Clinical characteristics.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is characterized by infantile-onset hypotonia, developmental delay, cognitive impairment, expressive language deficit, and mild ataxia. Epilepsy is present in about half of affected individuals and is more common in adults. Hyperkinetic behavior, aggression, self-injurious behaviors, hallucinations, and sleep disturbances have been reported in nearly half of all affected individuals, more commonly in those who are older. Basal ganglia signs including 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.

Individuals with SSADH deficiency typically have 4-hydroxybutyric aciduria present on urine organic acid analysis. Head MRI reveals T₂ hyperintensities in multiple regions, involving the globus pallidi, cerebellar dentate nuclei, subthalamic nuclei, subcortical white matter, and brain stem, as well as cerebral and sometimes cerebellar atrophy. EEG findings include background slowing and spike discharges that are usually generalized.

Diagnosis/testing.

The diagnosis of SSADH deficiency is established by the identification of biallelic pathogenic variants in ALDH5A1.

Management.

Treatment of manifestations: Management is most often symptomatic, directed at the treatment of seizures and neurobehavioral disturbances. A broad spectrum of antiepileptic medication has been used to treat this condition. While vigabatrin is an irreversible inhibitor of GABA-transaminase and thus inhibits the formation of succinic semialdehyde, it has shown inconsistent results in treatment of seizures associated with SSADH deficiency. Methylphenidate, thioridazine, risperidal, fluoxetine, and benzodiazepines have been used for treatment of increased anxiety, aggressiveness, and inattention. Additional, non-pharmacologic treatments may include physical and occupational therapy, sensory integration, feeding and/or speech therapy.

Surveillance: Regular neurologic and developmental assessments as indicated.

Agents/circumstances to avoid: Valproate 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 pathogenic variants have been identified in the family. Biochemical testing is not accurate or reliable for carrier determination. Prenatal testing for a pregnancy at increased risk is possible using molecular genetic testing if the pathogenic variants 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).

Suggestive Findings

Succinic semialdehyde dehydrogenase (SSADH) deficiency should be suspected in individuals with the following clinical, imaging, EEG, and supportive laboratory findings:

Clinical features. Late-infantile to early-childhood onset, slowly progressive or static encephalopathy characterized by:

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

Neuroimaging features

• Cranial MRI that demonstrates:
  • 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
  • T₂-hyperintensities of subcortical white matter and brain stem
  • Cerebral atrophy
  • Cerebellar atrophy
  • Delayed myelination
• Magnetic resonance spectroscopy that demonstrates elevated levels of GABA and related compounds in the Glx peak (e.g., GHB [gammahydroxybutyrate, also known as 4-hydroxybutyric acid], glutamate, and homocarnosine)

EEG findings. Background slowing and spike discharges that are usually generalized. Note: EEG studies are normal in about one third of affected individuals.

Supportive laboratory findings

• Absence of metabolic acidosis
• Urine organic acid analysis
  • 4-hydroxybutyric acid concentration of 100-1200 mmol/mol creatinine (normal: >0-7 mmol/mol creatinine)
  • Note: (1) 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]; (2) falsely elevated urinary concentrations of 4-hydroxybutyric acid (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 2011].
  • Small amounts of 4,5-dihydroxyhexanoic acid and 3-hydroxyproprionic acid and significant amounts of dicarboxylic acids may be detected. Urine organic acids can be confusing with the presence of elevated levels of d-2-hydroxyglutaric acid, but in the routine organic acid analysis this will only be reported as 2-hydroxyglutaric acid.
  • Increased glycine concentration
• Plasma amino/organic acid analysis
  • 4-hydroxybutyric acid concentration of 35-600 µmol/L (normal: 0-3 µmol/L)
  • Increased glycine concentration
• Cerebrospinal fluid (CSF) analysis
  • 4-hydroxybutyric acid concentration of 100-850 µmol/L (normal: 0-2 µmol/L)
  • A transient increase in CSF glycine concentration
  • Elevated free and total GABA and homocarnosine concentrations coupled to lowered glutamine

Note: Newborn screening is not routinely done for this disorder at this time.

Establishing the Diagnosis

The diagnosis of SSADH deficiency is established in a proband by the identification of biallelic pathogenic variants in ALDH5A1 on molecular genetic testing (see Table 1).

Molecular testing approaches can include single-gene testing or use of a multigene panel:

• Single-gene testing. Sequence analysis of ALDH5A1 is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
• A multigene panel that includes ALDH5A1 and other genes of interest (see Differential Diagnosis) may also be considered. 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 GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

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]. One study reported an adult man who was diagnosed in the sixth decade of life [Lapalme-Remis et al 2015]. 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].

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 [Wang et al 2016].

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

Seizures. Half of affected individuals have epilepsy, usually with generalized tonic-clonic or atypical absence seizures [Pearl et al 2003]. Epilepsy is more common in adults, and may be progressive [Lapalme-Remis et al 2015]. In one family two heterozygotes for SSADH deficiency (one parent and a sib of a proband with the disorder) had generalized spike-wave discharges, photosensitivity, and absence and myoclonic seizures [Dervent et al 2004].

Sleep disorders are common and manifest either as excessive daytime somnolence or as disorders of initiating or maintaining sleep [Philippe et al 2004, Arnulf et al 2005]. 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%) [Pearl et al 2009b]. Half of these individuals 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]. The authors are aware of two additional affected individuals who had SUDEP [Authors, unpublished data].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been observed.

Prevalence

Approximately 450 individuals have been diagnosed with SSADH deficiency [Gibson & Jakobs 2001; Gibson & Jakobs, personal communication], but it has been estimated to occur in 1:1,000,000 individuals [KM Gibson, unpublished data].

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, Yalçinkaya et al 2000].

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
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

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

Seizures. Antiseizure medications employed for the treatment of SSADH deficiency tend to be broad spectrum, although valproate is avoided when possible because of inhibition of potential residual enzymatic activity [Shinka et al 2003]. Vigabatrin, an irreversible inhibitor of GABA-transaminase, inhibits the formation of succinic semialdehyde [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, 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 child age eight years [Casarano et al 2012] and slow clinical improvement (although not unexpected based on natural history) in a child age 2.5 years [Escalera et al 2010].

Neurobehavioral symptoms. Methylphenidate, thioridazine, risperidal, fluoxetine, and benzodiazepines have been used for the treatment of increased anxiety, aggressiveness, and inattention [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].

Surveillance

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 decreases in 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 GABAergic activity in affected individuals versus controls [Pearl et al 2009a]. A single case of improvement 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]. However, an open-label study of eighteen individuals with SSADH deficiency treated with taurine did not show significant improvement in adaptive behavior scores. This study was assigned a class IV level of evidence because it did not involve a control group [Pearl et al 2014].

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]. A clinical trial of SGS-742 is currently enrolling (ClinicalTrials.gov).

Recent data demonstrated that administration of rapamycin to an SSADH-deficient mouse model reduced mTOR activity, reduced the elevated numbers of mitochondria in the liver and brain (due to improved mitophagy), and normalized aberrant antioxidant levels; mTOR inhibitors such as rapamycin may lead to the treatment of many diseases, including SSADH [Lakhani et al 2014].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Other

Animal experiments utilizing the murine model have demonstrated partial efficacy involving the amino acid taurine, vigabatrin, and GABA_B 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) is unknown [Knerr & Pearl 2008].

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 (i.e., carriers of one ALDH5A1 pathogenic variant).
• Heterozygotes (carriers) are typically asymptomatic. One report suggests that absence epilepsy with myoclonus 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.
• Heterozygotes (carriers) are typically asymptomatic.

Offspring of a proband. The offspring of an individual with SSADH are obligate heterozygotes (carriers) for a pathogenic variant in ALDH5A1.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier of an ALDH5A1 pathogenic variant.

Carrier (Heterozygote) Detection

Molecular genetic testing. Carrier testing for at-risk relatives requires prior identification of the ALDH5A1 pathogenic variants in the family.

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/preimplantation genetic 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the ALDH5A1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for SSADH deficiency are possible.

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].

Molecular 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.

Figure 1 outlines the normal SSADH GABA degradative pathway. A murine model demonstrates downregulation and decreased function of the GABA_A receptor, postulating an important role for GABA (gamma-aminobutyric acid) in the pathophysiology of at least the epileptic manifestations of SSADH deficiency [Wu et al 2006]. More specifically, Errington et al [2011] found that GABA_A receptor-mediated inhibitory gain of abnormal function may be a common feature in murine models of typical absence seizures.

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 GHB and GABA. (more...)

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

One case report described an individual who had early-onset SSADH with low-level glutathione (GSH), thus supporting the hypothesis of oxidative stress and mitochondrial dysfunction in SSADH deficiency that was previously described in in vitro studies [Niemi et al 2014].

Gene structure. The ALDH5A1 transcript NM_000090.3 comprises ten exons distributed over 38 kb of genomic DNA. A longer transcript variant has been described. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Of 27 novel variants identified in 48 unrelated families, six did not strongly affect enzymatic activity and were considered benign variants [Akaboshi et al 2003].

Pathogenic variants. A total of 44 pathogenic variants including missense, nonsense, and splicing errors have been identified. No hotspots were detected [Akaboshi et al 2003, Liu et al 2016]. Bekri et al [2004] reported a 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. Kwok et al [2012] reported a novel 34-bp insertion in exon 10 that predicted a truncated SSADH protein lacking 50 amino acids in the C-terminus. Exon deletions have also been reported [Akaboshi et al 2003].

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 then, by means of the enzyme succinic semialdehyde dehydrogenase, is oxidized to succinic acid.

Abnormal gene product. In the absence of succinic semialdehyde dehydrogenase, the transamination of GABA to succinic semialdehyde is quite likely followed by its reduction to GHB (gamma-hydroxybutyrate, 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 GABA_A and GABA_B 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 2013].

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.

Literature Cited

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• Pearl PL, Capp PK, Novotny EJ, Gibson KM. Inherited disorders of neurotransmitters in children and adults. Clin Biochem. 2005b;38:1051–8. [PubMed: 16298354]
• Pearl PL, Gibson KM. Clinical aspects of the disorders of GABA metabolism in children. Curr Opin Neurol. 2004;17:107–13. [PubMed: 15021235]
• Pearl PL, Gibson KM, Cortez MA, Wu Y, Carter Snead O 3rd, Knerr I, Forester K, Pettiford JM, Jakobs C, Theodore WH. Succinic semialdehyde dehydrogenase deficiency: lessons from mice and men. J Inherit Metab Dis. 2009a;32:343–52. [PMC free article: PMC2693236] [PubMed: 19172412]
• 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]
• Pearl PL, Schreiber J, Theodore WH, McCarter R, Barrios ES, Yu J, Wiggs E, He J, Gibson KM. Taurine trial in succinic semialdehyde dehydrogenase deficiency and elevated CNS GABA. Neurology. 2014;82:940–4. [PMC free article: PMC3963004] [PubMed: 24523482]
• 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]
• 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.
• 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]
• 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]
• 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.
• 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]
• 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]
• Tsuji M, Aida N, Obata T, Tomiyasu M, Furuya N, Kurosawa K, Errami A, Gibson KM, Salomons GS, Jakobs C, Osaka H. A new case of GABA transaminase deficiency facilitated by proton MR spectroscopy. J Inherit Metab Dis. 2010;33:85–90. [PMC free article: PMC2828554] [PubMed: 20052547]
• 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]
• 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. 2013;36:401–10. [PMC free article: PMC4349389] [PubMed: 22739941]
• 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. 2011;102:216–7. [PMC free article: PMC3654524] [PubMed: 20965758]
• Wang KY, Barker PB, Lin DD. A case of acute onset succinic semialdehyde dehydrogenase deficiency: neuroimaging findings and literature review. Childs Nerv Syst. 2016;32:1305–9. [PubMed: 26499347]
• Wu Y, Buzzi A, Frantseva M, Velazquez JP, Cortez M, Liu C, Shen L, Gibson KM, Snead OC 3rd. Status epilepticus in mice deficient for succinate semialdehyde dehydrogenase: GABAA receptor-mediated mechanisms. Ann Neurol. 2006;59:42–52. [PubMed: 16240371]
• Yalçinkaya C, Gibson KM, Gündüz E, Koçer N, Fiçicioğlu C, Küçükercan I. MRI findings in succinic semialdehyde dehydrogenase deficiency. Neuropediatrics. 2000;31:45–6. [PubMed: 10774997]

Acknowledgments

Supported in part by the NIH (NS 82286, NS 85369), 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)

Author History

Emily S Barrios; Children’s National Medical Center (2013-2016)
Jessica L Cabalza; George Washington University (2006-2010)
Philip K Capp; George Washington University (2004-2006)
Adrianne M Dorsey; Children’s National Medical Center (2013-2016)
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)
Jean-Baptiste Roullet, PhD (2016-present)
Emily Robbins; George Washington University (2004-2006)
Natrujee Wiwattanadittakul, MD (2016-present)

Revision History

• 28 April 2016 (ma) Comprehensive update posted live
• 19 September 2013 (me) Comprehensive update posted live
• 5 October 2010 (me) Comprehensive update posted live
• 25 July 2006 (me) Comprehensive update posted live
• 5 May 2004 (ca) Review posted live
• 16 September 2003 (pp) Original submission