DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for cerebral creatine deficiency syndrome — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCerebral creatine deficiency syndrome maps to a 3-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
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Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
approvedCreatineApproved drug
Structures already discussed alongside cerebral creatine deficiency syndrome in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
creatininase-product complex — Creatine has a real, experimentally solved structure in complex with this target (PDB 1V7Z, 1.6 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet crndrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1V7Z · 1.6 Å · ligand Creatine (CRN). Experimental structure, not a prediction.
What the evidence adds up to
Cerebral creatine transporter deficiency (CRTR-D) affects about 50% of patients with epilepsy of variable severity. In a retrospective series of seven patients, no correlation was found between residual creatine uptake in fibroblasts or the type of SLC6A8 mutation and the occurrence or pattern of seizures. No genotype–phenotype correlations could be demonstrated in that small series. One patient with the highest residual activity and a missense mutation had milder manifestations and no epilepsy, but refractory seizures had been reported in a previously published patient with the same mutation. The level of brain creatine by proton magnetic resonance spectroscopy was not associated with the occurrence or severity of epilepsy. Epilepsy could usually be controlled with classical antiepileptic drugs in monotherapy such as carbamazepine or valproate. A high risk of status epilepticus was observed in patients not treated with antiepileptic drugs or when treatment was discontinued, even after long-term good seizure control.
A 2023 case report describes a 20-month-old boy with failure to thrive and global developmental delay who was found to have persistently low serum creatinine levels and elevated urinary creatine-to-creatinine ratio. Brain magnetic resonance spectroscopy showed diffusely diminished creatine peaks. Molecular testing identified a maternally inherited hemizygous SLC6A8 variant. The child was started on creatine, arginine, and glycine supplementation and demonstrated improved development. The report notes that CRTR deficiency is likely underdiagnosed and that existing therapies exist, but does not provide controlled data on treatment outcomes.
A retrospective chart review of six patients from Irish national metabolic referral centres (four with X-linked CRTR, two with autosomal recessive GAMT deficiency) found a mean age at diagnosis of 7.5 years despite symptom onset before age two. Three patients with CRTR had epilepsy. Two patients with CRTR were treated with creatine and creatine/arginine/glycine/S-adenosylmethionine in combination, without notable effect on clinical symptoms or MR spectroscopy findings, which the authors state is in keeping with expectations for this condition. Both patients with GAMT deficiency had epilepsy that responded to treatment with creatine and ornithine.
A 2024 case report of a 44-month-old girl with speech delay, psychomotor regression, and proximal myopathy found no definable creatine peak at 3.0 ppm on multivoxel magnetic resonance spectroscopy. Follow-up spectroscopy after creatine monohydrate supplementation showed appearance of a creatine metabolite peak, suggesting treatment response. The report highlights MRS as a method for detecting cerebral creatine levels and documenting treatment response, but provides no data on clinical outcomes beyond the spectroscopic finding.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Epilepsia · 2009 · 19 citations · open access
Epilepsy spectrum in cerebral creatine transporter deficiency
AbstractTo the Editors: In the last decade, a novel group of inborn errors leading to cerebral creatine (Cr) deficiency has been described. They are characterized by absence or decrease of Cr in the brain measured by in vivo proton magnetic resonance spectroscopy (1H-MRS) (Schulze, 2003). Cerebral creatine transport deficiency (CRTR-D) is the most prevalent of these, and its biochemical hallmark is an increased urinary Cr-to-creatinine ratio. Final diagnosis is achieved by the study of CRTR activity in fibroblasts (Cr uptake) and by the mutational analysis of the SLC6A8 gene. Males with SLC6A8 mutations develop mental retardation, autistic features, language delay, and epilepsy. Epilepsy of variable severity affects about 50% of patients with CRTR-D (Cecil et al., 2001; Salomons et al., 2003; Anselm et al., 2006; Mancardi et al., 2007). Guanidino compounds such as Cr (α-N-methylguanidino acetic acid) and guanidinoacetate have epileptogenic potential (De Deyn et al., 1991; D’Hooge et al., 1992), acting as a partial γ-aminobutyric acid (GABA)A receptor agonist. This may generate a prolonged stimulation of postsynaptic GABAA receptor, and interference in inhibitory GABAergic circuits. We characterized epilepsy severity and treatment response, and investigated the possible relationships between SLC6A8 mutations and/or Cr uptake in fibroblasts with epilepsy severity in seven patients with CRTR-D. We selected all the patients diagnosed with CRTR-D who were followed up in the Hospital Sant Joan de Déu Pediatric-Neurology Department in the last 6 years. Five cases were unrelated and patients 5 and 6 were brothers. We retrospectively reviewed clinical data, seizure types (classified according to the International League Against Epilepsy, 1981), video-EEG (electroencephalography), treatment, seizure control, episodes of status epilepticus, seizure outcome, metabolic examinations in blood and urine, Cr signal in brain 1H-MRS, Cr uptake in fibroblasts, and SLC6A8 mutational analysis. Results are detailed in Table 1. Although no specific EEG pattern or seizure type has been reported so far in CRTR-D, our patients presented slow background activity for their ages in interictal video-EEG, without any specific paroxysmal activity. No correlation was observed between residual Cr uptake in fibroblasts or the type of mutation with the occurrence of seizures or with their pattern. Overall, no genotype–phenotype correlations could be demonstrated in this small series. Although one patient (3), who presented the highest residual activity in fibroblasts and a missense mutation, had milder clinical manifestations and no epilepsy, refractory seizures had been observed in previously published report of one patient with the same mutation (Mancardi et al., 2007). The level of brain Cr by H-MRS was not associated with the occurrence or severity of epilepsy. We did not find structural abnormalities in brain magnetic resonance imaging (MRI) of CRTR-D patients, although nonspecific white matter lesions related to prenatal hypoxic encephalopathy had been reported (Mancini et al., 2005). No additional reports of CRTR-D patients with hypoxic events or specific focal lesions in brain MRI have been published. Despite lack of effective treatment for patients with CRTR-D (Fons et al., 2008), epilepsy can usually be controlled with classical antiepileptic drugs (AEDs) in monotherapy (carbamazepine or valproate), as also observed in our patients. In conclusion, patients with mental retardation, autistic behavior, severe language delay, and mild or severe epilepsy who have presented episodes of status epilepticus (SE) or recurrent febrile seizures (FS) should be tested for cerebral creatine deficiency syndromes. We observed a high risk of developing SE in patients not treated with AEDs or when treatment is discontinued, despite normal EEG and long-term good seizure control. Therefore, we recommend pharmacologic treatment of patients with CRTR-D after a first seizure in order to protect them from occurrence or status epilepticus. Further studies in larger series are needed to better characterize the clinical phenotype and epilepsy spectrum. This work was supported by the Ministerio de Sanidad (FIS PI05/2080 and FIS PI05/1200) and Caixa Girona. G.S.S. is supported by the Dutch Society for Scientific Research (ZonMW/NWO), VIDI grant number 917.56.349. We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. None of the authors has any conflict of interest to disclosure.
Journal of Investigative Medicine High Impact Case Reports · 2023 · 3 citations · open access
Creatine Transporter Deficiency Presenting as Failure to Thrive: A Case Report of a Novel <i>SLC6A8</i> Variant Causing a Treatable but Likely Underdiagnosed Genetic Disorder
AbstractCerebral creatine deficiency syndromes (CCDS) are a rare group of inherited metabolic disorders (IMDs) that often present with nonspecific findings including global developmental delay (GDD), intellectual disability (ID), seizures, hypotonia, and behavioral differences. Creatine transporter (CRTR) deficiency is the most common CCDS, exhibiting X-linked inheritance and an estimated prevalence as high as 2.6% in individuals with neurodevelopmental disorders. Here, we present a 20-month-old boy with worsening failure to thrive (FTT) and GDD admitted for evaluation. He was found to have persistently low serum creatinine levels and a family history notable for a mother with learning disabilities and a maternal male cousin with GDD. Urine analyses revealed a marked elevation of creatine and elevated creatine:creatinine ratio suggestive of CRTR deficiency. Molecular genetic testing of SLC6A8 identified a maternally inherited hemizygous variant and brain magnetic resonance spectroscopy (MRS) showed diffusely diminished creatine peaks, further supporting the diagnosis of CRTR deficiency. The proband was started on creatine, arginine, and glycine supplementation and has demonstrated improved development. This case highlights that CRTR deficiency should be considered in all patients presenting with FTT and abnormal neurodevelopmental features, particularly if creatinine levels are low on serum chemistry studies. The nonspecific presentation of this condition in males and females likely has resulted in CRTR deficiency being underdiagnosed. There are existing therapies for individuals affected with CRTR deficiency and other CCDS, highlighting the importance of early diagnosis and intervention for affected individuals.
GP223 Creatine deficiency disorders the all-ireland experience
Abstract<h3>Background</h3> Cerebral creatine deficiency is caused by rare inherited disorders of either creatine biosynthesis (i.e. guanidinoacetate methyltransferase (GAMT) and arginine:glycine amidinotransferase (AGAT) deficiency), or creatine transport (i.e. creatine transporter deficiency, CRTR). Clinical features include variable hypotonia, speech delay (often the dominant feature), seizures, extrapyramidal signs and behavioural issues. Patients may have feeding issues and low weight. There is some evidence that early treatment of these disorders is successful, particularly in GAMT and AGAT deficiency. <h3>Method</h3> A retrospective chart review was undertaken of all patients who have attended the national metabolic referral centres at Dublin and Belfast with creatine deficiency. Details recorded included history, clinical findings, treatments and results of laboratory, genetic and radiological investigations. <h3>Results</h3> Six patients with current ages between 5 and 29 years were identified with a confirmed disorder of creatine metabolism – four male patients with X-linked CRTR and two female siblings with autosomal recessive GAMT deficiency. Initial diagnosis was made on urine biochemistry (analysis of creatine/creatinine and guanidinoacetate) in two patients, on MR spectroscopy in three patients (creatine peak significantly reduced) and via exome sequencing in one patient. All cases were confirmed biochemically and genetically. Despite onset of symptoms before the age of 2 years, mean age at diagnosis was 7.5 years, with range from 20 months to 17 years. Six patients had significant developmental delay, particularly in the domains of speech and behaviour. Three of the patients have weights <9th centile. Five of the patients had documented head circumferences, and all were normocephalic proportional to height and weight. Both patients with GAMT deficiency had epilepsy which responded to treatment with creatine and ornithine. Three patients with CRTR also had epilepsy. Two patients with CRTR have been treated with creatine and creatine/arginine/glycine/S-adenosylmethionine in combination, without notable effect on clinical symptoms or MR spectroscopy findings, which is in keeping with expectations for this condition. The four patients with CRTR are hemizygous for pathogenic mutations in the <i>SLC6A8</i> gene, <i>de novo</i> in two patients and maternally inherited in another, one has not had parental testing. The siblings with GAMT deficiency are compound heterozygous for mutations in the <i>GAMT</i> gene. <h3>Conclusion</h3> Although rare in Ireland, these treatable disorders are likely under-diagnosed. In a patient with developmental delay (particularly speech impairment) and behavioural difficulties, consideration should be given to sending a urine sample for analysis of creatine/creatinine ratio and guanidinoacetate, particularly if there is comorbid epilepsy.
Case Reports in Clinical Radiology · 2024 · 0 citations · open access
Magnetic resonance spectroscopy as a diagnostic tool in cerebral creatine deficiency syndrome 3
AbstractCerebral creatine deficiency syndrome-3 is a rare autosomal recessive disorder characterized by disturbance of expressive and cognitive speech, developmental delay, intellectual deficiency and myopathy. In some rare cases, it is associated with behavioral issues and seizures which usually have an early onset. A 44-month-old girl presented with complaints of speech delay, psychomotor regression, and features of proximal myopathy. Contrast-enhanced magnetic resonance imaging brain was essentially normal. Multivoxel magnetic resonance spectroscopy (MRS) demonstrated absence of definable creatine peak at 3.0 ppm. Follow-up MRS, post-creatine monohydrate supplementation revealed appearance of creatine metabolite peak at 3.0 ppm suggesting treatment response. In this case report, we are highlighting the potential of MRS as a reliable method of detecting cerebral creatine levels in the cerebral creatine deficiency syndrome as well as documentation of treatment response with oral creatine.
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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