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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Fatty Acid Hydroxylase-Associated Neurodegeneration - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="GeneReviews® [Internet]">
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<meta name="citation_title" content="Fatty Acid Hydroxylase-Associated Neurodegeneration">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2018/09/27">
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<meta name="citation_author" content="Allison Gregory">
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<meta name="citation_author" content="Sunita Venkateswaran">
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<meta name="citation_author" content="Susan J Hayflick">
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<meta name="citation_keywords" content="Spastic Paraplegia 35 (SPG35)">
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<meta name="citation_keywords" content="Spastic Paraplegia 35 (SPG35)">
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<meta name="citation_keywords" content="Fatty acid 2-hydroxylase">
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<meta name="citation_keywords" content="FA2H">
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<meta name="citation_keywords" content="Fatty Acid Hydroxylase-Associated Neurodegeneration">
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<meta name="DC.Title" content="Fatty Acid Hydroxylase-Associated Neurodegeneration">
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<meta name="DC.Publisher" content="University of Washington, Seattle">
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<meta name="DC.Contributor" content="Allison Gregory">
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<meta name="DC.Contributor" content="Sunita Venkateswaran">
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<meta name="DC.Contributor" content="Susan J Hayflick">
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<meta name="DC.Date" content="2018/09/27">
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<meta name="description" content="Fatty acid hydroxylase-associated neurodegeneration (FAHN) is characterized early in the disease course by central nervous system involvement including corticospinal tract involvement (spasticity), mixed movement disorder (ataxia/dystonia), and eye findings (optic atrophy, oculomotor abnormalities), and later in the disease course by progressive intellectual impairment and seizures. With disease progression, dystonia and spasticity compromise the ability to ambulate, leading to wheelchair dependence. Life expectancy is variable. FAHN is considered to be a subtype of neurodegeneration with brain iron accumulation (NBIA).">
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<meta name="og:description" content="Fatty acid hydroxylase-associated neurodegeneration (FAHN) is characterized early in the disease course by central nervous system involvement including corticospinal tract involvement (spasticity), mixed movement disorder (ataxia/dystonia), and eye findings (optic atrophy, oculomotor abnormalities), and later in the disease course by progressive intellectual impairment and seizures. With disease progression, dystonia and spasticity compromise the ability to ambulate, leading to wheelchair dependence. Life expectancy is variable. FAHN is considered to be a subtype of neurodegeneration with brain iron accumulation (NBIA).">
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yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK56080_"><span class="title" itemprop="name">Fatty Acid Hydroxylase-Associated Neurodegeneration</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonym: Spastic Paraplegia 35 (SPG35)</div><p class="contribs">Gregory A, Venkateswaran S, Hayflick SJ.</p><p class="fm-aai"><a href="#_NBK56080_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 18 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="fahn.Summary" itemprop="description"><h2 id="_fahn_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Fatty acid hydroxylase-associated neurodegeneration (FAHN) is characterized early in the disease course by central nervous system involvement including corticospinal tract involvement (spasticity), mixed movement disorder (ataxia/dystonia), and eye findings (optic atrophy, oculomotor abnormalities), and later in the disease course by progressive intellectual impairment and seizures. With disease progression, dystonia and spasticity compromise the ability to ambulate, leading to wheelchair dependence. Life expectancy is variable. FAHN is considered to be a subtype of neurodegeneration with brain iron accumulation (NBIA).</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of FAHN is established in a proband with suggestive findings and typically by identification of biallelic <i>FA2H</i> pathogenic variants on molecular genetic testing; however, on occasion uniparental disomy (UDP) is causative.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Symptomatic treatment focuses primarily on the dystonia, which can be debilitating. Therapies used with varying success include the oral medications baclofen, tizanidine, dantrolene, and anticholinergics; injection of botulinum toxin targeting abnormal co-contraction of selected muscle groups; and ablative pallidotomy or thalamotomy. Attention should be given to nutritional status and feeding.</p><p>Independence should be encouraged when possible through use of adaptive aids (e.g., walker or wheelchair for gait abnormalities, augmentative communication devices) and appropriate community resources (e.g., financial services, programs for the visually impaired, special education).</p><p><i>Surveillance:</i> Regular assessment of nutritional status and swallowing, vision, mobility and environmental adaptations, speech, and communication needs.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>Genetic counseling for fatty acid hydroxylase-associated neurodegeneration (FAHN) depends on the causative genetic mechanism: FAHN caused by transmission of one pathogenic variant from each parent is inherited in an autosomal recessive manner; FAHN caused by transmission of two pathogenic variants from one parent (as the result of uniparental disomy [UPD] for chromosome 16) is a <i>de novo</i> event and is unlikely to recur.</p><p>Autosomal recessive inheritance: At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. If the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.</p></div></div><div id="fahn.Diagnosis"><h2 id="_fahn_Diagnosis_">Diagnosis</h2><div id="fahn.Suggestive_Findings"><h3>Suggestive Findings</h3><p>Fatty acid hydroxylase-associated neurodegeneration (FAHN) <b>should be considered</b> in individuals with the following clinical findings, neuroimaging findings, and family history (see <a class="figpopup" href="/books/NBK56080/figure/fahn.F1/?report=objectonly" target="object" rid-figpopup="figfahnF1" rid-ob="figobfahnF1">Figure 1</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figfahnF1" co-legend-rid="figlgndfahnF1"><a href="/books/NBK56080/figure/fahn.F1/?report=objectonly" target="object" title="Figure 1. " class="img_link icnblk_img figpopup" rid-figpopup="figfahnF1" rid-ob="figobfahnF1"><img class="small-thumb" src="/books/NBK56080/bin/fahn-Image001.gif" src-large="/books/NBK56080/bin/fahn-Image001.jpg" alt="Figure 1. " /></a><div class="icnblk_cntnt" id="figlgndfahnF1"><h4 id="fahn.F1"><a href="/books/NBK56080/figure/fahn.F1/?report=objectonly" target="object" rid-ob="figobfahnF1">Figure 1. </a></h4><p class="float-caption no_bottom_margin">Neuroimaging features of FAHN (A) vs PKAN (B) The two forms of NBIA share T<sub>2-</sub>weighted / gradient-echo hypointensity. Distinguishing features include diffuse cerebral atrophy (seen in FAHN) and central globus pallidus T<sub>2-</sub>weighted hyperintensity (seen in <a href="/books/NBK56080/figure/fahn.F1/?report=objectonly" target="object" rid-ob="figobfahnF1">(more...)</a></p></div></div><p>
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<b>Clinical findings</b>
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</p><ul><li class="half_rhythm"><div>Onset within the first or second decade of life</div></li><li class="half_rhythm"><div>Corticospinal tract involvement:</div><ul><li class="half_rhythm"><div>Spastic paraplegia or quadriplegia (commonly given a clinical diagnosis of hereditary spastic paraplegia)</div></li><li class="half_rhythm"><div>Pyramidal tract signs (hypereflexia, clonus, Babinski sign, Hoffmann sign)</div></li></ul></li><li class="half_rhythm"><div>Movement disorder including one or both of the following:</div><ul><li class="half_rhythm"><div>Dystonia</div></li><li class="half_rhythm"><div>Ataxia</div></li></ul></li><li class="half_rhythm"><div>Dysarthria</div></li><li class="half_rhythm"><div>Dysphagia</div></li><li class="half_rhythm"><div>Eye findings:</div><ul><li class="half_rhythm"><div>Optic atrophy manifest as progressive loss of visual acuity, sectoral visual field loss, and impaired color vision</div></li><li class="half_rhythm"><div>In some individuals: strabismus, lateral-beating nystagmus, and supranuclear gaze palsy</div></li></ul></li><li class="half_rhythm"><div>Epilepsy</div></li><li class="half_rhythm"><div>Cognitive decline</div></li></ul><p><b>Neuroimaging findings.</b> Brain MRI findings typically may include (in order of likelihood):</p><ul><li class="half_rhythm"><div class="half_rhythm">On T<sub>2</sub>-weighted images: variable unilateral or bilateral symmetric white matter hyperintensity that may affect both periventricular and subcortical white matter, and may become confluent with time. U-fibers and cerebellar white matter appear to be affected to a lesser degree.</div></li><li class="half_rhythm"><div class="half_rhythm">Progressive atrophy of the cerebellar hemispheres, vermis, pons, medulla and spinal cord</div></li><li class="half_rhythm"><div class="half_rhythm">Thinning of the corpus callosum</div></li><li class="half_rhythm"><div class="half_rhythm">Optic atrophy</div></li><li class="half_rhythm"><div class="half_rhythm">T<sub>2</sub>-weighted hypointensity of the globus pallidus (may display blooming on T<sub>2</sub>*-weighted images).</div><div class="half_rhythm">Note: T<sub>2</sub>-weighted hypointensity coupled with an extrapyramidal movement disorder and intellectual decline is suggestive of a <a href="/books/n/gene/nbia-ov/?report=reader">neurodegeneration with brain iron accumulation (NBIA) disorder</a> (see <a href="#fahn.Differential_Diagnosis">Differential Diagnosis</a>). The "eye of the tiger" sign, pathognomonic for <a href="/books/n/gene/pkan/?report=reader">pantothenate kinase-associated neurodegeneration</a> (PKAN), another form of NBIA, is not seen in FAHN.</div></li></ul><p><b>Family history</b> is consistent with autosomal recessive inheritance, including parental consanguinity.</p></div><div id="fahn.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of FAHN <b>is established</b> in a proband with suggestive findings and biallelic <i>FA2H</i> pathogenic (or likely pathogenic) variants on molecular genetic testing (see <a href="/books/NBK56080/table/fahn.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobfahnTmoleculargenetictestingusedin">Table 1</a>).</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [<a class="bibr" href="#fahn.REF.richards.2015.405" rid="fahn.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic <i>FA2H</i> variants of uncertain significance (or of one known <i>FA2H</i> pathogenic variant and one <i>FA2H</i> variant of uncertain significance) does not establish or rule out the diagnosis.</p><p>Molecular genetic testing approaches can include a combination of <b>gene-targeted testing</b> (single-gene testing, multigene panel) and <b>comprehensive</b>
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<b>genomic testing</b> (exome sequencing, exome array, genome sequencing) depending on the phenotype.</p><p>Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in <a href="#fahn.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#fahn.Option_1">Option 1</a>), whereas those with findings indistinguishable from other neurodegenerative disorders with pyramidal and extrapyramidal involvement are more likely to be diagnosed with comprehensive genomic testing (see <a href="#fahn.Option_2">Option 2</a>).</p><div id="fahn.Option_1"><h4>Option 1</h4><p>When the phenotypic and imaging findings suggest the diagnosis of FAHN or a similar type of neurodegeneration with brain iron accumulation (see <a href="/books/n/gene/nbia-ov/?report=reader">NBIA Overview</a>), molecular genetic testing is most often a <b>multigene panel</b>.</p><p><b>A multigene panel</b> that includes <i>FA2H</i> and other genes of interest (see <a href="#fahn.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="fahn.Option_2"><h4>Option 2</h4><p>When the phenotype is indistinguishable from many other inherited neurodegenerative disorders with pyramidal and extrapyramidal involvement, <b>comprehensive</b>
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<b>genomic testing</b> (which does not require the clinician to determine which gene[s] are likely involved) is the best option. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> is also possible.</p><p>If exome sequencing is not diagnostic, <b>exome array</b> (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.</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="figfahnTmoleculargenetictestingusedin"><a href="/books/NBK56080/table/fahn.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobfahnTmoleculargenetictestingusedin"><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="fahn.T.molecular_genetic_testing_used_in"><a href="/books/NBK56080/table/fahn.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobfahnTmoleculargenetictestingusedin">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in Fatty Acid Hydroxylase-Associated Neurodegeneration (FAHN) </p></div></div></div></div></div><div id="fahn.Clinical_Characteristics"><h2 id="_fahn_Clinical_Characteristics_">Clinical Characteristics</h2><div id="fahn.Clinical_Description"><h3>Clinical Description</h3><p>Fatty acid hydroxylase-associated neurodegeneration (FAHN) is characterized early in the disease course by central nervous system involvement including corticospinal tract involvement (spasticity), mixed movement disorder (ataxia/dystonia), eye findings (optic atrophy, oculomotor abnormalities), and later in the disease course by progressive intellectual impairment and seizures. FAHN is a subtype of <a href="/books/n/gene/nbia-ov/?report=reader">neurodegeneration with brain iron accumulation</a> (NBIA) but is also included under the classifications of leukodystrophies and hereditary spastic paraplegias.</p><p>Of note, leukodystrophy and hereditary spastic paraplegia 35 (HSP35), two phenotypes previously considered distinct disorders based on clinical findings [<a class="bibr" href="#fahn.REF.dick.2008.248" rid="fahn.REF.dick.2008.248">Dick et al 2008</a>, <a class="bibr" href="#fahn.REF.edvardson.2008.643" rid="fahn.REF.edvardson.2008.643">Edvardson et al 2008</a>], are now included in the phenotypic spectrum of FAHN based on molecular genetic findings [<a class="bibr" href="#fahn.REF.dick.2010.e1251" rid="fahn.REF.dick.2010.e1251">Dick et al 2010</a>, <a class="bibr" href="#fahn.REF.kruer.2010.611" rid="fahn.REF.kruer.2010.611">Kruer et al 2010</a>].</p><p>The most frequent presenting finding is a subtle change in gait that may lead to increasingly frequent falls. This typically occurs in childhood or adolescence and may be the result of focal dystonia and/or corticospinal tract involvement.</p><p>The degree of spasticity resulting from corticospinal tract involvement can vary among persons with FAHN. Individuals affected to a lesser degree may develop spastic paraparesis but retain the ability to walk, while individuals with more severe disease may demonstrate a spastic quadriplegic pattern of disability and lose their ability to ambulate, instead relying on a wheelchair.</p><p>Dystonia may begin focally (e.g., affecting one foot) but typically spreads to assume a generalized pattern. The degree of dystonia seen in FAHN is generally milder than that in other forms of NBIA, such as PKAN, in which status dystonicus occurs.</p><p>Ataxia typically begins in childhood or adolescence and may emerge along with dystonia and/or spasticity. The ataxia that occurs in FAHN may affect both axial and appendicular function and, along with both dystonia and spasticity, can markedly impair gait.</p><p>Dysarthria may be prominent in FAHN. In some individuals, expressive speech can be impaired to the point of anarthria. Dysphagia, potentially necessitating gastrostomy tube placement, can also occur.</p><p>Optic atrophy in FAHN may begin as a subtle loss of visual acuity in childhood, but may progress to the point of functional blindness. The oculomotor abnormalities seen in FAHN may impair functional vision as well.</p><p>A few individuals with FAHN and peripheral neuropathy have been reported [<a class="bibr" href="#fahn.REF.donkervoort.2014.393" rid="fahn.REF.donkervoort.2014.393">Donkervoort et al 2014</a>, <a class="bibr" href="#fahn.REF.zaki.2015.95" rid="fahn.REF.zaki.2015.95">Zaki et al 2015</a>].</p><p>Seizures are not typically seen in the early stages of disease, but may occur later in the disease course. When present, seizures (which tend to be complex partial or generalized) are typically infrequent and respond relatively well to anticonvulsants.</p><p>While progressive intellectual impairment occurs in most persons with FAHN, more information on the cognitive phenotype and natural history are needed. Serial assessments have documented cognitive decline in two individuals [<a class="bibr" href="#fahn.REF.tonelli.2012.e127" rid="fahn.REF.tonelli.2012.e127">Tonelli et al 2012</a>]. One report suggests a psychiatric component to FAHN based on findings of anxiety, depression, and bipolar disorder in affected sibs [<a class="bibr" href="#fahn.REF.magariello.2017.347" rid="fahn.REF.magariello.2017.347">Magariello et al 2017</a>].</p><p>Although the neurodegeneration in FAHN is progressive, declines may be intermittent and punctuated by periods of relative clinical stability. However, lost skills are not usually regained. With disease progression, dystonia and spasticity compromise the ability to ambulate, leading to wheelchair dependence.</p><p><b>Life expectancy.</b> Although premature death often occurs in the 20s or 30s secondary to a combination of nutrition-related immunodeficiency and respiratory compromise, life expectancy is variable.</p><p><b>Neuropathologic features</b> for FAHN have not yet been reported. Bone marrow biopsy, although not necessary for diagnosis, may demonstrate accumulation of granular histiocytes.</p></div><div id="fahn.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>No genotype-phenotype correlations have been observed for pathogenic variants in <i>FA2H</i>.</p></div><div id="fahn.Nomenclature"><h3>Nomenclature</h3><p>Historically, the <i>FA2H</i>-related phenotype has been classified as either a genetic leukodystrophy [<a class="bibr" href="#fahn.REF.vanderver.2015.494" rid="fahn.REF.vanderver.2015.494">Vanderver et al 2015</a>] or a hereditary spastic paraplegia (SPG35) (see OMIM <a href="https://omim.org/entry/612319" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">612319</a>) [<a class="bibr" href="#fahn.REF.dick.2008.248" rid="fahn.REF.dick.2008.248">Dick et al 2008</a>, <a class="bibr" href="#fahn.REF.soehn.2016.186" rid="fahn.REF.soehn.2016.186">Soehn et al 2016</a>].</p><p>The authors prefer to refer to the <i>FA2H</i>-related phenotype as fatty acid hydroxylase-associated neurodegeneration because this term refers to the genetic basis of the disorder and encompasses all clinical classifications.</p></div><div id="fahn.Prevalence"><h3>Prevalence</h3><p>No reliable prevalence data are available. However, the prevalence is estimated to be lower than one in 1,000,000.</p></div></div><div id="fahn.Genetically_Related_Allelic_Disorde"><h2 id="_fahn_Genetically_Related_Allelic_Disorde_">Genetically Related (Allelic) Disorders</h2><p>No other phenotypes are known to be associated with biallelic <i>FA2H</i> pathogenic variants.</p></div><div id="fahn.Differential_Diagnosis"><h2 id="_fahn_Differential_Diagnosis_">Differential Diagnosis</h2><p>Fatty acid hydroxylase-associated neurodegeneration (FAHN) is a neurodegenerative disorder that shows clinical overlap with other early-onset neurodegenerative disorders. Disorders that may exhibit clinical and neuroimaging features similar to those seen in FAHN are summarized in <a href="/books/NBK56080/table/fahn.T.disorders_to_consider_in_the_diff/?report=objectonly" target="object" rid-ob="figobfahnTdisorderstoconsiderinthediff">Table 2</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figfahnTdisorderstoconsiderinthediff"><a href="/books/NBK56080/table/fahn.T.disorders_to_consider_in_the_diff/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobfahnTdisorderstoconsiderinthediff"><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="fahn.T.disorders_to_consider_in_the_diff"><a href="/books/NBK56080/table/fahn.T.disorders_to_consider_in_the_diff/?report=objectonly" target="object" rid-ob="figobfahnTdisorderstoconsiderinthediff">Table 2. </a></h4><p class="float-caption no_bottom_margin">Disorders to Consider in the Differential Diagnosis of FAHN </p></div></div></div><div id="fahn.Management"><h2 id="_fahn_Management_">Management</h2><div id="fahn.Evaluations_Following_Initial_Diagn"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease in an individual diagnosed with fatty acid hydroxylase-associated neurodegeneration (FAHN), the evaluations summarized in <a href="/books/NBK56080/table/fahn.T.recommended_evaluations_following/?report=objectonly" target="object" rid-ob="figobfahnTrecommendedevaluationsfollowing">Table 3</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="figfahnTrecommendedevaluationsfollowing"><a href="/books/NBK56080/table/fahn.T.recommended_evaluations_following/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobfahnTrecommendedevaluationsfollowing"><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="fahn.T.recommended_evaluations_following"><a href="/books/NBK56080/table/fahn.T.recommended_evaluations_following/?report=objectonly" target="object" rid-ob="figobfahnTrecommendedevaluationsfollowing">Table 3. </a></h4><p class="float-caption no_bottom_margin">Recommended Evaluations Following Initial Diagnosis in Individuals with Fatty Acid Hydroxylase-Associated Neurodegeneration (FAHN) </p></div></div></div><div id="fahn.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><div id="fahn.Eyes"><h4>Eyes</h4><p>Refer those with visual impairment to appropriate community resources.</p></div><div id="fahn.Feeding"><h4>Feeding</h4><p>Once swallowing evaluation and nutrition assessments indicate that the individual cannot maintain adequate nutrition and/or avoid the risk of aspiration with oral feeding, gastrostomy tube placement is indicated.</p></div><div id="fahn.Neurologic"><h4>Neurologic</h4><p>Pharmacologic and surgical interventions are focused on palliation of symptoms.</p><p><b>Dystonia and spasticity</b> can be debilitating. Symptomatic treatments used with varying success include the following:</p><ul><li class="half_rhythm"><div>Oral trihexyphenidyl, baclofen, tizanidine, benzodiazepines, and/or dantrolene. Of note, while levodopa could potentially provide benefit, it often does not; thus, a trial is reasonable, but should only be continued if there is clear benefit.</div></li><li class="half_rhythm"><div>Intramuscular botulinum toxin targeting abnormal co-contraction of selected muscle groups</div></li><li class="half_rhythm"><div>Ablative pallidotomy or thalamotomy. Dystonia may return despite this aggressive measure [<a class="bibr" href="#fahn.REF.justesen.1999.551" rid="fahn.REF.justesen.1999.551">Justesen et al 1999</a>].</div></li></ul><p><b>Ataxia.</b> Therapies for cerebellar ataxia can include use of weighted gloves to assist with dysmetria. Note that riluzole, recently recommended for cerebellar ataxia [<a class="bibr" href="#fahn.REF.ristori.2010.839" rid="fahn.REF.ristori.2010.839">Ristori et al 2010</a>], has not to the authors' knowledge undergone a therapeutic trial in FAHN.</p><p><b>Seizures.</b> Seizures respond well to traditional management with anti-seizure medication.</p><p>Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see <a href="https://www.epilepsy.com/tools-resources/forms-resources#Epilepsy-Foundation-Toolbox" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Epilepsy Foundation Toolbox</a>.</p></div><div id="fahn.Motor_Dysfunction"><h4>Motor Dysfunction</h4><p>
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<b>Gross motor dysfunction</b>
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</p><ul><li class="half_rhythm"><div>Physical therapy is recommended to maximize mobility.</div></li><li class="half_rhythm"><div>Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).</div></li></ul><p><b>Communication issues.</b> Consider evaluation for alternative means of communication (e.g., <a href="https://www.asha.org/NJC/AAC/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">augmentative and alternative communication</a> [AAC]) for individuals who have expressive language difficulties.</p></div><div id="fahn.Developmental_Delay__Intellectual_D"><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. In the US, early intervention is a federally funded program available in all states.</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.</p><p>
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<b>Ages 5-21 years</b>
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</p><ul><li class="half_rhythm"><div>In the US and Canada, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.</div></li><li class="half_rhythm"><div>Discussion about transition plans including financial and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.</div></li></ul><p><b>All ages.</b> Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.</p><p>Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.</p><p>In the US:</p><ul><li class="half_rhythm"><div>Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a 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="fahn.Surveillance"><h3>Surveillance</h3><p>The following should be performed on a regular basis:</p><ul><li class="half_rhythm"><div>Swallowing evaluation, nutrition assessment, and monitoring of height and weight to screen for evidence of worsening nutritional status</div></li><li class="half_rhythm"><div>Ophthalmologic assessment with particular attention to visual acuity.</div></li><li class="half_rhythm"><div>Assessment of mobility, self-help skills, and activities of daily living and need for adaptive devices</div></li><li class="half_rhythm"><div>Assessment of speech and communication needs</div></li></ul></div><div id="fahn.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#fahn.Related_Genetic_Counseling_Issues"><u>Genetic Counseling</u></a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="fahn.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p><b>Iron chelation.</b> Interest in iron chelation has reemerged as trials using deferiprone have been published in other disorders of brain iron accumulation, including <a href="/books/n/gene/friedreich/?report=reader">Friedreich ataxia</a> [<a class="bibr" href="#fahn.REF.boddaert.2007.401" rid="fahn.REF.boddaert.2007.401">Boddaert et al 2007</a>] and superficial siderosis [<a class="bibr" href="#fahn.REF.levy.2011.e1" rid="fahn.REF.levy.2011.e1">Levy & Llinas 2011</a>]. Deferiprone can cross the blood-brain barrier and remove intracellular iron. A multicenter, placebo controlled, double-blind trial comparing the efficacy and safety of 18 months of treatment with deferiprone versus placebo in patients with PKAN was completed in January of 2017 (see <a href="https://www.clinicaltrials.gov/ct2/show/NCT01741532?cond=PKAN&rank=3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Clinical Trials</a>). Data are currently being analyzed. Results, when published, may be generalizable to other NBIA disorders. However, long-term clinical trials of deferiprone in specific forms of NBIA will be necessary to further assess safety and efficacy.</p><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for information on clinical studies for a wide range of diseases and conditions.</p></div></div><div id="fahn.Genetic_Counseling"><h2 id="_fahn_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="fahn.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Genetic counseling for fatty acid hydroxylase-associated neurodegeneration (FAHN) depends on the causative genetic mechanism:</p><ul><li class="half_rhythm"><div>FAHN caused by transmission of one pathogenic variant from each parent is inherited in an autosomal recessive manner.</div></li><li class="half_rhythm"><div>FAHN caused by transmission of two pathogenic variants from one parent (as the result of uniparental disomy [UPD] for chromosome 16) is a <i>de novo</i> event and is unlikely to recur.</div></li></ul></div><div id="fahn.Autosomal_Recessive_Inheritance__Ri"><h3>Autosomal Recessive Inheritance – 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>The parents of an affected individual are obligate heterozygotes (i.e., carriers of one <i>FA2H</i> pathogenic variant).</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p>
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<b>Sibs of a proband</b>
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</p><ul><li class="half_rhythm"><div>At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p><b>Offspring of a proband.</b> The offspring of an individual with FAHN are obligate heterozygotes (carriers) for a pathogenic variant in <i>FA2H</i>.</p><p><b>Other family members.</b> Each sib of the proband's parents is at a 50% risk of being a carrier of an <i>FA2H</i> pathogenic variant.</p><p><b>Carrier detection.</b> Carrier testing for at-risk relatives requires prior identification of the <i>FA2H</i> pathogenic variants in the family.</p></div><div id="fahn.Uniparental_Disomy_of_Chromosome_16"><h3>Uniparental Disomy of Chromosome 16 (UPD16) – Risk to Family Members</h3><p>
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<b>Parents, sibs, and offspring of a proband</b>
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</p><ul><li class="half_rhythm"><div>The risk to parents, sibs, and offspring of an individual with FAHN caused by UPD16 is unlikely to be higher than the risk to the general population, as UPD16 is a <i>de novo</i>, typically non-recurrent event.</div></li><li class="half_rhythm"><div>If the proband has a chromosome abnormality in addition to UPD16, the risk to parents, sibs, and offspring is related to the specific abnormality identified in the proband.</div></li><li class="half_rhythm"><div>Note: UPD for chromosome 16 has led to four published cases of FAHN [<a class="bibr" href="#fahn.REF.soehn.2016.186" rid="fahn.REF.soehn.2016.186">Soehn et al 2016</a>].</div></li></ul></div><div id="fahn.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><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, clarification of carrier status, 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, are carriers, or are at risk of being carriers.</div></li></ul></div><div id="fahn.Prenatal_Testing_and_Preimplantatio"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>FA2H</i> pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.</p></div></div><div id="fahn.Resources"><h2 id="_fahn_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>NBIA Alliance</b>
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</div><div><b>Email:</b> Info@NBIAalliance.org</div><div>
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<a href="http://www.nbiaalliance.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.nbiaalliance.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>NBIA Canada</b>
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</div><div>PO Box 29</div><div>South River Newfoundland and Labrador A0A 3W0</div><div>Canada</div><div><b>Phone:</b> 709-786-7248</div><div><b>Email:</b> info@NBIAalliance.org</div><div>
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<a href="https://www.nbiacanada.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.nbiacanada.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>NBIA Disorders Association</b>
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</div><div>
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<a href="https://www.nbiadisorders.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.nbiadisorders.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>
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<a href="https://www.ninds.nih.gov/Disorders/All-Disorders/Hereditary-Spastic-Paraplegia-Information-Page" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Hereditary Spastic Paraplegia</a>
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</div></li><li class="half_rhythm"><div>
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<b>Spastic Paraplegia Foundation, Inc.</b>
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</div><div><b>Phone:</b> 877-773-4483</div><div><b>Email:</b> information@sp-foundation.org</div><div>
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<a href="http://sp-foundation.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">sp-foundation.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>NBIAcure</b>
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</div><div>Center of Excellence for NBIA Clinical Care and Research</div><div>International Registry for NBIA and Related Disorders</div><div>Oregon Health & Science University</div><div><b>Email:</b> info@nbiacure.org</div><div>
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<a href="http://nbiacure.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.nbiacure.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Treat Iron-Related Childhood Onset Neurodegeneration (TIRCON)</b>
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</div><div>Germany</div><div><b>Email:</b> TIRCON@med.uni-muenchen.de</div><div>
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<a href="https://tircon.eu/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.TIRCON.eu</a>
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</div></li></ul>
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</div><div id="fahn.Molecular_Genetics"><h2 id="_fahn_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="figfahnmolgenTA"><a href="/books/NBK56080/table/fahn.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobfahnmolgenTA"><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="fahn.molgen.TA"><a href="/books/NBK56080/table/fahn.molgen.TA/?report=objectonly" target="object" rid-ob="figobfahnmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">Fatty Acid Hydroxylase-Associated Neurodegeneration: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figfahnmolgenTB"><a href="/books/NBK56080/table/fahn.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobfahnmolgenTB"><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="fahn.molgen.TB"><a href="/books/NBK56080/table/fahn.molgen.TB/?report=objectonly" target="object" rid-ob="figobfahnmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for Fatty Acid Hydroxylase-Associated Neurodegeneration (View All in OMIM) </p></div></div><div id="fahn.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p>Human <i>FA2H</i> encodes the fatty acid 2-hydroxylase, an enzyme that alpha-hydroxylates nascent fatty acids that are subsequently incorporated into several diverse lipid species. Pathogenic variants in <i>FA2H</i> are believed to lead to fatty acid hydroxylase-associated neurodegeneration (FAHN) through a loss-of-function mechanism. This is supported by the identification of variants that predict premature truncation of the protein [<a class="bibr" href="#fahn.REF.kruer.2010.611" rid="fahn.REF.kruer.2010.611">Kruer et al 2010</a>], as well as in vitro evidence of decreased α-hydroxylation activity [<a class="bibr" href="#fahn.REF.dick.2010.e1251" rid="fahn.REF.dick.2010.e1251">Dick et al 2010</a>] and decreased protein abundance [<a class="bibr" href="#fahn.REF.kruer.2010.611" rid="fahn.REF.kruer.2010.611">Kruer et al 2010</a>] secondary to pathogenic variants associated with clinical FAHN.</p><p>In the peripheral nervous system, there is evidence that a second fatty acid-hydroxylating enzyme (perhaps phytanoyl coA 2-hydroxylase) may compensate for loss of FA2H activity [<a class="bibr" href="#fahn.REF.edvardson.2008.643" rid="fahn.REF.edvardson.2008.643">Edvardson et al 2008</a>]. However, in the central nervous system, this redundancy does not seem to exist. A decrease in 2-OH fatty acids may lead to abnormal white matter, as 2-OH sphingomyelin is an important myelin constituent [<a class="bibr" href="#fahn.REF.eckhardt.2005.245" rid="fahn.REF.eckhardt.2005.245">Eckhardt et al 2005</a>]. Deficiency of 2-OH fatty acids may also lead to an abnormal increase in membrane fluidity [<a class="bibr" href="#fahn.REF.guo.2010.25438" rid="fahn.REF.guo.2010.25438">Guo et al 2010</a>], with implications for the regulation of autophagy via the endosomal-lysosomal system. An important cell-cycle signaling role for <i>FA2H</i> has also been shown [<a class="bibr" href="#fahn.REF.alderson.2009.1203" rid="fahn.REF.alderson.2009.1203">Alderson & Hama 2009</a>]. However, further investigation is needed to better characterize the mechanism(s) by which loss of functional FA2H may lead to FAHN.</p><p><b>Gene structure.</b> The reference sequence <a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_024306.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_024306.4</a> has seven exons. For a detailed summary of gene and protein information, see <a href="/books/NBK56080/?report=reader#fahn.molgen.TA">Table A,</a>
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<b>Gene</b>.</p><p><b>Pathogenic variants.</b> Most sequence variants identified to date in persons with FAHN are unique variants. Based on data to date, partial or whole-gene deletions/duplications appear rare [<a class="bibr" href="#fahn.REF.pierson.2012.476" rid="fahn.REF.pierson.2012.476">Pierson et al 2012</a>]. A study of uniparental disomy in nonconsanguineous families with HSP identified four unrelated individuals with FAHN. Uniparental disomy for chromosome 16 had led to homozygosity for <i>FA2H</i> pathogenic variants in these individuals [<a class="bibr" href="#fahn.REF.soehn.2016.186" rid="fahn.REF.soehn.2016.186">Soehn et al 2016</a>].</p><p><b>Normal gene product.</b>
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<i>FA2H</i> encodes a 43-kd protein of 372 amino acid residues that is a functional fatty acid hydroxylase [<a class="bibr" href="#fahn.REF.alderson.2004.48562" rid="fahn.REF.alderson.2004.48562">Alderson et al 2004</a>]. This protein is localized to the endoplasmic reticulum and requires iron as a cofactor. Hydroxy fatty acids have important structural and signal transduction roles.</p><p><b>Abnormal gene product.</b> Pathogenic <i>FA2H</i> missense variants have been shown to lead to decreased protein abundance or enzyme activity. <i>FA2H</i> frameshift variants and a multiexon deletion support the notion of decreased function or loss of function as a cause of FAHN.</p></div></div><div id="fahn.Chapter_Notes"><h2 id="_fahn_Chapter_Notes_">Chapter Notes</h2><div id="fahn.Author_History"><h3>Author History</h3><p>Allison Gregory, MS (2011-present)<br />Susan J Hayflick, MD (2011-present)<br />Michael C Kruer, MD, University of South Dakota Sanford School of Medicine (2011-2018)<br />Sunita Venkateswaran, MD (2018-present)</p></div><div id="fahn.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>27 September 2018 (bp) Comprehensive update posted live</div></li><li class="half_rhythm"><div>20 September 2012 (cd) Revision: deletion/duplication analysis available clinically</div></li><li class="half_rhythm"><div>28 June 2011 (me) Review posted live</div></li><li class="half_rhythm"><div>3 January 2011 (mk) Original submission</div></li></ul></div></div><div id="fahn.References"><h2 id="_fahn_References_">References</h2><div id="fahn.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="fahn.REF.alderson.2009.1203">Alderson NL, Hama H. Fatty acid 2-hydroxylase regulates cAMP-induced cell cycle exit in D6P2T schwannoma cells. <span><span class="ref-journal">J Lipid Res. </span>2009;<span class="ref-vol">50</span>:1203–8.</span> [<a href="/pmc/articles/PMC2681402/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2681402</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19171550" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19171550</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fahn.REF.alderson.2004.48562">Alderson NL, Rembiesa BM, Walla MD, Bielawska A, Bielawski J, Hama H. The human FA2H gene encodes a fatty acid 2-hydroxylase. <span><span class="ref-journal">J Biol Chem. </span>2004;<span class="ref-vol">279</span>:48562–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15337768" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15337768</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fahn.REF.boddaert.2007.401">Boddaert N, Le Quan Sang KH, Rötig A, Leroy-Willig A, Gallet S, Brunelle F, Sidi D, Thalabard JC, Munnich A, Cabantchik ZI. Selective iron chelation in Friedreich ataxia: biologic and clinical implications. <span><span class="ref-journal">Blood. </span>2007;<span class="ref-vol">110</span>:401–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17379741" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17379741</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fahn.REF.dick.2008.248">Dick KJ, Al-Mjeni R, Baskir W, Koul R, Simpson MA, Patton MA, Raeburn S, Crosby AH. A novel locus for an autosomal recessive hereditary spastic paraplegia (SPG35) maps to 16q21-q23. <span><span class="ref-journal">Neurology. </span>2008;<span class="ref-vol">71</span>:248–52.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18463364" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18463364</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fahn.REF.dick.2010.e1251">Dick KJ, Eckhardt M, Paisán-Ruiz C, Alshehhi AA, Proukakis C, Sibtain NA, Maier H, Sharifi R, Patton MA, Bashir W, Koul R, Raeburn S, Gieselmann V, Houlden H, Crosby AH. Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35). <span><span class="ref-journal">Hum Mutat. </span>2010;<span class="ref-vol">31</span>:E1251–60.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20104589" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20104589</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fahn.REF.donkervoort.2014.393">Donkervoort S, Dastgir J, Hu Y, Zein WM, Marks H, Blackstone C, Bönnemann CG. Phenotypic variability of a likely FA2H founder mutation in a family with complicated hereditary spastic paraplegia. <span><span class="ref-journal">Clin Genet. </span>2014;<span class="ref-vol">85</span>:393–5.</span> [<a href="/pmc/articles/PMC5030767/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5030767</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23745665" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23745665</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fahn.REF.eckhardt.2005.245">Eckhardt M, Yaghootfam A, Fewou SN, Zöller I, Gieselmann V. A mammalian fatty acid hydroxylase responsible for the formation of alpha-hydroxylated galactosylceramide in myelin. <span><span class="ref-journal">Biochem J. </span>2005;<span class="ref-vol">388</span>:245–54.</span> [<a href="/pmc/articles/PMC1186713/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1186713</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/15658937" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15658937</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fahn.REF.edvardson.2008.643">Edvardson S, Hama H, Shaag A, Gomori JM, Berger I, Soffer D, Korman SH, Taustein I, Saada A, Elpeleg O. Mutations in the fatty acid 2-hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia. <span><span class="ref-journal">Am J Hum Genet. </span>2008;<span class="ref-vol">83</span>:643–8.</span> [<a href="/pmc/articles/PMC2668027/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2668027</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19068277" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19068277</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fahn.REF.guo.2010.25438">Guo L, Zhou D, Pryse KM, Okunade AL, Su X. Fatty acid 2-hydroxylase mediates diffusional mobility of Raft-associated lipids, GLUT4 level, and lipogenesis in 3T3-L1 adipocytes. <span><span class="ref-journal">J Biol Chem. </span>2010;<span class="ref-vol">285</span>:25438–47.</span> [<a href="/pmc/articles/PMC2919107/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2919107</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20519515" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20519515</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fahn.REF.justesen.1999.551">Justesen CR, Penn RD, Kroin JS, Egel RT. Stereotactic pallidotomy in a child with Hallervorden-Spatz disease. Case report. <span><span class="ref-journal">J Neurosurg. </span>1999;<span class="ref-vol">90</span>:551–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10067928" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10067928</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fahn.REF.kruer.2010.611">Kruer MC, Paisán-Ruiz C, Boddaert N, Yoon MY, Hama H, Gregory A, Malandrini A, Woltjer RL, Munnich A, Gobin S, Polster BJ, Palmeri S, Edvardson S, Hardy J, Houlden H, Hayflick SJ. Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). <span><span class="ref-journal">Ann Neurol. </span>2010;<span class="ref-vol">68</span>:611–8.</span> [<a href="/pmc/articles/PMC6059612/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6059612</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20853438" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20853438</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fahn.REF.levy.2011.e1">Levy M, Llinas RH. Deferiprone reduces hemosiderin deposits in the brain of a patient with superficial siderosis. <span><span class="ref-journal">AJNR Am J Neuroradiol. </span>2011;<span class="ref-vol">32</span>:E1–2.</span> [<a href="/pmc/articles/PMC7964941/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7964941</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21051507" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21051507</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fahn.REF.magariello.2017.347">Magariello A, Russo C, Citrigno L, Zuchner S, Patitucci A, Mazzei R, Conforti FL, Ferlazzo E, Aguglia U, Muglia M. Exome sequencing reveals two <em>FA2H</em> mutations in a family with a complicated form of Hereditary Spastic Paraplegia and psychiatric impairments. <span><span class="ref-journal">J Neurol Sci. </span>2017;<span class="ref-vol">372</span>:347–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28017243" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28017243</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fahn.REF.pierson.2012.476">Pierson TM, Simeonov DR, Sincan M, Adams DA, Markello T, Golas G, Fuentes-Fajardo K, Hansen NF, Cherukuri PF, Cruz P, Mullikin JC, Blackstone C, Tifft C, Boerkoel CF, Gahl WA., NISC Comparative Sequencing Program. Exome sequencing and SNP analysis detect novel compound heterozygosity in fatty acid hydroxylase-associated neurodegeneration. <span><span class="ref-journal">Eur J Hum Genet. </span>2012;<span class="ref-vol">20</span>:476–9.</span> [<a href="/pmc/articles/PMC3306865/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3306865</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22146942" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22146942</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fahn.REF.richards.2015.405">Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. <span><span class="ref-journal">Genet Med. </span>2015;<span class="ref-vol">17</span>:405–24.</span> [<a href="/pmc/articles/PMC4544753/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4544753</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25741868" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25741868</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fahn.REF.ristori.2010.839">Ristori G, Romano S, Visconti A, Cannoni S, Spadaro M, Frontali M, Pontieri FE, Vanacore N, Salvetti M. Riluzole in cerebellar ataxia: a randomized, double-blind, placebo-controlled pilot trial. <span><span class="ref-journal">Neurology. </span>2010;<span class="ref-vol">74</span>:839–45.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20211908" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20211908</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fahn.REF.soehn.2016.186">Soehn AS, Rattay TW, Beck-Wödl S, Schäferhoff K, Monk D, Döbler-Neumann M, Hörtnagel K, Schlüter A, Ruiz M, Pujol A, Züchner S, Riess O, Schüle R, Bauer P, Schöls L. Uniparental disomy of chromosome 16 unmasks recessive mutations of <em>FA2H</em>/SPG35 in 4 families. <span><span class="ref-journal">Neurology. </span>2016;<span class="ref-vol">87</span>:186–91.</span> [<a href="/pmc/articles/PMC4940069/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4940069</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27316240" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27316240</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fahn.REF.tonelli.2012.e127">Tonelli A, D’Angelo MG, Arrigoni F, Brighina E, Arnoldi A, Citterio A, Bresolin N, Bassi MT. Atypical adult onset complicated spastic paraparesis with thin corpus callosum in two patients carrying a novel <em>FA2H</em> mutation. <span><span class="ref-journal">Eur J Neurol. </span>2012;<span class="ref-vol">19</span>:e127–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22925154" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22925154</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fahn.REF.vanderver.2015.494">Vanderver A, Prust M, Tonduti D, Mochel F, Hussey HM, Helman G, Garbern J, Eichler F, Labauge P, Aubourg P, Rodriguez D, Patterson MC, Van Hove JL, Schmidt J, Wolf NI, Boespflug-Tanguy O, Schiffmann R, van der Knaap MS, et al. Case definition and classification of leukodystrophies and leukoencephalopathies. <span><span class="ref-journal">Mol Genet Metab. </span>2015;<span class="ref-vol">114</span>:494–500.</span> [<a href="/pmc/articles/PMC4390457/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4390457</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25649058" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25649058</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fahn.REF.zaki.2015.95">Zaki MS, Selim L, Mansour L, Mahmoud IG, Fenstermaker AG, Gabriel SB, Gleeson JG. Mutations in FA2H in three Arab families with a clinical spectrum of neurodegeneration and hereditary spastic paraparesis. <span><span class="ref-journal">Clin Genet. </span>2015;<span class="ref-vol">88</span>:95–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25496456" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25496456</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK56080_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Allison Gregory</span>, MS<div class="affiliation small">Department of Molecular and Medical Genetics<br />Oregon Health & Science University<br />Portland, Oregon<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.usho@ayrogerg" class="oemail">ude.usho@ayrogerg</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Sunita Venkateswaran</span>, MD<div class="affiliation small">Department of Neurology<br />Children's Hospital of Eastern Ontario<br />Ottawa, Ontario, Canada<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ac.no.oehc@narawsetaknevs" class="oemail">ac.no.oehc@narawsetaknevs</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Susan J Hayflick</span>, MD<div class="affiliation small">Departments of Molecular and Medical Genetics, Pediatrics, and Neurology<br />Oregon Health & Science University<br />Portland, Oregon<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.usho@kcilfyah" class="oemail">ude.usho@kcilfyah</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">June 28, 2011</span>; Last Update: <span itemprop="dateModified">September 27, 2018</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
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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>Gregory A, Venkateswaran S, Hayflick SJ. Fatty Acid Hydroxylase-Associated Neurodegeneration. 2011 Jun 28 [Updated 2018 Sep 27]. 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/fa/?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/feingold/?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="figobfahnTmoleculargenetictestingusedin"><div id="fahn.T.molecular_genetic_testing_used_in" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Fatty Acid Hydroxylase-Associated Neurodegeneration (FAHN)</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56080/table/fahn.T.molecular_genetic_testing_used_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fahn.T.molecular_genetic_testing_used_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_fahn.T.molecular_genetic_testing_used_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_fahn.T.molecular_genetic_testing_used_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_fahn.T.molecular_genetic_testing_used_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_fahn.T.molecular_genetic_testing_used_in_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>FA2H</i>
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</td><td headers="hd_h_fahn.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_fahn.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>95% <sup>4</sup></td></tr><tr><td headers="hd_h_fahn.T.molecular_genetic_testing_used_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>5</sup></td><td headers="hd_h_fahn.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 6.</td></tr><tr><td headers="hd_h_fahn.T.molecular_genetic_testing_used_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Uniparental disomy (UPD) analysis <sup>7</sup></td><td headers="hd_h_fahn.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 8.</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="fahn.TF.1.1"><p class="no_margin">See <a href="/books/NBK56080/?report=reader#fahn.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="fahn.TF.1.2"><p class="no_margin">See <a href="#fahn.Molecular_Genetics">Molecular Genetics</a> for information on allelic variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="fahn.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="fahn.TF.1.4"><p class="no_margin">
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<a class="bibr" href="#fahn.REF.kruer.2010.611" rid="fahn.REF.kruer.2010.611">Kruer et al [2010]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="fahn.TF.1.5"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="fahn.TF.1.6"><p class="no_margin">One reported to date [<a class="bibr" href="#fahn.REF.pierson.2012.476" rid="fahn.REF.pierson.2012.476">Pierson et al 2012</a>]</p></div></dd></dl><dl class="bkr_refwrap"><dt>7. </dt><dd><div id="fahn.TF.1.7"><p class="no_margin">Various methods can detect UPD in an apparent <i>FA2H</i> homozygote. Testing may require parental blood specimens.</p></div></dd></dl><dl class="bkr_refwrap"><dt>8. </dt><dd><div id="fahn.TF.1.8"><p class="no_margin">Four probands from nonconsanguineous families had uniparental disomy (UPD, maternal or paternal) [<a class="bibr" href="#fahn.REF.soehn.2016.186" rid="fahn.REF.soehn.2016.186">Soehn et al 2016</a>]. For probands with apparent homozygous <i>FA2H</i> pathogenic variants and no evidence of large gene deletions, parental testing and/or investigation of the proband for UPD are recommended. The presence of UPD will alter recurrence risks (see <a href="#fahn.Genetic_Counseling">Genetic Counseling</a>).</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobfahnTdisorderstoconsiderinthediff"><div id="fahn.T.disorders_to_consider_in_the_diff" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Disorders to Consider in the Differential Diagnosis of FAHN</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56080/table/fahn.T.disorders_to_consider_in_the_diff/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fahn.T.disorders_to_consider_in_the_diff_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_1" style="text-align:left;vertical-align:middle;">Phenotype</th><th id="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_2" style="text-align:left;vertical-align:middle;">DiffDx Disorder</th><th id="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_3" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="2" scope="col" colspan="1" headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_4" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5" colspan="2" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Additional Clinical & MRI Features of DiffDx Disorder</th></tr><tr><th headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5" id="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/FAHN</th><th headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5" id="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from FAHN</th></tr></thead><tbody><tr><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/nbia-ov/?report=reader">Other NBIA disorders</a>
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</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/mt-mpan/?report=reader">MPAN</a>
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</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>C19orf12</i>
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</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Cognitive decline</div></li><li class="half_rhythm"><div>Progressive spasticity & dystonia</div></li><li class="half_rhythm"><div>Optic atrophy</div></li></ul>
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</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hyperintense streaking of medial medullary lamina often observed on T<sub>2</sub>-weighted MRI</div></li><li class="half_rhythm"><div>Parkinsonism developing in later disease</div></li></ul>
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</td></tr><tr><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/pkan/?report=reader">PKAN</a>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>PANK2</i>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Progressive dystonia & dysarthria</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>"Eye of the tiger" sign</div></li><li class="half_rhythm"><div>More severe dystonia</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/inad/?report=reader">Juvenile PLAN (atypical NAD)</a>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>PLA2G6</i>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Progressive spasticity & dystonia</div></li><li class="half_rhythm"><div>Optic atrophy</div></li><li class="half_rhythm"><div>Cognitive decline</div></li><li class="half_rhythm"><div>Cerebellar atrophy</div></li></ul>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Fewer cerebellar findings</div></li><li class="half_rhythm"><div>Apparent claval hypertrophy</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">CoPAN</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>COASY</i>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Childhood-onset gait abnormalities w/cognitive/psychiatric features</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>More prominent extrapyramidal signs</div></li><li class="half_rhythm"><div>Pallidal iron</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurodegenerative mineral deposition disorder</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/wilson/?report=reader">Wilson disease</a>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>ATP7B</i>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Gait disturbance</div></li><li class="half_rhythm"><div>Spasticity</div></li><li class="half_rhythm"><div>Dystonia</div></li><li class="half_rhythm"><div>T<sub>2</sub>-weighted hypointensity of globus pallidus</div></li></ul>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Kayser-Fleischer rings</div></li><li class="half_rhythm"><div>Liver disease (most common 1st manifestation of Wilson disease in children)</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_1 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_2 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_3 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_1 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_2" colspan="6" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Clinical mimics w/spasticity, dystonia, ataxia, or combination</b>
|
|
</td></tr><tr><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_1" rowspan="10" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/ataxias/?report=reader">Hereditary ataxia</a>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/friedreich/?report=reader">Friedreich ataxia</a>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>FXN</i>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Spastic paraplegia</div></li><li class="half_rhythm"><div>Dysarthria</div></li><li class="half_rhythm"><div>Optic atrophy</div></li><li class="half_rhythm"><div>Peripheral neuropathy</div></li><li class="half_rhythm"><div>Cerebellar atrophy</div></li></ul>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>More prominent early gait ataxia (cerebellar & proprioceptive)</div></li><li class="half_rhythm"><div>Absence of early spasticity</div></li><li class="half_rhythm"><div>Cardiomyopathy</div></li><li class="half_rhythm"><div>Diabetes mellitus in later stages</div></li><li class="half_rhythm"><div>Prominent cervical cord atrophy & only later-onset cerebellar atrophy on MRI</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/arsacs/?report=reader">ARSACS</a>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>SACS</i>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Early childhood spastic ataxia</div></li><li class="half_rhythm"><div>Oculomotor abnormalities</div></li><li class="half_rhythm"><div>Teenage-onset of seizures</div></li></ul>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Unsteady at onset of gait</div></li><li class="half_rhythm"><div>Hypermyelinated retinal fibers</div></li><li class="half_rhythm"><div>Polyneuropathy</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><i>PLP1</i> null syndrome (See <a href="/books/n/gene/pmd/?report=reader"><i>PLP1</i>-Related Disorders</a>.)</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>PLP1</i>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Childhood-onset spasticity & ataxia</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multifocal demyelinating polyneuropathy</td></tr><tr><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Spastic paraplegia 2 (See <a href="/books/n/gene/pmd/?report=reader"><i>PLP1</i>-Related Disorders</a>.)</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>PLP1</i>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Childhood-onset spasticity ± ataxia</div></li><li class="half_rhythm"><div>Nystagmus</div></li></ul>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Preserved cognition</div></li><li class="half_rhythm"><div>Milder course</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Spastic paraplegia 44</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>GJC2</i>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Spasticity</div></li><li class="half_rhythm"><div>Hyperreflexia</div></li><li class="half_rhythm"><div>Intention tremor</div></li></ul>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Preservation of basal ganglia & no cerebellar atrophy</div></li><li class="half_rhythm"><div>Diffuse hypomyelination on MRI</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/spg11/?report=reader">Spastic paraplegia 11</a>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>SPG11</i>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Spastic paraparesis</div></li><li class="half_rhythm"><div>Mild cognitive delay</div></li><li class="half_rhythm"><div>Cerebellar & bulbar involvement</div></li><li class="half_rhythm"><div>Periventricular white matter abnormalities & thin corpus callosum on MRI</div></li></ul>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">More frequent peripheral neuropathy</td></tr><tr><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/spg15/?report=reader">Spastic paraplegia 15</a>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>ZFYVE26</i>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td></tr><tr><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/mld/?report=reader">Arylsulfatase A deficiency</a> (juvenile metachromatic leukodystrophy)</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>ARSA</i>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Early childhood motor regression</div></li><li class="half_rhythm"><div>Spasticity</div></li><li class="half_rhythm"><div>Dysarthria</div></li></ul>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Behavior & cognitive ability decline first</div></li><li class="half_rhythm"><div>More frequent peripheral neuropathy</div></li><li class="half_rhythm"><div>Periventricular demyelination on MRI</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Hypomyelination with atrophy of the basal ganglia and cerebellum (See <a href="/books/n/gene/tubb4a-leuk/?report=reader"><i>TUBB4A</i>-Related Leukodystrophy</a>.)</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>TUBB4A</i>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Variable-onset motor regression w/spasticity</div></li><li class="half_rhythm"><div>Dystonia</div></li><li class="half_rhythm"><div>Bulbar & cerebellar dysfunction</div></li><li class="half_rhythm"><div>Cerebellar atrophy on MRI</div></li></ul>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>More prominent extrapyramidal features</div></li><li class="half_rhythm"><div>Diffuse hypomyelination, atrophy of caudate & putamen, preservation of globus pallidus on MRI</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/pol3-leuk/?report=reader">POLR3-related leukodystrophy</a>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>POLR3A</i>
|
|
<br />
|
|
<i>POLR3B</i>
|
|
<br />
|
|
<i>POLR3C</i>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Spasticity</div></li><li class="half_rhythm"><div>Tremor</div></li><li class="half_rhythm"><div>Extrapyramidal symptoms</div></li><li class="half_rhythm"><div>MRI: thin corpus callosum w/cerebellar atrophy.</div></li></ul>
|
|
</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Cerebellar features predominate</div></li><li class="half_rhythm"><div>Abnormal dentition</div></li><li class="half_rhythm"><div>Endocrine abnormalities</div></li><li class="half_rhythm"><div>± myopia</div></li><li class="half_rhythm"><div>Hypomyelination pattern on MRI</div></li></ul>
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</td></tr><tr><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">Other disorders</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Juvenile & chronic <a href="/books/n/gene/tay-sachs/?report=reader">hexosaminidase A deficiency</a></td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>HEXA</i>
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</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Childhood or later onset spasticity, ataxia, & seizures</div></li><li class="half_rhythm"><div>± optic atrophy</div></li><li class="half_rhythm"><div>± cerebellar atrophy</div></li></ul>
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</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>± retinitis pigmentosa</div></li><li class="half_rhythm"><div>Juvenile form more aggressive</div></li></ul>
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</td></tr><tr><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/drd/?report=reader">GTP cyclohydrolase 1-deficient dopa-responsive dystonia</a>
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</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>GCH1</i>
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</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Childhood-onset gait abnormalities, spasticity, & brisk reflexes</td><td headers="hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_1_5 hd_h_fahn.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Diurinal fluctuation</div></li><li class="half_rhythm"><div>Improvement w/low-dose levodopa</div></li><li class="half_rhythm"><div>MRI: normal</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">AD = autosomal dominant; AR = autosomal recessive; ARSACS = autosomal recessive spastic ataxia of Charlevoix Saguenay; DiffDx = differential diagnosis; MOI = mode of inheritance; NBIA = neurodegeneration with brain iron accumulation; XL = X-linked</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobfahnTrecommendedevaluationsfollowing"><div id="fahn.T.recommended_evaluations_following" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with Fatty Acid Hydroxylase-Associated Neurodegeneration (FAHN)</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56080/table/fahn.T.recommended_evaluations_following/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fahn.T.recommended_evaluations_following_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_fahn.T.recommended_evaluations_following_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_fahn.T.recommended_evaluations_following_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_fahn.T.recommended_evaluations_following_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_fahn.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Eyes</b>
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</td><td headers="hd_h_fahn.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic eval</td><td headers="hd_h_fahn.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl visual acuity & exam for optic atrophy or eye movement abnormalities</td></tr><tr><td headers="hd_h_fahn.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Feeding</b>
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</td><td headers="hd_h_fahn.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multidisciplinary team eval</td><td headers="hd_h_fahn.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Attn to nutritional status & feeding</td></tr><tr><td headers="hd_h_fahn.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Musculoskeletal</b>
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</td><td headers="hd_h_fahn.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PT & OT</td><td headers="hd_h_fahn.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mobility & self-help skills</td></tr><tr><td headers="hd_h_fahn.T.recommended_evaluations_following_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_fahn.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic eval</td><td headers="hd_h_fahn.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For dystonia, ataxia, spasticity; incl EEG if question of seizures.</td></tr><tr><td headers="hd_h_fahn.T.recommended_evaluations_following_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Miscellaneous/</b>
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<br />
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<b>Other</b>
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</td><td headers="hd_h_fahn.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_fahn.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl motor, general cognitive, & vocational skills</td></tr><tr><td headers="hd_h_fahn.T.recommended_evaluations_following_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Speech & language pathologist</td><td headers="hd_h_fahn.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Speech & communication, augmentative devices</td></tr><tr><td headers="hd_h_fahn.T.recommended_evaluations_following_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Consultation w/clinical geneticist &/or genetic counselor</td><td headers="hd_h_fahn.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></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">OT = occupational therapy; PT = physical therapy</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobfahnmolgenTA"><div id="fahn.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Fatty Acid Hydroxylase-Associated Neurodegeneration: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56080/table/fahn.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fahn.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_fahn.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_fahn.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_fahn.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_fahn.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_fahn.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_fahn.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_fahn.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/79152" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>FA2H</i>
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</a>
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</td><td headers="hd_b_fahn.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=79152" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">16q23<wbr style="display:inline-block"></wbr>​.1</a>
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</td><td headers="hd_b_fahn.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.uniprot.org/uniprot/Q7L5A8" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Fatty acid 2-hydroxylase</a>
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</td><td headers="hd_b_fahn.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://databases.lovd.nl/shared/genes/FA2H" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FA2H database</a>
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</td><td headers="hd_b_fahn.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=FA2H" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FA2H</a>
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</td><td headers="hd_b_fahn.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=FA2H[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FA2H</a>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="fahn.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
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<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
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chromosome locus from
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<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
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protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
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For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
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<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobfahnmolgenTB"><div id="fahn.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Fatty Acid Hydroxylase-Associated Neurodegeneration (<a href="/omim/611026,612319" 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/NBK56080/table/fahn.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fahn.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/611026" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">611026</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">FATTY ACID 2-HYDROXYLASE; FA2H</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/612319" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">612319</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SPASTIC PARAPLEGIA 35, AUTOSOMAL RECESSIVE, WITH OR WITHOUT NEURODEGENERATION; SPG35</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobfahnF1"><div id="fahn.F1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK56080/bin/fahn-Image001.jpg" alt="Figure 1. " /></div><h3><span class="label">Figure 1. </span></h3><div class="caption"><p>Neuroimaging features of FAHN (A) vs PKAN (B)</p><p>The two forms of NBIA share T<sub>2-</sub>weighted / gradient-echo hypointensity. Distinguishing features include diffuse cerebral atrophy (seen in FAHN) and central globus pallidus T<sub>2-</sub>weighted hyperintensity (seen in PKAN), producing the characteristic "eye of the tiger" sign.</p></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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