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Succinic Semialdehyde Dehydrogenase Deficiency

Synonyms: 4-Hydroxybutyric Aciduria, Gamma-Hydroxybutyric Aciduria, SSADH Deficiency

, MD, , , and , PhD, FACMG.

Author Information
, MD
Professor, Pediatrics and Neurology
Children's National Medical Center
George Washington University School of Medicine & Health Sciences
Washington, DC
Department of Neurology
Children's National Medical Center
Washington, DC
Department of Neurology
Children's National Medical Center
Washington, DC
Professor and Head, Section of Clinical Pharmacology
College of Pharmacy
Washington State University Spokane
Spokane, Washington

Initial Posting: ; Last Update: September 19, 2013.


Disease characteristics. Succinic semialdehyde dehydrogenase (SSADH) deficiency is characterized by psychomotor retardation, childhood-onset hypotonia, and ataxia. Seizures occur in more than 50% of affected individuals. Hyperkinetic behavior, aggression, self-injurious behaviors, hallucinations, and sleep disturbances have been reported in nearly half of all patients, and are common in older individuals. Basal ganglia signs such as choreoathetosis, dystonia, and myoclonus have been reported in a few individuals with earlier-onset, more severe disease. Involvement beyond the central nervous system has not been described.

Diagnosis/testing. The diagnosis of SSADH deficiency is suspected in individuals with 4-hydroxybutyric aciduria present on urine organic acid analysis and is confirmed by assay of SSADH enzyme activity in leukocytes. Head MRI reveals T2 hyperintensities in multiple regions, involving the globus pallidi (43%), cerebellar dentate nucleus (17%), subcortical white matter (7%), and brain stem (7%), as well as other abnormalities. EEG findings include background slowing and spike discharges that are usually generalized. ALDH5A1 is the only gene in which mutations are known to cause SSADH deficiency. Sequence analysis detects 97% of disease-causing mutations. Such testing is clinically available.

Management. Treatment of manifestations: Management is most often symptomatic, directed at the treatment of seizures and neurobehavioral disturbances. Effective antiepileptic drugs (AEDs) include carbamazepine and lamotrigine (LTG). While vigabatrin, an irreversible inhibitor of GABA-transaminase that inhibits the formation of succinic semialdehyde, is one of the most widely prescribed AEDs, it has shown inconsistent results in treatment of seizures associated with SSADH deficiency. Methylphenidate, thioridazine, risperidal, fluoxetine, and benzodiazepines are effective therapies for anxiety, aggressiveness, inattention, and hallucinations. Additional, non-pharmacologic treatments may include physical and occupational therapy, sensory integration, and/or speech therapy.

Surveillance: regular neurologic and developmental assessments as indicated.

Agents/circumstances to avoid: Valproate is typically contraindicated as it may inhibit residual SSADH enzyme activity; however, valproate may be considered in individuals with refractory epilepsy who have failed other treatments.

Genetic counseling. SSADH deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives is possible if the disease-causing mutations have been identified in the family. Biochemical testing is not accurate or reliable for carrier determination. Prenatal diagnosis for pregnancies at increased risk is possible using molecular genetic testing if the disease-causing mutations have been identified in the family, or using biochemical testing (either measurement of 4-hydroxybutyric acid in amniotic fluid or assay of SSADH enzyme activity in chorionic villus tissue and cultured amniocytes).


Clinical Diagnosis

Succinic semialdehyde dehydrogenase (SSADH) deficiency may be suspected in individuals with a late-infantile to early-childhood onset, slowly progressive or static encephalopathy characterized by the following:

  • Cognitive deficiency
  • Prominent expressive language deficit
  • Hypotonia
  • Epilepsy
  • Hyporeflexia
  • Ataxia

Neuroimaging. Cranial MRI has been associated with a pallidodentatoluysian pattern [Pearl et al 2009c], showing increased T2-weighted signal involving the globus pallidi bilaterally and symmetrically, in addition to the cerebellar dentate nuclei and subthalamic nuclei. Variations on this pattern occur, occasionally with asymmetric involvement or only partial involvement of the structural triad. Other imaging findings include T2-hyperintensities of subcortical white matter and brain stem, cerebral atrophy, cerebellar atrophy, and delayed myelination [Yalcinkaya et al 2000, Ziyeh et al 2002].

Magnetic resonance spectroscopy edited for small molecules shows elevated levels of GABA and related compounds in the Glx peak (e.g., GHB and homocarnosine) [Ethofer et al 2004, Pearl & Gropman 2004].

FDG-PET studies have shown decreased cerebellar glucose metabolism in affected individuals with cerebellar atrophy demonstrated on structural MRI [Al-Essa et al 2000, Pearl et al 2003].

EEG findings. EEG findings include background slowing and spike discharges that are usually generalized [Pearl et al 2005b]. More rarely, photosensitivity and electrographic status epilepticus of slow wave sleep (ESES) are observed. EEG studies are normal in about one third of affected individuals.

In one family two heterozygotes for SSADH deficiency (one parent and a sibling of a proband with the disorder) had generalized spike-wave discharges, photosensitivity, and absence and myoclonic seizures [Dervent et al 2004].


The diagnosis of SSADH deficiency is suspected in individuals with 4-hydroxybutyric aciduria present on urine organic acid analysis and is confirmed by assay of SSADH enzyme activity in leukocytes. Figure 1 outlines the normal SSADH GABA degradative pathway. Dried blood spot (DBS) testing for GHB has been proposed as an effective methodology to screen for SSADH deficiency with applicability to newborn metabolic screening and earlier diagnosis [Forni et al 2013]. However, it should be noted that 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 [Wamelink et al 2010].

Figure 1


Figure 1. In the absence of SSADH, transamination of γ-aminobutyric acid (GABA) to succinic semialdehyde is followed by reduction to 4-hydroxybutyric acid (γ-hydroxybutyrate [GHB]). SSADH deficiency leads to significant accumulation of (more...)

4-hydroxybutyric acid concentration

  • Urine: 100-1200 mmol/mol creatinine (normal: >0-7 mmol/mol creatinine)
  • Plasma: 35-600 µmol/L (normal: 0-3 µmol/L)
  • CSF: 100-850 µmol/L (normal: 0-2 µmol/L)

Note: Specific ion monitoring may be required for the detection of this metabolite, as its presence is sometimes obscured by a large normal urea peak on routine organic acid qualitative studies [Pearl et al 2003].

Other findings consistent with (but not required for) diagnosis

  • Small amounts of 4,5-dihydroxyhexanoic acid and 3-hydroxyproprionic acid and significant amounts of dicarboxylic acids in the urine. These have been detected in the urine of some individuals with SSADH deficiency and may indicate a secondary inhibition of mitochondrial fatty acid beta-oxidation or propionyl-coenzyme A metabolism by succinic semialdehyde or its metabolites.
  • Increased glycine concentration in urine and plasma and, rarely, a transient increase in CSF glycine concentration. This elevation may be at least partially attributed to conversion from glycolic acid, which accumulates secondary to GHB metabolism through beta-oxidation. SSADH deficiency should be distinguished from glycine encephalopthy (non-ketotic hyperglycinemia) based on the presence of GHB.
  • Elevated free and total GABA and homocarnosine concentrations in CSF
  • Absence of metabolic acidosis

Assay of SSADH enzyme activity

  • Succinic semialdehyde dehydrogenase is an enzyme that catalyzes the oxidation of succinate semialdehyde to succinate, the second and final step of the degradation of the inhibitory neurotransmitter GABA. In individuals with SSADH deficiency, SSADH enzyme activity is low in lymphocytes (<5% compared to controls).
  • SSADH enzyme activity is decreased in carriers but not reliable for carrier detection.

Molecular Genetic Testing

Gene. ALDH5A1 is the only gene in which mutations are known to cause SSADH deficiency.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Succinic Semialdehyde Dehydrogenase Deficiency

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
ALDH5A1Sequence analysisSequence variants 497% 5
Deletion/duplication analysis 6Exonic or whole-gene deletionUnknown 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Fifty-four families [Akaboshi et al [2003]

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. A novel 34-bp insertion in exon 10 was reported resulting in a frameshift mutation leading to a truncated SSADH protein lacking 50 amino acids in the C-terminus [Kwok et al 2012].

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis of SSADH deficiency is suspected in individuals with 4-hydroxybutyric aciduria present on urine organic acid analysis and is confirmed by assay of SSADH enzyme activity in leukocytes or by molecular genetic testing of ALDH5A1.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

SSADH deficiency is characterized by a relatively non-progressive encephalopathy presenting with hypotonia and delayed acquisition of motor and language developmental milestones in the first two years of life. Common clinical features include intellectual disability, behavior problems, and motor dysfunction.

Symptoms are first reported at a mean age of 11 months (range 0-44 months) and the mean age at diagnosis is 6.6 years (range 0-25 years) [Pearl et al 2009a]. Psychiatric symptoms may be the most disabling; they include sometimes prominent ADHD and even aggression in early childhood, and anxiety and obsessive-compulsive disorder in adolescence and adulthood [Pearl & Gibson 2004, Knerr et al 2008].

Patients do not usually have episodic decompensation following metabolic stressors as is typical of other organic acidemias and metabolic encephalopathies, although some patients have been diagnosed after having unanticipated difficulty recovering from otherwise ordinary childhood illnesses. The latter has been attributable to underlying hypotonia not previously identified.

Approximately 10% of affected individuals have a more severe phenotype including early-onset prominent extrapyramidal manifestations and a regressive course [Pearl et al 2005b].

Half of patients have epilepsy, usually with generalized tonic-clonic or atypical absence seizures [Pearl et al 2003].

Sleep disorders are common and manifest either by excessive daytime somnolence or disorders of initiating or maintaining sleep [Philippe et al 2004, Arnulf et al 2005]. Ten patients 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%) [Pearl et al 2009b]. Half of patients showed a decrease in daytime mean sleep latency on MSLT, indicating excessive daytime somnolence. Overall, REM sleep appears to be reduced.

Neuropathology from one individual with a confirmed diagnosis revealed discoloration of the globus pallidus and leptomeningeal congestion on gross pathology. On microscopic examination, hyperemia and granular perivascular calcification of the globus pallidus and superior colliculus were identified, and interpreted as consistent with chronic excitotoxic injury. There was not significant neuronal loss or gliosis of CA1 of the hippocampus, the area that would have been considered most vulnerable to epileptic or hypoxic injury in this individual, who died with a clinical diagnosis of SUDEP (sudden unexpected death in epilepsy patients) after having had escalating seizures [Knerr et al 2010].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been observed.


Approximately 450 individuals have been diagnosed with SSADH deficiency [Gibson & Jakobs 2001; Gibson & Jakobs, personal communication].

Because of the nonspecific nature of SSADH deficiency and the related difficulty in diagnosing affected individuals, the disorder may be significantly underdiagnosed. Thus, the true prevalence is unknown [Pearl et al 2003].

Parental consanguinity has been reported in approximately 40% of all published cases [Gibson et al 1997a, Gibson et al 1997b, Al Essa et al 2000, Yalcinkaya et al 2000].

Differential Diagnosis

Other disorders of GABA metabolism:

  • 4-aminobutyrate aminotransferase (GABA-transaminase, GABA-T) deficiency. This extremely rare disorder of GABA degradation [Medina-Kauwe et al 1999] is characterized by psychomotor retardation, hypotonia, hyperreflexia, lethargy, refractory seizures, agenesis of the corpus callosum, and cerebellar hypoplasia. Mutations in ABAT are causative. Free and total GABA concentration levels are elevated in the CSF, without elevation in GHB.
  • Homocarnosinosis. Homocarnosine is a dipeptide of histidine and GABA. A single case of primary homocarnosinosis has been reported; the enzyme defect has not been conclusively proven [Gibson & Jakobs 2001].

SSADH deficiency cannot easily be differentiated clinically from other disorders that cause intellectual disability. Screening by urine organic acid analysis is necessary to detect SSADH deficiency.

Abnormal signal bilaterally in the globus pallidus can be seen in other organic acidurias, particularly methylmalonic aciduria (see Methylmalonic Acidemia and Organic Acidemias Overview), mitochondrial disorders (see Mitochondrial Diseases Overview), pantothenate kinase-associated neurodegeneration (PKAN), and neuroferritinopathy [Curtis et al 2001].

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 [Pearl et al 2003].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with succinic semialdehyde dehydrogenase (SSADH) deficiency, the following evaluations are recommended:

  • Neuroimaging (MRI)
  • EEG
  • Developmental evaluation
  • Medical genetics consultation

Treatment of Manifestations

The management of SSADH deficiency is most often symptomatic, directed at the treatment of seizures and neurobehavioral disturbances.

Seizures. Effective antiepileptic drugs (AEDs) for SSADH deficiency have included carbamazepine and lamotrigine (LTG). Lamotrigine, which may inhibit the release of excitatory amino acids (LTG primarily blocks Na+ channels), in particular the GABA precursor glutamate, has been successful in one individual in whom vigabatrin led to seizures [Gibson et al 1998].

Vigabatrin, an irreversible inhibitor of GABA-transaminase, inhibits the formation of succinic semialdehyde and thus is one of the most widely prescribed AEDs [Matern et al 1996]. However, vigabatrin has shown inconsistent results [Howells et al 1992, Gropman 2003], suggesting that it is not effective at inhibiting peripheral GABA-transaminase, leading to a peripheral supply of 4-hydroxybutyric acid to the brain and thus decreasing its own efficacy. Brain MRI signal changes, particularly prominent in the thalamus and basal ganglia, have been seen in infants treated with relatively high doses of vigabatrin [Pearl et al 2009c].

However, recent reports of uncontrolled, nonblinded trials of vigabatrin in two affected children described a decrease in plasma GHB concentrations and clinical improvement (specifically in verbal communication) in one eight-year-old [Casarano et al 2012] and slow clinical improvement (although not unexpected based on natural history) in a 2.5-year-old child [Escalera et al 2010].

Neurobehavioral symptoms. Methylphenidate, thioridazine, risperidal, fluoxetine, and benzodiazepines are effective therapies for anxiety, aggressiveness, inattention, and hallucinations [Gibson et al 2003].

Beneficial non-pharmacologic treatments include physical therapy directed at developing strength, endurance, and balance; occupational therapy for improvement of fine motor skills, feeding, and sensory integration; and speech therapy [Gropman 2003].

Prevention of Secondary Complications

Antiepileptic medications are indicated for patients who have active seizures.


Regular neurologic and developmental assessments are indicated.

Agents/Circumstances to Avoid

Valproate is generally contraindicated as it may inhibit residual SSADH enzyme activity [Shinka et al 2003]. However, Vanadia et al [2013] reported an individual with SSADH deficiency who had refractory epilepsy after possible limbic encephalitis. The refractory epilepsy was finally controlled with magnesium valproate. One year after initiation of magnesium valproate therapy, the affected individual remained seizure free and had marked behavioral improvements, including decreased aggression, coprolalia, and non-recognition of danger. In addition, the EEG demonstrated improved background organization.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Biomarkers have been studied with plans for utilization in clinical trials. Positron emission tomography (PET) with [11C]flumazenil (FMZ), a benzodiazepine receptor antagonist, showed reduced binding in cortical, basal ganglia, and cerebellar regions of interest versus controls consistent with downregulation of GABA receptors [Pearl et al 2007]. Transcranial magnetic stimulation similarly showed downregulation of GABA-ergic activity in patients versus controls [Pearl et al 2009a]. A single case of improvements in gait, coordination, and energy was reported as an abstract in a 30-month-old male administered 200 mg/kg/day of taurine [Saronwala et al 2008]. Clinical trials are in progress with taurine and SGS-742, a GABA-B receptor antagonist [Gibson et al 2013].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.


Animal experiments utilizing the murine model have demonstrated partial efficacy involving the amino acid taurine, vigabatrin, and GABAB and GHB receptor inhibitors [Gupta et al 2004].

A murine trial has demonstrated some efficacy of the ketogenic diet [Nylen et al 2008], although the mechanism of the observed changes (and thus the potential for success in a human trial) has been questioned [Knerr & Pearl 2008].

SGS 742, a GABA-B receptor antagonist demonstrated in the murine model a significant effect on electrocorticography when compared with topiramate [Pearl et al 2009a]. Liver-mediated gene therapy in the mouse model did lead to reductions in GHB levels in liver, kidney, serum, and brain extracts [Gupta et al 2004].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Succinic semialdehyde dehydrogenase (SSADH) deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are typically asymptomatic. One report suggests that absence epilepsy with myoclonias and photosensitivity may be related to the heterozygous state [Dervent et al 2004].

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

Offspring of a proband. The offspring of an individual with SSADH are obligate heterozygotes (carriers) for a disease-causing mutation in ALDH5A1.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Molecular genetic testing. Carrier testing is possible if the disease-causing mutations have been identified in the proband.

Biochemical testing. Carrier testing using biochemical testing is not accurate or reliable for carrier determination.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Biochemical testing

  • 4-hydroxybutyric acid can be measured accurately in amniotic fluid by means of a sensitive stable-isotope dilution gas chromatography-mass spectrometry assay method using deuterium-labeled 4-hydroxybutyric acid as the internal standard [Gibson & Jakobs 2001].
  • SSADH enzyme activity can be measured in biopsied chorionic villus tissue and cultured amniocytes.

Molecular genetic and biochemical testing. A combination of a metabolite analysis assay of enzyme activity with molecular genetic testing increases the accuracy of prenatal testing [Hogema et al 2001].

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified in an affected family member.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association for Neuro-Metabolic Disorders (ANMD)
    5223 Brookfield Lane
    Sylvania OH 43560-1809
    Phone: 419-885-1809; 419-885-1497
    Email: volk4olks@aol.com
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk
  • Pediatric Neurotransmitter Disease Association
    498 Lillian Court
    PO Box 180622
    Delafield WI 53018
    Phone: 603-733-8409
    Email: pnd@pndassoc.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Succinic Semialdehyde Dehydrogenase Deficiency: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Succinic Semialdehyde Dehydrogenase Deficiency (View All in OMIM)


Molecular Genetic Pathogenesis

Animal studies have shown loss of locomotor function following γ-hydroxybutyrate (GHB) administration, reversible with inhibition of the mixed amino oxidase (MAO) system, consistent with a dopaminergic effect [Pearl et al 2005a]. Whether the cognitive, epileptic, neurobehavioral, and gait deficits in SSADH deficiency (as well as the extrapyramidal findings in ~10% of affected individuals) are related to chronically elevated endogenous GHB levels is uncertain.

The mouse model demonstrates downregulation and decreased function of the GABAA receptor, postulating an important role for GABA in the pathophysiology of at least the epileptic manifestations of SSADH deficiency [Wu et al 2006]. More specifically, Errington et al [2011] found that GABAA receptor mediated inhibitory gain-of-function may be a common feature in murine models of typical absence seizures.

A murine model demonstrated significant cerebral and cerebellar volume loss in homozygous SSADH-deficient mutant mice while no differences in total brain volume were observed in heterozygous mice or wild type controls [Acosta et al 2010].

Normal allelic variants. The gene consists of ten exons encompassing 38 kb of DNA. Of 27 novel mutations identified in 48 unrelated families, six did not strongly affect enzymatic activity and were considered normal allelic variants [Akaboshi et al 2003].

Pathologic allelic variants. More than 35 mutations including missense, nonsense, and splicing errors have been identified. No hotspots were detected [Akaboshi et al 2003]. Bekri et al [2004] report a new 7-bp deletion in exon 10 in a family with an affected child having very low enzymatic activity and reported as having a mild but typical phenotype. A novel 34-bp insertion in exon 10 was recently reported resulting in a frameshift mutation leading to a truncated SSADH protein lacking 50 amino acids in the C-terminus, was recently reported [Kwok et al 2012].

Normal gene product. GABA is metabolized to succinic acid by the sequential action of GABA-transaminase, in which GABA is converted to succinic semialdehyde, which is then, by means of the enzyme succinic semialdehyde dehydrogenase, oxidized to succinic acid.

Abnormal gene product. In the absence of succinic semialdehyde dehydrogenase, the transamination of GABA to succinic semialdehyde is followed by its reduction to GHB, a short monocarboxylic fatty acid whose role is unclear [Gupta et al 2003]. GHB, which accumulates in the urine, serum, and CSF of individuals with SSADH deficiency, has historically been considered the neurotoxic agent most responsible for the clinical manifestations of the disease [Pearl et al 2005a]. However, receptor studies in SSADH-deficient mice have shown alterations of GABAA and GABAB receptors but no alterations in GHB receptor binding or number, suggesting that the role of primary neurotoxin may be fulfilled by GABA [Vogel et al 2012].

Siggberg et al [2011] reported a family with developmental delay segregating a duplication of 6p22.2 that included ALDH5A1. SSADH enzyme studies in cultured white cells revealed elevated SSADH activity, consistent with duplication as well as increased urinary SSA associated with oxidative stress. Hyperactive levels of SSADH activity may also have negative consequences for GABA metabolism and other metabolic sequences.

The main function of GHB in the central nervous system is the inhibition of presynaptic dopamine release. It is currently used to induce a model of absence in rodents and to control cateplexy and alcohol-withdrawal syndromes; GHB is also a recreationally abused drug.


Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

  1. Acosta MT, Munasinghe J, Pearl PL, Gupta M, Finegersh A, Gibson KM, Theodore WH. Cerebellar atrophy in human and murine succinic semialdehyde dehydrogenase deficiency. J Child Neurol. 2010;25:1457–61. [PMC free article: PMC3155424] [PubMed: 20445195]
  2. Akaboshi S, Hogema BM, Novelletto A, Malaspina P, Salomons GS, Maropoulos GD, Jakobs C, Grompe M, Gibson KM. Mutational spectrum of the succinate semialdehyde dehydrogenase (ALDH5A1) gene and functional analysis of 27 novel disease-causing mutations in patients with SSADH deficiency. Hum Mutat. 2003;22:442–50. [PubMed: 14635103]
  3. Al-Essa MA, Bakheet SM, Patay ZJ, Powe JE, Ozand PT. Clinical, fluorine-18 labeled 2-fluoro-2-deoxyglucose positron emission tomography (FDG PET), MRI of the brain and biochemical observations in a patient with 4-hydroxybutyric aciduria; a progressive neurometabolic disease. Brain Dev. 2000;22:127–31. [PubMed: 10722966]
  4. Arnulf I, Konofal E, Gibson KM, Rabier D, Beauvais P, Derenne JP, Philippe A. Effect of genetically caused excess of brain gamma-hydroxybutyric acid and GABA on sleep. Sleep. 2005;28:418–24. [PubMed: 16171286]
  5. Bekri S, Fossoud C, Plaza G, Guenne A, Salomons GS, Jakobs C, Van Obberghen E. The molecular basis of succinic semialdehyde dehydrogenase deficiency in one family. Mol Genet Metab. 2004;81:347–51. [PubMed: 15059623]
  6. Casarano M, Alessandrì MG, Salomons GS, Moretti E, Jakobs C, Gibson KM, Cioni G, Battini R. Efficacy of vigabatrin intervention in a mild phenotypic expression of succinic semialdehyde dehydrogenase deficiency. JIMD Rep. 2012;2:119–23. [PMC free article: PMC3509850] [PubMed: 23430864]
  7. Curtis AR, Fey C, Morris CM, Bindoff LA, Ince PG, Chinnery PF, Coulthard A, Jackson MJ, Jackson AP, McHale DP, Hay D, Barker WA, Markham AF, Bates D, Curtis A, Burn J. Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet. 2001;28:350–4. [PubMed: 11438811]
  8. Dervent A, Gibson KM, Pearl PL, Salomons GS, Jakobs C, Yalcinkaya C. Photosensitive absence epilepsy with myoclonias and heterozygosity for succinic semialdehyde dehydrogenase (SSADH) deficiency. Clin Neurophysiol. 2004;115:1417–22. [PubMed: 15134710]
  9. Errington AC, Gibson KM, Crunelli V, Cope DW. Aberrant GABA(A) receptor-mediated inhibition in cortico-thalamic networks of succinic semialdehyde dehydrogenase deficient mice. PLoS One. 2011;6:e19021. [PMC free article: PMC3079762] [PubMed: 21526163]
  10. Escalera GI, Ferrer I, Marina LC, Sala PR, Salomons GS, Jakobs C, Pérez-Cerdá C. Succinic semialdehyde dehydrogenase deficiency: decrease in 4-OH-butyric acid levels with low doses of vigabatrin. An Pediatr (Barc). 2010;72:128–32. [PubMed: 20018576]
  11. Ethofer T, Seeger U, Klose U, Erb M, Kardatzki B, Kraft E, Landwehrmeyer GB, Grodd W, Storch A. Proton MR spectroscopy in succinic semialdehyde dehydrogenase deficiency. Neurology. 2004;62:1016–8. [PubMed: 15037717]
  12. Forni S, Pearl PL, Gibson KM, Yu Y, Sweetman L. Quantitation of gamma-hydroxybutyric acid in dried blood spots: Feasibility assessment for newborn screening of succinic semialdehyde dehydrogenase (ssadh) deficiency. Mol Genet Metab. 2013;109:255–9. [PMC free article: PMC3881544] [PubMed: 23742746]
  13. Gibson KM, Jakobs C. Disorders of beta- and alpha-amino acids in free and peptide-linked forms. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. New York, NY: McGraw-Hill; 2001:2079-105.
  14. Gibson KM, Christensen E, Jakobs C, Fowler B, Clarke MA, Hammersen G, Raab K, Kobori J, Moosa A, Vollmer B, Rossier E, Iafolla AK, Matern D, Brouwer OF, Finkelstein J, Aksu F, Weber HP, Bakkeren JA, Gabreels FJ, Bluestone D, Barron TF, Beauvais P, Rabier D, Santos C, Lehnert W. The clinical phenotype of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria): case reports of 23 new patients. Pediatrics. 1997a;99:567–74. [PubMed: 9093300]
  15. Gibson KM, Doskey AE, Rabier D, Jakobs C, Morlat C. Differing clinical presentation of succinic semialdehyde dehydrogenase deficiency in adolescent siblings from Lifu Island, New Caledonia. J Inherit Metab Dis. 1997b;20:370–4. [PubMed: 9266358]
  16. Gibson KM, Gupta M, Pearl PL, Tuchman M, Vezina LG, Snead OC, Smit LM, Jakobs C. Significant behavioral disturbances in succinic semialdehyde dehydrogenase (SSADH) deficiency (gamma-hydroxybutyric aciduria). Biol Psychiatry. 2003;54:763–8. [PubMed: 14512218]
  17. Gibson KM, Hoffmann GF, Hodson AK, Bottiglieri T, Jakobs C. 4-Hydroxybutyric acid and the clinical phenotype of succinic semialdehyde dehydrogenase deficiency, an inborn error of GABA metabolism. Neuropediatrics. 1998;29:14–22. [PubMed: 9553943]
  18. Gibson KM, Schreiber J, Theodore WH, McCarter R, Wiggs E, Yu Y, He J, Pearl PL. Open-label trial of taurine in succinic semialdehyde dehydrogenase (SSADH) deficiency: preliminary outcomes. Barcelona, Spain: 12th International Congress of Inborn Errors of Metabolism. 2013.
  19. Gropman A. Vigabatrin and newer interventions in succinic semialdehyde dehydrogenase deficiency. Ann Neurol. 2003;54 Suppl 6:S66–72. [PubMed: 12891656]
  20. Gupta M, Hogema BM, Grompe M, Bottiglieri TG, Concas A, Biggio G, Sogliano C, Rigamonti AE, Pearl PL, Snead OC, Jakobs C, Gibson KM. Murine succinate semialdehyde dehydrogenase deficiency. Ann Neurol. 2003;54:S81–90. [PubMed: 12891658]
  21. Gupta M, Jansen EE, Senephansiri H, Jakobs C, Snead OC, Grompe M, Gibson KM. Liver-directed adenoviral gene transfer in murine succinate semialdehyde dehydrogenase deficiency. Mol Ther. 2004;9:527–39. [PubMed: 15093183]
  22. Hogema BM, Akaboshi S, Taylor M, Salomons GS, Jakobs C, Schutgens RB, Wilcken B, Worthington S, Maropoulos G, Grompe M, Gibson KM. Prenatal diagnosis of succinic semialdehyde dehydrogenase deficiency: increased accuracy employing DNA, enzyme, and metabolite analyses. Mol Genet Metab. 2001;72:218–22. [PubMed: 11243727]
  23. Howells D, Jakobs C, Kok RM, Wrennall J, Thompson GN. Vigabatrin therapy in succinic semialdehyde dehydrogenase deficiency. Mol Neuropharmacol. 1992;2:181–4.
  24. Knerr I, Gibson KM, Jakobs C, Pearl PL. Neuropsychiatric morbidity in adolescent and adult succinic semialdehyde dehydrogenase deficiency patients. CNS Spectr. 2008;13:598–605. [PMC free article: PMC2562649] [PubMed: 18622364]
  25. Knerr I, Gibson KM, Murdoch G, Salomons GS, Pope L, Jakobs C, Combs GA, Pearl PL. Neuropathology in succinic semialdehyde dehydrogenase deficiency. Pediatr Neurol. 2010;42:255–8. [PMC free article: PMC3155415] [PubMed: 20304328]
  26. Knerr I, Pearl PL. Ketogenic diet: stoking energy stores and still posing questions. Exp Neurol. 2008;211:11–3. [PubMed: 18374334]
  27. Kwok JS, Yuen CL, Law LK, Tang NL, Cherk SW, Yuen YP. A novel aldh5a1 mutation in a patient with succinic semialdehyde dehydrogenase deficiency. Pathology. 2012;44:280–282. [PubMed: 22437753]
  28. Matern D, Lehnert W, Gibson KM, Korinthenberg R. Seizures in a boy with succinic semialdehyde dehydrogenase deficiency treated with vigabatrin (gamma-vinyl-GABA). J Inherit Metab Dis. 1996;19:313–8. [PubMed: 8803774]
  29. Medina-Kauwe LK, Tobin AJ, De Meirleir L, Jaeken J, Jakobs C, Nyhan WL, Gibson KM. 4-Aminobutyrate aminotransferase (GABA-transaminase) deficiency. J Inherit Metab Dis. 1999;22:414–27. [PubMed: 10407778]
  30. Nylen K, Velazquez JL, Likhodii SS, Cortez MA, Shen L, Leshchenko Y, Adeli K, Gibson KM, Burnham WM, Snead OC. A ketogenic diet rescues the murine succinic semialdehyde dehydrogenase deficient phenotype. Exp Neurol. 2008;210:449–57. [PMC free article: PMC2362105] [PubMed: 18199435]
  31. Pearl PL, Acosta MT, Wallis DD, Bottiglieri T, Miotto K, Jakobs C, Gibson KM. Dyskinetic features of succinate semialdehyde dehydrogenase deficiency, a GABA degradative defect. In: Fernández-Alvarez E, Arzimanoglou A, Tolosa E, eds. Paediatric Movement Disorders: Progress in Understanding. Surrey, UK: John Libbey Eurotext; 2005a:203-12.
  32. Pearl PL, Capp PK, Novotny EJ, Gibson KM. Inherited disorders of neurotransmitters in children and adults. Clin Biochem. 2005b;38:1051–8. [PubMed: 16298354]
  33. Pearl PL, Gibson KM. Clinical aspects of the disorders of GABA metabolism in children. Curr Opin Neurol. 2004;17:107–13. [PubMed: 15021235]
  34. Pearl PL, Gibson KM, Acosta MT, Vezina LG, Theodore WH, Rogawski MA, Novotny EJ, Gropman A, Conry JA, Berry GT, Tuchman M. Clinical spectrum of succinic semialdehyde dehydrogenase deficiency. Neurology. 2003;60:1413–7. [PubMed: 12743223]
  35. Pearl PL, Gibson KM, Cortez MA, Wu Y, Snead OC, Knerr I, Forester K, Pettiford JM, Jakobs C, Theodore WH. Succinic semialdehyde dehydrogenase deficiency: Lessons from mice and men. J Inherit Metab Dis. 2009a;32:343–53. [PMC free article: PMC2693236] [PubMed: 19172412]
  36. Pearl PL, Gropman A. Monitoring gamma-hydroxybutyric acid levels in succinate-semialdehyde dehydrogenase deficiency. Ann Neurol. 2004;55:599. [PubMed: 15048909]
  37. Pearl PL, Shamim S, Theodore WH, Gibson KM, Forester K, Combs SE, Lewin D, Dustin I, Reeves-Tyer P, Jakobs C, Sato S. Polysomnographic abnormalities in succinic semialdehyde dehydrogenase (SSADH) deficiency. Sleep. 2009b;32:1645–8. [PMC free article: PMC2786049] [PubMed: 20041601]
  38. Pearl PL, Taylor JL, Trzcinski S, Sokohl A, Dustin I, Reeves-Tyer P, Herscovitch P, Carson R, Liew C, Shamim S, Quezado K, Gibson M, Theodore W. 11C-Flumazenil PET imaging in patients with SSADH deficiency. J Inherit Metab Dis. 2007;30 Suppl 1:43.
  39. Pearl PL, Vezina LG, Saneto RP, McCarter R, Molloy-Wells E, Heffron A, Trzcinski S, McClintock WM, Conry JA, Elling NJ, Goodkin HP, Sotero de Menezes M, Ferri R, Gilles E, Kadom N, Gaillard W. Cerebral MRI abnormalities associated with vigabatrin therapy. Epilepsia. 2009c;50:184–94. [PubMed: 18783433]
  40. Philippe A, Deron J, Genevieve D, de Lonlay P, Gibson KM, Rabier D, Munnich A. Neurodevelopmental pattern of succinic semialdehyde dehydrogenase deficiency (gamma-hydroxybutyric aciduria). Dev Med Child Neurol. 2004;46:564–8. [PubMed: 15287248]
  41. Saronwala A, Tournay A, Gargus, JJ. Taurine treatment of succinate semialdehyde dehydrogenase (SSADH) deficiency reverses MRI-documented globus lesion and clinical syndrome. Proc Am Coll Med Genet. 2008. Abstract.
  42. Shinka T, Ohfu M, Hirose S, Kuhara T. Effect of valproic acid on the urinary metabolic profile of a patient with succinic semialdehyde dehydrogenase deficiency. J Chromatogr B Analyt Technol Biomed Life Sci. 2003;792:99–106. [PubMed: 12829002]
  43. Siggberg L, Mustonen A, Schuit R, Salomons GS, Roos B, Gibson KM, Jakobs C, Ignatius J, Knuutila S. Familial 6p22.2 duplication associates with mild developmental delay and increased ssadh activity. Am J Med Genet B Neuropsychiatr Genet. 2011;156B:448–53. [PMC free article: PMC3082589] [PubMed: 21438145]
  44. Vanadia E, Gibson KM, Pearl PL, Trapolino E, Mangano S, Vanadia F. Therapeutic efficacy of magnesium valproate in succinic semialdehyde dehydrogenase deficiency. JIMD Rep. 2013;8:133–7. [PMC free article: PMC3565633] [PubMed: 23430529]
  45. Vogel KR, Pearl PL, Theodore WH, McCarter RC, Jakobs C, Gibson KM. Thirty years beyond discovery--clinical trials in succinic semialdehyde dehydrogenase deficiency, a disorder of gaba metabolism. J Inherit Metab Dis. 2012;36:401–10. [PubMed: 22739941]
  46. Wamelink MM, Roos B, Jansen EE, Mulder MF, Gibson KM, Jakobs C. 4-hydroxybutyric aciduria associated with catheter usage: A diagnostic pitfall in the identification of ssadh deficiency. Mol Genet Metab. 2010;102:216–7. [PMC free article: PMC3654524] [PubMed: 20965758]
  47. Wu Y, Buzzi A, Frantseva M, Velazquez JP, Cortez M, Liu C, Shen L, Gibson KM, Snead OC. Status epilepticus in mice deficient for succinate semialdehyde dehydrogenase: GABAA receptor-mediated mechanisms. Ann Neurol. 2006;59:42–52. [PubMed: 16240371]
  48. Yalcinkaya C, Gibson KM, Gunduz E, Kocer N, Ficicioglu C, Kucukercan I. MRI findings in succinic semialdehyde dehydrogenase deficiency. Neuropediatrics. 2000;31:45–6. [PubMed: 10774997]
  49. Ziyeh S, Berlis A, Korinthenberg R, Spreer J, Schumacher M. Selective involvement of the globus pallidus and dentate nucleus in succinic semialdehyde dehydrogenase deficiency. Pediatr Radiol. 2002;32:598–600. [PubMed: 12136353]

Chapter Notes

Author History

Emily S Barrios (2013-present)
Jessica L Cabalza; George Washington University (2006-2010)
Philip K Capp; George Washington University (2004-2006)
Adrianne M Dorsey (2013-present)
Ian Drillings; Children’s National Medical Center (2010-2013)
Maciej Gasior, MD, PhD; National Institutes of Health (2004-2006)
K Michael Gibson, PhD, FACMG (2004-present)
Thomas R Hartka, MS; George Washington University (2006-2010)
Phillip L Pearl, MD (2004-present)
Tom Reehal; Sheffield University (2010-2013)
Emily Robbins; George Washington University (2004-2006)


Supported in part by the NIH (NS 40270, NS 43137), Pediatric Neurotransmitter Diseases Association, March of Dimes National Birth Defects Foundation, and Partnership for Pediatric Epilepsy Research, including American Epilepsy Society, Epilepsy Foundation, Anna and Jim Fantaci, Fight Against Childhood Epilepsy and Seizures (FACES), Neurotherapy Ventures Charitable Research Fund, and Parents Against Childhood Epilepsy (PACE).

Revision History

  • 19 September 2013 (me) Comprehensive update posted live
  • 5 October 2010 (me) Comprehensive update posted live
  • 25 July 2006 (me) Comprehensive update posted to live Web site
  • 5 May 2004 (ca) Review posted to live Web site
  • 16 September 2003 (pp) Original submission
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