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.
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GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
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.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of 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.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
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 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. MRI reveals T2 hyperintensities in multiple regions, involving the globus pallidi (43%), cerebellar dentate nucleus (17%), subcortical white matter (7%), and brain stem (7%), and other abnormalities. EEG findings include background slowing and spike discharges that are usually generalized. ALDH5A1 is the only gene currently known to be associated with SSADH deficiency. Sequence analysis detects 97% of disease-causing mutations. Such testing is clinically available.
Management. Management of SSADH deficiency 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 includes regular neurologic and developmental assessments as indicated. Valproate is usually contraindicated as it may inhibit residual SSADH enzyme activity.
Genetic counseling. SSADH deficiency is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele. Heterozygotes (carriers) are typically asymptomatic. 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. Carrier testing is available using molecular genetic testing on a clinical basis once the mutations have been identified in the proband. Biochemical testing is not accurate or reliable for carrier determination. Prenatal diagnosis for pregnancies at increased risk is possible using molecular genetic testing and biochemical testing (either measurement of 4-hydroxybutyric acid in amniotic fluid or assay of SSADH enzyme activity in chorionic villus tissue and cultured amniocytes).
Succinic semialdehyde dehydrogenase deficiency (SSADH deficiency) may be suspected in individuals with a late-infantile to early-childhood onset, slowly progressive or static encephalopathy characterized by the following:
Ataxia
Hypotonia
Speech disturbance
Seizures
Variable mental retardation
Neuroimaging. Neuroimaging reveals T2 hyperintensities in multiple regions, involving the globus pallidi (43%), cerebral dentate nucleus (17%), subcortical white matter (7%), and brain stem (7%) [Pearl, Capp et al 2005]. Other abnormalities include cerebral atrophy (10%), cerebellar atrophy (7%), and delayed myelination (7%). MRI was normal in 43% of affected individuals.
Standard clinical magnetic resonance spectroscopy (MRS) has been normal [Pearl, Novotny et al 2003].
MRS utilizing special editing for neurotransmitters reveals a pattern consistent with elevated GABA and GHB concentrations in brain gray and white matter [Ethofer et al 2004].
EEG findings. EEG findings include background slowing and spike discharges that are usually generalized [Pearl, Capp et al 2005]. 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.
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.
Figure 1 outlines the normal SSADH GABA degradative pathway.
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, Gibson 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 (nonketotic 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. See
.
SSADH enzyme activity is decreased in carriers but not reliable for carrier detection.
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.—ED.
Gene. ALDH5A1 is the only gene currently known to be associated with SSADH deficiency.
Molecular genetic testing: Clinical uses
Confirmation of diagnosis
Carrier detection
Molecular genetic testing: Clinical method
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; only three alleles were not identified.
Table 1 summarizes molecular genetic testing for this disorder.
| Test Methods | Mutations Detected | Mutation Detection Rate 1 | Test Availability |
|---|---|---|---|
| Sequence analysis | ALDH5A1 mutations | 97% | Clinical
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Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
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.
No other phenotypes are known to be associated with mutations in ALDH5A1.
SSADH deficiency is characterized by hypotonia, psychomotor retardation, ataxia, and seizures. The index case was described by Jakobs et al (1981). Involvement beyond the central nervous system has not been described. In a clinical review, Pearl, Novotny et al (2003) described 60 affected individuals, including 14 from their own cohort. The age of diagnosis ranges from newborn to 25 years [Pearl, Gibson et al 2003].
Problems in affected neonates include prematurity, lethargy, hypoglycemia, poor feeding, and respiratory distress.
SSADH deficiency is characterized by childhood-onset hypotonia with a developmental cognitive disorder affecting verbal IQ more than performance IQ.
Non-progressive ataxia and hyporeflexia occur in approximately half of individuals with SSADH deficiency.
Seizures are observed in over half of affected individuals.
Hyperkinetic behavior, aggression, self-injurious behaviors, hallucinations, and sleep disturbances are common in older individuals [Gibson et al 2003; Pearl, Novotny et al 2003]. Deep sleep attacks have been described in an affected young adult who had a normal polysomnogram (PSG); otherwise nonspecific sleep abnormalities on PSG have been described [Philippe et al 2004, Arnulf et al 2005].
Basal ganglia signs such as choreoathetosis, dystonia, and myoclonus have been reported in 10% of affected individuals. The clinical phenotype in these individuals appears more severe, with earlier onset and a progressive course [Pearl, Acosta et al 2005].
Prognosis for individuals with SSADH deficiency is difficult to assess. Resolution of cerebellar ataxia has been observed. Although affected individuals usually do not exhibit intermittent symptoms or decompensation, such episodes have been noted [Pearl, Gibson et al 2003]. On occasion, death occurs in the newborn period or during early childhood.
Approximately 400 individuals have been diagnosed with SSADH deficiency [Gibson & Jakobs 2001].
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, Gibson et al 2003].
Parental consanguinity has been reported in approximately 40% of all published cases [Gibson, Christensen et al 1997; Gibson, Doskey et al 1997; Al Essa et al 2000; Yalcinkaya et al 2000].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Other disorders of GABA metabolism:
Pyridoxine-dependent seizures. Pyridoxine-dependent seizures were historically attributed to impaired synthesis of GABA, although more recent studies indicate that GABA is sequestered as a result of aminoadipic semialdehyde dehydrogenase deficiency [Mills et al 2006]. The condition is characterized by intractable seizures that are not controlled with anticonvulsants but that respond both clinically and electrographically to large daily supplements of pyridoxine. Although dramatic presentations consisting of prolonged seizures and recurrent episodes of status epilepticus are typical, recurrent self-limited events including partial seizures, generalized seizures, atonic seizures, myoclonic events, and infantile spasms also occur. Intellectual disability is common. Inheritance is autosomal recessive.
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 GABA-T 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, but the enzyme defect has not been conclusively proven [Gibson & Jakobs 2001].
SSADH deficiency cannot easily be differentiated clinically from other disorders that cause mental retardation. 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, 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, Gibson et al 2003].
Neuroimaging (MRI)
EEG
Developmental evaluation
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, Hoffmann 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 [Gropman 2003]; Howells et al (1992) suggested 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. Vigabatrin is not FDA approved because of reports of visual loss attributable to retinal toxicity.
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].
Regular neurologic and developmental assessments are indicated.
Valproate is usually contraindicated as it may inhibit residual SSADH enzyme activity [Shinka et al 2003].
Current clinical trials are in place at the NIH using diagnostic modalities.
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].
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 and GABAB and GHB receptor inhibitors [Gupta et al 2004]. Human trials have not been completed.
Genetics clinics are a source of 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.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Succinic semialdehyde dehydrogenase deficiency is inherited in an autosomal recessive manner.
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 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.
Molecular genetic testing. Carrier testing is available using molecular genetic testing on a clinical basis once the mutations have been identified in the proband.
Biochemical testing. Carrier testing using biochemical testing is not accurate or reliable for carrier determination.
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.
DNA banking. 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. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.
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 about 15-18 weeks' gestation or through chorionic villus sampling (CVS) at about 10-12 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 utilizing 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, Akaboshi 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
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| ALDH5A1 | 6p22 | Succinate semialdehyde dehydrogenase |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| 271980 | SUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY |
| 610045 | ALDEHYDE DEHYDROGENASE 5 FAMILY, MEMBER A1; ALDH5A1 |
| Gene Symbol | Locus Specific | Entrez Gene | HGMD |
|---|---|---|---|
| ALDH5A1 | ALDH5A1 | 7915 (MIM No. 271980) | ALDH5A1 |
For a description of the genomic databases listed, click here.
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, Acosta et al 2005]. 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 GABAA 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 non-pathogenic allelic variants [Akaboshi et al 2003].
Pathologic allelic variants: Over 35 mutations have been identified including missense, nonsense, and splicing errors. No hotspots were detected [Akaboshi et al 2003]. Bekri et al (2004) report a new seven base pair 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 to be the neurotoxic agent most responsible for the clinical manifestations of the disease [Pearl, Acosta et al 2003].
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, to control cateplexy and alcohol-withdrawal syndromes, and as a recreationally abused drug.
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
Association for Neuro-Metabolic Disorders (ANMD)
PO Box 0202/L3220
1500 Medical Center Drive
Ann Arbor MI 48109-0202
Phone: 313-763-4697
Fax: 313-764-7502
Children Living with Inherited Metabolic Diseases (CLIMB)
Climb Building
176 Nantwich Road
Crewe CW2 6BG
United Kingdom
Phone: (+44) 0870 7700 326
Fax: (+44) 0870 7700 327
Email: steve@climb.org.uk
www.climb.org.uk
Pediatric Neurotransmitter Disease Association
Six Nathan Drive
Plainview NY 11803
Phone: 516-937-0049
Email: pnd@pndassoc.org
www.pndassoc.org
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
Supported in part by the NIH (NS 40270, NS 43137), Pediatric Neurotransmitter Diseases Association, March of Dimes National Birth Defects Foundation, and the Partnership for Pediatric Epilepsy Research, including the American Epilepsy Society, the Epilepsy Foundation, Anna and Jim Fantaci, Fight Against Childhood Epilepsy and Seizures (FACES), Neurotherapy Ventures Charitable Research Fund, and Parents Against Childhood Epilepsy (PACE).
Jessica L Cabalza (2006-present)
Philip K Capp; George Washington University (2003-2006)
Maciej Gasior, MD, PhD; National Institutes of Health (2003-2006)
K Michael Gibson, PhD, FACMG (2003-present)
Thomas R Hartka, MS (2006-present)
Phillip L Pearl, MD (2003-present)
Emily Robbins; George Washington University (2003-2006)
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
