DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for glycine encephalopathy 1 — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleGlycine encephalopathy 1 maps to a 2-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 glycine encephalopathy 1 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
glycine decarboxylase (GLDC) — GLDC 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 plgdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6I35 · 2.0 Å · ligand N-GLYCINE-[3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YL-METHANE] (PLG). Experimental structure, not a prediction.
What the evidence adds up to
Glycine encephalopathy, also called nonketotic hyperglycinemia, is an autosomal recessive disorder caused by a defect in the glycine cleavage enzyme system, leading to glycine accumulation in body fluids. The classic neonatal form presents in the first days of life with hypotonia, lethargy, apnoea, and seizures, and usually results in death by one year of age. Two case reports from 2005 describe neonatal glycine encephalopathy accompanied by isolated pes equinovarus deformity. A 2013 report describes an unusual infantile-onset case presenting at eight weeks with symptoms suggestive of gastro-oesophageal reflux, after a normal neonatal developmental course; the authors state this is the first such presentation reported. A 2015 case report notes that a paradoxical increase in seizure frequency on starting sodium valproate led to the diagnosis of glycine encephalopathy.
In a 1982 paper, the authors state that the inherited defect in glycine cleavage enzyme has not responded to current innovative methods of therapy. They recommend future clinical evaluation of vitamin-responsiveness (pyridoxine, folate, lipoic acid), methionine, N5,N10-methylene tetrahydrofolate, and alpha-methylserine therapy during the critical period of neonatal brain growth and development. No clinical trial results for these agents are reported in the abstracts provided.
A 2012 review of glycine receptor mutants in mice discusses defects in glycinergic inhibition that result in hyperekplexia in humans and similar phenotypes in rodents. The review notes that mutations in the Glra1 or Glrb genes are much less tolerated in mice than in humans, and that presynaptic and postsynaptic compensatory mechanisms, including by GABA(A) receptors and extra-synaptic glycine receptors, remain a matter of debate. No therapeutic application to human glycine encephalopathy is established from this mouse work.
What is still missing: no controlled clinical trials of any therapy for glycine encephalopathy are reported in these abstracts. The 1982 recommendations for vitamin and metabolite therapies have not been followed by published efficacy data. No validated patient stratification or biomarker for treatment response exists. Funding for systematic clinical evaluation of these proposed interventions is 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.
Frontiers in Molecular Neuroscience · 2012 · 24 citations · open access
Glycine receptor mutants of the mouse: what are possible routes of inhibitory compensation?
AbstractDefects in glycinergic inhibition result in a complex neuromotor disorder in humans known as hyperekplexia (OMIM 149400) with similar phenotypes in rodents characterized by an exaggerated startle reflex and hypertonia. Analogous to genetic defects in humans single point mutations, microdeletions, or insertions in the Glra1 gene but also in the Glrb gene underlie the pathology in mice. The mutations either localized in the α (spasmodic, oscillator, cincinnati, Nmf11) or the β (spastic) subunit of the glycine receptor (GlyR) are much less tolerated in mice than in humans, leaving the question for the existence of different regulatory elements of the pathomechanisms in humans and rodents. In addition to the spontaneous mutations, new insights into understanding of the regulatory pathways in hyperekplexia or glycine encephalopathy arose from the constantly increasing number of knock-out as well as knock-in mutants of GlyRs. Over the last five years, various efforts using in vivo whole cell recordings provided a detailed analysis of the kinetic parameters underlying glycinergic dysfunction. Presynaptic compensation as well as postsynaptic compensatory mechanisms in these mice by other GlyR subunits or GABA(A) receptors, and the role of extra-synaptic GlyRs is still a matter of debate. A recent study on the mouse mutant oscillator displayed a novel aspect for compensation of functionality by complementation of receptor domains that fold independently. This review focuses on defects in glycinergic neurotransmission in mice discussed with the background of human hyperekplexia en route to strategies of compensation.
Journal of Pediatric Neurosciences · 2015 · 10 citations
A rare case of glycine encephalopathy unveiled by valproate therapy
AbstractGlycine encephalopathy (GE) or nonketotic hyperglycinemia is an autosomal recessive disorder due to a primary defect in glycine cleavage enzyme system. It is characterized by elevated levels of glycine in plasma and cerebrospinal fluid usually presenting with seizures, hypotonia, and developmental delay. In our case, paradoxical increase in seizure frequency on starting sodium valproate led us to diagnose GE.
Journal of Neurological Disorders · 2013 · 2 citations · open access
The Calm before the Storm”: Late Onset Glycine Encephalopathy Masquerading as Gastro-oesophageal Reflux
AbstractGlycine encephalopathy also known as ‘Nonketotic Hyperglycinemia (NKH)’ is an autosomal recessive disorder caused by a defect in the glycine cleavage enzyme complex (GCS). The classic neonatal form typically presents with generalised hypotonia, lethargy, seizures, apnoeas and usually death by one year of age. In this report, we describe an unusual presentation of an infantile onset glycine encephalopathy presenting at 8 weeks of age with symptoms suggestive of gastro-oesophageal reflux (GOR) episodes. A normal neonatal developmental course in the first few months of life is the exception in this phenotype and has been rarely described in the literature. To the best of our knowledge this is the first case of glycine encephalopathy reported with initial symptoms suggestive of GOR.
Two Cases of Glycine Encephalopathy Accompanied by Pes Equinovarus
AbstractGlycine encephalopathy is a rare autosomal recessive metabolic disease characterized by glycine accumulation in body fluids owing to a defect in the glycine cleavage system. There are several forms of glycine encephalopathy. In the classic or neonatal form, symptoms usually develop as neurologic symptoms in the first few days of life. It characteristically presents with hypotonia, lethargy, apnea, and seizures and usually results in death by 1 year of age. In this report, we present two cases of neonatal glycine encephalopathy accompanied by isolated pes equinovarus deformity.
Journal of Intellectual Disability Research · 1982 · 1 citations
A STRATEGY FOR GLYCINE ENCEPHALOPATHY THERAPY
AbstractAn inherited defect in the glycine cleavage enzyme results in the condition of neonatal glycine encephalopathy which has not responded to the current innovative methods of therapy. A re-examination of the enzyme structure and metabolic pathways, leads us to recommend future clinical evaluation of (1) vitamin-responsiveness, e.g., pyridoxine, folate and lipoic acid, (2) methionine, (3) N5, N10-methylene tetrahydrofolate and (4) alpha-methylserine therapy during the critical period of neonatal brain growth and development.
Two Cases of Glycine Encephalopathy Accompanied by Pes Equinovarus
AbstractGlycine encephalopathy is a rare autosomal recessive metabolic disease characterized by glycine accumulation in body fluids owing to a defect in the glycine cleavage system. There are several forms of glycine encephalopathy. In the classic or neonatal form, symptoms usually develop as neurologic symptoms in the first few days of life. It characteristically presents with hypotonia, lethargy, apnea, and seizures and usually results in death by 1 year of age. In this report, we present two cases of neonatal glycine encephalopathy accompanied by isolated pes equinovarus deformity. ( J Child Neurol 2005;20:533-535).
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.
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