Alternative titles; symbols
SNOMEDCT: 49748000; ICD10CM: E72.81; ORPHA: 22; DO: 0060175;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p22.3 | Succinic semialdehyde dehydrogenase deficiency | 271980 | Autosomal recessive | 3 | ALDH5A1 | 610045 |
A number sign (#) is used with this entry because of evidence that succinic semialdehyde dehydrogenase deficiency (SSADHD) is caused by homozygous or compound heterozygous mutation in the ALDH5A1 gene (610045) on chromosome 6p22.
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).
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 pallidus. 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.
DiBacco et al. (2020) described 24 patients from 22 unrelated families with SSADH deficiency. Seven of the patients (5 of whom were older than 12 years of age) had seizures, 23 had impaired intellectual development, 24 had fine motor delay and gross motor and speech delay, 16 had sleep disturbances, and 24 had hypotonia. Correlation between clinical features and age showed increased presence and severity of epilepsy and obsessive-compulsive disorder with increasing age. Neuropsychologic testing in 21 of the patients revealed a median IQ of 53. Autism Diagnostic Observation Scale (ADOS) evaluations in 18 patients showed that 6 patients had scores consistent with autism, 4 had scores consistent with autism spectrum, and 8 were not on the autism spectrum. The only patient with a maximum clinical severity score was an 8-year-old girl who presented with neonatal hypotonia, followed by infantile spasms, hypsarrhythmia on EEG, and, at 14 months of age, status epilepticus with developmental regression.
Using transcranial magnetic stimulation (TMS), Reis et al. (2012) found that patients with SSADH deficiency had GABA-B (see 603540)-ergic cortical motor dysfunction as evidenced by reduced long interval intracortical inhibition and shortened cortical silent period compared to heterozygous parents and controls. This suggested reduced GABAergic inhibition in SSADH-deficient patients. The phenotype was consistent with use-dependent downregulation of postsynaptic GABA-B receptors resulting from chronically elevated GABA and GHB. The results also suggested that patients with SSADH deficiency may have reduced secretion of GABA intro the synaptic cleft by presynaptic GABA-B receptors. These neurotransmitter changes may be responsible for some of the clinical features of the disorder.
Parental consanguinity and intermediate levels of SSADH enzyme in parents of affected children support autosomal recessive inheritance (Gibson et al., 1984).
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.
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.
Pop et al. (2020) reported in vitro SSADH enzyme activity resulting from 34 missense mutations in the ALDH5A1 gene, including 22 novel mutations in 24 patients. Twenty-eight of the 34 missense mutations resulted in SSADH enzyme activity to less than 15% of normal activity. Of the remaining 7 mutations, SSADH enzyme activity was more mildly reduced compared to normal activity in 6 and was normal in 1. Pop et al. (2020) found that the enzymatic activity and in silico prediction tools were in agreement with the majority of the mutations resulting in low SSADH enzyme activity.
Among 24 patients from 22 unrelated families with SSADH deficiency, DiBacco et al. (2020) found that 21 patients were compound heterozygous and 3 patients were homozygous for mutations in the ALDH5A1 gene. Twenty-three disease-causing mutations were identified, 7 of which were novel (2 missense mutations (see, e.g., G441R, 610045.0007), 3 splice site mutations, and 2 frameshift mutations). Overexpression studies of ALDH5A1 with the 2 novel missense mutations (G441R and A139D) in HEK293 cells showed that each mutation resulted in normal gene and protein expression but absent enzyme function.
Vernau et al. (2020) described clinical, molecular, and biochemical features of spontaneously occurring SSADH deficiency in 7 Saluki dogs. The pedigrees of the 7 dogs could be traced to a single common ancestor. Clinical symptoms began at 6 to 10 weeks of age and included ataxia, bilateral absent menace response, and delayed proprioceptive limb positioning. Later symptoms included seizures and spontaneous vocalizations. Brain MRIs of 2 affected dogs demonstrated prominent sulci, which was consistent with diffuse cortical atrophy, and bilateral signal abnormalities in the diencephalon, deep cerebellar nuclei, midbrain, and multiple basal nuclei. Histopathology of brain tissue showed symmetric spongiform changes and proliferation of enlarged astrocytes. Genomewide association studies in all 7 affected dogs and whole-genome sequencing in 3 affected dogs identified homozygosity for a c.866G-A transition in the ALDH5A1 gene, resulting in a gly288-to-asp substitution. SSADH enzyme activity in brain tissue was reduced in the affected dogs compared to control dogs. Biochemical studies in affected dogs showed elevated urine succinic semialdehyde levels but normal urine gamma-hydroxybutyrate levels. Serum and CSF gamma-hydroxybutyrate levels were also elevated in affected dogs.
Akaboshi, S., Hogema, B. M., Novelletto, A., Malaspina, P., Salomons, G. S., Maropoulos, G. D., Jakobs, C., Grompe, M., Gibson, K. M. 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. 22: 442-450, 2003. [PubMed: 14635103] [Full Text: https://doi.org/10.1002/humu.10288]
Blasi, P., Palmerio, F., Caldarola, S., Rizzo, C., Carrozzo, R., Gibson, K. M., Novelletto, A., Deodato, F., Cappa, M., Dionisi-Vici, C., Malaspina, P. Succinic semialdehyde dehydrogenase deficiency: clinical, biochemical and molecular characterization of a new patient with severe phenotype and a novel mutation. (Letter) Clin. Genet. 69: 294-296, 2006. [PubMed: 16542398] [Full Text: https://doi.org/10.1111/j.1399-0004.2006.00579.x]
Chambliss, K. L., Hinson, D. D., Trettel, F., Malaspina, P., Novelletto, A., Jakobs, C., Gibson, K. M. Two exon-skipping mutations as the molecular basis of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria). Am. J. Hum. Genet. 63: 399-408, 1998. [PubMed: 9683595] [Full Text: https://doi.org/10.1086/301964]
DiBacco, M. L., Pop, A., Salomons, G. S., Hanson, E., Roullet, J.-B., Gibson, K. M., Pearl, P. L. Novel ALDH5A1 variants and genotype: phenotype correlation in SSADH deficiency. Neurology 95: e2675-e2682, 2020. Note: Electronic Article. [PubMed: 32887777] [Full Text: https://doi.org/10.1212/WNL.0000000000010730]
Divry, P., Baltassat, P., Rolland, M. O., Cotte, J., Hermier, M., Duran, M., Wadman, S. K. A new patient with 4-hydroxybutyric aciduria, a possible defect of 4-aminobutyrate metabolism. Clin. Chim. Acta 129: 303-309, 1983. [PubMed: 6133657] [Full Text: https://doi.org/10.1016/0009-8981(83)90033-5]
Gibson, K. M., Christensen, E., Jakobs, C., Fowler, B., Clarke, M. A., Hammersen, G., Raab, K., Kobori, J., Moosa, A., Vollmer, B., Rossier, E., Iafolla, A. K., and 14 others. The clinical phenotype of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria): case reports of 23 new patients. Pediatrics 99: 567-574, 1997. [PubMed: 9093300] [Full Text: https://doi.org/10.1542/peds.99.4.567]
Gibson, K. M., Doskey, A. E., 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. 20: 370-374, 1997. [PubMed: 9266358] [Full Text: https://doi.org/10.1023/a:1005334129412]
Gibson, K. M., Hoffmann, G. F., Hodson, A. K., Bottiglieri, T., Jakobs, C. 4-Hydroxybutyric acid and the clinical phenotype of succinic semialdehyde dehydrogenase deficiency, an inborn error of GABA metabolism. Neuropediatrics 29: 14-22, 1998. [PubMed: 9553943] [Full Text: https://doi.org/10.1055/s-2007-973527]
Gibson, K. M., Sweetman, L., Nyhan, W. L., Jakobs, C., Rating, D., Siemes, H., Hanefeld, F. Succinic semialdehyde dehydrogenase deficiency: an inborn error of gamma-aminobutyric acid metabolism. Clin. Chim. Acta 133: 33-42, 1983. [PubMed: 6627675] [Full Text: https://doi.org/10.1016/0009-8981(83)90018-9]
Gibson, K. M., Sweetman, L., Nyhan, W. L., Lenoir, G., Divry, P. Defective succinic semialdehyde dehydrogenase activity in 4-hydroxybutyric aciduria. Europ. J. Pediat. 142: 257-259, 1984. [PubMed: 6489377] [Full Text: https://doi.org/10.1007/BF00540247]
Gibson, K. M., Sweetman, L., Nyhan, W. L., Rating, D. Succinic semialdehyde dehydrogenase deficiency. J. Neurogenet. 1: 213-218, 1984. [PubMed: 6536727] [Full Text: https://doi.org/10.3109/01677068409107087]
Haan, E. A., Brown, G. K., Mitchell, D., Danks, D. M. Succinic semialdehyde dehydrogenase deficiency--a further case. J. Inherit. Metab. Dis. 8: 99 only, 1985. [PubMed: 2433500] [Full Text: https://doi.org/10.1007/BF01819287]
Jakobs, C., Bojasch, M., Monch, E., Rating, D., Siemes, H., Hanefeld, F. Urinary excretion of gamma-hydroxybutyric acid in a patient with neurological abnormalities: the probability of a new inborn error of metabolism. Clin. Chim. Acta 111: 169-178, 1981. [PubMed: 7226548] [Full Text: https://doi.org/10.1016/0009-8981(81)90184-4]
Jakobs, C., Ogier, H., Rabier, D., Gibson, K. M. Prenatal detection of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria). (Letter) Prenatal Diag. 13: 150 only, 1993. [PubMed: 8464836] [Full Text: https://doi.org/10.1002/pd.1970130213]
Leuzzi, V., Di Sabato, M. L., Deodato, F., Rizzo, C., Boenzi, S., Carducci, C., Malaspina, P., Liberanome, C., Dionisi-Vici, C. Vigabatrin improves paroxysmal dystonia in succinic semialdehyde dehydrogenase deficiency. Neurology 68: 1320-1321, 2007. [PubMed: 17438226] [Full Text: https://doi.org/10.1212/01.wnl.0000259537.54082.6d]
O'Rourke, D. J., Ryan, S., King, M. D. Head bobbing due to succinic semialdehyde dehydrogenase deficiency. Neurology 74: 2025 only, 2010. [PubMed: 20548048] [Full Text: https://doi.org/10.1212/WNL.0b013e3181e398cf]
Pearl, P. L., Gibson, K. M., Acosta, M. T., Vezina, L. G., Theodore, W. H., Rogawski, M. A., Novotny, E. J., Gropman, A., Conry, J. A., Berry, G. T., Tuchman, M. Clinical spectrum of succinic semialdehyde dehydrogenase deficiency. Neurology 60: 1413-1417, 2003. [PubMed: 12743223] [Full Text: https://doi.org/10.1212/01.wnl.0000059549.70717.80]
Pop, A., Smith, D. E. C., Kirby, T., Walters, D., Gibson, K. M., Mahmoudi, S., van Dooren, S. J. M., Kanhai, W. A., Fernandez-Ojeda, M. R., Wever, E. J. M., Koster, J., Waterham, H. R., Grob, B., Roos, B., Wamelink, M. M. C., Chen, J., Natesan, S., Salomons, G. S. Functional analysis of thirty-four suspected pathogenic missense variants in ALDH5A1 gene associated with succinic semialdehyde dehydrogenase deficiency. Molec. Genet. Metab. 130: 172-178, 2020. [PubMed: 32402538] [Full Text: https://doi.org/10.1016/j.ymgme.2020.04.004]
Rating, D., Siemes, H., Hanefeld, F., Kneer, J., Jakobs, C., Gibson, K. M., Sweetman, L., Nyhan, W. L. An inborn error of GABA-metabolism in atactic syndromes. (Abstract) Europ. J. Pediat. 139: 317 only, 1982.
Reis, J., Cohen, L. G., Pearl, P. L., Fritsch, B., Jung, N. H., Dustin, I., Theodore, W. H. GABA-B-ergic motor cortex dysfunction in SSADH deficiency. Neurology 79: 47-54, 2012. [PubMed: 22722631] [Full Text: https://doi.org/10.1212/WNL.0b013e31825dcf71]
Roesel, R. A., Hartlage, P. L., Carroll, J. E., Hommes, F. A., Blankenship, P. R., Gibson, K. M. 4-Hydroxybutyric aciduria and glycinuria in two siblings. (Abstract) Am. J. Hum. Genet. 41: A16 only, 1987.
Vernau, K. M., Struys, E., Letko, A., Woolard, K. D., Aguilar, M., Brown, E. A., Cissell, D. D., Dickinson, P. J., Shelton, G. D., Broome, M. R., Gibson, K. M., Pearl, P. L., and 10 others. A missense variant in ALDH5A1 associated with canine succinic semialdehyde dehydrogenase deficiency (SSADHD) in the Saluki dog. Genes (Basel) 11: 1033, 2020. [PubMed: 32887425] [Full Text: https://doi.org/10.3390/genes11091033]