DeCure for Congenital brain dysgenesis due to glutamine synthetase deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for congenital brain dysgenesis due to glutamine synthetase 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 moduleCongenital brain dysgenesis due to glutamine synthetase 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
approvedL-GlutamineApproved drug
Structures already discussed alongside congenital brain dysgenesis due to glutamine synthetase deficiency in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
glutamate-ammonia ligase (GLUL) — GLUL is one of the genes in this disease's Open Targets module — part of the target space DeCure's repurposing candidates point at. The protein backbone is drawn as a cartoon. The structure has adenosine-5'-diphosphate bound in it, shown as sticks.
Loading structure…
helix sheet adpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9NM5 · 1.85 Å · ligand ADENOSINE-5'-DIPHOSPHATE (ADP). Experimental structure, not a prediction.
What the evidence adds up to
Only three unrelated patients with congenital glutamine synthetase deficiency had been reported by 2016, all with neonatal onset severe epileptic encephalopathy, decreased glutamine in body fluids, and chronic hyperammonemia. A 2018 paper added a fourth patient, a 30-month-old girl with developmental delay, seizures beginning at 5 months, microcephaly, hypotonia, near-normal plasma glutamine, and mild hyperammonemia; cranial MRI showed mild changes. She was seizure-free for 5 months on valproic acid and vigabatrin. Whole exome sequencing found a homozygous c.121C>T (p.R41C) pathogenic variant in GLUL. Treatment with L-glutamine and nicotinamide was begun, and biochemical improvements were observed at 6 months of follow-up.
A separate 2018 study identified loss-of-function mutations in GLS, the gene encoding glutaminase, in four infants from two unrelated families. All four died less than 40 days after birth with therapy-refractory early neonatal seizures, status epilepticus, suppression bursts, respiratory insufficiency, simplified gyral structures, diffuse brain volume loss, and cerebral edema. Glutamine was increased in affected children (z scores 3.2 and 11.7). The authors theorised that reduced glutamate and excess glutamine caused the central nervous system abnormalities. This disorder is distinct from glutamine synthetase deficiency.
Two mutations of human glutamine synthetase (R324C and R341C) were linked to congenital glutamine deficiency with severe brain malformations resulting in neonatal death; a third mutation (R324S) was identified in a single neurologically compromised patient. As of 2015, the underlying molecular mechanisms of GS deactivation by these mutations had not been understood. The 2016 review argued the disorder is possibly underdiagnosed because decreased metabolite concentrations receive insufficient attention, and that early detection might improve outcome if patients could be treated early with missing metabolites. What remains missing is systematic newborn screening for low glutamine, prospective data on L-glutamine and nicotinamide treatment beyond a single patient with six months of follow-up, and any trial design that could distinguish treatment effect from natural history in an ultra-rare disease where patient numbers are in the single digits.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
New England Journal of Medicine · 2005 · 211 citations
Congenital Glutamine Deficiency with Glutamine Synthetase Mutations
AbstractGlutamine synthetase plays a major role in ammonia detoxification, interorgan nitrogen flux, acid-base homeostasis, and cell signaling. We report on two unrelated newborns who had congenital human glutamine synthetase deficiency with severe brain malformations resulting in multiorgan failure and neonatal death. Glutamine was largely absent from their serum, urine, and cerebrospinal fluid. Each infant had a homozygous mutation in the glutamine synthetase gene (R324C and R341C). Studies that used immortalized lymphocytes expressing R324C glutamine synthetase (R324C-GS) and COS7 cells expressing R341C-GS suggest that these mutations are associated with reduced glutamine synthetase activity.
Journal of Inherited Metabolic Disease · 2005 · 86 citations
Inborn error of amino acid synthesis: Human glutamine synthetase deficiency
AbstractGlutamine synthetase (GS) is ubiquitously expressed in human tissues, being involved in ammonia detoxification and interorgan nitrogen flux. Inherited systemic deficiency of glutamine based on a defect of glutamine synthetase was recently described in two newborns with an early fatal course of disease. Glutamine was largely absent in their serum, urine and cerebrospinal fluid. Each of the patients had a homozygous mutation in the glutamine synthetase gene and enzymatic investigations confirmed that these mutations lead to a severely reduced glutamine synthetase activity. From the observation in the first patients with congenital glutamine synthetase deficiency, brain malformation can be expected as one of the leading signs. In addition, other organ systems are probably involved as observed in one of the index patients who suffered from severe enteropathy and necrolytic erythema of the skin. Deficiency of GS has to be added to the list of inherited metabolic disorders as a rare example of a defect in the biosynthesis of an amino acid.
Minireview on Glutamine Synthetase Deficiency, an Ultra-Rare Inborn Error of Amino Acid Biosynthesis
AbstractGlutamine synthetase (GS) is a cytosolic enzyme that produces glutamine, the most abundant free amino acid in the human body. Glutamine is a major substrate for various metabolic pathways, and is thus an important factor for the functioning of many organs; therefore, deficiency of glutamine due to a defect in GS is incompatible with normal life. Mutations in the human GLUL gene (encoding for GS) can cause an ultra-rare recessive inborn error of metabolism—congenital glutamine synthetase deficiency. This disease was reported until now in only three unrelated patients, all of whom suffered from neonatal onset severe epileptic encephalopathy. The hallmark of GS deficiency in these patients was decreased levels of glutamine in body fluids, associated with chronic hyperammonemia. This review aims at recapitulating the clinical history of the three known patients with congenital GS deficiency and summarizes the findings from studies done along with the work-up of these patients. It is the aim of this paper to convince the reader that (i) this disorder is possibly underdiagnosed, since decreased concentrations of metabolites do not receive the attention they deserve; and (ii) early detection of GS deficiency may help to improve the outcome of patients who could be treated early with metabolites that are lacking in this condition.
JAMA Neurology · 2018 · 56 citations · open access
Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy
AbstractImportance: The identification and understanding of the monogenic causes of neurodevelopmental disorders are of high importance for personalized treatment and genetic counseling. Objective: To identify and characterize novel genes for a specific neurodevelopmental disorder characterized by refractory seizures, respiratory failure, brain abnormalities, and death in the neonatal period; describe the outcome of glutaminase deficiency in humans; and understand the underlying pathological mechanisms. Design, Setting, and Participants: We performed exome sequencing of cases of neurodevelopmental disorders without a clear genetic diagnosis, followed by genetic and bioinformatic evaluation of candidate variants and genes. Establishing pathogenicity of the variants was achieved by measuring metabolites in dried blood spots by a hydrophilic interaction liquid chromatography method coupled with tandem mass spectrometry. The participants are 2 families with a total of 4 children who each had lethal, therapy-refractory early neonatal seizures with status epilepticus and suppression bursts, respiratory insufficiency, simplified gyral structures, diffuse volume loss of the brain, and cerebral edema. Data analysis occurred from October 2017 to June 2018. Main Outcomes and Measures: Early neonatal epileptic encephalopathy with glutaminase deficiency and lethal outcome. Results: A total of 4 infants from 2 unrelated families, each of whom died less than 40 days after birth, were included. We identified a homozygous frameshift variant p.(Asp232Glufs*2) in GLS in the first family, as well as compound heterozygous variants p.(Gln81*) and p.(Arg272Lys) in GLS in the second family. The GLS gene encodes glutaminase (Enzyme Commission 3.5.1.2), which plays a major role in the conversion of glutamine into glutamate, the main excitatory neurotransmitter of the central nervous system. All 3 variants probably lead to a loss of function and thus glutaminase deficiency. Indeed, glutamine was increased in affected children (available z scores, 3.2 and 11.7). We theorize that the potential reduction of glutamate and the excess of glutamine were a probable cause of the described physiological and structural abnormalities of the central nervous system. Conclusions and Relevance: We identified a novel autosomal recessive neurometabolic disorder of loss of function of glutaminase that leads to lethal early neonatal encephalopathy. This inborn error of metabolism underlines the importance of GLS for appropriate glutamine homeostasis and respiratory regulation, signal transduction, and survival.
A Very Rare Etiology of Hypotonia and Seizures: Congenital Glutamine Synthetase Deficiency
AbstractAbstract Mutations in the human GLUL gene, which encodes the enzyme glutamine synthetase (GS), may cause congenital glutamine synthetase deficiency. The disease was first described in 2005 and only three patients have been reported to date. We report a fourth patient suffering from congenital GS deficiency who was found to have some distinctive clinical findings. The patient was a 30-month-old girl who was referred to us due to developmental delay and seizures which began at 5 months of age. She was seizure free for 5 months with valproic acid and vigabatrin. At presentation, she was found to have microcephaly and hypotonia. Her plasma glutamine concentration was near normal and she had mild hyperammonemia. Cranial magnetic resonance imaging (MRI) showed mild changes. Whole exome sequencing (WES) revealed a homozygous c.121C > T (p.R41C) (p.Arg41Cys) pathogenic variant of the GLUL gene. The diagnosis of this patient underlines the importance of careful evaluation of patients with borderline low glutamine levels. Treatment was begun with L-glutamine and nicotinamide and biochemical improvements have been observed at 6 months of follow-up. The outcome of this patient may provide important data about the effectiveness of glutamine and nicotinamide treatment in patients with congenital GS deficiency.
Zeitschrift für Gastroenterologie · 2015 · 0 citations
Determining the molecular consequences of clinically relevant glutamine synthetase mutations
AbstractGlutamine synthetase (GS) catalyzes the ligation of ammonia and glutamate to glutamine under the use of ATP and is, thus, essential for nitrogen metabolism [1,2]. Loss of hepatic GS activity has been linked to serious clinical conditions [3]. In particular, two mutations of human GS (R324C and R341C) were connected to congenital glutamine deficiency with severe brain malformations resulting in neonatal death [4]. In a single case known to date, to the best of our knowledge, another GS mutation (R324S) was identified in a neurologically compromised patient [5]. However, the underlying molecular mechanisms of GS deactivation by these mutations have not been understood yet.
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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