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 patients 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].

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. Figure 1 outlines the normal SSADH GABA degradative pathway.

Figure

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). Such testing is clinically available.

• SSADH enzyme activity is decreased in carriers but not reliable for carrier detection.

Molecular Genetic Testing

Gene. ALDH5A1 is the only gene currently known to be associated with SSADH deficiency.

Clinical testing

• Sequence analysis. Using sequence analysis of genomic DNA and/or cDNA in 54 families not known to be related, Akaboshi et al [2003] detected 97% of mutations.

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

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
ALDH5A1	Sequence analysis	Sequence variants 2	97% 3	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Akaboshi et al [2003]

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

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.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in ALDH5A1.

Natural History

SSADH deficiency is characterized by a relatively nonprogressive 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 and 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 2008].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been observed.

Prevalence

Approximately 450 individuals have been diagnosed with SSADH deficiency [Gibson & Jakobs 2001; KM Gibson & C 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].

Evaluations Following Initial Diagnosis

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

• Neuroimaging (MRI)

• EEG

• Developmental evaluation

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. 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].

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.

Surveillance

Regular neurologic and developmental assessments are indicated.

Agents/Circumstances to Avoid

Valproate is usually contraindicated as it may inhibit residual SSADH enzyme activity [Shinka et al 2003].

Testing 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].

Search ClinicalTrials.gov 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]. It has been questioned as to how this could be transferred into a human trial due to improved nutritional status of the diet-fed mice versus chow-fed mice and possible elevated levels of 4-hydroxybutyric acid caused by the diet [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].

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 the ALDH5A1 gene.

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 affected, 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. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or through chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

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 available for families in which the disease-causing mutations have been identified in an affected family member. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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 approximately 10% of affected individuals, are related to chronically elevated endogenous GHB levels is uncertain.

The mouse model demonstrates downregulation and decreased function of the GABA_A receptor, postulating an important role for GABA in the pathophysiology of at least the epileptic manifestations of SSADH deficiency [Wu et al 2006].

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.

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].

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

1. 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]
2. 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]
3. 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]
4. 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]
5. 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]
6. 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]
7. 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]
8. 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: McGraw-Hill; 2001:2079-105.
9. 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. et al. The clinical phenotype of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria): case reports of 23 new patients. Pediatrics. 1997a;99:567–74. [PubMed: 9093300]
10. 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]
11. 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]
12. 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]
13. Gropman A. Vigabatrin and newer interventions in succinic semialdehyde dehydrogenase deficiency. Ann Neurol. 2003;54 Suppl 6:S66–72. [PubMed: 12891656]
14. 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]
15. 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]
16. 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]
17. Howells D, Jakobs C, Kok RM, Wrennall J, Thompson GN. Vigabatrin therapy in succinic semialdehyde dehydrogenase deficiency. Mol Neuropharmacol. 1992;2:181–4.
18. Knerr I, Gibson KM, Murdoch G, Salomons GS, Pope L, Jakobs C, Catanese GA, Pearl PL. Neuropathology of SSADH deficiency. J Inherit Metab Dis 31(Suppl 1): 26Knerr I, Gibson KM, Jakobs C, and Pearl PL (2008) Neuropsychiatric morbidity in adolescent and adult succinic semialdehyde dehydrogenase deficiency patients. CNS Spectr. 2008;13:598–605. [PMC free article: PMC2562649] [PubMed: 18622364]
19. Knerr I, Pearl PL. Ketogenic diet: stoking energy stores and still posing questions. Exp Neurol. 2008;211(1):11–3. [PubMed: 18374334]
20. 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]
21. 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]
22. 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]
23. 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: Fernandez-Alvarez E, Arzimanoglou A, Tolosa E, eds. Paediatric Movement Disorders. Montrouge, France: John Libbey Eurotext; 2005a.
24. Pearl PL, Capp PK, Novotny EJ, Gibson KM. Inherited disorders of neurotransmitters in children and adults. Clin Biochem. 2005b;38:1051–8. [PubMed: 16298354]
25. Pearl PL, Gibson KM. Clinical aspects of the disorders of GABA metabolism in children. Curr Opin Neurol. 2004;17:107–13. [PubMed: 15021235]
26. 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]
27. 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]
28. Pearl PL, Gropman A. Monitoring gamma-hydroxybutyric acid levels in succinate-semialdehyde dehydrogenase deficiency. Ann Neurol. 2004;55:599. [PubMed: 15048909]
29. 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]
30. Pearl PL, Taylor JL, Trzcinski S. et al. 11C-Flumazenil PET imaging in patients with SSADH deficiency. J Inherit Metab Dis. 2007;30 Suppl 1:43.
31. 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]
32. 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]
33. 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.
34. 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]
35. 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]
36. 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]
37. 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]

Author History

Jessica L Cabalza, George Washington University (2006-2010)
Philip K Capp; George Washington University (2003-2006)
Ian Drillings (2010-present)
Maciej Gasior, MD, PhD; National Institutes of Health (2003-2006)
K Michael Gibson, PhD, FACMG (2003-present)
Thomas R Hartka, MS; George Washington University (2006-2010)
Phillip L Pearl, MD (2003-present)
Tom Reehal (2010-present)
Emily Robbins; George Washington University (2003-2006)

Acknowledgments

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

• 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