DeCure for Succinic semialdehyde dehydrogenase deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for succinic semialdehyde dehydrogenase deficiency — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleSuccinic semialdehyde dehydrogenase deficiency maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for succinic semialdehyde dehydrogenase deficiency is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
aldehyde dehydrogenase 5 family member A1 (ALDH5A1) — ALDH5A1 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet sindrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2W8Q · 2.4 Å · ligand SUCCINIC ACID (SIN). Experimental structure, not a prediction.
What the evidence adds up to
Succinic semialdehyde dehydrogenase deficiency is a rare monogenic disorder caused by pathogenic variants in the ALDH5A1 gene. The resulting enzymatic dysfunction leads to accumulation of the metabolites γ-hydroxybutyrate (GHB) and 4-hydroxybutyric acid (4-HBA). A 2020 study identified a novel missense variant, c.728T>C, which replaces leucine with proline at residue 243 within the NAD+ binding domain. The proline side chain is conformationally rigid and disrupts protein secondary structures. The patient carrying this variant had a severe phenotype. The same study also examined all previously described disease-causing variants and computationally assessed all biologically possible missense variants of ALDH5A1 to identify mutational hotspots. No treatment or outcome data were reported.
A 2004 case report describes a boy with an unresolved severe neurological disorder who had intermittent elevation of 4-HBA in serum and cerebrospinal fluid. This elevation was later shown to result from iatrogenic administration of 4-HBA for sedation, not from SSADH deficiency. The report serves as a caution that exogenous GHB can mimic the biochemical hallmark of the disease.
A 2015 review notes that SSADH deficiency is a relatively recently described autosomal recessive organic aciduria. The presence of γ-hydroxybutyric acid in urine is suggestive, and diagnosis is confirmed by enzyme activity measurement or ALDH5A1 gene sequencing. The review does not report any clinical trial results or treatment outcomes. No drug therapy is evaluated in any of these abstracts.
What is still missing: no clinical trial has tested a drug for SSADH deficiency in a controlled setting. There is no randomised evidence for any intervention. Patient registries and natural history studies are needed to stratify patients by genotype and phenotype before any therapy can be properly evaluated. Funding for such trials and for the development of outcome measures remains absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Neurogenetics · 1984 · 45 citations
Succinic Semialdehyde Dehydrogenase Deficiency
AbstractA coupled assay using [14C]4-aminobutyric acid and a direct assay using [14C]succinic semialdehyde have been designed to assay te activity of succinic semialdehyde dehydrogenase in a patient with 4-hydroxybutyric aciduria and family members. In the coupled assay less than 3% of control succinic semialdehyde dehydrogenase activity was found in lysates of lymphocytes isolated from whole blood of the patient. In the direct assay there was no detectable activity of the enzyme in lysates of isolated lymphocytes or cultured lymphoblasts. Results indicated the parents to be heterozygous carriers carriers of the abnormal gene, consistent with an autosomal recessive inheritance.
International Journal of Molecular Sciences · 2020 · 11 citations · open access
Succinic Semialdehyde Dehydrogenase Deficiency: In Vitro and In Silico Characterization of a Novel Pathogenic Missense Variant and Analysis of the Mutational Spectrum of ALDH5A1
AbstractSuccinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare, monogenic disorder affecting the degradation of the main inhibitory neurotransmitter γ-amino butyric acid (GABA). Pathogenic variants in the ALDH5A1 gene that cause an enzymatic dysfunction of succinic semialdehyde dehydrogenase (SSADH) lead to an accumulation of potentially toxic metabolites, including γ-hydroxybutyrate (GHB). Here, we present a patient with a severe phenotype of SSADHD caused by a novel genetic variant c.728T > C that leads to an exchange of leucine to proline at residue 243, located within the highly conserved nicotinamide adenine dinucleotide (NAD)+ binding domain of SSADH. Proline harbors a pyrrolidine within its side chain known for its conformational rigidity and disruption of protein secondary structures. We investigate the effect of this novel variant in vivo, in vitro, and in silico. We furthermore examine the mutational spectrum of all previously described disease-causing variants and computationally assess all biologically possible missense variants of ALDH5A1 to identify mutational hotspots.
Journal of Inherited Metabolic Disease · 2004 · 9 citations · open access
Sedation with 4‐hydroxybutyric acid: A potential pitfall in the diagnosis of SSADH deficiency
AbstractDeficiency of succinic semialdehyde dehydrogenase (SSADH) is a rare neurometabolic disorder with accumulation of 4-hydroxybutyric acid (4-HBA) as a biochemical hallmark. We present a boy with an unresolved severe neurological disorder and intermittent elevation of 4-HBA in serum and CSF which was later shown to result from iatrogenic administration of 4-HBA for sedation purposes.
AbstractIn rare diseases, the advent of potential therapies spurs early diagnosis, natural history studies, and the creation of patient registries. Succinic semialdehyde dehydrogenase (SSADH) deficiency is a relatively recently described autosomal recessive organic aciduria that is due to an inborn error of the second and final step of γ-aminobutyric acid metabolism.1 The presence of γ-hydroxybutyric acid in the urine is suggestive of a diagnosis of SSADH deficiency, which may then be confirmed either by direct measurement of the activity of the enzyme or by sequencing of the ALDH5A1 gene.2,3
Research Square · 2023 · 1 citations · open access
Clinical features and ALDH5A1 gene findings in 13 Chinese cases with succinic semialdehyde dehydrogenase deficiency
Abstract<title>Abstract</title> <bold>Background and aims:</bold> To investigate the clinical features, <italic>ALDH5A1</italic>gene variations, treatment, and prognosis of patients with succinic semialdehyde dehydrogenase (SSADH) deficiency. <bold>Materials and</bold> <bold>methods:</bold> This retrospective study evaluated the findings in 13 Chinese patients with SSADH deficiency admitted to the Pediatric Department of Peking University First Hospital from September 2013 to September 2023. <bold>Results:</bold> 13 patients (seven male and six female patients; two sibling sisters) were diagnosed as SSADH deficiency aged from 4 months to 15 years. Their urine 4-hydroxybutyrate acid levels were elevated and were accompanied by mildly increased serum lactate levels. Brain MRI showed symmetric abnormal signals in both sides of the globus pallidus and other areas. All 13 patients had psychomotor retardation, with seven showing epileptic seizures. Among the 18 variants of the <italic>ALDH5A1</italic> gene identified in these 13 patients, six were previously reported, while 12 were novel variants. Among 12 novel variants, three (c.85_116del, c.206_222dup, c.762C>G) were pathogenic variants; four (c.427delA, c.515G>A, c.755G>T, c.1274T>C) were likely pathogenic; and the remaining five (c.454G>C, c.479C>T, c.637C>T, c.1480G>A, c.1501G>C) were variants of uncertain significance (VUS). The patients received drugs such as L-carnitine, vigabatrin and taurine, along with symptomatic treatment. Their urine 4-hydroxybutyric acid levels showed variable degrees of reduction. <bold>Conclusions:</bold> A cohort of 13 cases with early-onset SSADH deficiency were analyzed. Onset of symptoms occurred from 1 month to 1 year of age. 12 novel variants were identified from ALDH5A1 Gene.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
