr" href="#alexander.REF.van_der_knaap.2005.327" rid="alexander.REF.van_der_knaap.2005.327">van der Knaap et al 2005</a>].</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobalexanderTmoleculargenetictestingus"><div id="alexander.T.molecular_genetic_testing_us" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Alexander Disease</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1172/table/alexander.T.molecular_genetic_testing_us/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alexander.T.molecular_genetic_testing_us_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alexander.T.molecular_genetic_testing_us_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_alexander.T.molecular_genetic_testing_us_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_alexander.T.molecular_genetic_testing_us_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_alexander.T.molecular_genetic_testing_us_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>GFAP</i>
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</td><td headers="hd_h_alexander.T.molecular_genetic_testing_us_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_alexander.T.molecular_genetic_testing_us_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">98% <sup>4</sup></td></tr><tr><td headers="hd_h_alexander.T.molecular_genetic_testing_us_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Deletion/duplication analysis <sup>5</sup></td><td headers="hd_h_alexander.T.molecular_genetic_testing_us_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">One reported <sup>6</sup></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="alexander.TF.2.1"><p class="no_margin">See <a href="/books/NBK1172/?report=reader#alexander.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="alexander.TF.2.2"><p class="no_margin">See <a href="#alexander.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="alexander.TF.2.3"><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="alexander.TF.2.4"><p class="no_margin">Based on a summary of prior published reports in which 293 of 299 (98%) individuals tested had a <i>GFAP</i> pathogenic variant. Of note, the numerator and denominator include ten asymptomatic individuals who had a pathogenic <i>GFAP</i> variant (see <a href="/books/NBK1172/bin/alexander-table3.pdf">Table 3</a> [pdf]).</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="alexander.TF.2.5"><p class="no_margin">Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="alexander.TF.2.6"><p class="no_margin">Deletion of exon 5, an in-frame exon, has been reported [<a class="bibr" href="#alexander.REF.green.2018.118" rid="alexander.REF.green.2018.118">Green et al 2018</a>].</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobalexanderTalexanderdiseasecomparison"><div id="alexander.T.alexander_disease_comparison" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Alexander Disease: Comparison of Forms by Select Features</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1172/table/alexander.T.alexander_disease_comparison/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alexander.T.alexander_disease_comparison_lrgtbl__"><table><thead><tr><th id="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th id="hd_h_alexander.T.alexander_disease_comparison_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neonatal</th><th id="hd_h_alexander.T.alexander_disease_comparison_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Infantile</th><th id="hd_h_alexander.T.alexander_disease_comparison_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Juvenile</th><th id="hd_h_alexander.T.alexander_disease_comparison_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adult</th></tr></thead><tbody><tr><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Typical age at presentation</b>
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</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1st mo of life</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Infancy or childhood</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Childhood or adolescence</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adolescence or adulthood</td></tr><tr><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Core neurologic manifestations</b>
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</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lack of developmental progression; motor impairment w/o spasticity; seizures; megalencephaly; hydrocephalus</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental delay or developmental regression; seizures; megalencephaly</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Bulbar/pseudobulbar signs w/nasal speech, dysphagia, dysphonia; failure to thrive; intractable vomiting; scoliosis; autonomic dysfunction</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pyramidal involvement; bulbar dysfunction; autonomic dysfunction</td></tr><tr><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Other findings</b>
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</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feeding difficulties (failure to thrive)</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Failure to thrive</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Short stature</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cerebellar involvement; palatal myoclonus; normocephaly</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobalexanderTalexanderdiseasecomparison1"><div id="alexander.T.alexander_disease_comparison_1" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Alexander Disease: Comparison of Classification Systems</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1172/table/alexander.T.alexander_disease_comparison_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alexander.T.alexander_disease_comparison_1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_1" style="text-align:left;vertical-align:middle;">Classification System</th><th id="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_2" colspan="4" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Typical Age at Presentation</th></tr><tr><th headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_2" id="hd_h_alexander.T.alexander_disease_comparison_1_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">First Month of Life</th><th headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_2" id="hd_h_alexander.T.alexander_disease_comparison_1_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Infancy or Childhood</th><th headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_2" id="hd_h_alexander.T.alexander_disease_comparison_1_1_1_2_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Childhood or Adolescence</th><th headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_2" id="hd_h_alexander.T.alexander_disease_comparison_1_1_1_2_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adolescence or Adulthood</th></tr></thead><tbody><tr><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">4-group system by age of onset</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_2 hd_h_alexander.T.alexander_disease_comparison_1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neonatal form</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_2 hd_h_alexander.T.alexander_disease_comparison_1_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Infantile form</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_2 hd_h_alexander.T.alexander_disease_comparison_1_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Juvenile form</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_2 hd_h_alexander.T.alexander_disease_comparison_1_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adult form</td></tr><tr><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2-group system by symptoms at onset <sup>1</sup></td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_2 hd_h_alexander.T.alexander_disease_comparison_1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Type I</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_2 hd_h_alexander.T.alexander_disease_comparison_1_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Type I</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_2 hd_h_alexander.T.alexander_disease_comparison_1_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Type II</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_2 hd_h_alexander.T.alexander_disease_comparison_1_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Type II</td></tr><tr><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3-group system by MRI features <sup>2</sup></td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_2 hd_h_alexander.T.alexander_disease_comparison_1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cerebral</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_2 hd_h_alexander.T.alexander_disease_comparison_1_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cerebral</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_2 hd_h_alexander.T.alexander_disease_comparison_1_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Intermediate</td><td headers="hd_h_alexander.T.alexander_disease_comparison_1_1_1_1_2 hd_h_alexander.T.alexander_disease_comparison_1_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Bulbospinal</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="alexander.TF.5.1"><p class="no_margin"><a class="bibr" href="#alexander.REF.prust.2011.1287" rid="alexander.REF.prust.2011.1287">Prust et al [2011]</a> classification based on clinical findings, not age</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="alexander.TF.5.2"><p class="no_margin"><a class="bibr" href="#alexander.REF.yoshida.2011.1998" rid="alexander.REF.yoshida.2011.1998">Yoshida et al [2011]</a> classification based on brain MRI findings</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobalexanderTgenesofinterestinthedif"><div id="alexander.T.genes_of_interest_in_the_dif" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Genes of Interest in the Differential Diagnosis of the Neonatal, Infantile, and Juvenile Forms of Alexander Disease</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1172/table/alexander.T.genes_of_interest_in_the_dif/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alexander.T.genes_of_interest_in_the_dif_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_3" colspan="2" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Features of Differential Diagnosis Disorder</th></tr><tr><th headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_3" id="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/<br />Alexander disease</th><th headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_3" id="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from Alexander disease</th></tr></thead><tbody><tr><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ABCD1</i>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/x-ald/?report=reader">X-linked adrenoleukodystrophy</a> (X-ALD)</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_3 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Male children present w/regression in motor & cognitive skills.</div></li><li class="half_rhythm"><div>Spasticity & gait abnormalities</div></li></ul>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_3 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MRI: mostly sparing of subcortical WM; involvement of deep WM primarily (most severe in parietal & occipital lobes w/anterior progression); leading edge enhancement of involved WM</td></tr><tr><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ARSA</i>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/mld/?report=reader">Arylsulfatase A deficiency</a> (metachromatic leukodystrophy, MLD) <sup>1</sup></td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_3 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Developmental regression in early childhood</div></li><li class="half_rhythm"><div>Spasticity w/preserved cognitive function</div></li></ul>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_3 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MRI: involvement of deep WM primarily w/sparing of subcortical WM early in disease course; enhancement of cranial nerves; tigroid pattern (stripes/spots of spared perivascular WM) w/o abnormal periventricular WM</td></tr><tr><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ASPA</i>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/canavan/?report=reader">Canavan disease</a> <sup>1</sup></td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_3 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hypotonia, head lag, macrocephaly, & difficulties w/suck & swallow</div></li><li class="half_rhythm"><div>DD ± regression</div></li><li class="half_rhythm"><div>MRI: involvement of subcortical WM & globus pallidus & thalami</div></li></ul>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_3 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Elevation in N-acetylcysteine on MR spectroscopy</div></li><li class="half_rhythm"><div>MRI: diffuse WM changes w/o frontal predominance; sparing of putamen</div></li></ul>
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</td></tr><tr><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>GALC</i>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/krabbe/?report=reader">Krabbe disease</a> <sup>1</sup></td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_3 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Early feeding difficulties, hypotonia, & irritability</div></li><li class="half_rhythm"><div>Developmental regression & seizures</div></li><li class="half_rhythm"><div>MRI: involvement of thalami & cerebellar WM</div></li></ul>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_3 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Macrocephaly not present</div></li><li class="half_rhythm"><div>MRI: involvement of deep WM primarily w/sparing of subcortical WM until later in disease course; thickening/enhancement of optic nerves & peripheral nerves</div></li></ul>
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</td></tr><tr><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>GCDH</i>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/glutaric-a1/?report=reader">Glutaric acidemia type 1</a> <sup>1</sup></td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_3 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Macrocephaly, DD, extrapyramidal signs (often preceded by an acute encephalopathy during infancy)</div></li><li class="half_rhythm"><div>MRI: involvement of basal ganglia</div></li></ul>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_3 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MRI: lack of enhancement of affected structures; widening of sylvian fissures & expansion of CSF spaces</td></tr><tr><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>HEPACAM</i>
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<br />
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<i>MLC1</i>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/mlc/?report=reader">Megalencephalic leukoencephalopathy w/subcortical cysts</a> 1 & 2A <sup>1</sup></td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_3 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Megalencephaly during infancy, DD, seizures</div></li><li class="half_rhythm"><div>MRI: involvement of subcortical WM</div></li></ul>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_3 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MRI: subcortical cysts, relative sparing of cerebellar WM, sparing of basal ganglia</td></tr><tr><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>L2HGDH</i>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">L-2-hydroxyglutaric aciduria (OMIM <a href="https://omim.org/entry/236792" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">236792</a>) <sup>1</sup></td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_3 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>DD, seizures, dysarthria, ataxia (often w/insidious progression)</div></li><li class="half_rhythm"><div>MRI: involvement of subcortical, WM & basal ganglia; anterior to posterior involvement of WM</div></li></ul>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_3 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MRI: sparing of brain stem & cerebellum; no enhancement</td></tr><tr><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>PEX1</i><br /><i>PEX6</i><br /><i>PEX12</i><br />(13 assoc genes) <sup>2</sup></td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/pbd/?report=reader">Zellweger spectrum disorder</a> (ZSD)</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_3 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Neonatal-infantile onset: hypotonia, feeding difficulties, & seizures</div></li><li class="half_rhythm"><div>Childhood onset: hypotonia, DD, regression, & diffuse involvement of WM incl cerebrum, brain stem, & cerebellum</div></li><li class="half_rhythm"><div>Adolescent-adult onset: variable ID, pyramidal signs, & ataxia</div></li></ul>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_3 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>May be assoc w/liver, heart, kidney, & skeletal system dysfunction; distinct facial features</div></li><li class="half_rhythm"><div>Neonatal-infantile onset of ZSD MRI findings: cortical dysplasia, generalized ↓ in WM volume, delayed myelination, & ventricular dilatation</div></li><li class="half_rhythm"><div>Childhood onset of ZSD MRI findings: involvement of parietooccipital WM progressing to entire cerebral WM</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></dt><dd><div><p class="no_margin">CSF = cerebrospinal fluid; DD = developmental delay; ID = intellectual disability; WM = white matter</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="alexander.TF.6.1"><p class="no_margin">Mode of inheritance is autosomal recessive.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="alexander.TF.6.2"><p class="no_margin">Biallelic pathogenic variants in <i>PEX1</i>, <i>PEX6</i>, <i>PEX12</i> account for 60.5%, 14.5%, and 7.6% of Zellweger spectrum disorder (ZSD), respectively. ZSD is also known to be caused by biallelic pathogenic variants in <i>PEX2</i>, <i>PEX3</i>, <i>PEX10</i>, <i>PEX5</i>, <i>PEX11β</i>, <i>PEX13</i>, <i>PEX14</i>, <i>PEX16</i>, <i>PEX19</i>, or <i>PEX26</i>. ZSD is typically inherited in an autosomal recessive manner. One <i>PEX6</i> variant, p.Arg860Trp, has been associated with ZSD in the heterozygous state.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobalexanderTgenesofinterestinthedif1"><div id="alexander.T.genes_of_interest_in_the_dif_1" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Genes of Interest in the Differential Diagnosis of the Adult Form of Alexander Disease</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1172/table/alexander.T.genes_of_interest_in_the_dif_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alexander.T.genes_of_interest_in_the_dif_1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_2" style="text-align:left;vertical-align:middle;">Differential Diagnosis Disorder</th><th id="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_3" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_4" colspan="2" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Features of Differential Diagnosis Disorder</th></tr><tr><th headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_4" id="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/<br />Alexander disease</th><th headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_4" id="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from Alexander disease</th></tr></thead><tbody><tr><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ABCD1</i>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/x-ald/?report=reader">X-linked adrenoleukodystrophy</a> (X-ALD)</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_4 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Progressive gait disorder, spasticity or weakness, & abnormalities of sphincter control</div></li><li class="half_rhythm"><div>MRI: cerebellar lesions & demyelination</div></li></ul>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_4 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Abnormal VLCFAs</div></li><li class="half_rhythm"><div>MRI: T<sub>2</sub>-weighted hyperintensity in CC, occipital periventricular WM, & internal capsule</div></li></ul>
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</td></tr><tr><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>DARS2</i>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/lbsl/?report=reader">Leukoencephalopathy w/brain stem & spinal cord involvement & lactate elevation</a>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_4 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Spastic paraplegia or progressive gait impairment</div></li><li class="half_rhythm"><div>Ataxia</div></li><li class="half_rhythm"><div>Cognitive decline</div></li><li class="half_rhythm"><div>MRI: abnormalities in medulla & upper cervical cord</div></li></ul>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_4 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>↓ position & vibratory sensation</div></li><li class="half_rhythm"><div>MRI: abnormalities visualized in dorsal columns & lateral corticospinal tracts of spinal cord, splenium of CC, posterior limb of internal capsule, intraparenchymal part of trigeminal nerve, & mesencephalic trigeminal tracts <sup>2</sup></div></li></ul>
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</td></tr><tr><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>EIF2B1</i>
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<br />
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<i>EIF2B2</i>
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<br />
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<i>EIF2B3</i>
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<br />
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<i>EIF2B4</i>
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<br />
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<i>EIF2B5</i>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Vanishing WM disease (See <a href="/books/n/gene/cach/?report=reader">CACH/VWM</a>.)</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_4 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ataxia & cognitive decline</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_4 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MRI: bilateral confluent T<sub>2</sub>-weighted hyperintensities w/WM rarefaction & global atrophy</td></tr><tr><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>NOTCH3</i>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/cadasil/?report=reader">Cerebral autosomal dominant arteriopathy w/subcortical infarcts & leukoencephalopathy</a> (CADASIL)</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_4 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mild cognitive decline</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_4 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Ischemic stroke & migraine w/aura</div></li><li class="half_rhythm"><div>MRI: T<sub>2</sub>-weighted hyperintense lesions in temporal poles</div></li></ul>
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</td></tr><tr><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>PLP1</i>
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</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pelizaeus-Merzbacher disease (See <a href="/books/n/gene/pmd/?report=reader"><i>PLP1 </i>Disorders</a>.)</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_4 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Spastic gait, ataxia, bowel & bladder dysfunction</td><td headers="hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_1_4 hd_h_alexander.T.genes_of_interest_in_the_dif_1_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MRI: patchy T<sub>2</sub>-weighted hyperintensities or more diffuse hypomyelination</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">AD = autosomal dominant; AR = autosomal recessive; CACH/VWM = childhood ataxia with central nervous system hypomyelination / vanishing white matter; CC = corpus callosum; MOI = mode of inheritance; VLCFA = very long chain fatty acid; WM = white matter; XL = X-linked</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="alexander.TF.7.1"><p class="no_margin">
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<a class="bibr" href="#alexander.REF.de_beer.2014.2227" rid="alexander.REF.de_beer.2014.2227">de Beer et al [2014]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="alexander.TF.7.2"><p class="no_margin">
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<a class="bibr" href="#alexander.REF.lynch.2017.1204" rid="alexander.REF.lynch.2017.1204">Lynch et al [2017]</a>
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</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobalexanderTrecommendedevaluationsfoll"><div id="alexander.T.recommended_evaluations_foll" class="table"><h3><span class="label">Table 8. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with Alexander Disease</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1172/table/alexander.T.recommended_evaluations_foll/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alexander.T.recommended_evaluations_foll_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Specialist</th><th id="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurologic</b>
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</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Complete neurologic assessment incl history, physical exam, & eval of head circumference</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Review clinical & MRI findings w/affected individual & caregivers.</div></li><li class="half_rhythm"><div>Perform formal, age-appropriate developmental assessment (in children).</div></li><li class="half_rhythm"><div>Discuss symptomatic therapy.</div></li><li class="half_rhythm"><div>Determine if EEG is needed.</div></li></ul>
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</td></tr><tr><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Primary care</b>
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<br />
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<b>physician</b>
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</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">History & physical exam</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To facilitate care coordination after receiving info about diagnosis & mgmt plan</td></tr><tr><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Genetic</b>
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<br />
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<b>counseling</b>
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</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Discussion led by genetics professionals <sup>1</sup></td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform patients & their families re nature, MOI, & implications of Alexander disease to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Family support/</b>
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<br />
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<b>resources</b>
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</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Discussion w/patient, family, & caregivers</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess family & social structure to determine availability of adequate support system, need for social work involvement & parental or caregiver support, need for home nursing referral, & use of community or <a href="#alexander.Resources">online resources</a> such as <a href="https://www.p2pusa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parent to Parent</a></td></tr><tr><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Speech/language</b>
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<br />
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<b>pathologist or</b>
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<br />
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<b>feeding specialist</b>
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</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Swallow eval</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Some programs may offer a clinical eval while others may recommend a study, such as videofluoroscopic swallowing study (also called modified barium swallow) or fiberoptic endoscopic eval.</td></tr><tr><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Speech/language</b>
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<br />
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<b>pathologist</b>
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</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Speech/language eval</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To identify impairments in receptive & expressive language & determine if speech/language therapy &/or AAC would help improve communication skills</td></tr><tr><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Physical therapist</b>
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</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical eval</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate range of motion, strength, coordination, & tone; & develop a plan for improving gross motor function (e.g., ambulation, mobility)</td></tr><tr><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Occupational</b>
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<br />
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<b>therapist</b>
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</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical eval</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate fine motor activities (incl dexterity & handwriting) & develop plan to improve self-care skills (e.g., dressing, toileting, & grooming)</td></tr><tr><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Physiatrist</b>
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<br />
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<b>(rehab doctor)</b>
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</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">History & physical exam</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate function & guide team in maximizing abilities</td></tr><tr><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Orthopedic</b>
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<br />
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<b>specialist</b>
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</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">History & physical exam</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate scoliosis & hip dislocation (may be done in conjunction w/physiatry)</td></tr><tr><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Gastroenterologist</b>
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</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">History & physical exam</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess feeding/eating, digestive problems (incl constipation & gastroesophageal reflux), & nutrition using history, growth measurements, & (if needed) gastrointestinal investigations</td></tr><tr><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Nutritionist</b>
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</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Review caloric intake & expended energy</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To determine nutritional & fluid needs to ensure adequate growth</td></tr><tr><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Pulmonologist</b>
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<br />
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<b>(or sleep medicine</b>
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<br />
|
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<b>physician)</b>
|
|
</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lung & breathing eval</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To determine whether respiratory compromise is present (from weakness, scoliosis, or aspiration) & assess for sleep apnea (often central in etiology)</td></tr><tr><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Urologist</b>
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</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Review bladder function</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To determine if upper or lower motor neuron involvement of bladder requires intervention</td></tr><tr><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Psychologist</b>
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|
</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Discussion of medical diagnosis</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Psychological assessment for older patients to determine awareness & understanding of disease & its consequences</td></tr><tr><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neuropsychologist</b>
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</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Formal eval (when age appropriate) to incl standardized metrics of cognition & other areas of brain development</td><td headers="hd_h_alexander.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To determine impact of disrupted cerebral pathways on learning & cognitive development, as well as develop plan to optimize learning strategies</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">AAC = augmentative alternative communication; MOI = mode of inheritance</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="alexander.TF.8.1"><p class="no_margin">Medical geneticist, certified genetic counselor, or certified advanced genetic nurse</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobalexanderTtreatmentofmanifestations"><div id="alexander.T.treatment_of_manifestations" class="table"><h3><span class="label">Table 9. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with Alexander Disease</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1172/table/alexander.T.treatment_of_manifestations/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alexander.T.treatment_of_manifestations_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alexander.T.treatment_of_manifestations_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/<br />Concern</th><th id="hd_h_alexander.T.treatment_of_manifestations_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_alexander.T.treatment_of_manifestations_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations</th></tr></thead><tbody><tr><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>DD/ID</b>
|
|
</td><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#alexander.Developmental_Delay__Intellect">Developmental Delay / Intellectual Disability Management Issues</a>.</td><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Seizures</b>
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|
</td><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ASM</td><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologists may wish to consider initiating ASM even in setting of provoked seizures (by illness) or a single seizure w/normal EEG, given high risk for epilepsy & regression.</td></tr><tr><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Speech/</b>
|
|
<br />
|
|
<b>Language</b>
|
|
</td><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Speech/language therapy</td><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider need for assistive communication devices.</td></tr><tr><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Vomiting</b>
|
|
</td><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reflux medications, valproic acid</td><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Follow nutritional status & growth.</td></tr><tr><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Nutritional</b>
|
|
<br />
|
|
<b>support</b>
|
|
</td><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Additional calories, medications that stimulate appetite</td><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider gastrostomy tube for persons w/significant dysphagia.</td></tr><tr><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Constipation</b>
|
|
</td><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Motility agents, stool softeners, enemas</td><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Constipation may contribute to vomiting & should be considered in persons for whom vomiting is major symptom.</td></tr><tr><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Tone</b>
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|
</td><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Spasticity medications for ↑ tone</td><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Botox/phenol injections may also be considered for targeted approach.</td></tr><tr><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Treatment for scoliosis</td><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Particularly in those w/low tone</td></tr><tr><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Tremor</b>
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</td><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Various medications can be tried to ↓ tremor, incl but not limited to carbidopa/levodopa.</td><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/OT for non-medical strategies may be considered.</td></tr><tr><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>UTI or other</b>
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<br />
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<b>bacterial illness</b>
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</td><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Antibiotics if appropriate</td><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Additional prevention strategies may be considered.</td></tr><tr><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Bone health</b>
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</td><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Vitamin D</td><td headers="hd_h_alexander.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider checking serum levels of vitamin D 25-OH.</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">ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; OT = occupational therapist; UTI = urinary tract infection</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobalexanderTrecommendedsurveillancefor"><div id="alexander.T.recommended_surveillance_for" class="table"><h3><span class="label">Table 10. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with Alexander Disease</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1172/table/alexander.T.recommended_surveillance_for/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alexander.T.recommended_surveillance_for_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alexander.T.recommended_surveillance_for_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_alexander.T.recommended_surveillance_for_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_alexander.T.recommended_surveillance_for_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Growth</b>
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<br />
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<b>parameters</b>
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</td><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Height, weight, head circumference, heart rate, vital signs</td><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 6 mos</td></tr><tr><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurology</b>
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</td><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic exam</td><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 3-6 mos (Younger persons & those early in disease course may require more frequent assessment.)</td></tr><tr><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Development</b>
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</td><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor developmental progress & educational needs.</td><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>PT/OT</b>
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</td><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gross & fine motor rating scales</td><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per therapist</td></tr><tr><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Swallow eval</b>
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</td><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical or radiologic eval</td><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually <sup>1</sup></td></tr><tr><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Speech/</b>
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<br />
|
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<b>Language</b>
|
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</td><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Expressive & receptive language skills</td><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per therapist</td></tr><tr><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Gastrointestinal</b>
|
|
</td><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">History & eval of GI tract for esophageal dysfunction, reflux, vomiting, & constipation</td><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_3" rowspan="7" colspan="1" style="text-align:left;vertical-align:middle;">Annually <sup>1</sup></td></tr><tr><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Orthopedics</b>
|
|
</td><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical or radiographic assessment for scoliosis</td></tr><tr><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Orthostatic</b>
|
|
<br />
|
|
<b>vitals</b>
|
|
</td><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Measurement of heart rate & blood pressure while lying, sitting, & standing</td></tr><tr><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Psychiatry/</b>
|
|
<br />
|
|
<b>Psychology</b>
|
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</td><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Discussion of impact of diagnosis on patient's physical & mental health</td></tr><tr><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Pulmonary</b>
|
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</td><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment of respiratory function</td></tr><tr><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Sleep medicine</b>
|
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</td><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Discussion about sleep apnea & sleep study, if indicated</td></tr><tr><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Urology</b>
|
|
</td><td headers="hd_h_alexander.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Review of urinary tract symptoms & bladder scan or other testing, if indicated</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">GI = gastrointestinal; OT = occupational therapy; PT = physical therapy</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="alexander.TF.10.1"><p class="no_margin">Active issues may require more frequent evaluations</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobalexandermolgenTA"><div id="alexander.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Alexander Disease: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1172/table/alexander.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alexander.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_alexander.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_alexander.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_alexander.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_alexander.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_alexander.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_alexander.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_alexander.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="/gene/2670" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
|
<i>GFAP</i>
|
|
</a>
|
|
</td><td headers="hd_b_alexander.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=2670" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">17q21<wbr style="display:inline-block"></wbr>​.31</a>
|
|
</td><td headers="hd_b_alexander.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.uniprot.org/uniprot/P14136" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Glial fibrillary acidic protein</a>
|
|
</td><td headers="hd_b_alexander.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.interfil.org/details.php?id=NM_002055" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Human Intermediate Filament Database GFAP</a>
|
|
<br />
|
|
<a href="http://databases.lovd.nl/shared/genes/GFAP" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GFAP database</a>
|
|
</td><td headers="hd_b_alexander.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=GFAP" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GFAP</a>
|
|
</td><td headers="hd_b_alexander.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=GFAP[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GFAP</a>
|
|
</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="alexander.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
|
|
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
|
chromosome locus 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/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobalexandermolgenTB"><div id="alexander.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Alexander Disease (<a href="/omim/137780,203450" 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/NBK1172/table/alexander.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alexander.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/137780" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">137780</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GLIAL FIBRILLARY ACIDIC PROTEIN; GFAP</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/203450" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">203450</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ALEXANDER DISEASE; ALXDRD</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobalexanderTnotablegfappathogenicvari"><div id="alexander.T.notable_gfap_pathogenic_vari" class="table"><h3><span class="label">Table 11. </span></h3><div class="caption"><p>Notable <i>GFAP</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1172/table/alexander.T.notable_gfap_pathogenic_vari/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alexander.T.notable_gfap_pathogenic_vari_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide<br />Change</th><th id="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein<br />Change <sup>1</sup></th><th id="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_1" rowspan="30" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_002055.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_002055<wbr style="display:inline-block"></wbr>​.4</a>
|
|
<br />
|
|
<a href="https://www.ncbi.nlm.nih.gov/protein/4503979" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_002046<wbr style="display:inline-block"></wbr>​.1</a>
|
|
</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.218T>C</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Met73Thr</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_4" rowspan="13" colspan="1" style="text-align:left;vertical-align:middle;">Recurrent pathogenic variants commonly (but not necessarily exclusively) observed in the infantile form (See <a href="/books/NBK1172/bin/alexander-table3.pdf">Table 3</a> [pdf].)</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.226C>T</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Leu76Phe</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.230A>G</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Asn77Ser</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.235C>T</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg79Cys</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.262C>T</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg88Cys</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.290T>C</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Leu97Pro</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.715C>T</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg239Cys</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.716G>A</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg239His</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.716G>T</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg239Leu</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.716G>C</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg239Pro</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1055T>C</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Leu352Pro</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1117G>A</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Glu373Lys</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1249delG</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Asp417MetfsTer15</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.235C>T</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg79Cys</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_4" rowspan="6" colspan="1" style="text-align:left;vertical-align:middle;">Recurrent pathogenic variants commonly (but not necessarily exclusively) observed in the juvenile form (See <a href="/books/NBK1172/bin/alexander-table3.pdf">Table 3</a> [pdf].)</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.262C>T</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg88Cys</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.628G>A</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Glu210Lys</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.704T>C</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Leu235Pro</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.715C>T</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg239Cys</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1246C>T</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg416Trp</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.197G>A</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg66Gln</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_4" rowspan="11" colspan="1" style="text-align:left;vertical-align:middle;">Recurrent pathogenic variants commonly (but not necessarily exclusively) observed in the adult form (See <a href="/books/NBK1172/bin/alexander-table3.pdf">Table 3</a> [pdf].)</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.208C>T</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg70Trp</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.209G>A</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg70Gln</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.221T>C</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Met74Thr</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.613G>A</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Glu205Lys</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.772C>T</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg258Cys</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.827G>T</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg276Leu</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1076T>C</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Leu359Pro</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1090G>C</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ala364Thr</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1178G>T</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ser393Ile</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1246C>T</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg416Trp</td></tr><tr><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001131019.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_001131019<wbr style="display:inline-block"></wbr>​.2</a>
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<br />
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<a href="https://www.ncbi.nlm.nih.gov/protein/NP_001124491.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_001124491<wbr style="display:inline-block"></wbr>​.1</a>
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</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1289G>A</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg430His</td><td headers="hd_h_alexander.T.notable_gfap_pathogenic_vari_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Recurrent pathogenic variant reported on alternate transcript [<a class="bibr" href="#alexander.REF.melchionda.2013.66" rid="alexander.REF.melchionda.2013.66">Melchionda et al 2013</a>, <a class="bibr" href="#alexander.REF.karp.2019.235" rid="alexander.REF.karp.2019.235">Karp et al 2019</a>, <a class="bibr" href="#alexander.REF.helman.2020.1131" rid="alexander.REF.helman.2020.1131">Helman et al 2020</a>]</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 authors. GeneReviews 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">GeneReviews 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 class="bkr_refwrap"><dt>1. </dt><dd><div id="alexander.TF.11.1"><p class="no_margin">The most common pathogenic variants occur at the three amino acid residues p.Arg79, p.Arg88, and p.Arg239.</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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