Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive neurologic disorder in which an enzyme defect in the GABA degradation pathway causes a consecutive elevation of gamma-hydroxybutyric acid (GHB) and GABA. The clinical features include developmental delay, ... Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive neurologic disorder in which an enzyme defect in the GABA degradation pathway causes a consecutive elevation of gamma-hydroxybutyric acid (GHB) and GABA. The clinical features include developmental delay, hypotonia, mental retardation, ataxia, seizures, hyperkinetic behavior, aggression, and sleep disturbances (summary by Reis et al., 2012).
Pearl et al. (2003) noted that standard organic acid assays commonly miss increased urinary excretion of 4-hydroxybutyric acid because it is a highly volatile compound. The authors suggested that selective ion monitoring gas chromatography-mass spectrometry for specific compounds ... Pearl et al. (2003) noted that standard organic acid assays commonly miss increased urinary excretion of 4-hydroxybutyric acid because it is a highly volatile compound. The authors suggested that selective ion monitoring gas chromatography-mass spectrometry for specific compounds yields more accurate results. - Prenatal Diagnosis Jakobs et al. (1993) reported prenatal diagnosis of SSADH deficiency by metabolite measurement and enzyme analysis in amniotic fluid and cells.
Jakobs et al. (1981) reported a patient with neurologic abnormalities and urinary excretion of gamma-hydroxybutyric acid.
Gibson et al. (1983) demonstrated deficiency of the succinic semialdehyde dehydrogenase enzyme in lymphocyte lysates from 2 patients with gamma-hydroxybutyric ... Jakobs et al. (1981) reported a patient with neurologic abnormalities and urinary excretion of gamma-hydroxybutyric acid. Gibson et al. (1983) demonstrated deficiency of the succinic semialdehyde dehydrogenase enzyme in lymphocyte lysates from 2 patients with gamma-hydroxybutyric aciduria. Enzyme activity was 9 to 13% of control values. Gibson et al. (1984) demonstrated levels of SSADH enzyme activity consistent with heterozygosity in both parents of the first reported affected child (Jakobs et al., 1981), who was the offspring of consanguineous Turkish parents. Psychomotor development was mildly retarded but ataxia was severe. He also had marked hypotonia without weakness. Follow-up at age 5 showed no progression or improvement. Increased concentrations of gamma-aminobutyric acid (GABA) were found in the urine and CSF. Haan et al. (1985) described a 3-year-old boy, born of first-cousin Maltese parents, with SSADH deficiency. Delayed development was the main feature. He did not have ataxia, oculomotor apraxia, or seizures. Roesel et al. (1987) observed this disorder in a brother and sister who also showed increased glycine excretion. Gibson et al. (1997) described differing clinical presentation of SSADH deficiency in an adolescent brother and sister from Lifu Island, New Caledonia. The 2 affected sibs were from a sibship of 7 whose parents were first cousins. The 15-year-old male had global psychomotor and intellectual retardation, functioning at the developmental level of 4 years. His sight was said to be poor, and growth was subnormal. Genitalia were underdeveloped and there were no secondary sexual characteristics. The younger female sib was more severely affected. As in the case of her brother, her eyesight was thought to be poor. At age 11, she developed tonic/clonic seizures, which were only partially controlled by valproic acid. Treatment with vigabatrin aggravated the convulsive disorder. Gibson et al. (1997) reported 23 new patients with SSADH deficiency. The most frequent clinical features included developmental delay of motor, mental, and language skills, hypotonia, seizures, hyporeflexia, ataxia, behavioral problems, and EEG abnormalities. Less common features included abnormal eye movements and psychosis in older patients. Approximately 30% of patients had normal early development and there was wide variability in the severity of mental retardation. Chambliss et al. (1998) stated that SSADH deficiency had been identified in approximately 150 patients. Affected individuals accumulate large quantities of 2 neuroactive compounds in physiologic fluids: GABA and 4-hydroxybutyric acid (GHB). Gibson et al. (1998) provided a review of succinic semialdehyde dehydrogenase deficiency and contrasted the clinical and biochemical findings in patients with neuropharmacologic data on 4-hydroxybutyric acid accumulation in animals and humans. Pearl et al. (2003) stated that SSADH deficiency had been diagnosed in approximately 350 patients. They reported 11 additional patients and reviewed the clinical features of 51 previously reported patients. Age at diagnosis ranged from 1 to 21 years. The main clinical features included mild to moderate mental retardation, disproportionate language dysfunction, hypotonia, hyporeflexia, autistic behaviors, seizures, and hallucinations. Brain MRI of 5 patients showed symmetric increased T2 signal in the globus pallidi. Pearl et al. (2003) noted that GHB has neuroactive properties and has been used to manage cataplexy and alcohol- and opiate-withdrawal syndromes. Blasi et al. (2006) reported a female infant with SSADH deficiency confirmed by genetic analysis (see 610045.0006). She presented at age 9 months with psychomotor delay, strabismus, and generalized hypotonia. Biochemical studies showed severely decreased SSADH enzyme activity. Leuzzi et al. (2007) reported 2 Italian sibs with SSADH deficiency who developed paroxysmal exercise-induced dystonia at age 16 and 12 years, respectively. Their prior phenotypes were classic for SSADH deficiency. Treatment with vigabatrin improved the paroxysmal dystonia in both patients and also improved gait clumsiness and seizures in 1 patient. O'Rourke et al. (2010) reported a 9-month-old boy with mild global delay who presented with 'yes-yes' head bobbing. Brain imaging showed abnormal signal hyperintensities in the globus pallidus and white matter on T2-weighted MRI, and brain magnetic resonance spectroscopy (MRS) showed high lactate, consistent with SSADH deficiency. The authors suggested that increased gamma-hydroxybutyrate may affect diencephalic extrapyramidal pathways, resulting in abnormal movement.
In 4 patients from 2 unrelated families with SSADH deficiency, Chambliss et al. (1998) identified homozygosity for 2 different splice site mutations in the ALD5A1 gene (610045.0001; 610045.0002). Unaffected parents and sibs were heterozygous for the mutations. ... In 4 patients from 2 unrelated families with SSADH deficiency, Chambliss et al. (1998) identified homozygosity for 2 different splice site mutations in the ALD5A1 gene (610045.0001; 610045.0002). Unaffected parents and sibs were heterozygous for the mutations. Akaboshi et al. (2003) stated that the underlying mutation in SSADH deficiency had been reported in patients from 6 families worldwide and 8 different mutations were described. They reported the mutational spectrum in 48 additional unrelated patients of different geographic origin. They detected 27 novel mutations in the ALDH5A1 gene (see, e.g., 610045.0003-610045.0005). Almost all the missense mutations reduced the SSADH activity to less than 5% of the normal activity in an in vitro expression system. The findings suggested that residual protein expression is not likely to be an important factor contributing to the very large phenotypic differences observed among different families and even among sibs, suggesting that other modifying factors are of great importance in disease pathology.
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:...
Diagnosis
Clinical DiagnosisSuccinic 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 deficiencyProminent expressive language deficitHypotonia Epilepsy HyporeflexiaAtaxiaNeuroimaging. 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]. TestingThe 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. FigureFigure 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 activitySuccinic 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 TestingGene. 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 DeficiencyView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityALDH5A1Sequence analysis
Sequence variants 297% 3Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in ALDH5A1.
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....
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].
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].
To establish the extent of disease in an individual diagnosed with succinic semialdehyde dehydrogenase (SSADH) deficiency, the following evaluations are recommended:...
Management
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 ManifestationsThe 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 ComplicationsAntiepileptic medications are indicated for patients who have active seizures.SurveillanceRegular neurologic and developmental assessments are indicated.Agents/Circumstances to AvoidValproate is usually contraindicated as it may inhibit residual SSADH enzyme activity [Shinka et al 2003].Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationBiomarkers 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.OtherAnimal 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]. 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].
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDALDH5A16p22.3
Succinate-semialdehyde dehydrogenase, mitochondrialAldehyde Dehydrogenase Gene Superfamily Resource ALDH5A1 @ LOVDALDH5A1Data 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) View in own window 271980SUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY; SSADHD 610045ALDEHYDE DEHYDROGENASE 5 FAMILY, MEMBER A1; ALDH5A1Molecular Genetic PathogenesisAnimal 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 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. ALDH5A1 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.