DeCure for Hyperinsulinism-hyperammonemia syndrome
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for hyperinsulinism-hyperammonemia syndrome — 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 moduleHyperinsulinism-hyperammonemia syndrome 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 hyperinsulinism-hyperammonemia syndrome 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
glutamate dehydrogenase 1 (GLUD1) — GLUD1 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8SK8 · 2.31 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
The hyperinsulinism-hyperammonemia syndrome is caused by activating mutations in the glutamate dehydrogenase gene (GLUD1). In 1998, eight unrelated children — six sporadic, two familial — were found to have heterozygous mutations in the allosteric domain of the enzyme. The sensitivity of glutamate dehydrogenase to inhibition by guanosine 5'-triphosphate was reduced to a quarter of normal in sporadic cases and half of normal in familial cases, consistent with overactivity of the enzyme. The degree of enzyme insensitivity correlated with the severity of hypoglycemia. Four different mutations were identified among the six sporadic patients; the two familial patients shared a fifth mutation.
A 2025 retrospective case series from Saudi Arabia included five patients (four children, one adult) with confirmed GLUD1 mutations. All presented with hypoglycemia, elevated insulin, and persistent hyperammonemia. Two patients shared the c.1493C>T (p.Ser498Leu) variant. Diazoxide controlled hypoglycemia in most patients. Two patients had seizures and developmental delay. One adult underwent pancreatectomy, which improved hypoglycaemia control, but chronic neurological sequelae remained. Brain MRI abnormalities and secondary genetic variants were found in two cases.
A 2009 case report describes a 16-year-old admitted for acute encephalopathy and hyperammonemia. After excluding hepatic failure, empirical treatment for urea cycle disorders was started. Brain edema was treated and ammonia was cleared, but the patient died four days later. The authors note that only early identification of the cause of hyperammonemia can reduce the high morbidity and mortality.
What is still missing are prospective, multicentre studies with long-term follow-up to understand outcomes across different populations. The 2025 series is small and retrospective. No controlled trial of diazoxide versus other interventions exists for this specific syndrome. Patient stratification by mutation type and age at diagnosis is not yet standardised, and the role of pancreatectomy remains unclear. Funding for such studies is lacking.
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 · 1998 · 672 citations · open access
Hyperinsulinism and Hyperammonemia in Infants with Regulatory Mutations of the Glutamate Dehydrogenase Gene
AbstractBACKGROUND: A new form of congenital hyperinsulinism characterized by hypoglycemia and hyperammonemia was described recently. We hypothesized that this syndrome of hyperinsulinism and hyperammonemia was caused by excessive activity of glutamate dehydrogenase, which oxidizes glutamate to alpha-ketoglutarate and which is a potential regulator of insulin secretion in pancreatic beta cells and of ureagenesis in the liver. METHODS: We measured glutamate dehydrogenase activity in lymphoblasts from eight unrelated children with the hyperinsulinism-hyperammonemia syndrome: six with sporadic cases and two with familial cases. We identified mutations in the glutamate dehydrogenase gene by sequencing glutamate dehydrogenase complementary DNA prepared from lymphoblast messenger RNA. Site-directed mutagenesis was used to express the mutations in COS-7 cells. RESULTS: The sensitivity of glutamate dehydrogenase to inhibition by guanosine 5'-triphosphate was a quarter of the normal level in the patients with sporadic hyperinsulinism-hyperammonemia syndrome and half the normal level in patients with familial cases and their affected relatives, findings consistent with overactivity of the enzyme. These differences in enzyme insensitivity correlated with differences in the severity of hypoglycemia in the two groups. All eight children were heterozygous for the wild-type allele and had a mutation in the proposed allosteric domain of the enzyme. Four different mutations were identified in the six patients with sporadic cases; the two patients with familial cases shared a fifth mutation. In two clones of COS-7 cells transfected with the mutant sequence from one patient, the sensitivity of the enzyme to guanosine 5'-triphosphate was reduced, findings similar to those in the child's lymphoblasts. CONCLUSIONS: The hyperinsulinism-hyperammonemia syndrome is caused by mutations in the glutamate dehydrogenase gene that impair the control of enzyme activity.
Journal of Medical Case Reports · 2025 · 0 citations · open access
Hyperinsulinism–hyperammonemia syndrome associated with GLUD1 gene mutation: a case series
AbstractBACKGROUND: Congenital hyperinsulinism is a rare disorder characterized by inappropriate insulin secretion, leading to persistent hypoglycemia. One genetic subtype, hyperinsulinism-hyperammonemia syndrome, results from activating mutations in the GLUD1 gene. This study aimed to describe the clinical spectrum, genetic variants, and outcomes of patients with GLUD1-related hyperinsulinism-hyperammonemia syndrome treated at a tertiary care center in Saudi Arabia. METHODS: This retrospective case series included five patients of Saudi ethnicity diagnosed with GLUD1-associated hyperinsulinism-hyperammonemia syndrome between September and November 2023 at King Faisal Specialist Hospital and Research Centre. Clinical, biochemical, imaging, and genetic data were collected from medical records. Descriptive statistics were used to summarize the findings. RESULTS: All five patients (four pediatric, one adult) presented with hypoglycemia, elevated insulin levels, and persistent hyperammonemia. Genetic testing confirmed GLUD1 mutations in all cases, with two patients sharing the c.1493C > T (p.Ser498Leu) variant. Diazoxide therapy effectively controlled hypoglycemia in most patients. Two patients experienced significant neurological complications, including seizures and developmental delay. One adult patient underwent pancreatectomy with improvement in hypoglycemia control but retained chronic neurological sequelae. Brain magnetic resonance imaging abnormalities and secondary genetic variants were identified in two cases. CONCLUSION: GLUD1-related hyperinsulinism-hyperammonemia syndrome presents with a wide clinical spectrum, often with early onset and risk of neurological impairment if not promptly treated. Early diagnosis and individualized management-including genetic testing and diazoxide therapy-are essential to prevent irreversible complications. Further multicenter studies are warranted to better understand long-term outcomes in affected populations.
Anales del Sistema Sanitario de Navarra · 2009 · 0 citations · open access
Encefalopatía por hiperamoniemia en el adolescente
AbstractBACKGROUND: Hyperammonemia causes several alterations, mainly in the central nervous system. If hepatic failure is not its etiology, other less frequent causes must be investigated in the search for a definitive diagnosis. CLINICAL CASE: We report the case of a 16 year old patient admitted for acute encephalopathy and hyperammonemia. After analysis, brain CT, ultrasound and abdominal Doppler, we began empirical treatment of hyperammonemia secondary to disorders of the urea cycle. We treated the brain edema and eliminated ammonia but we did not obtain favourable results and the patient died four days later. CONCLUSIONS: The complex management of hyperammonemia and the high morbidity and mortality involved require a multidisciplinary approach. Only early treatment and identification of the hyperammonemia's etiology can avoid high morbidity and mortality in these patients.
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.
