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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Familial Dysautonomia - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_title" content="Familial Dysautonomia">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2021/11/04">
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<meta name="citation_author" content="Bat-El Bar-Aluma">
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<meta name="citation_keywords" content="Hereditary Sensory and Autonomic Neuropathy Type III (HSAN III)">
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<meta name="citation_keywords" content="Riley-Day Syndrome">
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<meta name="citation_keywords" content="Riley-Day Syndrome">
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<meta name="citation_keywords" content="Hereditary Sensory and Autonomic Neuropathy Type III (HSAN III)">
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<meta name="citation_keywords" content="Elongator complex protein 1">
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<meta name="citation_keywords" content="Familial Dysautonomia">
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<meta name="DC.Title" content="Familial Dysautonomia">
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<meta name="description" content="Familial dysautonomia, which affects the development and survival of sensory, sympathetic, and parasympathetic neurons, is a debilitating disorder present from birth. Neuronal degeneration progresses throughout life. Affected individuals have gastrointestinal dysfunction, autonomic crises (i.e., hypertensive vomiting attacks), recurrent pneumonia, altered pain sensitivity, altered temperature perception, and blood pressure instability. Hypotonia contributes to delay in acquisition of motor milestones. Optic neuropathy results in progressive vision loss. Older individuals often have a broad-based and ataxic gait that deteriorates over time. Developmental delay / intellectual disability occur in about 21% of individuals. Life expectancy is decreased.">
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<meta name="og:description" content="Familial dysautonomia, which affects the development and survival of sensory, sympathetic, and parasympathetic neurons, is a debilitating disorder present from birth. Neuronal degeneration progresses throughout life. Affected individuals have gastrointestinal dysfunction, autonomic crises (i.e., hypertensive vomiting attacks), recurrent pneumonia, altered pain sensitivity, altered temperature perception, and blood pressure instability. Hypotonia contributes to delay in acquisition of motor milestones. Optic neuropathy results in progressive vision loss. Older individuals often have a broad-based and ataxic gait that deteriorates over time. Developmental delay / intellectual disability occur in about 21% of individuals. Life expectancy is decreased.">
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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="_NBK1180_"><span class="title" itemprop="name">Familial Dysautonomia</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: Hereditary Sensory and Autonomic Neuropathy Type III (HSAN III), Riley-Day Syndrome</div><p class="contribs">Bar-Aluma BE.</p><p class="fm-aai"><a href="#_NBK1180_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 32 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="fd.Summary" itemprop="description"><h2 id="_fd_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Familial dysautonomia, which affects the development and survival of sensory, sympathetic, and parasympathetic neurons, is a debilitating disorder present from birth. Neuronal degeneration progresses throughout life. Affected individuals have gastrointestinal dysfunction, autonomic crises (i.e., hypertensive vomiting attacks), recurrent pneumonia, altered pain sensitivity, altered temperature perception, and blood pressure instability. Hypotonia contributes to delay in acquisition of motor milestones. Optic neuropathy results in progressive vision loss. Older individuals often have a broad-based and ataxic gait that deteriorates over time. Developmental delay / intellectual disability occur in about 21% of individuals. Life expectancy is decreased.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of familial dysautonomia is established in a proband with suggestive findings and biallelic pathogenic variants in <i>ELP1</i> (formerly <i>IKBKAP</i>) identified by molecular genetic testing.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations</i>: Affected individuals are often managed by multidisciplinary specialists that include neurologists, physiatrists, orthopedic surgeons, physical and occupational therapists, speech-language pathologists, pulmonologists, cardiologists, nephrologists, ophthalmologists, dentists and dental hygienists, and social workers. Feeding teams manage neurogenic dysphagia; mental health professionals treat anxiety.</p><p><i>Surveillance</i>: Routine monitoring of the following: weight, nutrition, safety of oral feeding, developmental/educational progress, mental status, pulmonary function, sleep-disordered breathing, frequency and severity of dysautonomic crises, blood pressure lability, vision and low vision needs, ataxia and activities of daily living, spine for scoliosis, dental care and needs; assessment of caregiver needs.</p><p><i>Agents/circumstances to avoid</i>: The following can exacerbate symptoms: hot or humid weather; full bladder.</p><p><i>Pregnancy management</i>: Pregnancies in women with FD are considered high risk because of blood pressure lability. Visceral pain related to contractions during labor is perceived normally; therefore, analgesia should be provided.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>Familial dysautonomia is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an <i>ELP1</i> pathogenic variant, each sib of an affected individual has at conception 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. Once the <i>ELP1</i> 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. Carrier screening is available on a population basis for individuals of Ashkenazi Jewish heritage.</p></div></div><div id="fd.Diagnosis"><h2 id="_fd_Diagnosis_">Diagnosis</h2><p>The five cardinal clinical diagnostic criteria for familial dysautonomia are absence of fungiform papillae on the tongue, absence of flare after injection of intradermal histamine, decreased or absent deep-tendon reflexes, absence of overflow emotional tears, and Ashkenazi Jewish descent [<a class="bibr" href="#fd.REF.axelrod.1984.947" rid="fd.REF.axelrod.1984.947">Axelrod & Pearson 1984</a>]. This last criterion, however, was rebutted after the discovery of three rare non-Jewish <i>ELP1</i> variants [<a class="bibr" href="#fd.REF.leyne.2003.305" rid="fd.REF.leyne.2003.305">Leyne et al 2003</a>].</p><div id="fd.Suggestive_Findings"><h3>Suggestive Findings</h3><p>
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<b>Clinical findings</b>
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</p><ul><li class="half_rhythm"><div>Gastrointestinal dysfunction with vomiting crises</div></li><li class="half_rhythm"><div>Recurrent aspiration pneumonia</div></li><li class="half_rhythm"><div>Altered sensitivity to pain and temperature</div></li><li class="half_rhythm"><div>Extreme blood pressure variability with postural hypotension</div></li><li class="half_rhythm"><div>Hypotonia</div></li><li class="half_rhythm"><div>Decreased or absent deep tendon reflexes</div></li><li class="half_rhythm"><div>Decreased taste and absence of fungiform papillae of the tongue, giving it a smooth, pale appearance</div></li><li class="half_rhythm"><div>Absence of overflow tears with emotional crying (alacrima) determined either by history in infants older than age three months or the Schirmer test (See <b>Specialized testing</b>.)</div></li></ul><p>
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<b>Specialized testing</b>
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</p><ul><li class="half_rhythm"><div><b>Schirmer test.</b> As newborns do not cry tears, the Schirmer test must be performed after age six months. In the Schirmer test, the end of a filter paper, 5 mm wide and 35 mm long, is placed in the lateral portion of a lower eyelid. Less than 10 mm of wetting of the filter paper after five minutes indicates diminished baseline and reflex tear secretion.</div></li><li class="half_rhythm"><div><b>Absence of axon flare response</b> after intradermal histamine injection</div></li><li class="half_rhythm"><div><b>Pupillary hypersensitivity to parasympathomimetic agents</b>. Topical administration of methacholine 2.5% or pilocarpine 0.0625% has no observable effect on the normal pupil but causes miosis after approximately 20 minutes in almost all individuals with FD.</div></li></ul><p><b>Heritage.</b> Infant is of Ashkenazi Jewish heritage. (Absence of known Ashkenazi Jewish heritage does not exclude the diagnosis.)</p></div><div id="fd.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of familial dysautonomia is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in <i>ELP1</i> (formerly <i>IKBKAP</i>) identified by molecular genetic testing.</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="#fd.REF.richards.2015.405" rid="fd.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>ELP1</i> variants of uncertain significance (or identification of one known <i>ELP1</i> pathogenic variant and one <i>ELP1</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 or multigene panel) and <b>comprehensive</b>
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<b>genomic testing</b> (exome sequencing, genome sequencing) depending on the phenotype.</p><p>Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in <a href="#fd.Suggestive_Findings">Suggestive Findings</a> are more likely to be diagnosed using gene-targeted testing (see <a href="#fd.Option_1">Option 1</a>), whereas those in whom the diagnosis of familial dysautonomia has not been considered may be more likely to be diagnosed using genomic testing (see <a href="#fd.Option_2">Option 2</a>).</p><div id="fd.Option_1"><h4>Option 1</h4><p><b>Single-gene testing.</b> Sequence analysis of <i>ELP1</i> is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. Typically, if only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications; however, to date such variants have not been identified as a cause of this disorder.</p><p>In individuals of Ashkenazi Jewish heritage, targeted analysis for the <i>ELP1</i> variant <a href="/books/NBK1180/table/fd.T.notable_elp1_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobfdTnotableelp1pathogenicvariants">c.2204+6T>C</a> (formerly IVS20+6T>C) can be performed first. This founder variant accounts for more than 99% of pathogenic variants among Ashkenazi Jewish individuals with FD.</p><p><b>A hereditary neuropathy multigene panel</b> that includes <i>ELP1</i> and other genes of interest (see <a href="#fd.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="fd.Option_2"><h4>Option 2</h4><p>When the diagnosis of familial dysautonomia has not been considered because an individual has atypical phenotypic features and/or is not known to have Ashkenazi Jewish heritage, <b>comprehensive</b>
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<b>genomic testing,</b> which does not require the clinician to determine which gene is likely involved, is the best option. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> is also possible.</p><p>For an introduction to comprehensive genomic testing click <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figfdTmoleculargenetictestingusedinf"><a href="/books/NBK1180/table/fd.T.molecular_genetic_testing_used_in_f/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobfdTmoleculargenetictestingusedinf"><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="fd.T.molecular_genetic_testing_used_in_f"><a href="/books/NBK1180/table/fd.T.molecular_genetic_testing_used_in_f/?report=objectonly" target="object" rid-ob="figobfdTmoleculargenetictestingusedinf">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in Familial Dysautonomia </p></div></div></div></div></div><div id="fd.Clinical_Characteristics"><h2 id="_fd_Clinical_Characteristics_">Clinical Characteristics</h2><div id="fd.Clinical_Description"><h3>Clinical Description</h3><p>Familial dysautonomia (FD) affects the development and survival of sensory, sympathetic, and parasympathetic neurons. It is a debilitating disease present from birth. Neuronal degeneration progresses throughout life. Affected individuals have gastrointestinal dysfunction, autonomic crises (I.e., hypertensive vomiting attacks), recurrent pneumonia, altered pain sensitivity, altered temperature perception, and cardiovascular instability. Hypotonia contributes to delay in acquisition of motor milestones. Older individuals often have a broad-based and ataxic gait that deteriorates over time. Developmental delay / intellectual disability occur in about 21% of individuals. Life expectancy is decreased [<a class="bibr" href="#fd.REF.welton.1979.708" rid="fd.REF.welton.1979.708">Welton et al 1979</a>].</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figfdTclinicalmanifestationsoffamilial"><a href="/books/NBK1180/table/fd.T.clinical_manifestations_of_familial/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobfdTclinicalmanifestationsoffamilial"><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="fd.T.clinical_manifestations_of_familial"><a href="/books/NBK1180/table/fd.T.clinical_manifestations_of_familial/?report=objectonly" target="object" rid-ob="figobfdTclinicalmanifestationsoffamilial">Table 2. </a></h4><p class="float-caption no_bottom_margin">Clinical Manifestations of Familial Dysautonomia </p></div></div><p>Most infants with familial dysautonomia are born after an uncomplicated term pregnancy. However, there is an increased rate of polyhydramnios and breech presentation.</p><p><b>Autonomic dysfunction.</b> Neonates (i.e., infants age ≤28 days) typically have impaired oropharyngeal incoordination (i.e., neurogenic dysphagia) manifest as poor initiation of sucking and poor swallowing mechanisms. Protective airway reflexes (including cough) are decreased or lacking; the risk of aspiration and aspiration pneumonia shortly after birth is extremely high. Additional gastrointestinal problems that can interfere with eating and weight gain include esophageal dysmotility and GERD.</p><p>Infants with FD may have difficulties maintaining normal body temperature and may be indifferent to pain stimuli.</p><p>Sympathetic nervous system involvement results in orthostatic hypotension that is exacerbated by exercise and warm environments. Syncope is surprisingly infrequent, and usually indicates volume depletion, anemia, or hypoxia.</p><p>Urinary stress incontinence is common in adolescent and adult women [<a class="bibr" href="#fd.REF.saini.2003.209" rid="fd.REF.saini.2003.209">Saini et al 2003</a>].</p><p>Episodic somnolence has been reported.</p><p>Autonomic crises, also described as hypertensive vomiting attacks, occur in about 40% of individuals. Attacks occur when stimuli increase sympathetic outflow causing an uncontrolled release of catecholamines (neurotransmitters such as epinephrine and dopamine) into the circulation. Common triggers include emotion, illness, abdominal discomfort, and bladder distension; however, sometimes the crises are unpredictable and without obvious cause. Dopamine, which is believed to activate receptors in the chemoreceptor trigger zone of the area postrema (located in the medulla oblongata), cause cyclic vomiting (or retching in persons who have undergone fundoplication). These dopaminergic crises can also be associated with tachycardia, hyperhidrosis, irritability, and personality changes. Crises may last several days.</p><p><b>Sensory disturbances</b> are significant. Pain and temperature thresholds are greatly elevated; affected individuals report a relative indifference to pain. The risk for decubitus ulcers, burns, and other minor injuries to become infected is increased. Failure to recognize fractures has also been described.</p><p><b>Motor development.</b> Infants and young children have varying degrees of hypotonia that contribute to delay in motor milestones. Although some infants may acquire motor skills in the usual timeframe, most infants demonstrate some degree of delay in acquisition of motor skills. Sitting without support is usually achieved around age 12-18 months, standing alone around age one to two years, and walking independently around age two to three years [Sheba Medical Center Familial Dysautonomia Database, unpublished data].</p><p>Older individuals often have a broad-based, ataxic gait that progressively deteriorates over time. Individuals with FD have difficulty performing rapid movements and maintaining their balance while changing direction or turning. By age 20 years 3% of affected individuals require assistance walking; this percentage increases linearly to 14% by age 30 years, 27% by age 40 years, and 49% by age 50 years [<a class="bibr" href="#fd.REF.macefield.2011.3198" rid="fd.REF.macefield.2011.3198">Macefield et al 2011</a>].</p><p><b>Ophthalmologic.</b> Recurrent corneal ulcers and occasionally permanent opacities result from alacrima and corneal hypoesthesia.</p><p>The major cause of visual loss in FD is optic neuropathy affecting mostly the P-type retinal ganglion cells. Beginning early in life, all individuals with FD experience progressive loss of retinal ganglion cell axons. The temporal retinal nerve fiber layer (RNFL) is the most affected. The less energy-dependent ganglion cells are relatively spared, whereas the more energy-dependent maculopapillary ganglion cells are selectively damaged [<a class="bibr" href="#fd.REF.mendozasantiesteban.2014.702" rid="fd.REF.mendozasantiesteban.2014.702">Mendoza-Santiesteban et al 2014</a>]. The accelerated retinal damage continues until the third decade of life and then plateaus [<a class="bibr" href="#fd.REF.kfir.2021.1402" rid="fd.REF.kfir.2021.1402">Kfir et al 2021</a>]. Visual impairment frequently begins at an early age and can progress to blindness usually after the third decade of life.</p><p>Eye movement disorders such as strabismus are very common.</p><p><b>Respiratory</b> illness is common. According to the New York University Familial Dysautonomia Patient Registry [<a class="bibr" href="#fd.REF.kazachkov.2018.37" rid="fd.REF.kazachkov.2018.37">Kazachkov et al 2018</a>], upper-airway obstruction is present in 83%, lower-airway disease in 85%, and restrictive lung disease in 94% [<a class="bibr" href="#fd.REF.palma.2019.10" rid="fd.REF.palma.2019.10">Palma et al 2019</a>].</p><p>Although most individuals undergo gastrostomy with Nissen fundoplication upon diagnosis, recurrent lower-airway infections remain common. Most individuals with FD develop chronic lung disease secondary to recurrent aspiration. CT imaging of the lungs shows bronchiectasis in 26% of affected individuals.</p><p>Lack of input from the peripheral chemoreceptors results in almost absent ventilatory responses to hypoxemia; the chemoreceptor ventilatory responses to hypercapnia are also reduced, but to a lesser extent.</p><p>The majority of children and adults with FD have some degree of sleep-disordered breathing. Central apnea is more frequent in children; obstructive apnea is more frequent in adults.</p><p>The increased incidence of sudden death during sleep can be attributed to the following risk factors: treatment with fludrocortisone, plasma potassium concentrations <4 mEq/L, and untreated sleep apnea [<a class="bibr" href="#fd.REF.palma.2017.zsx083" rid="fd.REF.palma.2017.zsx083">Palma et al 2017</a>].</p><p><b>Kyphoscoliosis,</b> a common finding, develops during the first two decades. By age 20 years, 80% of affected individuals have some degree of spinal deformity, possibly due to abnormal posture of the trunk as needed to maintain balance.</p><p><b>Renal.</b> Chronic kidney disease is common. Renal function tends to deteriorate with advancing age. Almost all persons with FD who reach their fourth decade have a markedly decreased estimated glomerular filtration rate (eGFR) [<a class="bibr" href="#fd.REF.elkayam.2006.780" rid="fd.REF.elkayam.2006.780">Elkayam et al 2006</a>].</p><p>Baroreflex failure, manifest as excessive increases or decreases in blood pressure with wide fluctuations, is associated with a faster progression of renal disease. Some individuals progress to end-stage renal disease and may require dialysis. A few renal transplants have been performed.</p><p>Renal tubular acidosis, requiring treatment, is common. Hyperkalemia, which is also common, is not always explained by the degree of renal insufficiency.</p><p>There is also an increased incidence of congenital renal defects, including a single kidney, horseshoe kidney, and crossed renal ectopia (i.e., a kidney that has crossed from its side to the other side such that the kidneys are both located on one side of the body) [<a class="bibr" href="#fd.REF.norcliffekaufmann.2013a.51" rid="fd.REF.norcliffekaufmann.2013a.51">Norcliffe-Kaufmann et al 2013a</a>].</p><p><b>Cognitive function</b> differs widely among affected individuals. Both learning difficulties and poor concentration are common. Although acquisition of verbal skills is delayed during the first nine years, verbal skills subsequently improve to within the normal range for age [<a class="bibr" href="#fd.REF.palma.2014.2653" rid="fd.REF.palma.2014.2653">Palma et al 2014</a>].</p><p><b>Personality issues.</b> Anxiety is the most common psychiatric problem. Skin or nail picking and trichotillomania occur in around 10% of individuals [<a class="bibr" href="#fd.REF.palma.2014.2653" rid="fd.REF.palma.2014.2653">Palma et al 2014</a>].</p><p>
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<b>Other</b>
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</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Craniofacial findings</b> include small jaw, mandibular retrognathia, malocclusion, dental crowding, and smaller tooth size [<a class="bibr" href="#fd.REF.mass.2016.490" rid="fd.REF.mass.2016.490">Mass 2016</a>].</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Dental trauma</b> occurs in 60% of individuals (often from frequent falling due to ataxia and balance issues); 32% have orodental self-mutilation (i.e., chewing the gums without noticing).</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Sexual maturation</b> is frequently delayed; however, sexual development is normal in both sexes. Women with FD have delivered normal infants following uncomplicated pregnancies. Fertility in males has been reported; one male has fathered six children.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Growth.</b> Neonates with FD are usually born appropriate for gestational age with head circumference within the normal range. Individuals with FD often fall severely below their projected midparental adjusted height; the reported average adult height for males is 158 centimeters and for females is 150 centimeters.</div><div class="half_rhythm">Although poor linear growth velocity, low-to-normal insulin-like growth factor-I (IGFI) levels, and delayed skeletal age are reported in FD, challenge tests for growth hormone deficiency have been inconclusive. Growth hormone treatment in individuals in an open-label study resulted in growth velocity that exceeded pre-treatment rates in 12 of the 13 treated individuals [<a class="bibr" href="#fd.REF.kamboj.2004.63" rid="fd.REF.kamboj.2004.63">Kamboj et al 2004</a>].</div></li></ul><p><b>Quality of life.</b> Using a questionnaire to evaluate the quality of life in persons with FD, <a class="bibr" href="#fd.REF.sands.2006.457" rid="fd.REF.sands.2006.457">Sands et al [2006]</a> determined that FD imposed a greater physical than psychosocial burden on children, whereas young adults reported both mental and physical quality of life within the average range. Self-esteem was problematic and improved with age. Both age groups reported decreasing physical quality of life with age, with worsening general health that limited their roles at school or work.</p><p><b>Prognosis.</b> FD has always been recognized as a potentially life-threatening disorder with a high mortality rate and a high incidence of sudden death. Causes of death are primarily pulmonary (26%) and unexplained (38%); the latter may result from unopposed vagal stimulation. Sepsis is also a significant cause of death (11%) [<a class="bibr" href="#fd.REF.axelrod.2002.518" rid="fd.REF.axelrod.2002.518">Axelrod et al 2002</a>].</p></div><div id="fd.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>No genotype-phenotype correlations have been observed [<a class="bibr" href="#fd.REF.blumenfeld.1999.1110" rid="fd.REF.blumenfeld.1999.1110">Blumenfeld et al 1999</a>].</p><p>The <a href="/books/NBK1180/table/fd.T.notable_elp1_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobfdTnotableelp1pathogenicvariants">p.Arg696Pro</a> pathogenic variant is extremely rare in the Ashkenazi Jewish population and has never been detected in the homozygous state; therefore, the phenotype associated with p.Arg696Pro homozygosity is unknown.</p></div><div id="fd.Prevalence"><h3>Prevalence</h3><p>The incidence of FD among the Ashkenazim is 1:3,700 live births, which corresponds to a carrier frequency of 1:36 [<a class="bibr" href="#fd.REF.slaugenhaupt.2001.598" rid="fd.REF.slaugenhaupt.2001.598">Slaugenhaupt et al 2001</a>].</p><p>A study by <a class="bibr" href="#fd.REF.lehavi.2003.139" rid="fd.REF.lehavi.2003.139">Lehavi et al [2003]</a> from Israel identified 34 carriers among 1100 individuals of full Ashkenazi Jewish parentage (carrier rate 1:32). Further analysis revealed different carrier frequencies among a subset of Polish Ashkenazi Jews: Among the 195 individuals of full Polish background, 11 carriers were detected (1:18), in contrast to only three of the 298 of full non-Polish background (1:99).</p></div></div><div id="fd.Genetically_Related_Allelic_Disorders"><h2 id="_fd_Genetically_Related_Allelic_Disorders_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with germline pathogenic variants in <i>ELP1</i> (<i>IKBKAP</i>).</p></div><div id="fd.Differential_Diagnosis"><h2 id="_fd_Differential_Diagnosis_">Differential Diagnosis</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figfdTgenesanddisordersofinterestin"><a href="/books/NBK1180/table/fd.T.genes_and_disorders_of_interest_in/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobfdTgenesanddisordersofinterestin"><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="fd.T.genes_and_disorders_of_interest_in"><a href="/books/NBK1180/table/fd.T.genes_and_disorders_of_interest_in/?report=objectonly" target="object" rid-ob="figobfdTgenesanddisordersofinterestin">Table 3. </a></h4><p class="float-caption no_bottom_margin">Genes and Disorders of Interest in the Differential Diagnosis </p></div></div><p><b>HSAN1B</b> (OMIM <a href="https://omim.org/entry/608088" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">608088</a>), a disorder of unknown genetic cause, can also be considered in the differential diagnosis. HSAN1B is characterized by cough and gastroesophageal reflux; loss of pain & temperature sensation; osteomyelitis; lancinating pain; distal motor involvement (variable); and facultative deafness. There are no visceral signs of autonomic involvement.</p></div><div id="fd.Management"><h2 id="_fd_Management_">Management</h2><p>Clinical practice guidelines have been published [<a class="bibr" href="#fd.REF.kazachkov.2018.37" rid="fd.REF.kazachkov.2018.37">Kazachkov et al 2018</a>] (<a href="https://www.sciencedirect.com/science/article/pii/S0954611118302087?via%3Dihub" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">full text</a>).</p><div id="fd.Evaluations_Following_Initial_Diagnos"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with familial dysautonomia, the evaluations summarized in <a href="/books/NBK1180/table/fd.T.recommended_evaluations_following_i/?report=objectonly" target="object" rid-ob="figobfdTrecommendedevaluationsfollowingi">Table 4</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="figfdTrecommendedevaluationsfollowingi"><a href="/books/NBK1180/table/fd.T.recommended_evaluations_following_i/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobfdTrecommendedevaluationsfollowingi"><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="fd.T.recommended_evaluations_following_i"><a href="/books/NBK1180/table/fd.T.recommended_evaluations_following_i/?report=objectonly" target="object" rid-ob="figobfdTrecommendedevaluationsfollowingi">Table 4. </a></h4><p class="float-caption no_bottom_margin">Recommended Evaluations Following Initial Diagnosis in Individuals with Familial Dysautonomia </p></div></div></div><div id="fd.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>There is no curative therapy for familial dysautonomia. Treatment is supportive.</p><p>Affected individuals are often managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, physical and occupational therapists, speech-language pathologists, pulmonologists, and social workers (see <a href="/books/NBK1180/table/fd.T.treatment_of_manifestations_in_indi/?report=objectonly" target="object" rid-ob="figobfdTtreatmentofmanifestationsinindi">Table 5</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figfdTtreatmentofmanifestationsinindi"><a href="/books/NBK1180/table/fd.T.treatment_of_manifestations_in_indi/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figobfdTtreatmentofmanifestationsinindi"><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="fd.T.treatment_of_manifestations_in_indi"><a href="/books/NBK1180/table/fd.T.treatment_of_manifestations_in_indi/?report=objectonly" target="object" rid-ob="figobfdTtreatmentofmanifestationsinindi">Table 5. </a></h4><p class="float-caption no_bottom_margin">Treatment of Manifestations in Individuals with Familial Dysautonomia </p></div></div><div id="fd.Developmental_Delay__Intellectual_Dis"><h4>Developmental Delay / Intellectual Disability Management Issues</h4><p>The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.</p><p><b>Ages 0-3 years.</b> Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.</p><p><b>Ages 3-5 years.</b> In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.</p><p><b>All ages.</b> Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:</p><ul><li class="half_rhythm"><div>Individualized education plan (IEP) services:</div><ul><li class="half_rhythm"><div>An IEP provides specially designed instruction and related services to children who qualify.</div></li><li class="half_rhythm"><div>IEP services will be reviewed annually to determine whether any changes are needed.</div></li><li class="half_rhythm"><div>Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.</div></li><li class="half_rhythm"><div>Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.</div></li><li class="half_rhythm"><div>PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.</div></li><li class="half_rhythm"><div>As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.</div></li></ul></li><li class="half_rhythm"><div>A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.</div></li><li class="half_rhythm"><div>Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.</div></li><li class="half_rhythm"><div>Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.</div></li></ul></div></div><div id="fd.Surveillance"><h3>Surveillance</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figfdTrecommendedsurveillanceforindivi"><a href="/books/NBK1180/table/fd.T.recommended_surveillance_for_indivi/?report=objectonly" target="object" title="Table 6. " class="img_link icnblk_img" rid-ob="figobfdTrecommendedsurveillanceforindivi"><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="fd.T.recommended_surveillance_for_indivi"><a href="/books/NBK1180/table/fd.T.recommended_surveillance_for_indivi/?report=objectonly" target="object" rid-ob="figobfdTrecommendedsurveillanceforindivi">Table 6. </a></h4><p class="float-caption no_bottom_margin">Recommended Surveillance for Individuals with Familial Dysautonomia </p></div></div></div><div id="fd.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Symptoms tend to be worse in hot or humid weather; affected individuals should try to avoid being outdoors in such conditions as much as possible.</p><p>Other situations that can exacerbate disease manifestations include a full bladder; frequent visits to the lavatory are recommended [<a class="bibr" href="#fd.REF.axelrod.2007.39" rid="fd.REF.axelrod.2007.39">Axelrod & Gold-von Simson 2007</a>].</p><p>Since long car rides, coming out of a movie theater, or fatigue can also worsen symptoms, such situations should be avoided as much as possible [<a class="bibr" href="#fd.REF.axelrod.2007.39" rid="fd.REF.axelrod.2007.39">Axelrod & Gold-von Simson 2007</a>].</p><p>Episodic hypertension can occur in response to emotional stress or visceral pain, and therefore should be avoided when possible [<a class="bibr" href="#fd.REF.axelrod.2007.39" rid="fd.REF.axelrod.2007.39">Axelrod & Gold-von Simson 2007</a>].</p><p>Environmental situations associated with hypobaric hypoxia (e.g., aircraft flight or ascent to high altitude) pose a potential risk to individuals with daytime hypercapnia [<a class="bibr" href="#fd.REF.palma.2014.2653" rid="fd.REF.palma.2014.2653">Palma et al 2014</a>].</p></div><div id="fd.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#fd.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="fd.Pregnancy_Management"><h3>Pregnancy Management</h3><p>Pregnancies in women with FD are considered high risk because of abrupt changes in blood pressure.</p><p>High blood pressure secondary to FD is difficult to differentiate from toxemia or other causes of pregnancy-related high blood pressure.</p><p>Awareness of volume loss and low blood pressure is important because of the absence of reflex tachycardia to low blood pressure.</p><p>Visceral pain related to contractions during labor is perceived normally; therefore, analgesia should be provided. Epidural anesthesia is preferable due to blood pressure lability during general anesthesia or spinal block [<a class="bibr" href="#fd.REF.maayan.2000.679" rid="fd.REF.maayan.2000.679">Maayan et al 2000</a>].</p></div><div id="fd.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="fd.Genetic_Counseling"><h2 id="_fd_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="fd.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Familial dysautonomia (FD) is inherited in an autosomal recessive manner.</p></div><div id="fd.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one <i>ELP1</i> [<i>IKBKAP</i>] pathogenic variant based on family history).</div></li><li class="half_rhythm"><div>Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an <i>ELP1</i> pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:</div><ul><li class="half_rhythm"><div>One of the pathogenic variants identified in the proband occurred as a <i>de novo</i> event in the proband or as a postzygotic <i>de novo</i> event in a mosaic parent [<a class="bibr" href="#fd.REF.j_nsson.2017.519" rid="fd.REF.j_nsson.2017.519">Jónsson et al 2017</a>].</div></li><li class="half_rhythm"><div>Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.</div></li></ul></li><li class="half_rhythm"><div>Heterozygotes 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>If both parents are known to be heterozygous for an <i>ELP1</i> pathogenic variant, each sib of an affected individual has at conception 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>
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<b>Offspring of a proband</b>
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</p><ul><li class="half_rhythm"><div>All offspring of an individual with FD inherit a pathogenic variant in <i>ELP1</i> from their affected parent.</div></li><li class="half_rhythm"><div>The risk that the Ashkenazi Jewish reproductive partner of an individual with FD is heterozygous for an <i>ELP1</i> disease-causing allele is 1:32 (see <a href="#fd.Prevalence">Prevalence</a>). Thus, the risk to the offspring of an affected individual and an Ashkenazi Jewish partner of having FD is approximately 1.5%. (The risk that a person of non-Ashkenazi Jewish ancestry is a carrier of FD is <1:150. For offspring of an individual with FD and a non-Ashkenazi Jewish reproductive partner, the risk of having FD is <1:300.)</div></li><li class="half_rhythm"><div>It is appropriate to offer molecular genetic testing of <i>ELP1</i> to the reproductive partner of an individual with FD (see <a href="#fd.Related_Genetic_Counseling_Issues">Related Genetic Counseling Issues</a>, <b>Population screening</b>).</div></li></ul><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>ELP1</i> pathogenic variant.</p></div><div id="fd.Carrier_Detection"><h3>Carrier Detection</h3><p>Carrier testing for at-risk relatives requires prior identification of the <i>ELP1</i> pathogenic variants in the family.</p><p>See <a href="#fd.Related_Genetic_Counseling_Issues">Related Genetic Counseling Issues</a>, <b>Population screening</b> for information about carrier testing in individuals who do not have a family history of FD.</p></div><div id="fd.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>
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<b>Population screening</b>
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</p><ul><li class="half_rhythm"><div>Because of the increased carrier rate for FD in individuals of Ashkenazi Jewish heritage (see <a href="#fd.Prevalence">Prevalence</a>), the American College of Obstetricians and Gynecologists recommends offering carrier screening for FD to individuals of Jewish descent [<a class="bibr" href="#fd.REF1" rid="fd.REF1">ACOG 2017</a>] (<a href="https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2017/03/carrier-screening-for-genetic-conditions" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">full text</a>). Targeted analysis for pathogenic variants in <i>ELP1</i> is often included in panels of "Ashkenazi Jewish pathogenic variants" offered to individuals interested in preconception or prenatal risk assessment modification.</div></li><li class="half_rhythm"><div>If an individual has FD or is known to be a carrier of an <i>ELP1</i> pathogenic variant, it is appropriate to offer molecular genetic testing of <i>ELP1</i> to the individual's reproductive partner regardless of the reproductive partner’s heritage.</div></li></ul><p>
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<b>Family planning</b>
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</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.</div></li></ul></div><div id="fd.Prenatal_Testing_and_Preimplantation"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>ELP1</i> pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for FD are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="fd.Resources"><h2 id="_fd_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>Autonomic Disorders Consortium</b>
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</div><div>
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<a href="https://www.rarediseasesnetwork.org/news/autonomic-disorders-consortium" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Autonomic Disorders Consortium</a>
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</div></li><li class="half_rhythm"><div>
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<b>Familial Dysautonomia Foundation, Inc.</b>
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</div><div>315 West 39th Street</div><div>Suite 701</div><div>New York NY 10018</div><div><b>Phone:</b> 212-279-1066</div><div><b>Email:</b> info@famdys.org</div><div>
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<a href="http://www.familialdysautonomia.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.familialdysautonomia.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Familial Dysautonomia Now Foundation</b>
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</div><div><b>Phone:</b> 847-913-0455</div><div><b>Email:</b> info@fdnow.org</div><div>
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<a href="https://fdnow.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.fdnow.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>MedlinePlus</b>
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</div><div>
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<a href="https://medlineplus.gov/genetics/condition/familial-dysautonomia/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Familial dysautonomia</a>
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</div></li><li class="half_rhythm"><div>
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<b>Norton & Elaine Sarnoff Center for Jewish Genetics</b>
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</div><div><b>Phone:</b> 312-357-4718</div><div><b>Email:</b> jewishgenetics@juf.org</div><div>
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<a href="https://www.juf.org/cjg/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.juf.org/cjg</a>
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</div></li></ul>
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</div><div id="fd.Molecular_Genetics"><h2 id="_fd_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="figfdmolgenTA"><a href="/books/NBK1180/table/fd.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobfdmolgenTA"><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="fd.molgen.TA"><a href="/books/NBK1180/table/fd.molgen.TA/?report=objectonly" target="object" rid-ob="figobfdmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">Familial Dysautonomia: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figfdmolgenTB"><a href="/books/NBK1180/table/fd.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobfdmolgenTB"><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="fd.molgen.TB"><a href="/books/NBK1180/table/fd.molgen.TB/?report=objectonly" target="object" rid-ob="figobfdmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for Familial Dysautonomia (View All in OMIM) </p></div></div><div id="fd.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p>ELP1 protein is one of the six subunits of the Elongator complex, which facilitates transcriptional elongation, and is required for efficient translation of proteins. During embryogenesis, ELP1 is expressed first in the central and peripheral nervous systems and in the gastrointestinal tract. It is then expressed in secretory tissues and cartilage, and finally in muscle. Once the organs are formed, ELP1 expression appears in the skin and mucosal tissue. Overall, expression is more prominent in the nervous system and retina, and to a lesser extent in other organs. The complete absence of ELP1 leads to embryonic lethality with failure of vasculogenesis and neurulation [<a class="bibr" href="#fd.REF.norcliffekaufmann.2017.131" rid="fd.REF.norcliffekaufmann.2017.131">Norcliffe-Kaufmann et al 2017</a>]. Individuals with biallelic <i>ELP1</i> pathogenic variants have at birth multiple lesions affecting mostly sensory (afferent) nerve fibers.</p><p><b>Mechanism of disease causation.</b> The <a href="/books/NBK1180/table/fd.T.notable_elp1_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobfdTnotableelp1pathogenicvariants">c.2204+6T>C</a> founder variant affects the intronic splice donor site in <i>ELP1</i> exon 20. The skipping of exon 20 leads to a frameshift and generation of a premature termination codon in exon 21 of <i>ELP1</i> mRNA. The aberrant skipping of exon 20 is tissue specific, mostly in neurons.</p><p><b><i>ELP1</i>-specific laboratory technical considerations.</b> Information on two other rare variants that have not yet been published is available in the NYU Center for Dysautonomia's <a href="https://familialdysautonomia.org/application/files/5216/2696/1813/Research_Booklet_2020-2021_PDF.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">2020-2021 Year in Review</a> (pdf).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figfdTnotableelp1pathogenicvariants"><a href="/books/NBK1180/table/fd.T.notable_elp1_pathogenic_variants/?report=objectonly" target="object" title="Table 7. " class="img_link icnblk_img" rid-ob="figobfdTnotableelp1pathogenicvariants"><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="fd.T.notable_elp1_pathogenic_variants"><a href="/books/NBK1180/table/fd.T.notable_elp1_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobfdTnotableelp1pathogenicvariants">Table 7. </a></h4><p class="float-caption no_bottom_margin">Notable <i>ELP1</i> Pathogenic Variants </p></div></div></div></div><div id="fd.Chapter_Notes"><h2 id="_fd_Chapter_Notes_">Chapter Notes</h2><div id="fd.Acknowledgments"><h3>Acknowledgments</h3><p>I would like to thank my supervisor, Professor Ori Efrati, Head of the Pediatric Pulmonary Unit at Sheba Medical Center, for establishing the National Center for Familial Dysautonomia as a part of our unit.</p><p>I would also like to thank Professor Horacio Kaufmann, Head of the Dysautonomia Center, New York University School of Medicine, for his support and guidance during my training at the Dysautonomia Center.</p></div><div id="fd.Author_History"><h3>Author History</h3><p>Bat-El Bar-Aluma, MD (2021-present)<br />Gabrielle J Halpern, MB, ChB; Beilinson Hospital, Petah Tikva (1999-2014)<br />Mordechai Shohat, MD; Sheba Medical Center at Tel HaShomer (1999-2021)<br />Monika Weisz Hubshman, MD, PhD; Rabin Medical Center, Beilinson Hospital (2014-2021)</p></div><div id="fd.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>4 November 2021 (bp) Comprehensive update posted live</div></li><li class="half_rhythm"><div>18 December 2014 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>1 June 2010 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>22 October 2007 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>10 January 2005 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>21 January 2003 (me) Review posted live</div></li><li class="half_rhythm"><div>6 November 1999 (bp) Original submission</div></li></ul></div></div><div id="fd.References"><h2 id="_fd_References_">References</h2><div id="fd.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="fd.REF1">ACOG. 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Sudden unexpected death during sleep in familial dysautonomia: a case-control study. <span><span class="ref-journal">Sleep. </span>2017;<span class="ref-vol">40</span>:zsx083. </span> [<a href="/pmc/articles/PMC5806542/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5806542</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28521050" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28521050</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fd.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="fd.REF.saini.2003.209">Saini J, Axelrod FB, Maayan C, Stringer J, Smilen SW. Urinary incontinence in familial dysautonomia. <span><span class="ref-journal">Int Urogynecol J Pelvic Floor Dysfunct. </span>2003;<span class="ref-vol">14</span>:209–13.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12955345" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12955345</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fd.REF.sands.2006.457">Sands SA, Giarraffa P, Jacobson CM, Axelrod FB. Familial dysautonomia's impact on quality of life in childhood, adolescence, and adulthood. <span><span class="ref-journal">Acta Paediatr. </span>2006;<span class="ref-vol">95</span>:457–62.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16720494" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16720494</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fd.REF.slaugenhaupt.2001.598">Slaugenhaupt SA, Blumenfeld A, Gill SP, Leyne M, Mull J, Cuajungco MP, Liebert CB, Chadwick B, Idelson M, Reznik L, Robbins C, Makalowska I, Brownstein M, Krappmann D, Scheidereit C, Maayan C, Axelrod FB, Gusella JF. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. <span><span class="ref-journal">Am J Hum Genet. </span>2001;<span class="ref-vol">68</span>:598–605.</span> [<a href="/pmc/articles/PMC1274473/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1274473</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11179008" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11179008</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fd.REF.spalink.2017.279">Spalink CL, Barnes E, Palma JA, Norcliffe-Kaufmann L, Kaufmann H. Intranasal dexmedetomidine for adrenergic crisis in familial dysautonomia. <span><span class="ref-journal">Clin Auton Res. </span>2017;<span class="ref-vol">27</span>:279–82.</span> [<a href="/pmc/articles/PMC5555081/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5555081</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28674865" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28674865</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fd.REF.stenson.2020.1197">Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. <span><span class="ref-journal">Hum Genet. </span>2020;<span class="ref-vol">139</span>:1197–207.</span> [<a href="/pmc/articles/PMC7497289/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7497289</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32596782" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32596782</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fd.REF.verhoeven.2003.722">Verhoeven K, De Jonghe P, Coen K, Verpoorten N, Auer-Grumbach M, Kwon JM, FitzPatrick D, Schmedding E, De Vriendt E, Jacobs A, Van Gerwen V, Wagner K, Hartung HP, Timmerman V. Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. <span><span class="ref-journal">Am J Hum Genet. </span>2003;<span class="ref-vol">72</span>:722–7.</span> [<a href="/pmc/articles/PMC1180247/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1180247</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12545426" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12545426</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="fd.REF.welton.1979.708">Welton W, Clayson D, Axelrod FB, Levine DB. Intellectual development and familial dysautonomia. <span><span class="ref-journal">Pediatrics. </span>1979;<span class="ref-vol">63</span>:708–12.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/440890" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 440890</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK1180_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Bat-El Bar-Aluma</span>, MD<div class="affiliation small">Pediatric Pulmonology Unit<br />National Center for Familial Dysautonomia<br />Edmond and Lily Safra Children's Hospital<br />Sheba Medical Center;<br />Sackler Faculty of Medicine<br />Tel Aviv University<br />Tel Aviv, Israel<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="li.vog.htlaeh.abehs@amularab.letab" class="oemail">li.vog.htlaeh.abehs@amularab.letab</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">January 21, 2003</span>; Last Update: <span itemprop="dateModified">November 4, 2021</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>Bar-Aluma BE. Familial Dysautonomia. 2003 Jan 21 [Updated 2021 Nov 4]. 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/fch/?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/fevr/?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="figobfdTmoleculargenetictestingusedinf"><div id="fd.T.molecular_genetic_testing_used_in_f" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Familial Dysautonomia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1180/table/fd.T.molecular_genetic_testing_used_in_f/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fd.T.molecular_genetic_testing_used_in_f_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_fd.T.molecular_genetic_testing_used_in_f_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_fd.T.molecular_genetic_testing_used_in_f_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_fd.T.molecular_genetic_testing_used_in_f_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_fd.T.molecular_genetic_testing_used_in_f_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;"><i>ELP1</i> (<i>IKBKAP</i>)</td><td headers="hd_h_fd.T.molecular_genetic_testing_used_in_f_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Targeted analysis for pathogenic variants <sup>3</sup></td><td headers="hd_h_fd.T.molecular_genetic_testing_used_in_f_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>99% (Ashkenazi Jewish population) <sup>4</sup></td></tr><tr><td headers="hd_h_fd.T.molecular_genetic_testing_used_in_f_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>5</sup></td><td headers="hd_h_fd.T.molecular_genetic_testing_used_in_f_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>99% <sup>4</sup></td></tr><tr><td headers="hd_h_fd.T.molecular_genetic_testing_used_in_f_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Deletion/duplication analysis <sup>6</sup></td><td headers="hd_h_fd.T.molecular_genetic_testing_used_in_f_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None detected to date</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="fd.TF.1.1"><p class="no_margin">See <a href="/books/NBK1180/?report=reader#fd.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein name.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="fd.TF.1.2"><p class="no_margin">See <a href="#fd.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="fd.TF.1.3"><p class="no_margin">For pathogenic variants <a href="/books/NBK1180/table/fd.T.notable_elp1_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobfdTnotableelp1pathogenicvariants">c.2204+6T>C</a> and/or <a href="/books/NBK1180/table/fd.T.notable_elp1_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobfdTnotableelp1pathogenicvariants">p.Arg696Pro</a> [<a class="bibr" href="#fd.REF.dong.2002.253" rid="fd.REF.dong.2002.253">Dong et al 2002</a>]</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="fd.TF.1.4"><p class="no_margin">Data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bibr" href="#fd.REF.stenson.2020.1197" rid="fd.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="fd.TF.1.5"><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>6. </dt><dd><div id="fd.TF.1.6"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobfdTclinicalmanifestationsoffamilial"><div id="fd.T.clinical_manifestations_of_familial" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Clinical Manifestations of Familial Dysautonomia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1180/table/fd.T.clinical_manifestations_of_familial/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fd.T.clinical_manifestations_of_familial_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_fd.T.clinical_manifestations_of_familial_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System<br />Involved</th><th id="hd_h_fd.T.clinical_manifestations_of_familial_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical Manifestations</th></tr></thead><tbody><tr><td headers="hd_h_fd.T.clinical_manifestations_of_familial_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Autonomic</b>
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<br />
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<b>system</b>
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</td><td headers="hd_h_fd.T.clinical_manifestations_of_familial_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Oropharyngeal incoordination (60% of neonates)</div></li><li class="half_rhythm"><div>Esophageal dysmotility, GERD <sup>1</sup></div></li><li class="half_rhythm"><div>Insensitivity to hypercapnia and hypoxia <sup>2</sup></div></li><li class="half_rhythm"><div>Breath holding</div></li><li class="half_rhythm"><div>Orthostatic hypotension w/o compensatory tachycardia <sup>1, 3</sup></div></li><li class="half_rhythm"><div>Supine hypertension <sup>1</sup></div></li><li class="half_rhythm"><div>Autonomic crises (i.e., hypertensive vomiting attacks) (40%)</div></li></ul>
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</td></tr><tr><td headers="hd_h_fd.T.clinical_manifestations_of_familial_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Sensory</b>
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<br />
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<b>system</b>
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</td><td headers="hd_h_fd.T.clinical_manifestations_of_familial_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Insensitivity to pain (sparing hands, soles of feet, neck, & genital areas) <sup>1</sup></div></li><li class="half_rhythm"><div>Abnormal temperature perception on trunk & lower extremities <sup>1</sup></div></li><li class="half_rhythm"><div>Depressed patellar reflexes</div></li></ul>
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</td></tr><tr><td headers="hd_h_fd.T.clinical_manifestations_of_familial_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Motor</b>
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<br />
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<b>system</b>
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</td><td headers="hd_h_fd.T.clinical_manifestations_of_familial_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hypotonia</div></li><li class="half_rhythm"><div>Mild/moderate motor DD</div></li><li class="half_rhythm"><div>Broad-based or mildly ataxic gait <sup>1</sup></div></li><li class="half_rhythm"><div>Spinal curvature (95%; esp kyphosis) <sup>1</sup></div></li></ul>
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</td></tr><tr><td headers="hd_h_fd.T.clinical_manifestations_of_familial_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cranial</b>
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<br />
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<b>nerves</b>
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</td><td headers="hd_h_fd.T.clinical_manifestations_of_familial_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Absence of overflow tears</div></li><li class="half_rhythm"><div>Depressed corneal reflexes</div></li><li class="half_rhythm"><div>Optic nerve atrophy <sup>1</sup></div></li><li class="half_rhythm"><div>Strabismus</div></li><li class="half_rhythm"><div>Deficient taste, esp sweet</div></li><li class="half_rhythm"><div>Dysarthric, nasal speech</div></li></ul>
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</td></tr><tr><td headers="hd_h_fd.T.clinical_manifestations_of_familial_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Respiratory <sup>4</sup></b>
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</td><td headers="hd_h_fd.T.clinical_manifestations_of_familial_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Chronic aspiration & recurrent aspiration pneumonia</div></li><li class="half_rhythm"><div>Suppurative lung disease & bronchiectasis</div></li><li class="half_rhythm"><div>Restrictive lung disease</div></li><li class="half_rhythm"><div>Upper-airway obstruction due to cranial dimorphism & ↓ muscle tone of pharyngeal muscles, → obstructive sleep apnea</div></li><li class="half_rhythm"><div>Obstructive lung disease & airway hyperreactivity</div></li><li class="half_rhythm"><div>Sleep-disordered breathing (obstructive & central sleep apnea)</div></li><li class="half_rhythm"><div>Daytime hypoventilation</div></li></ul>
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</td></tr><tr><td headers="hd_h_fd.T.clinical_manifestations_of_familial_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Renal <sup>5</sup></b>
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</td><td headers="hd_h_fd.T.clinical_manifestations_of_familial_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>CKD w/histopathologic features of chronic hypertensive nephrosclerosis</div></li><li class="half_rhythm"><div>Tubular atrophy</div></li><li class="half_rhythm"><div>Lack of sympathetic innervation of renal vasculature</div></li><li class="half_rhythm"><div>↑ incidence of rare kidney malformations & hydronephrosis</div></li></ul>
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</td></tr><tr><td headers="hd_h_fd.T.clinical_manifestations_of_familial_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cognitive</b>
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<br />
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<b>ability /</b>
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<br />
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<b>Personality</b>
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</td><td headers="hd_h_fd.T.clinical_manifestations_of_familial_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Usually normal intellect (verbal skills better than motor)</div></li><li class="half_rhythm"><div>Concrete or literal thinking</div></li><li class="half_rhythm"><div>Skin picking (esp fingers & nose)</div></li><li class="half_rhythm"><div>Resistance to change (phobias) <sup>1</sup></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">Adapted from <a class="bibr" href="#fd.REF.axelrod.1996" rid="fd.REF.axelrod.1996">Axelrod [1996]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">CKD = chronic kidney disease; DD = developmental delay; GERD = gastroesophageal reflux disease</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="fd.TF.2.1"><p class="no_margin">Progressive neurologic abnormalities</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="fd.TF.2.2"><p class="no_margin">
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<a class="bibr" href="#fd.REF.bernardi.2003.141" rid="fd.REF.bernardi.2003.141">Bernardi et al [2003]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="fd.TF.2.3"><p class="no_margin">
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<a class="bibr" href="#fd.REF.brown.2003.163" rid="fd.REF.brown.2003.163">Brown et al [2003]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="fd.TF.2.4"><p class="no_margin">
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<a class="bibr" href="#fd.REF.kazachkov.2018.37" rid="fd.REF.kazachkov.2018.37">Kazachkov et al [2018]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="fd.TF.2.5"><p class="no_margin">
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<a class="bibr" href="#fd.REF.norcliffekaufmann.2013b.1611" rid="fd.REF.norcliffekaufmann.2013b.1611">Norcliffe-Kaufmann et al [2013b]</a>
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</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobfdTgenesanddisordersofinterestin"><div id="fd.T.genes_and_disorders_of_interest_in" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Genes and Disorders of Interest in the Differential Diagnosis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1180/table/fd.T.genes_and_disorders_of_interest_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fd.T.genes_and_disorders_of_interest_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical Characteristics / Comment</th></tr></thead><tbody><tr><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ATL1</i>
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</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">HSN1D (See <a href="/books/n/gene/spg3a/?report=reader">Spastic Paraplegia 3A</a>.)</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Loss of pain & temperature sensation; osteomyelitis; lancinating pain; distal motor involvement (variable); facultative deafness; no visceral signs of autonomic involvement</td></tr><tr><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ATL3</i>
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</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">HSN1F (OMIM <a href="https://omim.org/entry/615632" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615632</a>)</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Loss of pain & temperature sensation; osteomyelitis; lancinating pain; distal motor involvement (variable); facultative deafness; no visceral signs of autonomic involvement</div></li><li class="half_rhythm"><div>Similar to HSN1D <sup>1</sup></div></li></ul>
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</td></tr><tr><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>CLTCL1</i>
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<br />
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<i>NGF</i>
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<br />
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<i>NTRK1</i>
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<br />
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<i>PRDM12</i>
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<br />
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<i>SCN9A</i>
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<br />
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<i>SCN11A</i>
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<br />
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<i>ZFHX2</i>
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</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/cip-overview/?report=reader">Congenital insensitivity to pain</a> (See also <a href="/books/n/gene/hsan4/?report=reader"><i>NTRK1</i> Congenital Insensitivity to Pain with Anhidrosis</a>.)</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR<br />AD</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Inability to perceive pain from birth from any noxious stimuli leading to repeated injuries & prevention of normal healing. Painless fractures & joint damage frequently occur & can lead to permanent damage; corneal injuries; anhidrosis that disturbs thermoregulation & can lead to recurrent episodes of unexplained fever (Note: marked hyperhidrosis is observed in assoc w/<i>SCN11A</i> c.2432T>C [p.Leu811Pro].)</div></li><li class="half_rhythm"><div>Self-mutilating injuries of the fingers (biting off fingertips) & oral cavity (incl loss of the tongue tip, injuries to the inside of the teeth/gums, & avulsion of teeth) are common.</div></li></ul>
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</td></tr><tr><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>DNMT1</i>
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</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/dnmt1-ddsn/?report=reader">HSN1E</a>
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</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Loss of pain & temperature sensation; osteomyelitis; lancinating pain; distal motor involvement (variable); facultative deafness; no visceral signs of autonomic involvement</div></li><li class="half_rhythm"><div>Distinguished by hearing loss, dementia, & narcolepsy</div></li></ul>
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</td></tr><tr><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>DST</i>
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</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">HSAN6 (OMIM <a href="https://omim.org/entry/614653" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">614653</a>)</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dysautonomic symptoms; absent tearing, feeding difficulties, absent deep tendon reflexes, abnormal histamine test w/no axon flare, distal contractures, motionless open-mouthed facies, severe ID/DD, early death <sup>-2</sup></td></tr><tr><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>KIF1A</i>
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<br />
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<i>RETREG1</i>
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<br />
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<i>SCN9A</i>
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<br />
|
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<i>WNK1</i>
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</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/hsan2/?report=reader">HSAN2</a>
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</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Progressively ↓ sensation to pain, temperature, & touch. Onset can be at birth & is often before puberty. Sensory deficit is predominantly distal (lower limbs more severely affected than upper limbs). Over time sensory function becomes severely ↓. Unnoticed injuries & neuropathic skin promote ulcerations & infections → spontaneous amputation of digits or need for surgical amputation. Osteomyelitis is common. Painless fractures can complicate the disease. Autonomic disturbances are variable.</td></tr><tr><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>LIFR</i>
|
|
</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Stüve-Wiedemann syndrome (OMIM <a href="https://omim.org/entry/601559" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">601559</a>)</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Combination of autonomic nervous system manifestations resembling FD & characteristic bony changes (bowing of long bones, camptodactyly) <sup>3</sup></td></tr><tr><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<i>MPZ</i>
|
|
</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CMT2IJ (See <a href="/books/n/gene/cmt/?report=reader">CMT Overview</a>.)</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Thr124Met is assoc w/severe sensory loss, shooting pains, & occasional pseudo-Argyl-Robertson pupils but no ulcerations.</td></tr><tr><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>RAB7A</i>
|
|
</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CMT2B (See <a href="/books/n/gene/cmt/?report=reader">CMT Overview</a>.)</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Acral ulcero-mutilating sensory neuropathy; sensory loss of all modalities w/a high frequency of foot ulcers necessitating amputations</div></li><li class="half_rhythm"><div>Motor features are common; distal muscle weakness & wasting are often the 1st & most prominent features.<sup>4</sup></div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>SPTLC1</i>
|
|
</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/hsn1/?report=reader">HSAN1A</a>
|
|
</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Prominent early sensory loss & later positive sensory phenomena (e.g., dysesthesia & characteristic "lightning" or "shooting" pains); painless injuries, which, if unrecognized, result in slow wound healing & subsequent osteomyelitis requiring distal amputations; motor involvement is present in all advanced cases & can be severe; SNHL is variable; onset ranges from teens to 6th decade.</td></tr><tr><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>SPTLC2</i>
|
|
</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">HSAN1C</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Phenotypically similar to <a href="/books/n/gene/hsn1/?report=reader">HSAN1A</a></td></tr><tr><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<i>TECPR2</i>
|
|
</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/tecpr2-hsan-id/?report=reader"><i>TECPR2</i>-related HSAN with ID</a>
|
|
</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_fd.T.genes_and_disorders_of_interest_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DD/ID, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, & central/nocturnal hypopnea</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; DD = developmental delay; FD = familial dysautonomia; HSAN = hereditary sensory and autonomic neuropathy; ID = intellectual disability; MOI = mode of inheritance; SNHL = sensorineural hearing loss; XL = X-linked</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="fd.TF.3.1"><p class="no_margin"><a class="bibr" href="#fd.REF.fischer.2014.e286" rid="fd.REF.fischer.2014.e286">Fischer et al [2014]</a>, <a class="bibr" href="#fd.REF.kornak.2014.683" rid="fd.REF.kornak.2014.683">Kornak et al [2014]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="fd.TF.3.2"><p class="no_margin">Only one affected family has been reported to date [<a class="bibr" href="#fd.REF.edvardson.2012.569" rid="fd.REF.edvardson.2012.569">Edvardson et al 2012</a>].</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="fd.TF.3.3"><p class="no_margin">
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<a class="bibr" href="#fd.REF.di_rocco.2003.362" rid="fd.REF.di_rocco.2003.362">Di Rocco et al [2003]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="fd.TF.3.4"><p class="no_margin">
|
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<a class="bibr" href="#fd.REF.verhoeven.2003.722" rid="fd.REF.verhoeven.2003.722">Verhoeven et al [2003]</a>
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</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobfdTrecommendedevaluationsfollowingi"><div id="fd.T.recommended_evaluations_following_i" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with Familial Dysautonomia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1180/table/fd.T.recommended_evaluations_following_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fd.T.recommended_evaluations_following_i_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_1" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_fd.T.recommended_evaluations_following_i_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_fd.T.recommended_evaluations_following_i_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<b>Growth</b>
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</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Measure height, weight, head circumference</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Neurologic involvement</b>
|
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</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By pediatric neurologist</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Comprehensive neurologic exam w/attn to sensory ataxia, abnormalities in proprioception</div></li><li class="half_rhythm"><div>Positive Romberg sign; ↓ or absent deep tendon & H-reflexes</div></li><li class="half_rhythm"><div>Consider: (1) MRI if concerns re worsening gait ataxia &/or balance; (2) EEG if concerns re seizures.</div></li></ul>
|
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</td></tr><tr><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Development</b>
|
|
</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment for infants/young children</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To incl motor, adaptive, & cognitive eval</div></li><li class="half_rhythm"><div>Eval by speech-language pathologist</div></li><li class="half_rhythm"><div>Eval for early childhood intervention programs / special education</div></li></ul>
|
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</td></tr><tr><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Cognitive abilities</b>
|
|
</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standardized testing</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Psychiatric/behavioral</b>
|
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<br />
|
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<b>issues</b>
|
|
</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment by mental health professional as needed</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Anxiety is the most common psychiatric problem.</td></tr><tr><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Neurogenic dysphagia</b>
|
|
</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multidisciplinary incl pulmonologist, neurologist, nutritionist, gastroenterologist, speech-language pathologist, chest physiotherapist, & caregivers</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Baseline eval by multidisciplinary team w/video fluoroscopic swallow study to define safe consistencies of food & best oral hygiene</td></tr><tr><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Blood pressure</b>
|
|
<br />
|
|
<b>instability</b>
|
|
</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">24-hr blood pressure monitoring & orthostatic challenge</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Decreased sensitivity</b>
|
|
<br />
|
|
<b>to pain</b>
|
|
</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Skin exam</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For decubitus ulcers & pressure sores (e.g., from shoes & devices such as back brace)</td></tr><tr><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Sleep-disordered breathing</b>
|
|
</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Full (in-laboratory) polysomnography incl end-tidal CO<sub>2</sub> measurements</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Perform even if no clinical manifestations. Transcutaneous CO<sub>2</sub> measurements may be unreliable.</td></tr><tr><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Airway</b>
|
|
<br />
|
|
<b>disease</b>
|
|
</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Upper-airway</b>
|
|
<br />
|
|
<b>obstruction</b>
|
|
</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Laryngoscopy, sleep endoscopy</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Perform awake flexible laryngoscopy when breathing is noisy. If no anatomic obstruction is found, consider sleep laryngoscopy.</td></tr><tr><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Lower-airway</b>
|
|
<br />
|
|
<b>disease</b>
|
|
</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pulmonary function tests, sputum cultures, bronchoscopy, & bronchoalveolar lavage</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Spirometry & response to bronchodilators may help assess airway obstruction.</div></li><li class="half_rhythm"><div>Obtain culture from lower airways when clinical evidence suggests suppurative lung disease.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Restrictive</b>
|
|
<br />
|
|
<b>lung disease</b>
|
|
</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lung volume measurements via plethysmography or nitrogen washout</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Secondary to hyperkyphotic (usually upper thoracic) scoliosis, mostly during 2nd decade</td></tr><tr><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Acute</b>
|
|
<br />
|
|
<b>respiratory</b>
|
|
<br />
|
|
<b>exacerbation</b>
|
|
</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Respiratory exam & chest x-ray</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Acute respiratory exacerbation may present w/minimal symptoms despite significant hypoxemia & hypercarbia; because respiratory drive remains depressed even during acute respiratory exacerbations, patients do not appear dyspneic or tachypneic.</div></li><li class="half_rhythm"><div>Dysautonomic crises may occur during acute respiratory exacerbations & are often the presenting manifestation.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Dysautonomic crises</b>
|
|
</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As determined by medical history</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hyperadrenergic vomiting attacks may continue for several days.</td></tr><tr><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Ophthalmologic</b>
|
|
<br />
|
|
<b>involvement</b>
|
|
</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic exam</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Incl assessment of best corrected visual acuity, cornea for possible injury due to ↓ corneal sensation, fundoscopic exam for evidence of optic atrophy.</div></li><li class="half_rhythm"><div>Assessment of retina to incl OCT w/measurements of mean RNFL & macular GCIPL thickness</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_1" rowspan="2" colspan="2" scope="row" style="text-align:left;vertical-align:middle;">
|
|
<b>Musculoskeletal</b>
|
|
</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical medicine & rehab / PT / OT eval</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl assessment of:
|
|
<ul><li class="half_rhythm"><div>Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)</div></li><li class="half_rhythm"><div>Need for AFOs, specialized shoes</div></li><li class="half_rhythm"><div>Mobility, activities of daily living, & need for adaptive devices/durable equipment</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Eval by pediatric orthopedist</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess amount & progression of spinal curvature & extent of foot deformities.</td></tr><tr><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_1" rowspan="3" colspan="2" scope="row" style="text-align:left;vertical-align:middle;">
|
|
<b>Dental</b>
|
|
</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval by dental hygienist</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>↑ saliva flow may ↓ incidence of dental caries, but changes in composition of saliva → more plaque & ↑ in periodontal disease.</div></li><li class="half_rhythm"><div>Evaluate for dental, gingival, & tongue trauma (usually due to self-mutilation).</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">General dental eval</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluate for dental, gingival, & tongue trauma (usually due to self-mutilation).</td></tr><tr><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Eval by orthodontists & maxillofacial professionals</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess abnormalities of bite & dental spacing</td></tr><tr><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Genetic counseling</b>
|
|
</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected persons & their families re nature, MOI, & implications of FD in order to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Family support &</b>
|
|
<br />
|
|
<b>resources</b>
|
|
</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess:
|
|
<ul><li class="half_rhythm"><div>Use of community or <a href="#fd.Resources">online resources</a> such as <a href="https://www.p2pusa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parent to Parent</a>;</div></li><li class="half_rhythm"><div>Need for social work involvement for parental support.</div></li></ul>
|
|
</td><td headers="hd_h_fd.T.recommended_evaluations_following_i_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">AFO = ankle/foot orthoses; FD = familial dysautonomia; GCIPL = ganglion cell and inner plexiform layer; MOI = mode of inheritance; OCT = optic coherence tomography; RNFL = retinal nerve fiber layer</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="fd.TF.4.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobfdTtreatmentofmanifestationsinindi"><div id="fd.T.treatment_of_manifestations_in_indi" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with Familial Dysautonomia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1180/table/fd.T.treatment_of_manifestations_in_indi/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fd.T.treatment_of_manifestations_in_indi_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Short stature</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Growth hormone treatment may be effective & should be considered based on guidelines re height, growth velocity, & bone maturation. <sup>1</sup></td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>GH stimulation testing may not be reliable.</div></li><li class="half_rhythm"><div>Monitor spinal curvature, as it tends to worsen during accelerated growth.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Neurogenic dysphagia</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per feeding team; for infants, thickened formula & different-shaped nipples to manage oropharyngeal incoordination</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Low threshold for gastrostomy tube & Nissen fundoplication to maintain nutritional status & ↓ risk of aspiration</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>GERD</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Upright positioning w/feeds, prokinetic agents, H<sub>2</sub> antagonists, proton pump inhibitors, & gastrostomy w/or w/o fundoplication are appropriate.</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">A diagnosis of GERD should be confirmed w/esophageal impedance & manometry.</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>DD / Educational issues</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#fd.Developmental_Delay__Intellectual_Dis">Developmental Delay / Intellectual Disability Management Issues</a>.</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Psychiatric/behavioral</b>
|
|
<br />
|
|
<b>issues</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By mental health professional</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Selective serotonin reuptake inhibitors are sometimes effective in treating anxiety; psychotherapy & behavioral techniques may also help.</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Blood pressure</b>
|
|
<br />
|
|
<b>instability</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Carbidopa is effective in reducing blood pressure variability. <sup>2</sup></td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Decreased sensitivity</b>
|
|
<br />
|
|
<b>to pain</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Close attn to decubitus ulcers, burns, & other minor injuries, joint swelling & bone deformity. Signs of local or systemic infection should be monitored & treated w/antibiotics.</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Sleep-disordered</b>
|
|
<br />
|
|
<b>breathing</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CPAP or BiPAP</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Due to chemoreflex failure, begin noninvasive ventilation even when sleep-disordered breathing is mild to ↓ risk of sudden unexpected death during sleep. <sup>3</sup></td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" rowspan="5" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Airway</b>
|
|
<br />
|
|
<b>disease</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Upper-airway</b>
|
|
<br />
|
|
<b>obstruction</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Tonsillectomy & adenoidectomy.</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">If upper-airway obstruction is not resolved, refer to airway mgmt specialist.</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Lower-airway</b>
|
|
<br />
|
|
<b>disease</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treat suppurative lung disease/bronchiectasis w/daily chest physiotherapy.</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Cough augmentation is most effective in clearing airway mucus & best achieved by mechanical insufflation/exsufflation methods.</div></li><li class="half_rhythm"><div>Inhaled hypertonic saline may be beneficial.</div></li><li class="half_rhythm"><div>Treat acute exacerbation promptly w/antibiotics.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Restrictive</b>
|
|
<br />
|
|
<b>lung disease</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Airway mucus clearance w/manually assisted coughing or mechanical insufflation/exsufflation methods</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Consider surgical correction of scoliosis on a case-by-case basis. Surgical complications can be severe; data re respiratory function pre- & post-surgery are lacking.</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Acute</b>
|
|
<br />
|
|
<b>respiratory</b>
|
|
<br />
|
|
<b>exacerbation</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Start antibiotics covering aspiration flora promptly, preferably after obtaining sputum culture.</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><ul><li class="half_rhythm"><div>Oral antibiotics for 14 days</div></li><li class="half_rhythm"><div>Initiation of IV antibiotics depends on baseline respiratory status; consider when no improvement after oral antibiotics.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Chronic lung</b>
|
|
<br />
|
|
<b>disease</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Daily chest physiotherapy (nebulization, bronchodilators, cough augmentation, incentive spirometry, & postural drainage)</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Early diagnosis & treatment of pneumonia & infections (secondary to aspiration)</div></li><li class="half_rhythm"><div>Treatment w/oseltamivir is indicated for influenza virus infections. <sup>4</sup></div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" rowspan="5" colspan="2" scope="row" style="text-align:left;vertical-align:middle;">
|
|
<b>Dysautonomic crises</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Instructions to manage crises at home w/fluids & medications via gastrostomy</div></li><li class="half_rhythm"><div>Guidance re when to visit ER for more extensive eval & treatment</div></li></ul>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Careful attn to dehydration & electrolyte imbalance; investigate underlying cause when crises are refractory to treatment or other symptoms are present.</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Benzodiazepines ↓ retching/vomiting. As ventilation may be suppressed, noninvasive ventilation is recommended as a precaution.</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">IV benzodiazepine may cause prolonged apnea & should only be administered in ER or ICU settings.</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Clonidine (centrally acting α2-adrenergic agonist) may ↓ sympathetic activity.</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May be given via gastrostomy, sublingually, or transdermally</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Intranasal dexmedetomidine may be a feasible & safe acute treatment for adrenergic crisis. <sup>5</sup></td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In severe cases IV dexmedetomidine may be used, but only in ICU settings. <sup>6</sup></td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Carbidopa (dopa-decarboxylase inhibitor) given daily may ↓ frequency & severity of hypertensive vomiting attacks. <sup>7</sup></td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Bradyarrhythmia</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pacemaker</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For those w/history of syncope &/or cardiac arrest</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Orthostatic</b>
|
|
<br />
|
|
<b>hypotension</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Physical countermaneuvers to ↑ venous return & PT to ↑ muscle strength in legs help prevent orthostatic hypotension.</div></li><li class="half_rhythm"><div>Treatment w/midodrine may be effective for short periods; use as needed prior to physical activity that may cause orthostatic hypotension.</div></li><li class="half_rhythm"><div>Hydration is useful only for short periods due to impaired osmopressor response (most likely due to ↓ function of peripheral osmosensory pathway).</div></li></ul>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment of orthostatic hypotension w/high doses of fludrocortisone aggravates renal damage.</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" rowspan="2" colspan="2" scope="row" style="text-align:left;vertical-align:middle;">
|
|
<b>Hypertension</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Attn to factors precipitating hypertension (rather than use of antihypertensive agents) as blood pressure is labile</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sleeping w/20°-40° elevation of head of bed ↓s supine hypertension & nocturnal pressure-diuresis & ↑s intravascular volume in the AM.</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Standard treatment of hypertension in persons w/CKD</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Kidney</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Adequate control of blood pressure</div></li><li class="half_rhythm"><div>Treat renal tubular acidosis w/bicarbonate.</div></li><li class="half_rhythm"><div>Low-potassium diet for hyperkalemia</div></li></ul>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Ophthal-</b>
|
|
<br />
|
|
<b>mologic</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Optic</b>
|
|
<br />
|
|
<b>neuropathy</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Low vision aids</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per low vision clinic</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Corneal</b>
|
|
<br />
|
|
<b>ulceration</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Artificial tear solutions (w/methylcellulose) 3-6x/day, maintenance of normal body hydration, & moisture chamber spectacle attachments</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Soft contact lenses can promote healing.</div></li><li class="half_rhythm"><div>Tarsorrhaphy only for corneal injury unresponsive to routine measures</div></li><li class="half_rhythm"><div>Corneal transplantation offers limited success.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Chronic</b>
|
|
<br />
|
|
<b>blepharitis</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Combined topical antibiotic/corticosteroid ointment</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Strabismus</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Early surgical correction may help.</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Sensory ataxia</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">OT/PT</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Many adults use walkers or wheelchairs when outside the home.</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Musculo-</b>
|
|
<br />
|
|
<b>skeletal</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Foot</b>
|
|
<br />
|
|
<b>deformity</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PT to preserve flexibility; special shoes w/good ankle support &/or AFOs to correct foot drop & aid walking</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Excellent ongoing foot care to avoid development of ulcers at pressure points</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Spine</b>
|
|
<br />
|
|
<b>deformities</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PT to preserve flexibility</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Bracing is not effective & may cause pressure ulcers; spinal fusion may be necessary.</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Dental</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Sialorrhea</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Botulinum toxin injections in major salivary glands</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Surgical approaches & anticholinergic drugs were used in the past.</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Excessive</b>
|
|
<br />
|
|
<b>plaque &</b>
|
|
<br />
|
|
<b>calculus</b>
|
|
<br />
|
|
<b>accumulation</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dental cleaning & preventive care</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Biannually by dental hygienist</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Periodontal</b>
|
|
<br />
|
|
<b>disease, dental</b>
|
|
<br />
|
|
<b>trauma, & self-</b>
|
|
<br />
|
|
<b>mutilation</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dental eval & care</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for occult biting of oral mucosa & establish plan for tooth extraction when needed.</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Small jaw</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Care by maxillofacial professionals</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As needed for dental crowding & moderate/severe malocclusion</td></tr><tr><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Family support &</b>
|
|
<br />
|
|
<b>resources</b>
|
|
</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Address caregiver needs (e.g., respite care, home nursing, coordination of multiple subspecialty appointments, equipment, medications, & supplies).</td><td headers="hd_h_fd.T.treatment_of_manifestations_in_indi_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">AFOs = ankle/foot orthoses; BiPAP = bi-level positive airway pressure; CKD = chronic kidney disease; CPAP = continuous positive airway pressure; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="fd.TF.5.1"><p class="no_margin">
|
|
<a class="bibr" href="#fd.REF.kamboj.2004.63" rid="fd.REF.kamboj.2004.63">Kamboj et al [2004]</a>
|
|
</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="fd.TF.5.2"><p class="no_margin">
|
|
<a class="bibr" href="#fd.REF.norcliffekaufmann.2020.724" rid="fd.REF.norcliffekaufmann.2020.724">Norcliffe-Kaufmann et al [2020]</a>
|
|
</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="fd.TF.5.3"><p class="no_margin">
|
|
<a class="bibr" href="#fd.REF.palma.2017.zsx083" rid="fd.REF.palma.2017.zsx083">Palma et al [2017]</a>
|
|
</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="fd.TF.5.4"><p class="no_margin">
|
|
<a class="bibr" href="#fd.REF.palma.2014.2653" rid="fd.REF.palma.2014.2653">Palma et al [2014]</a>
|
|
</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="fd.TF.5.5"><p class="no_margin">
|
|
<a class="bibr" href="#fd.REF.spalink.2017.279" rid="fd.REF.spalink.2017.279">Spalink et al [2017]</a>
|
|
</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="fd.TF.5.6"><p class="no_margin">
|
|
<a class="bibr" href="#fd.REF.dillon.2017.7" rid="fd.REF.dillon.2017.7">Dillon et al [2017]</a>
|
|
</p></div></dd></dl><dl class="bkr_refwrap"><dt>7. </dt><dd><div id="fd.TF.5.7"><p class="no_margin">
|
|
<a class="bibr" href="#fd.REF.norcliffekaufmann.2013b.1611" rid="fd.REF.norcliffekaufmann.2013b.1611">Norcliffe-Kaufmann et al [2013b]</a>
|
|
</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobfdTrecommendedsurveillanceforindivi"><div id="fd.T.recommended_surveillance_for_indivi" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with Familial Dysautonomia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1180/table/fd.T.recommended_surveillance_for_indivi/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fd.T.recommended_surveillance_for_indivi_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Constitutional</b>
|
|
</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess height & weight, head circumference.</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Routinely in growing children</td></tr><tr><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Neurogenic</b>
|
|
<br />
|
|
<b>dysphagia</b>
|
|
</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess weight, nutrition, safety of oral feeding.</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>In growing children: routinely</div></li><li class="half_rhythm"><div>In adults: when respiratory function ↓s or respiratory infections ↑</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>DD / Educational</b>
|
|
<br />
|
|
<b>issues</b>
|
|
</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess developmental/educational progress.</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At least annually</td></tr><tr><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Behavior</b>
|
|
</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluate mental status.</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Routinely during interim visits</td></tr><tr><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Respiratory</b>
|
|
</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pulmonary function tests:
|
|
<ul><li class="half_rhythm"><div>Spirometry before & after bronchodilator challenge to diagnose reversible obstructive disease</div></li><li class="half_rhythm"><div>Quantitative measure of MIP & MEP to document disease progression & inform mgmt</div></li></ul>
|
|
</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually in all capable persons regardless of respiratory status; more frequently in those w/significant respiratory involvement</td></tr><tr><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Sleep-disordered</b>
|
|
<br />
|
|
<b>breathing</b>
|
|
</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Full laboratory polysomnography incl end-tidal CO<sub>2</sub> measurements</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Annually regardless of previous normal studies</div></li><li class="half_rhythm"><div>Before & 6-8 weeks after starting growth hormone therapy</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Dysautonomic</b>
|
|
<br />
|
|
<b>crises</b>
|
|
</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency & severity of hyperadrenergic crises</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Annually</td></tr><tr><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Bradyarrhythmia</b>
|
|
</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">24-48-hr Holter monitoring regardless of previous normal studies</td></tr><tr><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Orthostatic</b>
|
|
<br />
|
|
<b>hypotension</b>
|
|
</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval of symptoms & orthostatic challenge tests</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Perform during interim visits.</td></tr><tr><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Blood pressure</b>
|
|
</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor BP to assure optimal mgmt of BP lability to help limit neurologic progression w/age (which can be assoc w/compromised cerebral perfusion)</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annual 24-hr BP monitoring</td></tr><tr><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Kidney</b>
|
|
</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess kidney function to assure early detection of renal disease</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Persons w/normal kidney function: annually</div></li><li class="half_rhythm"><div>Persons w/CKD: per treating nephrologist</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Monitor existing kidney disease.</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per treating physician</td></tr><tr><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Ophthalmologic</b>
|
|
</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor eye movements, visual acuity, strabismus, corneal issues.</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per treating ophthalmologist</td></tr><tr><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Optic coherence tomography</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Repeat annually due to accelerated & significant loss of RNFL & GCIPL.</td></tr><tr><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Low vision needs</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per treating low vision clinic</td></tr><tr><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Sensory ataxia</b>
|
|
</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">OT/PT assessment re activities of daily living, durable equipment needs, safety of the home/living environment</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Musculoskeletal</b>
|
|
</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Spine exam</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually during growth period; less frequently thereafter</td></tr><tr><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Dental</b>
|
|
</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dental cleaning</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Biannually</td></tr><tr><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:top;">General dental exam for evidence of occult biting (e.g., of buccal mucosa, tongue) & possible need for preventive dental extraction</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually</td></tr><tr><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:top;">Orthodontists & maxillofacial professionals re abnormal bite & dental crowding</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per treating dental professionals</td></tr><tr><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Family support</b>
|
|
<br />
|
|
<b>& resources</b>
|
|
</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assessment of caregiver needs (e.g., respite care, home nursing, coordination of multiple subspecialty appointments, equipment, medications, & supplies)</td><td headers="hd_h_fd.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</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">BP = blood pressure; GCIPL = ganglion cell and inner plexiform layer; MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure; OT = occupational therapist; PT = physical therapist; RNFL = retinal nerve fiber layer</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobfdmolgenTA"><div id="fd.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Familial Dysautonomia: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1180/table/fd.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fd.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_fd.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_fd.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_fd.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_fd.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_fd.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_fd.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_fd.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="/gene/8518" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
|
<i>ELP1</i>
|
|
</a>
|
|
</td><td headers="hd_b_fd.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=8518" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">9q31<wbr style="display:inline-block"></wbr>​.3</a>
|
|
</td><td headers="hd_b_fd.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.uniprot.org/uniprot/O95163" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Elongator complex protein 1</a>
|
|
</td><td headers="hd_b_fd.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://databases.lovd.nl/shared/genes/IKBKAP" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">IKBKAP homepage - Leiden Muscular Dystrophy pages</a>
|
|
</td><td headers="hd_b_fd.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=ELP1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ELP1</a>
|
|
</td><td headers="hd_b_fd.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=ELP1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ELP1</a>
|
|
</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="fd.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
|
|
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
|
chromosome locus from
|
|
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
|
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
|
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
|
<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobfdmolgenTB"><div id="fd.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Familial Dysautonomia (<a href="/omim/223900,603722" 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/NBK1180/table/fd.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fd.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/223900" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">223900</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE III; HSAN3</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/603722" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">603722</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ELONGATOR COMPLEX PROTEIN 1; ELP1</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobfdTnotableelp1pathogenicvariants"><div id="fd.T.notable_elp1_pathogenic_variants" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Notable <i>ELP1</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1180/table/fd.T.notable_elp1_pathogenic_variants/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fd.T.notable_elp1_pathogenic_variants_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_fd.T.notable_elp1_pathogenic_variants_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_fd.T.notable_elp1_pathogenic_variants_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change<br />(Alias <sup>1</sup>)</th><th id="hd_h_fd.T.notable_elp1_pathogenic_variants_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_fd.T.notable_elp1_pathogenic_variants_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_fd.T.notable_elp1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_003640" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_003640<wbr style="display:inline-block"></wbr>​.5</a>
|
|
<br />
|
|
<a href="https://www.ncbi.nlm.nih.gov/protein/38569394" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_003631<wbr style="display:inline-block"></wbr>​.2</a>
|
|
</td><td headers="hd_h_fd.T.notable_elp1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.2087G>C</td><td headers="hd_h_fd.T.notable_elp1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg696Pro</td><td headers="hd_h_fd.T.notable_elp1_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">A rare variant identified in Ashkenazi Jews [<a class="bibr" href="#fd.REF.dong.2002.253" rid="fd.REF.dong.2002.253">Dong et al 2002</a>]</td></tr><tr><td headers="hd_h_fd.T.notable_elp1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_003640" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_003640<wbr style="display:inline-block"></wbr>​.5</a>
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</td><td headers="hd_h_fd.T.notable_elp1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.2204+6T>C<br />(IVS20+6T>C)</td><td headers="hd_h_fd.T.notable_elp1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">--</td><td headers="hd_h_fd.T.notable_elp1_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Founder variant that accounts for >99.5% of pathogenic variants in Ashkenazi Jews [<a class="bibr" href="#fd.REF.dong.2002.253" rid="fd.REF.dong.2002.253">Dong et al 2002</a>]</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the author. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>​.hgvs.org</a>). See <a href="/books/n/gene/app3/?report=reader">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="fd.TF.7.1"><p class="no_margin">Variant designation that does not conform to current naming conventions</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script></div></div>
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