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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Succinic Semialdehyde Dehydrogenase Deficiency - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_title" content="Succinic Semialdehyde Dehydrogenase Deficiency">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2025/01/09">
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<meta name="citation_author" content="Itay Tokatly Latzer">
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<meta name="citation_author" content="Phillip L Pearl">
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<meta name="citation_author" content="Jean-Baptiste Roullet">
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<meta name="citation_keywords" content="4-Hydroxybutyric Aciduria">
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<meta name="citation_keywords" content="Gamma-Hydroxybutyric Aciduria">
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<meta name="citation_keywords" content="SSADH Deficiency">
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<meta name="citation_keywords" content="4-Hydroxybutyric Aciduria">
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<meta name="citation_keywords" content="Gamma-Hydroxybutyric Aciduria">
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<meta name="citation_keywords" content="SSADH Deficiency">
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<meta name="citation_keywords" content="Succinate-semialdehyde dehydrogenase, mitochondrial">
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<meta name="citation_keywords" content="ALDH5A1">
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<meta name="citation_keywords" content="Succinic Semialdehyde Dehydrogenase Deficiency">
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<meta name="DC.Title" content="Succinic Semialdehyde Dehydrogenase Deficiency">
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<meta name="DC.Publisher" content="University of Washington, Seattle">
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<meta name="DC.Contributor" content="Itay Tokatly Latzer">
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<meta name="DC.Contributor" content="Phillip L Pearl">
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<meta name="DC.Contributor" content="Jean-Baptiste Roullet">
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<meta name="DC.Date" content="2025/01/09">
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<meta name="description" content="Succinic semialdehyde dehydrogenase (SSADH) deficiency is characterized by a relatively non-progressive encephalopathy typically presenting with hypotonia and delayed acquisition of motor and language developmental milestones in the first two years of life. Common clinical features include an almost universal intellectual disability and adaptive function deficits, as well as epilepsy, autism spectrum disorder, movement disorders (such as ataxia, dystonia, and exertional dyskinesia), sleep disturbances, attention problems, anxiety, and obsessive-compulsive behaviors. Notably, seizures, autism spectrum disorder features, and behavioral problems tend to worsen around the time of late childhood or early adolescence. Affected individuals do not usually have episodic decompensation following metabolic stressors, as is typical of other organic acidemias and metabolic encephalopathies, although some have been diagnosed after having unanticipated difficulty recovering from otherwise ordinary childhood illnesses. Clinical presentation with acute onset of generalized hypotonia and choreiform movement following upper-respiratory tract infection has been observed.">
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<meta name="og:description" content="Succinic semialdehyde dehydrogenase (SSADH) deficiency is characterized by a relatively non-progressive encephalopathy typically presenting with hypotonia and delayed acquisition of motor and language developmental milestones in the first two years of life. Common clinical features include an almost universal intellectual disability and adaptive function deficits, as well as epilepsy, autism spectrum disorder, movement disorders (such as ataxia, dystonia, and exertional dyskinesia), sleep disturbances, attention problems, anxiety, and obsessive-compulsive behaviors. Notably, seizures, autism spectrum disorder features, and behavioral problems tend to worsen around the time of late childhood or early adolescence. Affected individuals do not usually have episodic decompensation following metabolic stressors, as is typical of other organic acidemias and metabolic encephalopathies, although some have been diagnosed after having unanticipated difficulty recovering from otherwise ordinary childhood illnesses. Clinical presentation with acute onset of generalized hypotonia and choreiform movement following upper-respiratory tract infection has been observed.">
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yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK1195_"><span class="title" itemprop="name">Succinic Semialdehyde Dehydrogenase Deficiency</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: 4-Hydroxybutyric Aciduria, Gamma-Hydroxybutyric Aciduria, SSADH Deficiency</div><p class="contribs">Tokatly Latzer I, Pearl PL, Roullet JB.</p><p class="fm-aai"><a href="#_NBK1195_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 27 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="ssadh.Summary" itemprop="description"><h2 id="_ssadh_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Succinic semialdehyde dehydrogenase (SSADH) deficiency is characterized by a relatively non-progressive encephalopathy typically presenting with hypotonia and delayed acquisition of motor and language developmental milestones in the first two years of life. Common clinical features include an almost universal intellectual disability and adaptive function deficits, as well as epilepsy, autism spectrum disorder, movement disorders (such as ataxia, dystonia, and exertional dyskinesia), sleep disturbances, attention problems, anxiety, and obsessive-compulsive behaviors. Notably, seizures, autism spectrum disorder features, and behavioral problems tend to worsen around the time of late childhood or early adolescence. Affected individuals do not usually have episodic decompensation following metabolic stressors, as is typical of other organic acidemias and metabolic encephalopathies, although some have been diagnosed after having unanticipated difficulty recovering from otherwise ordinary childhood illnesses. Clinical presentation with acute onset of generalized hypotonia and choreiform movement following upper-respiratory tract infection has been observed.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>Increased gamma-hydroxybutyric aciduria (GHB) on a urinary organic acid analysis is suggestive of the condition; however, the diagnosis of SSADH deficiency is established in a proband with consistent analyte findings and/or suggestive clinical features by identification of biallelic pathogenic variants in <i>ALDH5A1</i> by molecular genetic testing.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Many anti-seizure medications (ASMs) may be effective for seizures; none has been demonstrated effective specifically for this disorder. In general, valproate is avoided except in circumstances such as drug-resistant generalized spike-wave EEG pattern when other ASMs are ineffective. Vigabatrin is not generally recommended. Standard treatment for ataxia/movement disorder, sleep disturbance, developmental delay / cognitive issues, and neurobehavioral and psychiatric issues.</p><p><i>Surveillance</i>: At each visit, monitor those with seizures as clinically indicated; assess for new manifestations such as seizures, ataxia, or movement disorders; monitor developmental progress and educational needs; assess for anxiety, ADHD, OCD, and aggression; monitor for evidence of sleep disturbances, such as excessive daytime sleepiness.</p><p><i>Agents/circumstances to avoid:</i> Vigabatrin may result in elevated gamma-aminobutyric acid (GABA) and exacerbation of manifestations, and its clinical utility has been inconsistent. Tiagabine could also lead to an increase in GABA levels and is not recommended for individuals with SSADH deficiency. Valproate is not recommended as a first-line ASM in people with SSADH deficiency, but it may be considered in drug-resistant epilepsy or generalized spike-wave epilepsy.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>SSADH deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an <i>ALDH5A1</i> pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Once the <i>ALDH5A1</i> pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for at-risk relatives and prenatal/preimplantation genetic testing for SSADH deficiency are possible.</p></div></div><div id="ssadh.Diagnosis"><h2 id="_ssadh_Diagnosis_">Diagnosis</h2><div id="ssadh.Suggestive_Findings"><h3>Suggestive Findings</h3><p>Succinic semialdehyde dehydrogenase (SSADH) deficiency <b>should be suspected</b> in individuals with the following clinical, imaging, and supportive laboratory findings and family history.</p><p><b>Clinical findings.</b> Late-infantile to early-childhood onset, slowly progressive or static encephalopathy characterized by:</p><ul><li class="half_rhythm"><div>Developmental delay and/or cognitive deficiency, often with prominent expressive language deficit</div></li><li class="half_rhythm"><div>Neurobehavioral/psychiatric manifestations, such as autism spectrum disorder, attention-deficit/hyperactivity disorder, and behavioral issues, including obsessive-compulsive disorder, anxiety, and affective issues</div></li><li class="half_rhythm"><div>Hypotonia</div></li><li class="half_rhythm"><div>Epilepsy</div></li><li class="half_rhythm"><div>Hyporeflexia</div></li><li class="half_rhythm"><div>Movement disorders, such as ataxia, dystonia, and exertional dyskinesia</div></li><li class="half_rhythm"><div>Sleep disturbances</div></li></ul><p>
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<b>Neuroimaging findings</b>
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</p><ul><li class="half_rhythm"><div>Cranial MRI that demonstrates:</div><ul><li class="half_rhythm"><div>A pallidodentatoluysian pattern, showing increased T<sub>2</sub>-weighted signal involving the globus pallidus bilaterally and symmetrically, in addition to the cerebellar dentate nucleus and subthalamic nucleus</div></li><li class="half_rhythm"><div>T<sub>2</sub>-hyperintensities of subcortical white matter and brain stem</div></li><li class="half_rhythm"><div>Cerebral atrophy</div></li><li class="half_rhythm"><div>Cerebellar atrophy</div></li><li class="half_rhythm"><div>Delayed myelination</div></li></ul></li><li class="half_rhythm"><div>Magnetic resonance spectroscopy that demonstrates elevated levels of gamma-aminobutyric acid (GABA) and related compounds in the Glx peak (e.g., gamma-hydroxybutyrate [GHB], also known as 4-hydroxybutyric acid], glutamate, and homocarnosine)</div></li></ul><p>
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<b>Supportive laboratory findings</b>
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</p><ul><li class="half_rhythm"><div>Absence of metabolic acidosis</div></li><li class="half_rhythm"><div>Suggestive pattern of findings on urine organic acid, plasma amino/organic acid, and cerebrospinal fluid (CSF) analyses (see Establishing the Diagnosis, <a href="#ssadh.Analyte_Diagnosis">Analyte Diagnosis</a>)</div></li></ul><p>Note: Newborn screening is not routinely done for this disorder at this time. However, ongoing efforts to develop targeted genetic therapies for SSADH deficiency may provide a more substantial justification for newborn screening for this disorder in the future.</p><p><b>Family history</b> is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.</p></div><div id="ssadh.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><div id="ssadh.Analyte_Diagnosis"><h4>Analyte Diagnosis</h4><p>The following <b>analyte pattern</b> in a proband <b>is consistent with</b> a diagnosis of succinic semialdehyde dehydrogenase (SSADH) deficiency:</p><ul><li class="half_rhythm"><div class="half_rhythm">Urine organic analysis demonstrating:</div><ul><li class="half_rhythm"><div>4-hydroxybutyric acid (GHB) concentration of 100-1200 mmol/mol creatinine (normal: >0-7 mmol/mol creatinine)</div></li><li class="half_rhythm"><div>Small amounts of 4,5-dihydroxyhexanoic acid and 3-hydroxyproprionic acid</div></li><li class="half_rhythm"><div>Significant amounts of dicarboxylic acids</div></li><li class="half_rhythm"><div>Increased glycine concentration</div></li></ul><div class="half_rhythm">Note: (1) Specific ion monitoring may be required for the detection of GHB, as its presence is sometimes obscured by a large normal urea peak on routine organic acid qualitative studies. (2) Falsely elevated urinary concentrations of GHB have been reported in individuals in whom the urine sample was obtained using Coloplast SpeediCath catheters, which have been found to have GHB concentrations as high as 11 mmol/L [<a class="bibr" href="#ssadh.REF.wamelink.2011.216" rid="ssadh.REF.wamelink.2011.216">Wamelink et al 2011</a>]. (3) Urine organic acids can be confusing with the presence of elevated levels of D-2-hydroxyglutaric acid, but in routine organic acid analysis this will only be reported as 2-hydroxyglutaric acid.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Plasma amino/organic acid analysis</b> demonstrating a GHB concentration of 35-600 µmol/L (normal: 0-3 µmol/L) and increased glycine concentration</div></li><li class="half_rhythm"><div class="half_rhythm"><b>CSF analysis</b> demonstrating GHB concentration of 100-850 µmol/L (normal: 0-2 µmol/L), a transient increase in CSF glycine concentration, and elevated free and total GABA and homocarnosine concentrations coupled to lowered glutamine</div></li></ul></div><div id="ssadh.Molecular_Diagnosis"><h4>Molecular Diagnosis</h4><p>The molecular diagnosis of SSADH deficiency <b>is established</b> in a proband with consistent <a href="#ssadh.Analyte_Diagnosis">analyte findings</a> and/or <a href="#ssadh.Suggestive_Findings">suggestive clinical features</a> by identification of biallelic pathogenic (or likely pathogenic) variants in <i>ALDH5A1</i> by molecular genetic testing (see <a href="/books/NBK1195/table/ssadh.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobssadhTmoleculargenetictestingusedi">Table 1</a>).</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [<a class="bibr" href="#ssadh.REF.richards.2015.405" rid="ssadh.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include likely pathogenic variants. (2) Identification of biallelic <i>ALDH5A1</i> variants of uncertain significance (or of one known <i>ALDH5A1</i> pathogenic variant and one <i>ALDH5A1</i> variant of uncertain significance) does not establish or rule out the diagnosis.</p><p>Molecular genetic testing approaches can include a combination of <b>gene-targeted testing</b> (single gene testing, multigene panel) and <b>comprehensive</b>
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<b>genomic testing</b> (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see <a href="#ssadh.Option_1">Option 1</a>), whereas comprehensive genomic testing does not (see <a href="#ssadh.Option_2">Option 2</a>).</p><div id="ssadh.Option_1"><h5>
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<b>Option 1</b>
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</h5><p>When the phenotypic and laboratory findings suggest the diagnosis of SSADH deficiency, molecular genetic testing approaches can include <b>single-gene testing</b> or use of a <b>multigene panel</b>.</p><ul><li class="half_rhythm"><div><b>Single-gene testing.</b> Sequence analysis of <i>ALDH5A1</i> is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. 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.</div></li><li class="half_rhythm"><div><b>A multigene panel</b> that includes <i>ALDH5A1</i> and other genes of interest (see <a href="#ssadh.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.</div></li></ul><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="ssadh.Option_2"><h5>
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<b>Option 2</b>
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</h5><p><b>Exome or genome sequencing</b> can be used. Ordering rapid-turnaround-time exome or genome sequencing may be considered when newborns or infants are critically ill. To date, most <i>ALDH5A1</i> pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing [<a class="bibr" href="#ssadh.REF.stenson.2020.1197" rid="ssadh.REF.stenson.2020.1197">Stenson et al 2020</a>, <a class="bibr" href="#ssadh.REF.tokatly_latzer.2023c.1596" rid="ssadh.REF.tokatly_latzer.2023c.1596">Tokatly Latzer et al 2023c</a>].</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="figssadhTmoleculargenetictestingusedi"><a href="/books/NBK1195/table/ssadh.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobssadhTmoleculargenetictestingusedi"><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="ssadh.T.molecular_genetic_testing_used_i"><a href="/books/NBK1195/table/ssadh.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobssadhTmoleculargenetictestingusedi">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in Succinic Semialdehyde Dehydrogenase Deficiency </p></div></div></div></div></div></div><div id="ssadh.Clinical_Characteristics"><h2 id="_ssadh_Clinical_Characteristics_">Clinical Characteristics</h2><div id="ssadh.Clinical_Description"><h3>Clinical Description</h3><p>Succinic semialdehyde dehydrogenase (SSADH) deficiency is characterized by a relatively non-progressive encephalopathy typically presenting with hypotonia and delayed acquisition of motor and language developmental milestones in the first two years of life. Common clinical features include an almost universal intellectual disability and adaptive function deficits, as well as epilepsy, autism spectrum disorder, movement disorders (such as ataxia, dystonia, and exertional dyskinesia), sleep disturbances, attention problems, anxiety, and obsessive-compulsive behaviors. Notably, seizures, autism spectrum disorder features, and behavioral problems tend to worsen around the time of late childhood or early adolescence [<a class="bibr" href="#ssadh.REF.tokatly_latzer.2023a.1755" rid="ssadh.REF.tokatly_latzer.2023a.1755">Tokatly Latzer et al 2023a</a>, <a class="bibr" href="#ssadh.REF.tokatly_latzer.2023b.1516" rid="ssadh.REF.tokatly_latzer.2023b.1516">Tokatly Latzer et al 2023b</a>, <a class="bibr" href="#ssadh.REF.tokatly_latzer.2023d.992" rid="ssadh.REF.tokatly_latzer.2023d.992">Tokatly Latzer et al 2023d</a>]. Affected individuals do not usually have episodic decompensation following metabolic stressors, as is typical of other organic acidemias and metabolic encephalopathies, although some have been diagnosed after having unanticipated difficulty recovering from otherwise ordinary childhood illnesses. Clinical presentation with acute onset of generalized hypotonia and choreiform movement following upper-respiratory tract infection has been reported [<a class="bibr" href="#ssadh.REF.wang.2016.1305" rid="ssadh.REF.wang.2016.1305">Wang et al 2016</a>, <a class="bibr" href="#ssadh.REF.zeiger.2016.113" rid="ssadh.REF.zeiger.2016.113">Zeiger et al 2016</a>]. <a href="/books/NBK1195/table/ssadh.T.succinic_semialdehyde_dehydrogen/?report=objectonly" target="object" rid-ob="figobssadhTsuccinicsemialdehydedehydrogen">Table 2</a> summarizes the common features seen in this condition.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figssadhTsuccinicsemialdehydedehydrogen"><a href="/books/NBK1195/table/ssadh.T.succinic_semialdehyde_dehydrogen/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobssadhTsuccinicsemialdehydedehydrogen"><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="ssadh.T.succinic_semialdehyde_dehydrogen"><a href="/books/NBK1195/table/ssadh.T.succinic_semialdehyde_dehydrogen/?report=objectonly" target="object" rid-ob="figobssadhTsuccinicsemialdehydedehydrogen">Table 2. </a></h4><p class="float-caption no_bottom_margin">Succinic Semialdehyde Dehydrogenase Deficiency: Frequency of Select Features </p></div></div><p><b>Developmental delay (DD) and intellectual disability (ID).</b> Caregiver-reported symptom onset, typically consisting of developmental delay, is around age six months; however, the diagnosis of SSADH deficiency is often not established until approximately age 3.5 years, with several reported individuals being diagnosed in adolescence and adulthood.</p><ul><li class="half_rhythm"><div>
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<b>Motor skills</b>
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</div><ul><li class="half_rhythm"><div>The majority of individuals with SSADH deficiency attain head control (98%), can sit unsupported (97%), and walk unsupported (90%) at median (IQR) ages of 6 months (4-7 months), 11 months (7-12 months), and 19 months (16-30 months), respectively.</div></li><li class="half_rhythm"><div>The vast majority of affected individuals are only mildly delayed in motor abilities, and only 10% require support for walking [<a class="bibr" href="#ssadh.REF.tokatly_latzer.2024b.21" rid="ssadh.REF.tokatly_latzer.2024b.21">Tokatly Latzer et al 2024b</a>].</div></li></ul></li><li class="half_rhythm"><div><b>Speech/language.</b> Language delays are more prominent than motor delays [<a class="bibr" href="#ssadh.REF.tokatly_latzer.2024b.21" rid="ssadh.REF.tokatly_latzer.2024b.21">Tokatly Latzer et al 2024b</a>].</div><ul><li class="half_rhythm"><div>Roughly 90% of individuals acquire the ability to express some words, and the median (IQR) age of the first expressed word is 28 (20-48) months (see <a href="/books/NBK1195/table/ssadh.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobssadhTmoleculargenetictestingusedi">Table 1</a>).</div></li><li class="half_rhythm"><div>However, both expressive and receptive language deficits are almost universal, with expressive language deficits more pronounced than receptive language deficits.</div></li></ul></li><li class="half_rhythm"><div><b>Cognition.</b> The majority of individuals with SSADH deficiency have cognitive impairments, with an IQ ranging from 50 to 65. Some 10%-20% of individuals have an IQ below 50, and rarely do affected individuals have IQs exceeding 70.</div></li></ul><p>
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<b>Other neurodevelopmental features</b>
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</p><ul><li class="half_rhythm"><div>Hypotonia is present in roughly 65% of individuals, tends to improve over time, and is typically not severe enough to require a feeding tube.</div></li><li class="half_rhythm"><div>Ataxia occurs in about 40% of individuals and does not tend to improve with age.</div></li><li class="half_rhythm"><div>Movement disorders, such as dystonia and dyskinesia, occur in 20%-30% of individuals, with exertional dyskinesias, including ballismus, appearing in late adolescence [<a class="bibr" href="#ssadh.REF.leuzzi.2007.1320" rid="ssadh.REF.leuzzi.2007.1320">Leuzzi et al 2007</a>].</div></li></ul><p><b>Neurobehavioral/psychiatric manifestations.</b> About 50% of affected individuals have an autism spectrum disorder diagnosis. Behavioral problems are observed in ~70% of affected individuals and are predominated by obsessive-compulsive behaviors and attention problems. Other features may include affective problems, anxiety, and rarely aggression and possible psychosis. Increased internalizing, externalizing, and overall psychiatric morbidity is seen with increasing age.</p><p><b>Epilepsy.</b> Epilepsy is present in ~50% of individuals with SSADH deficiency. In about one third of affected individuals, seizures increase in severity over time, and are typically medically refractory in those individuals. The typical age of seizure onset is ~9 years [<a class="bibr" href="#ssadh.REF.tokatly_latzer.2023a.1755" rid="ssadh.REF.tokatly_latzer.2023a.1755">Tokatly Latzer et al 2023a</a>]. The incidence of sudden unexpected death in epilepsy (SUDEP) is nearly 15% in affected adults [<a class="bibr" href="#ssadh.REF.dibacco.2018.114" rid="ssadh.REF.dibacco.2018.114">DiBacco et al 2018</a>].</p><p><b>EEG findings</b> are abnormal in ~70% of affected individuals. Abnormalities are nonspecific, with diffuse background slowing seen more commonly than epileptiform patterns. Older individuals are significantly more prone to EEG abnormalities coexisting with clinical seizures [<a class="bibr" href="#ssadh.REF.tokatly_latzer.2023a.1755" rid="ssadh.REF.tokatly_latzer.2023a.1755">Tokatly Latzer et al 2023a</a>].</p><p><b>Brain MRI findings.</b> The typical neuroimaging findings of SSADH deficiency include MRI T<sub>2</sub>-weighted signal hyperintensities in the globus pallidus, subthalamic nucleus, and cerebellar dentate nucleus [<a class="bibr" href="#ssadh.REF.afacan.2021.1162" rid="ssadh.REF.afacan.2021.1162">Afacan et al 2021</a>]. Less commonly, cortical and cerebellar atrophy are seen. Enlarged perivascular spaces may also be observed [<a class="bibr" href="#ssadh.REF.tokatly_latzer.2024c.e14105" rid="ssadh.REF.tokatly_latzer.2024c.e14105">Tokatly Latzer et al 2024c</a>]. Magnetic resonance spectroscopy may show an increased gamma-aminobutyric acid (GABA)-to-N-acetylaspartate (NAA) ratio [<a class="bibr" href="#ssadh.REF.afacan.2021.1162" rid="ssadh.REF.afacan.2021.1162">Afacan et al 2021</a>]. Notably, these findings are not diagnostic of SSADH deficiency, nor do they have specific therapeutic implications [<a class="bibr" href="#ssadh.REF.tokatly_latzer.2024a.108363" rid="ssadh.REF.tokatly_latzer.2024a.108363">Tokatly Latzer et al 2024a</a>].</p><p><b>Sleep disorders</b> are common and manifest either as excessive daytime somnolence or disorders of initiating or maintaining sleep.</p><ul><li class="half_rhythm"><div>Ten affected individuals studied with overnight polysomnography and daytime multiple sleep latency testing (MLST) had prolonged REM latency (mean: 272±89 min) and reduced stage REM percentage (mean: 8.9%; range: 0.3%-13.8%) [<a class="bibr" href="#ssadh.REF.pearl.2009.1645" rid="ssadh.REF.pearl.2009.1645">Pearl et al 2009</a>].</div></li><li class="half_rhythm"><div>Half of these individuals showed a decrease in daytime mean sleep latency on MSLT, indicating excessive daytime somnolence.</div></li><li class="half_rhythm"><div>Overall, REM sleep appears to be reduced.</div></li><li class="half_rhythm"><div>Notably, the severity of glymphatic dysfunction, as reflected by an increased burden of perivascular spaces, is associated with worse sleeping disturbances (such as parasomnias, sleep-disordered breathing problems, and daytime sleepiness) [<a class="bibr" href="#ssadh.REF.tokatly_latzer.2024c.e14105" rid="ssadh.REF.tokatly_latzer.2024c.e14105">Tokatly Latzer et al 2024c</a>].</div></li></ul></div><div id="ssadh.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>SSADH deficiency is caused by biallelic pathogenic variants and SSADH is an oligomeric protein; therefore, knowledge of the <i>ALDH5A1</i> biallelic pathogenic variants is informative only if their resultant global molecular effect on the SSADH protein is elucidated.</p><p>In general, individuals with pathogenic <i>ALDH5A1</i> variants resulting in truncated SSADH or lack of SSADH altogether (as opposed to having single homotetramers or a mixed population of homo- and heterotetramers) or that lead to impairment in the SSADH catalytic sites (as opposed to impairments in its folding, stability, or oligomerization) have a more severe phenotype [<a class="bibr" href="#ssadh.REF.tokatly_latzer.2023c.1596" rid="ssadh.REF.tokatly_latzer.2023c.1596">Tokatly Latzer et al 2023c</a>].</p></div><div id="ssadh.Prevalence"><h3>Prevalence</h3><p>While the actual incidence and prevalence of SSADH deficiency are currently unknown, at least 450 individuals have been described worldwide [<a class="bibr" href="#ssadh.REF.pearl.2021.1153" rid="ssadh.REF.pearl.2021.1153">Pearl et al 2021</a>]. According to a population-based exome and whole genome interrogation of <i>ALDH5A1</i> pathogenic / likely pathogenic variants, the estimated worldwide prevalence of SSADH deficiency ranges from 1:223,000 to 1:564,000 [<a class="bibr" href="#ssadh.REF.glinton.2024.1405468" rid="ssadh.REF.glinton.2024.1405468">Glinton et al 2024</a>].</p></div></div><div id="ssadh.Genetically_Related_Allelic_Disord"><h2 id="_ssadh_Genetically_Related_Allelic_Disord_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those described in this <i>GeneReview</i> are known to be associated with germline pathogenic variants in <i>ALDH5A1</i>.</p><p><b>Contiguous gene duplication.</b> One family (3 affected individuals) with developmental delay and a small chromosome duplication involving several genes including <i>ALDH5A1</i> has been described [<a class="bibr" href="#ssadh.REF.siggberg.2011.448" rid="ssadh.REF.siggberg.2011.448">Siggberg et al 2011</a>]. Elevated SSADH enzymatic activity in the affected individuals was confirmed in cultured white blood cells and may have a negative impact on gamma-aminobutyric acid metabolism, possibly leading or contributing to the phenotype.</p></div><div id="ssadh.Differential_Diagnosis"><h2 id="_ssadh_Differential_Diagnosis_">Differential Diagnosis</h2><p><b>Disorder of gamma-aminobutyric acid (GABA) metabolism.</b> 4-aminobutyrate aminotransferase (also known as GABA transaminase or GABA-T) deficiency (OMIM <a href="https://omim.org/entry/613163" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">613163</a>) is characterized by psychomotor delay, hypotonia, hyperreflexia, lethargy, refractory seizures of neonatal or infantile onset, agenesis of the corpus callosum, and cerebellar hypoplasia. Free and total GABA concentration levels are elevated in the cerebrospinal fluid, without elevation in 4-hydroxybutyric acid (GHB). Biallelic pathogenic variants in <i>ABAT</i> are causative. Inheritance is autosomal recessive.</p><p><b>Elevated glycine</b> can be seen in glycine encephalopathy (i.e., <a href="/books/n/gene/nkh/?report=reader">nonketotic hyperglycinemia</a> and other neurologic disorders caused by disturbance of glycine metabolism and transport), which is distinguished from succinic semialdehyde dehydrogenase (SSADH) deficiency by the absence of elevated GHB in individuals with glycine encephalopathy.</p><p><b>Abnormal signal bilaterally in the globus pallidus</b> can be seen in other organic acidurias, particularly <a href="/books/n/gene/mma/?report=reader">isolated methylmalonic acidemia</a>, <a href="/books/n/gene/mt-overview/?report=reader">primary mitochondrial disorders</a>, <a href="/books/n/gene/pkan/?report=reader">pantothenate kinase-associated neurodegeneration</a> (PKAN), and <a href="/books/n/gene/neuroferritin/?report=reader">neuroferritinopathy</a> [<a class="bibr" href="#ssadh.REF.curtis.2001.350" rid="ssadh.REF.curtis.2001.350">Curtis et al 2001</a>].</p><p><b>Intellectual disability.</b> SSADH deficiency cannot easily be differentiated clinically from other disorders that cause intellectual disability. See OMIM Phenotypic Series for genes associated with:</p><ul><li class="half_rhythm"><div>
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<a href="https://www.omim.org/phenotypicSeries/PS156200" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Autosomal dominant intellectual developmental disorders</a>
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</div></li><li class="half_rhythm"><div>
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<a href="https://omim.org/phenotypicSeries/PS249500" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Autosomal recessive intellectual developmental disorders</a>
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</div></li><li class="half_rhythm"><div>
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<a href="https://omim.org/phenotypicSeries/PS309530" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Nonsyndromic X-linked intellectual developmental disorders</a>
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</div></li><li class="half_rhythm"><div>
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<a href="https://omim.org/phenotypicSeries/PS309510" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Syndromic X-linked intellectual developmental disorders</a>
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</div></li></ul><p><b>Note.</b> Unlike other metabolic encephalopathies and some other organic acidurias, SSADH deficiency does not usually present with metabolic stroke, megalencephaly, episodic hypoglycemia, hyperammonemia, acidosis, or intermittent decompensation [<a class="bibr" href="#ssadh.REF.tokatly_latzer.2024a.108363" rid="ssadh.REF.tokatly_latzer.2024a.108363">Tokatly Latzer et al 2024a</a>].</p></div><div id="ssadh.Management"><h2 id="_ssadh_Management_">Management</h2><p>Consensus clinical management guidelines for succinic semialdehyde dehydrogenase (SSADH) deficiency have been published [<a class="bibr" href="#ssadh.REF.tokatly_latzer.2024a.108363" rid="ssadh.REF.tokatly_latzer.2024a.108363">Tokatly Latzer et al 2024a</a>].</p><div id="ssadh.Evaluations_Following_Initial_Diag"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with SSADH deficiency, the evaluations summarized in <a href="/books/NBK1195/table/ssadh.T.succinic_semialdehyde_dehydrogen_1/?report=objectonly" target="object" rid-ob="figobssadhTsuccinicsemialdehydedehydrogen1">Table 3</a> (if not performed as part of the evaluation that led to diagnosis) are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figssadhTsuccinicsemialdehydedehydrogen1"><a href="/books/NBK1195/table/ssadh.T.succinic_semialdehyde_dehydrogen_1/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobssadhTsuccinicsemialdehydedehydrogen1"><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="ssadh.T.succinic_semialdehyde_dehydrogen_1"><a href="/books/NBK1195/table/ssadh.T.succinic_semialdehyde_dehydrogen_1/?report=objectonly" target="object" rid-ob="figobssadhTsuccinicsemialdehydedehydrogen1">Table 3. </a></h4><p class="float-caption no_bottom_margin">Succinic Semialdehyde Dehydrogenase Deficiency: Recommended Evaluations Following Initial Diagnosis </p></div></div></div><div id="ssadh.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>There is no cure for SSADH deficiency. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see <a href="/books/NBK1195/table/ssadh.T.succinic_semialdehyde_dehydrogen_2/?report=objectonly" target="object" rid-ob="figobssadhTsuccinicsemialdehydedehydrogen2">Table 4</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figssadhTsuccinicsemialdehydedehydrogen2"><a href="/books/NBK1195/table/ssadh.T.succinic_semialdehyde_dehydrogen_2/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobssadhTsuccinicsemialdehydedehydrogen2"><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="ssadh.T.succinic_semialdehyde_dehydrogen_2"><a href="/books/NBK1195/table/ssadh.T.succinic_semialdehyde_dehydrogen_2/?report=objectonly" target="object" rid-ob="figobssadhTsuccinicsemialdehydedehydrogen2">Table 4. </a></h4><p class="float-caption no_bottom_margin">Succinic Semialdehyde Dehydrogenase Deficiency: Treatment of Manifestations </p></div></div><div id="ssadh.Developmental_Delay__Intellectual"><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>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 id="ssadh.Motor_Dysfunction"><h4>Motor Dysfunction</h4><p>
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<b>Gross motor dysfunction</b>
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</p><ul><li class="half_rhythm"><div>Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications.</div></li><li class="half_rhythm"><div>Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).</div></li></ul><p><b>Fine motor dysfunction.</b> Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.</p><p><b>Oral motor dysfunction</b> should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues.</p><p><b>Communication issues.</b> Consider evaluation for alternative means of communication (e.g., <a href="https://www.asha.org/NJC/AAC/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">augmentative and alternative communication</a> [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.</p></div><div id="ssadh.NeurobehavioralPsychiatric_Concern"><h4>Neurobehavioral/Psychiatric Concerns</h4><p>Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.</p><p>Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Methylphenidate, thioridazine, risperidal, fluoxetine, and benzodiazepines have been used for the treatment of increased anxiety, aggressiveness, and inattention [<a class="bibr" href="#ssadh.REF.gibson.2003.763" rid="ssadh.REF.gibson.2003.763">Gibson et al 2003</a>].</p></div></div><div id="ssadh.Surveillance"><h3>Surveillance</h3><p>To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in <a href="/books/NBK1195/table/ssadh.T.succinic_semialdehyde_dehydrogen_3/?report=objectonly" target="object" rid-ob="figobssadhTsuccinicsemialdehydedehydrogen3">Table 5</a> are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figssadhTsuccinicsemialdehydedehydrogen3"><a href="/books/NBK1195/table/ssadh.T.succinic_semialdehyde_dehydrogen_3/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figobssadhTsuccinicsemialdehydedehydrogen3"><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="ssadh.T.succinic_semialdehyde_dehydrogen_3"><a href="/books/NBK1195/table/ssadh.T.succinic_semialdehyde_dehydrogen_3/?report=objectonly" target="object" rid-ob="figobssadhTsuccinicsemialdehydedehydrogen3">Table 5. </a></h4><p class="float-caption no_bottom_margin">Succinic Semialdehyde Dehydrogenase Deficiency: Recommended Surveillance </p></div></div></div><div id="ssadh.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Vigabatrin could be a rational therapy in people with SSADH deficiency due to its property of gamma-aminobutyric acid transaminase (GABA-T) inhibition leading to decreased 4-hydroxybutyric acid (GHB) levels. However, it may result in elevated GABA and the exacerbation of manifestations, and its clinical utility has been inconsistent. For these reasons and its potential for retinal toxicity, vigabatrin is not generally recommended as an anti-seizure medication (ASM) for individuals with SSADH deficiency.</p><p>Tiagabine could also lead to an increase in GABA levels and is not recommended for individuals with SSADH deficiency.</p><p>Valproate may lead to inhibition of residual SSADH activity; however, its efficacy in individuals with SSADH deficiency has been occasionally described. Valproate is not recommended as a first-line ASM in those with SSADH deficiency, but it may be considered in drug-resistant epilepsy or generalized spike-wave epilepsy [<a class="bibr" href="#ssadh.REF.tokatly_latzer.2023a.1755" rid="ssadh.REF.tokatly_latzer.2023a.1755">Tokatly Latzer et al 2023a</a>, <a class="bibr" href="#ssadh.REF.tokatly_latzer.2024a.108363" rid="ssadh.REF.tokatly_latzer.2024a.108363">Tokatly Latzer et al 2024a</a>].</p></div><div id="ssadh.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#ssadh.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="ssadh.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Ongoing work on gene replacement therapy for people with SSADH deficiency involves disease-specific modeling, viral vector testing, and development of clinical biomarkers assessing indices of cortical inhibition such as transcranial magnetic stimulation [<a class="bibr" href="#ssadh.REF.tsuboyama.2021.1169" rid="ssadh.REF.tsuboyama.2021.1169">Tsuboyama et al 2021</a>]. For disease modeling, a novel Aldh5a1 lox-STOP mouse enables gene restoration "on demand" and the assessment of successful phenotypic rescue. Current work is also focused on development of a custom-designed adeno-associated virus vector encompassing an <i>ALDH5A1</i>-specific promoter tethered with the human <i>ALDH5A1</i> coding sequence [<a class="bibr" href="#ssadh.REF.lee.2022.2606" rid="ssadh.REF.lee.2022.2606">Lee et al 2022</a>, <a class="bibr" href="#ssadh.REF.lee.2024.476" rid="ssadh.REF.lee.2024.476">Lee et al 2024</a>]. Additionally, human induced pluripotent stem cell models that are being established provide a meaningful human genomic testing platform.</p><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions.</p></div></div><div id="ssadh.Genetic_Counseling"><h2 id="_ssadh_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="ssadh.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Succinic semialdehyde dehydrogenase (SSADH) deficiency is inherited in an autosomal recessive manner.</p></div><div id="ssadh.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 presumed to be heterozygous for an <i>ALDH5A1</i> pathogenic variant.</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>ALDH5A1</i> pathogenic variant and to allow reliable recurrence risk assessment.</div></li><li class="half_rhythm"><div>If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that 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="#ssadh.REF.j_nsson.2017.519" rid="ssadh.REF.j_nsson.2017.519">Jónsson et al 2017</a>]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:</div><ul><li class="half_rhythm"><div>A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;</div></li><li class="half_rhythm"><div>Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.</div></li></ul></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic.</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>ALDH5A1</i> pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic.</div></li></ul><p><b>Offspring of a proband.</b> Unless an affected individual's reproductive partner also has SSADH deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in <i>ALDH5A1</i>.</p><p><b>Other family members.</b> Each sib of the proband's parents is at a 50% risk of being a carrier of an <i>ALDH5A1</i> pathogenic variant.</p></div><div id="ssadh.Carrier_Detection"><h3>Carrier Detection</h3><p>Molecular genetic carrier testing for at-risk relatives requires prior identification of the <i>ALDH5A1</i> pathogenic variants in the family.</p><p>Note: Biochemical testing is not accurate or reliable for carrier determination.</p></div><div id="ssadh.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>
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<b>Family planning</b>
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</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk 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 carriers or are at risk of being carriers.</div></li><li class="half_rhythm"><div>It is appropriate to offer <i>ALDH5A1</i> molecular genetic testing to the reproductive partners of individuals known to be heterozygous for an <i>ALDH5A1</i> pathogenic variant, particularly if consanguinity is likely.</div></li></ul></div><div id="ssadh.Prenatal_Testing_and_Preimplantati"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p><b>Molecular genetic testing.</b> Once the <i>ALDH5A1</i> pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for SSADH deficiency are possible.</p><p><b>Biochemical testing.</b> 4-hydroxybutyric acid (GHB) can be measured accurately in amniotic fluid by means of a sensitive stable-isotope dilution gas chromatography-mass spectrometry assay method using deuterium-labeled GHB as the internal standard [<a class="bibr" href="#ssadh.REF.gibson.2001" rid="ssadh.REF.gibson.2001">Gibson & Jakobs 2001</a>].</p><p><b>Molecular genetic and biochemical testing.</b> A combination of a metabolite analysis / urine organic acid assay with molecular genetic testing increases the accuracy of prenatal testing, especially if there are concerns about genetic variants of uncertain significance [<a class="bibr" href="#ssadh.REF.hogema.2001.218" rid="ssadh.REF.hogema.2001.218">Hogema et al 2001</a>].</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="ssadh.Resources"><h2 id="_ssadh_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>Succinic Semialdehyde Dehydrogenase Deficiency (SSADH) Association</b>
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</div><div><b>Phone:</b> 262-646-5133</div><div><b>Email:</b> ssadh@ssadh.net</div><div>
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<a href="https://www.ssadh.net/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">sadh.net</a>
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</div></li><li class="half_rhythm"><div>
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<b>Metabolic Support UK</b>
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</div><div>United Kingdom</div><div><b>Phone:</b> 0845 241 2173</div><div>
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<a href="https://metabolicsupportuk.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">metabolicsupportuk.org</a>
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</div></li></ul>
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</div><div id="ssadh.Molecular_Genetics"><h2 id="_ssadh_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="figssadhmolgenTA"><a href="/books/NBK1195/table/ssadh.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobssadhmolgenTA"><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="ssadh.molgen.TA"><a href="/books/NBK1195/table/ssadh.molgen.TA/?report=objectonly" target="object" rid-ob="figobssadhmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">Succinic Semialdehyde Dehydrogenase Deficiency: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figssadhmolgenTB"><a href="/books/NBK1195/table/ssadh.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobssadhmolgenTB"><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="ssadh.molgen.TB"><a href="/books/NBK1195/table/ssadh.molgen.TB/?report=objectonly" target="object" rid-ob="figobssadhmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for Succinic Semialdehyde Dehydrogenase Deficiency (View All in OMIM) </p></div></div><div id="ssadh.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><a class="figpopup" href="/books/NBK1195/figure/ssadh.F1/?report=objectonly" target="object" rid-figpopup="figssadhF1" rid-ob="figobssadhF1">Figure 1</a> outlines the normal role of succinic semialdehyde dehydrogenase (SSADH) in the gamma-aminobutyric acid (GABA) degradative pathway. GABA is metabolized to succinic acid by the sequential action of GABA-transaminase, in which GABA is converted to succinic semialdehyde, which then, by means of the enzyme SSADH, is oxidized to succinic acid.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figssadhF1" co-legend-rid="figlgndssadhF1"><a href="/books/NBK1195/figure/ssadh.F1/?report=objectonly" target="object" title="Figure 1. " class="img_link icnblk_img figpopup" rid-figpopup="figssadhF1" rid-ob="figobssadhF1"><img class="small-thumb" src="/books/NBK1195/bin/ssadh-Image001.gif" src-large="/books/NBK1195/bin/ssadh-Image001.jpg" alt="Figure 1. . In the absence of succinic semialdehyde dehydrogenase (SSADH), transamination of gamma-aminobutyric acid (GABA) to succinic semialdehyde is followed by reduction to 4-hydroxybutyric acid (gamma-hydroxybutyrate [GHB])." /></a><div class="icnblk_cntnt" id="figlgndssadhF1"><h4 id="ssadh.F1"><a href="/books/NBK1195/figure/ssadh.F1/?report=objectonly" target="object" rid-ob="figobssadhF1">Figure 1. </a></h4><p class="float-caption no_bottom_margin">In the absence of succinic semialdehyde dehydrogenase (SSADH), transamination of gamma-aminobutyric acid (GABA) to succinic semialdehyde is followed by reduction to 4-hydroxybutyric acid (gamma-hydroxybutyrate [GHB]). SSADH deficiency leads to significant <a href="/books/NBK1195/figure/ssadh.F1/?report=objectonly" target="object" rid-ob="figobssadhF1">(more...)</a></p></div></div><p>In the absence of SSADH, the transamination of GABA to succinic semialdehyde is interrupted, leading to a pathologic accumulation of GABA and 4-hydroxybutyric acid (GHB). Persistent levels of GABA lead to user-dependent down-regulation of GABA<sub>A</sub> receptors, which possibly results in the overall reduced inhibitory tone and clinical manifestations that emerge and worsen in late childhood, such as seizures, autism spectrum disorder behaviors, and other behavioral problems. The increased GHB may also be a significant contributor to the pathophysiology of SSADH deficiency. In addition to the high affinity GHB has to GHB receptors, when present in excess, it also has affinity to GABA<sub>A</sub> and GABA<sub>B</sub> receptors. The intracellular signaling pathways mediated by GHB are likely to be diverse and have also been associated with a decrease in adenylyl cyclase production, inhibition of dopamine release in the striatum, and blockade of multiple neurotransmitter receptor systems [<a class="bibr" href="#ssadh.REF.lee.2022.2606" rid="ssadh.REF.lee.2022.2606">Lee et al 2022</a>].</p><p><b>Mechanism of disease causation.</b> Loss of function</p></div></div><div id="ssadh.Chapter_Notes"><h2 id="_ssadh_Chapter_Notes_">Chapter Notes</h2><div id="ssadh.Author_Notes"><h3>Author Notes</h3><p>Boston Children's Hospital, Boston, Massachusetts, USA, is leading a natural history study of patients with succinic semialdehyde dehydrogenase (SSADH) deficiency. For more information and to contact the study team, see <a href="https://www.childrenshospital.org/clinical-trials/nct03758521" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.childrenshospital.org</a>.</p><p>Itay Tokatly Latzer, MD (<a href="mailto:dev@null" data-email="ude.dravrah.snerdlihc@reztalyltakot.yati" class="oemail">ude.dravrah.snerdlihc@reztalyltakot.yati</a>), and Phillip L Pearl, MD (<a href="mailto:dev@null" data-email="ude.dravrah.snerdlihc@lraep.pillihp" class="oemail">ude.dravrah.snerdlihc@lraep.pillihp</a>), are actively involved in clinical research regarding individuals with SSADH deficiency. They would be happy to communicate with persons who have any questions regarding diagnosis of SSADH deficiency or other considerations. They are also interested in hearing from clinicians treating families affected by epilepsy suspected to be caused by an inherited metabolic disorder in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.</p></div><div id="ssadh.Acknowledgments"><h3>Acknowledgments</h3><p>Supported in part by the National Institutes of Health (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) grant (1R01HD091142), a Boston Children's Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC) grant (P50 HD105351), an exploratory/developmental research grant award (R21NS121858), and the SSADH Association.</p></div><div id="ssadh.Author_History"><h3>Author History</h3><p>Emily S Barrios; Children's National Medical Center (2013-2016)<br />Jessica L Cabalza; George Washington University (2006-2010) <br />Philip K Capp; George Washington University (2004-2006)
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<br />Adrianne M Dorsey; Children's National Medical Center (2013-2016)<br />Ian Drillings; Children's National Medical Center (2010-2013)<br />Maciej Gasior, MD, PhD; National Institutes of Health (2004-2006)
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<br />K Michael Gibson, PhD, FACMG; Washington State University (2004-2025) <br />Thomas R Hartka, MS; George Washington University (2006-2010) <br />Phillip L Pearl, MD (2004-present) <br />Tom Reehal; Sheffield University (2010-2013)<br />Jean-Baptiste Roullet, PhD (2016-present)<br />Emily Robbins; George Washington University (2004-2006) <br />Itay Tokatly Latzer, MD (2024-present)<br />Natrujee Wiwattanadittakul, MD; Chiang Mai University (2016-2025)</p></div><div id="ssadh.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>9 January 2025 (ma) Comprehensive update posted live</div></li><li class="half_rhythm"><div>28 April 2016 (ma) Comprehensive update posted live</div></li><li class="half_rhythm"><div>19 September 2013 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>5 October 2010 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>25 July 2006 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>5 May 2004 (ca) Review posted live</div></li><li class="half_rhythm"><div>16 September 2003 (pp) Original submission</div></li></ul></div></div><div id="ssadh.References"><h2 id="_ssadh_References_">References</h2><div id="ssadh.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="ssadh.REF.afacan.2021.1162">Afacan
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I, Roullet
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PL. Establishment and validation of a clinical severity scoring system for succinic semialdehyde dehydrogenase deficiency.
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I, Yang
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PL. Glymphatic dysfunction coincides with lower GABA levels and sleep disturbances in succinic semialdehyde dehydrogenase deficiency.
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M, Liu
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A. Transcranial magnetic stimulation in succinic semialdehyde dehydrogenase deficiency: a measure of maturational trajectory of cortical excitability.
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MM, Roos
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B, Jansen
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EE, Mulder
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MF, Gibson
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C. 4-Hydroxybutyric aciduria associated with catheter usage: a diagnostic pitfall in the identification of SSADH deficiency.
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2011;102:216–7.
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[<a href="/pmc/articles/PMC3654524/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3654524</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20965758" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20965758</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ssadh.REF.wang.2016.1305">Wang
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KY, Barker
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DD. A case of acute onset succinic semialdehyde dehydrogenase deficiency: neuroimaging findings and literature review.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/26499347" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26499347</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ssadh.REF.zeiger.2016.113">Zeiger
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WA, Sun
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LR, Bosemani
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T, Pearl
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PL, Stafstrom
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CE. Acute infantile encephalopathy as presentation of succinic semialdehyde dehydrogenase deficiency.
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Pediatr Neurol
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2016; 58:113-5.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/27268762" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27268762</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK1195_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Itay Tokatly Latzer</span>, MD<div class="affiliation small">Department of Neurology<br />Boston Children's Hospital<br />Boston, Massachusetts</div><div class="affiliation small">Assistant Professor, School of Medicine<br />Faculty of Medical and Health Sciences<br />Tel Aviv University<br />Tel Aviv, Israel<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.dravrah.snerdlihc@reztalyltakot.yati" class="oemail">ude.dravrah.snerdlihc@reztalyltakot.yati</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Phillip L Pearl</span>, MD<div class="affiliation small">Professor of Neurology, Boston Children’s Hospital<br />Harvard Medical School<br />Boston, Massachusetts<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.dravrah.snerdlihc@lraep.pillihp" class="oemail">ude.dravrah.snerdlihc@lraep.pillihp</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Jean-Baptiste Roullet</span>, PhD<div class="affiliation small">Professor, College of Pharmacology<br />Washington State University<br />Spokane, Washington<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.usw@telluor.j" class="oemail">ude.usw@telluor.j</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">May 5, 2004</span>; Last Update: <span itemprop="dateModified">January 9, 2025</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>Tokatly Latzer I, Pearl PL, Roullet JB. Succinic Semialdehyde Dehydrogenase Deficiency. 2004 May 5 [Updated 2025 Jan 9]. 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/stromme/?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/iiae3/?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="figobssadhTmoleculargenetictestingusedi"><div id="ssadh.T.molecular_genetic_testing_used_i" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Succinic Semialdehyde Dehydrogenase Deficiency</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1195/table/ssadh.T.molecular_genetic_testing_used_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ssadh.T.molecular_genetic_testing_used_i_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ssadh.T.molecular_genetic_testing_used_i_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_ssadh.T.molecular_genetic_testing_used_i_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_ssadh.T.molecular_genetic_testing_used_i_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Identified by Method</th></tr></thead><tbody><tr><td headers="hd_h_ssadh.T.molecular_genetic_testing_used_i_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ALDH5A1</i>
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</td><td headers="hd_h_ssadh.T.molecular_genetic_testing_used_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_ssadh.T.molecular_genetic_testing_used_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">97% <sup>4</sup></td></tr><tr><td headers="hd_h_ssadh.T.molecular_genetic_testing_used_i_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>5</sup></td><td headers="hd_h_ssadh.T.molecular_genetic_testing_used_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare <sup>6</sup></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="ssadh.TF.1.1"><p class="no_margin">See <a href="/books/NBK1195/?report=reader#ssadh.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="ssadh.TF.1.2"><p class="no_margin">See <a href="#ssadh.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="ssadh.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="ssadh.TF.1.4"><p class="no_margin">Sixty-two families [<a class="bibr" href="#ssadh.REF.liu.2016.441" rid="ssadh.REF.liu.2016.441">Liu et al 2016</a>] and data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bibr" href="#ssadh.REF.stenson.2020.1197" rid="ssadh.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="ssadh.TF.1.5"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="ssadh.TF.1.6"><p class="no_margin"><a class="bibr" href="#ssadh.REF.kwok.2012.280" rid="ssadh.REF.kwok.2012.280">Kwok et al [2012]</a> reported a novel 34-bp insertion in exon 10 that resulted in a pathogenic frameshift variant leading to a truncated SSADH protein lacking 50 amino acids in the C terminus. Several other larger deletions have also been identified [<a class="bibr" href="#ssadh.REF.stenson.2020.1197" rid="ssadh.REF.stenson.2020.1197">Stenson et al 2020</a>].</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobssadhTsuccinicsemialdehydedehydrogen"><div id="ssadh.T.succinic_semialdehyde_dehydrogen" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Succinic Semialdehyde Dehydrogenase Deficiency: Frequency of Select Features</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1195/table/ssadh.T.succinic_semialdehyde_dehydrogen/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ssadh.T.succinic_semialdehyde_dehydrogen_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of Persons w/Feature</th><th id="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_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_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental delay / cognitive impairment</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nearly 100%</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Incl prominent expressive speech deficits</td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurobehavioral manifestations</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">70%</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Incl ADHD, anxiety, obsessive-compulsive behaviors, & rarely aggression & possibly psychosis</td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sleep disturbances</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">60%-80%</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hypotonia</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">60%-70%</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Autism spectrum disorder</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">50%-60%</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Epilepsy</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">50%</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Drug-resistant epilepsy is observed in about 15%-20% of affected persons.</td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ataxia</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">40%</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Movement disorders</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">20%-30%</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Incl dystonia & dyskinesia</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">Based on <a class="bibr" href="#ssadh.REF.juliapalacios.2024.447" rid="ssadh.REF.juliapalacios.2024.447">Julia-Palacios et al [2024]</a>, <a class="bibr" href="#ssadh.REF.tokatly_latzer.2024b.21" rid="ssadh.REF.tokatly_latzer.2024b.21">Tokatly Latzer et al [2024b]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">ADHD = attention-deficit/hyperactivity disorder</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobssadhTsuccinicsemialdehydedehydrogen1"><div id="ssadh.T.succinic_semialdehyde_dehydrogen_1" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Succinic Semialdehyde Dehydrogenase Deficiency: Recommended Evaluations Following Initial Diagnosis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1195/table/ssadh.T.succinic_semialdehyde_dehydrogen_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ssadh.T.succinic_semialdehyde_dehydrogen_1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_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_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurologic</b>
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</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic eval, incl assessments for ataxia & movement disorders</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Neuroimaging is not specifically indicated for SSADH deficiency, unless neurologic signs warranting a neuroimaging assessment are present.</div></li><li class="half_rhythm"><div>An EEG is indicated in SSADH deficiency only if there is clinical suspicion of seizures.</div></li></ul>
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</td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Ataxia /</b>
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<br />
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<b>Movement disorder</b>
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</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Orthopedics / physical medicine & rehab / PT & OT eval</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl assessment of:
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<ul><li class="half_rhythm"><div>Gross motor & fine motor skills</div></li><li class="half_rhythm"><div>Mobility, ADL, & need for adaptive devices</div></li><li class="half_rhythm"><div>Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)</div></li></ul>
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</td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Development</b>
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</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_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, & speech-language eval</div></li><li class="half_rhythm"><div>Eval for early intervention / special education</div></li></ul>
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</td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurobehavioral/</b>
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<br />
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<b>Psychiatric</b>
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</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neuropsychiatric eval</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">It is recommended to screen for ASD, sleep disturbances, ADHD, & other behavioral & psychiatric issues in those age >1 yr.</td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Respiratory</b>
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</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider overnight polysomnogram in those w/excessive daytime sleepiness.</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider referral to sleep medicine specialist.</td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Gastrointestinal/</b>
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<br />
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<b>Feeding</b>
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</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gastroenterology / nutrition / feeding team eval</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To incl eval of aspiration risk & nutritional status</div></li><li class="half_rhythm"><div>Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.</div></li></ul>
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</td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Genetic counseling</b>
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</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_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_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of SSADH deficiency to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Family support</b>
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<br />
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<b>& resources</b>
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</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By clinicians, wider care team, & family support organizations</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment of family & social structure to determine need for:
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<ul><li class="half_rhythm"><div>Community or <a href="#ssadh.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>Social work involvement for parental support</div></li><li class="half_rhythm"><div>Home nursing referral</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">ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SSADH = succinic semialdehyde dehydrogenase</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="ssadh.TF.3.1"><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="figobssadhTsuccinicsemialdehydedehydrogen2"><div id="ssadh.T.succinic_semialdehyde_dehydrogen_2" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Succinic Semialdehyde Dehydrogenase Deficiency: Treatment of Manifestations</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1195/table/ssadh.T.succinic_semialdehyde_dehydrogen_2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ssadh.T.succinic_semialdehyde_dehydrogen_2_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_2_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_2_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_2_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_ssadh.T.succinic_semialdehyde_dehydrogen_2_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Developmental delay /</b>
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<br />
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<b>Intellectual disability /</b>
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<br />
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<b>Neurobehavioral/</b>
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<br />
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<b>psychiatric issues</b>
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</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#ssadh.Developmental_Delay__Intellectual">Developmental Delay / Intellectual Disability Management Issues</a>.</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_2_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Epilepsy</b>
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</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standardized treatment w/ASM by experienced neurologist</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.</div></li><li class="half_rhythm"><div>Valproate is avoided when possible because of inhibition of potential residual enzymatic activity. However, it may be considered in circumstances such as drug-resistant generalized spike-wave EEG pattern when other ASMs are ineffective. <sup>1, 2</sup></div></li><li class="half_rhythm"><div>Vigabatrin is not generally recommended as an ASM for persons w/SSADH deficiency. <sup>1, 2</sup></div></li><li class="half_rhythm"><div>Ketogenic diet is not clearly indicated as standard therapy in persons w/SSADH deficiency; however, if adherence is possible, it is not contraindicated & may be attempted. <sup>1</sup></div></li><li class="half_rhythm"><div>Education of parents/caregivers <sup>3</sup></div></li></ul>
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</td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_2_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Ataxia /</b>
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<br />
|
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<b>Movement disorder</b>
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</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider need for positioning & mobility devices, disability parking placard.</td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_2_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Sleep disturbance</b>
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</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per sleep medicine specialist</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_2_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Transition to adult care</b>
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</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Develop realistic plans for adult life (see <a href="https://www.aesnet.org/docs/default-source/pdfs-clinical/aestransitionspracticetool-devdelayedfinalapproved4-21-132.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">American Epilepsy Society Transitions from Pediatric Epilepsy to Adult Epilepsy Care</a>).</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Starting by age ~10 yrs</td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_2_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Family/Community</b>
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</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Ensure appropriate social work involvement to connect families w/local resources, respite, & support.</div></li><li class="half_rhythm"><div>Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.</div></li></ul>
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|
</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider involvement in adaptive sports or <a href="https://www.specialolympics.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Special Olympics</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">ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="ssadh.TF.4.1"><p class="no_margin">
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<a class="bibr" href="#ssadh.REF.tokatly_latzer.2024a.108363" rid="ssadh.REF.tokatly_latzer.2024a.108363">Tokatly Latzer et al [2024a]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="ssadh.TF.4.2"><p class="no_margin">
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<a class="bibr" href="#ssadh.REF.tokatly_latzer.2023a.1755" rid="ssadh.REF.tokatly_latzer.2023a.1755">Tokatly Latzer et al [2023a]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="ssadh.TF.4.3"><p class="no_margin">Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see <a href="https://www.epilepsy.com/tools-resources/forms-resources#Epilepsy-Foundation-Toolbox" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Epilepsy Foundation Toolbox</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobssadhTsuccinicsemialdehydedehydrogen3"><div id="ssadh.T.succinic_semialdehyde_dehydrogen_3" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Succinic Semialdehyde Dehydrogenase Deficiency: Recommended Surveillance</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1195/table/ssadh.T.succinic_semialdehyde_dehydrogen_3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ssadh.T.succinic_semialdehyde_dehydrogen_3_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_3_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_3_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_3_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_ssadh.T.succinic_semialdehyde_dehydrogen_3_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurologic</b>
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</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Monitor those w/seizures as clinically indicated.</div></li><li class="half_rhythm"><div>Assess for new manifestations such as seizures, ataxia, or movement disorders.</div></li></ul>
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</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_3_1_1_1_3" rowspan="5" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_3_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Development</b>
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</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor developmental progress & educational needs.</td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_3_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurobehavioral/</b>
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<br />
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<b>Psychiatric</b>
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</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for anxiety, ADHD, OCD, & aggression.</td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_3_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Respiratory</b>
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</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor for evidence of sleep disturbance, such as excessive daytime sleepiness.</td></tr><tr><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_3_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Family/Community</b>
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</td><td headers="hd_h_ssadh.T.succinic_semialdehyde_dehydrogen_3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).</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">ADHD = attention-deficit/hyperactivity disorder; OCD = obsessive-compulsive disorder</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobssadhmolgenTA"><div id="ssadh.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Succinic Semialdehyde Dehydrogenase Deficiency: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1195/table/ssadh.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ssadh.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_ssadh.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_ssadh.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_ssadh.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_ssadh.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_ssadh.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_ssadh.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_ssadh.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/7915" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>ALDH5A1</i>
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</a>
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</td><td headers="hd_b_ssadh.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=7915" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">6p22<wbr style="display:inline-block"></wbr>​.3</a>
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</td><td headers="hd_b_ssadh.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.uniprot.org/uniprot/P51649" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Succinate-semialdehyde dehydrogenase, mitochondrial</a>
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</td><td headers="hd_b_ssadh.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.LOVD.nl/ALDH5A1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ALDH5A1 @ LOVD</a>
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</td><td headers="hd_b_ssadh.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=ALDH5A1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ALDH5A1</a>
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</td><td headers="hd_b_ssadh.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=ALDH5A1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ALDH5A1</a>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="ssadh.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
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<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
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chromosome locus from
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<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
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protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
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For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
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<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobssadhmolgenTB"><div id="ssadh.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Succinic Semialdehyde Dehydrogenase Deficiency (<a href="/omim/271980,610045" 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/NBK1195/table/ssadh.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ssadh.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/271980" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">271980</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY; SSADHD</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/610045" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">610045</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ALDEHYDE DEHYDROGENASE 5 FAMILY, MEMBER A1; ALDH5A1</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobssadhF1"><div id="ssadh.F1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK1195/bin/ssadh-Image001.jpg" alt="Figure 1. . In the absence of succinic semialdehyde dehydrogenase (SSADH), transamination of gamma-aminobutyric acid (GABA) to succinic semialdehyde is followed by reduction to 4-hydroxybutyric acid (gamma-hydroxybutyrate [GHB])." /></div><h3><span class="label">Figure 1. </span></h3><div class="caption"><p>In the absence of succinic semialdehyde dehydrogenase (SSADH), transamination of gamma-aminobutyric acid (GABA) to succinic semialdehyde is followed by reduction to 4-hydroxybutyric acid (gamma-hydroxybutyrate [GHB]). SSADH deficiency leads to significant accumulation of GHB and GABA.</p></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script></div></div>
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