Alternative titles; symbols
HGNC Approved Gene Symbol: ALDH5A1
SNOMEDCT: 49748000; ICD10CM: E72.81;
Cytogenetic location: 6p22.3 Genomic coordinates (GRCh38) : 6:24,494,969-24,537,207 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p22.3 | Succinic semialdehyde dehydrogenase deficiency | 271980 | Autosomal recessive | 3 |
Succinic semialdehyde dehydrogenase (SSADH; EC 1.2.1.24; succinate-semialdehyde:NAD(+)oxidoreductase) is involved in the catabolism of the neurotransmitter gamma-aminobutyric acid (GABA) (summary by Chambliss et al., 1995).
Chambliss et al. (1995) isolated SSADH cDNA clones from rat brain and human liver. The 2 proteins share 91% sequence identity. In both species, Northern blot analysis revealed 2 differentially expressed SSADH mRNA transcripts of approximately 2.0 and 6.0 kb. In the human, genomic Southern blots indicated that the 2 SSADH transcripts are encoded by a single-copy gene more than 20 kb long. The mammalian SSADH bears significant homology to bacterial NADP(+)-SSADH and conserved regions of aldehyde dehydrogenases, suggesting that it is a member of the aldehyde dehydrogenase superfamily of proteins.
Trettel et al. (1997) added further cDNA and protein data and determined the amino acid sequence of the mature SSADH polypeptide. Chambliss et al. (1998) reported that the full-length mature SSADH protein contains 488 amino acids.
The ALDH5A1 gene contains 10 exons (Chambliss et al., 1998).
Trettel et al. (1997) mapped the SSADH gene to chromosome 6p22 by somatic cell hybridization.
In 4 patients from 2 unrelated families with SSADH deficiency (SSADHD; 271980), Chambliss et al. (1998) identified homozygosity for 2 different splice site mutations in the ALDH5A1 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 that 8 different mutations had been described. They reported the mutational spectrum in 48 additional unrelated patients of different geographic origins. They detected 27 novel mutations at the cDNA level, of which 26 could be attributed to changes at the genomic level (see, e.g., 610045.0003-610045.0005). Twenty of the mutations were found in only 1 family. In all, 25 point mutations, 4 small insertions, and 5 small deletions had been described. Splice junctions were affected by 7 of the mutations, 7 were nonsense mutations, and 12 were missense mutations. Although there were no mutation hotspots or prevalent mutations responsible for a significant number of cases, 14 of 37 (38%) of the missense alleles were present in exon 4 or 5. 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 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) used an in vitro system to evaluate SSADH enzyme activity resulting from 34 missense mutations in the ALDH5A1 gene, 22 of which were novel. Through transient transfections of individual constructs containing the missense mutations in HEK293 cells, Pop et al. (2020) found that 27 of the mutations resulted in SSADH enzyme activity less than 15% of normal. In the remaining 7 ALDH5A1 gene mutations with higher enzyme activity, Pop et al. (2020) stably transfected mutant ALDH5A1 constructs into an SSADH-deficiency HEK293-Flp-In cell line, and found that 6 of the variants had reduced SSADH activity compared to the activity identified in the transient studies, one of which was reduced to 4% of normal. 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.
Hogema et al. (2001) developed Aldh5a1-deficient mice. At postnatal days 16 to 22, null mice displayed ataxia and developed generalized seizures leading to rapid death. They showed increased amounts of gamma-hydroxybutyric acid and total GABA in urine, brain, and liver homogenates, and significant gliosis was detected in the hippocampus of Aldh5a1 -/- mice. Intervention with phenobarbital or phenytoin was ineffective, whereas intervention with vigabatrin or with a GABA(B) receptor antagonist prevented tonic/clonic convulsions and significantly enhanced survival of mutant mice. Because neurologic deterioration coincided with weaning, they hypothesized the presence of a protective compound in breast milk. Indeed, treatment of mutant mice with the amino acid taurine rescued Aldh5a1 -/- mice. The findings provided insight into pathomechanisms and may have therapeutic relevance for human SSADH deficiency disease and 4-hydroxybutyric acid overdose and toxicity.
Aldh5a1-deficient mice demonstrate seizures that evolve from absence to myoclonic to full convulsive seizures and status epilepticus during the second to third postnatal weeks of life. Wu et al. (2006) found that the mutant mice had significantly decreased binding to GABA-A receptors that diminished progressively until the third postnatal week compared to wildtype mice. Immunohistochemistry showed a specific decreased expression of GABA-A receptor subunit B2 (GABRB2; 600232) in the mutant mice. In vitro electrophysiologic studies showed hippocampal hyperexcitability as well as a defect in GABA-A receptor-mediated postsynaptic inhibition. Wu et al. (2006) provided a unitary hypothesis to explain the age-dependent seizure transition in Aldh5a1-deficient mice: absence seizures that appear in the second week of life may result from increased brain levels of 4-hydroxybutyric acid, whereas generalized convulsive seizures and status epilepticus that appear during the third week may result from decreased GABA-A receptor-mediated inhibition induced by downregulation of GABA receptors secondary to increased levels of brain GABA.
Vernau et al. (2020) described clinical, molecular, and biochemical features of spontaneously occurring SSADH deficiency in 7 Saluki dogs. The pedigrees of the 7 affected 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 7 affected dogs and whole-genome sequencing in 3 affected dogs identified homozygosity for a c.866G-A transition (XM_014110559.2) 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 but normal urine gamma-hydroxybutyrate levels. Serum and CSF gamma-hydroxybutyrate levels were also elevated in affected dogs.
In a consanguineous family in which 2 sibs and their cousin had succinic semialdehyde dehydrogenase deficiency (SSADHD; 271980), Chambliss et al. (1998) demonstrated a homozygous G-to-T transversion in the ALDH5A1 gene at the first base of intron 9 in the splice-donor site. The mutation resulted in deletion of exon 9 and a frameshift after amino acid 401 followed by 52 nonsense residues before a stop codon was reached. The 2 sibs in this family exhibited hypotonia in addition to developmental and speech delays, hyporeflexia, and behavioral problems, including mild autism. The cousin was an unusual incidence of this disorder in an adult and was 23 years old at the time of examination.
In affected members of 5 unrelated families with SSADH deficiency, Akaboshi et al. (2003) identified homozygosity for the IVS9+1G-T splice site mutation.
In a patient with succinic semialdehyde dehydrogenase deficiency (SSADHD; 271980), Chambliss et al. (1998) identified a homozygous G-to-A transition in the ALDH5A1 gene at the first base of intron 5 in the splice-donor site. The deletion resulted in the skipping of exon 5 and an in-frame excision of 48 amino acid residues (196 to 242). Both parents were heterozygous for this base change. The patient was moderately affected, exhibiting developmental and speech delays, hyporeflexia, and behavioral problems, including mild autism.
In 8 unrelated families of European ancestry, Akaboshi et al. (2003) found that succinic semialdehyde dehydrogenase deficiency (SSADHD; 271980) was associated with a 612G-A transition in the ALDH5A1 gene, resulting in a trp204-to-ter (W204X) substitution. The mutation was found in homozygous or compound heterozygous state. Common ancestry suggested a founder effect for this mutation.
In a 9-year-old boy with SSADH deficiency, DiBacco et al. (2020) identified compound heterozygosity for 2 mutations in the ALDH5A1 gene: W204X and a c.321G-A transition resulting in a gly441-to-arg (G441R; 610045.0007) substitution. Overexpression studies of ALDH5A1 with the G441R mutation in HEK293 cells showed that the mutation resulted in normal gene and protein expression but absent enzyme function. This patient had a normal IQ, leading DiBacco et al. (2020) to hypothesize that the G441R mutation may result in a milder phenotype.
In 7 unrelated families from various geographic origins, Akaboshi et al. (2003) found that succinic semialdehyde dehydrogenase deficiency (SSADHD; 271980) was associated with a 1234C-T transition in the ALDH5A1 gene, resulting in an arg412-to-ter (R412X) substitution. The mutation occurred in homozygous or compound heterozygous state.
In 6 unrelated families, Akaboshi et al. (2003) found that succinic semialdehyde dehydrogenase deficiency (SSADHD; 271980) was associated with a 1226G-A transition in the ALDH5A1 gene, resulting in a gly409-to-asp (G409D) substitution. The mutation occurred in homozygous or compound heterozygous state.
In a female infant with succinic semialdehyde dehydrogenase deficiency (SSADHD; 271980), Blasi et al. (2006) identified a 159-bp deletion in the coding region of the ALDH5A1 gene, corresponding to in-frame skipping of exon 7. Further sequencing the patient's genomic DNA showed the first 0.7 kb of IVS6 followed by 0.8 kb of IVS7. The resulting protein is predicted to lack amino acids 292-344 of the mature protein. As there was no family history because the child was adopted, Blasi et al. (2006) suggested the mutation may be homozygous, although a large deletion involving the entire gene on 1 of the chromosomes could not be excluded.
For discussion of the c.321G-A transition (c.321G-A, NM_001080.3) in the ALDH5A1 gene, resulting in a gly441-to-arg (G441R) substitution, that was found in compound heterozygous state in a patient with succinic semialdehyde dehydrogenase deficiency (SSADHD; 271980) by DiBacco et al. (2020), see 610045.0003.
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., Caudle, D. L., Hinson, D. D., Moomaw, C. R., Slaughter, C. A., Jakobs, C., Gibson, K. M. Molecular cloning of the mature NAD(+)-dependent succinic semialdehyde dehydrogenase from rat and human: cDNA isolation, evolutionary homology, and tissue expression. J. Biol. Chem. 270: 461-467, 1995. [PubMed: 7814412] [Full Text: https://doi.org/10.1074/jbc.270.1.461]
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]
Hogema, B. M., Gupta, M., Senephansiri, H., Burlingame, T. G., Taylor, M., Jakobs, C., Schutgens, R. B. H., Froestl, W., Snead, O. C., Diaz-Arrastia, R., Bottiglieri, T., Grompe, M., Gibson, K. M. Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase. Nature Genet. 29: 212-216, 2001. [PubMed: 11544478] [Full Text: https://doi.org/10.1038/ng727]
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]
Trettel, F., Malaspina, P., Jodice, C., Novelletto, A., Slaughter, C. A., Caudle, D. L., Hinson, D. D., Chambliss, K. L., Gibson, K. M. Human succinic semialdehyde dehydrogenase: molecular cloning and chromosomal localization. Adv. Exp. Med. Biol. 414: 253-260, 1997. [PubMed: 9059628]
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]
Wu, Y., Buzzi, A., Frantseva, M., Velazquez, J. P. L., Cortez, M., Liu, C., Shen, L., Gibson, K. M., Snead, O. C., III. Status epilepticus in mice deficient for succinate semialdehyde dehydrogenase: GABA-A receptor-mediated mechanisms. Ann. Neurol. 59: 42-52, 2006. [PubMed: 16240371] [Full Text: https://doi.org/10.1002/ana.20686]