DeCure for Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures — 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 modulePachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures 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 pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures 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.
What the evidence adds up to
No drug treatment is tested or proposed in any of these abstracts. The four reports describe only genetic findings and clinical imaging. A 13-year-old male with a mosaic DCX gene deletion (c.30-31 deletion) had pachygyria of frontal and temporal lobes on MRI at age 5, developmental delay, autism spectrum disorder diagnosed at age 5, and new-onset seizures at age 13; he did not have infantile seizures, severe intellectual disability, or microcephaly, which the authors note is unusual for DCX mutation. A preteen Saudi female had infantile seizures, developmental delay, and MRI showing the classic “leopard” and “tigroid” white matter changes with cortical thickening and shallow sulci, but no genetic assay had been performed at the time of publication. A girl with infantile spasms that became drug-resistant epilepsy despite multiple antiseizure medications had pachygyria on MRI at 14 months and severe developmental delay and mental retardation by age 4; whole-exome sequencing identified a de novo heterozygous DYNC1H1 mutation (p.Arg292Trp).
A literature review of 129 patients from 43 studies (including that girl) found that DYNC1H1 mutations confer high odds of epilepsy (OR 33.67, 95% CI 11.59 to 97.84) and intellectual disability or developmental delay (OR 52.64, 95% CI 16.27 to 170.38). Among patients with mutations in the protein stalk or microtubule-binding domain, 95% had malformations of cortical development, whereas 63% of those with tail-domain mutations did not show such malformations. No abstract reports any attempt to treat pachygyria, microcephaly, developmental delay, or seizures with a repurposed drug. The only intervention mentioned is antiseizure medication, and in the DYNC1H1 case it failed to control epilepsy.
What is missing is any clinical trial, any drug intervention, any patient stratification by specific mutation type beyond the broad domain-level analysis, and any funding for a treatment study. Without these, the literature remains a collection of genetic case reports with no therapeutic data.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
American Journal of Medical Genetics Part A · 2003 · 18 citations
Autosomal recessive frontotemporal pachygyria
AbstractPachygyria is a cortical malformation that results from the abnormal migration of neurons. Regions of the brain with pachygyria have an abnormally thick cortex that lacks normal folding and has deficient layering. We describe three siblings, born to nonconsanguineous Mexican parents, who have bilateral frontotemporal pachygyria without polymicrogyria. The pachygyria is accompanied by moderate mental retardation, esotropia, and either hypertelorism or telecanthus. They are otherwise morphologically normal and do not have microcephaly. Two experienced a single seizure in infancy. The characteristic phenotype present in this family suggests a new genetic syndrome that is likely inherited as an autosomal recessive trait.
Child Neurology Open · 2019 · 8 citations · open access
Doublecortin Mutation in an Adolescent Male
AbstractDoublecortin (DCX) mutations cause abnormal development of the DCX protein that normally aids in neuronal migration during fetal development. These mutations lead to lissencephaly, or the appearance of a "smooth brain," which is varying levels of pachygyria or agyria in severe cases. Many genetic variants of the mutation have been identified, and an even greater range of phenotypic presentations have been described in the literature. The X-linked lissencephaly (DCX) mutation leads to an X-linked gender-dependent condition that causes subcortical heterotopia in females and lissencephaly in males. The authors report the case of a 13-year-old male who presented to our clinic for new-onset seizure disorder. He had a past medical history of developmental delay and features of autism spectrum disorder which was diagnosed at age 5 years at an outside clinic. Magnetic resonance imaging (MRI) brain at age 5 years showed pachygyria of the frontal and temporal lobes. After extensive genetic testing over the course of over a decade, the patient was found to have a de novo mutation in the DCX gene diagnosed via whole-exome sequencing. Specifically, he was found to have a mosaic mutation of the DCX gene as a c.30-31 deletion. His previous MRI findings were consistent with a diagnosis of X-linked sporadic lissencephaly sequence and included mainly a diffuse bilateral pachygyria (isolated lissencephaly sequence X chromosome). Thickening of the cortex and pachygyria or agyria are classic findings of lissencephaly, but do not help specify any mutation in the gene, of which there are over 70 possibilities. Our patient is unique in that most individuals with DCX mutation have infantile seizures, severe intellectual disability, orthopedic complications, and postnatal microcephaly, which our patient does not have.
Journal of Clinical Images and Medical Case Reports · 2022 · 0 citations · open access
Pachygyria in a Saudi preteen female: A case report and review of literature
AbstractPachygyria is a component of a spectrum of malformation of cerebral neuronal migration. MRI is a fundamental neuroimaging tool for adequate description of cerebral structural pathology. As a component of lissencephaly-pachygyria spectrum, there are severe intertwined clinical and pathological manifestations, with/without other brain and systemic malformations. Clinical features include protracted seizures, delay or absence of developmental milestones, and varying degrees of mental retardation. This is a case of a preteen with previous infantile seizures and delay in developmental milestones. Her MRI showed uncommon but classic “leopord” and “tigroid” appearances of deep white matter changes, as well as the typical shallow and few cerebral cortical sulci, as well as cortical thickening of pachygyria. Despite several established genetic mutations documented in various disorders of cerebral neural migration, there was however no genetic assay yet for the patient at the time of this publication. Keywords: pachygyria; lissencephaly; neuronal-migration; heterotopia.
Table_1_Case report: Genotype and phenotype of DYNC1H1-related malformations of cortical development: a case report and literature review.DOCX
AbstractBackground<p>Mutations in the dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) gene are linked to malformations of cortical development (MCD), which may be accompanied by central nervous system (CNS) manifestations. Here, we present the case of a patient with MCD harboring a variant of DYNC1H1 and review the relevant literature to explore genotype-phenotype relationships.</p>Case presentation<p>A girl having infantile spasms, was unsuccessfully administered multiple antiseizure medications and developed drug-resistant epilepsy. Brain magnetic resonance imaging (MRI) at 14 months-of-age revealed pachygyria. At 4 years-of-age, the patient exhibited severe developmental delay and mental retardation. A de novo heterozygous mutation (p.Arg292Trp) in the DYNC1H1 gene was identified. A search of multiple databases, including PubMed and Embase, using the search strategy DYNC1H1 AND [malformations of cortical development OR seizure OR intellectual OR clinical symptoms] up to June 2022, identified 129 patients from 43 studies (including the case presented herein). A review of these cases showed that patients with DYNC1H1-related MCD had higher risks of epilepsy (odds ratio [OR] = 33.67, 95% confidence interval [CI] = 11.59, 97.84) and intellectual disability/developmental delay (OR = 52.64, 95% CI = 16.27, 170.38). Patients with the variants in the regions encoding the protein stalk or microtubule-binding domain had the most prevalence of MCD (95%).</p>Conclusion<p>MCD, particularly pachygyria, is a common neurodevelopmental disorder in patients with DYNC1H1 mutations. Literature searches reveales that most (95%) patients who carried mutations in the protein stalk or microtubule binding domains exhibited DYNC1H1-related MCD, whereas almost two-thirds of patients (63%) who carried mutations in the tail domain did not display MCD. Patients with DYNC1H1 mutations may experience central nervous system (CNS) manifestations due to MCD.</p>
Image_1_Case report: Genotype and phenotype of DYNC1H1-related malformations of cortical development: a case report and literature review.pdf
AbstractBackground<p>Mutations in the dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) gene are linked to malformations of cortical development (MCD), which may be accompanied by central nervous system (CNS) manifestations. Here, we present the case of a patient with MCD harboring a variant of DYNC1H1 and review the relevant literature to explore genotype-phenotype relationships.</p>Case presentation<p>A girl having infantile spasms, was unsuccessfully administered multiple antiseizure medications and developed drug-resistant epilepsy. Brain magnetic resonance imaging (MRI) at 14 months-of-age revealed pachygyria. At 4 years-of-age, the patient exhibited severe developmental delay and mental retardation. A de novo heterozygous mutation (p.Arg292Trp) in the DYNC1H1 gene was identified. A search of multiple databases, including PubMed and Embase, using the search strategy DYNC1H1 AND [malformations of cortical development OR seizure OR intellectual OR clinical symptoms] up to June 2022, identified 129 patients from 43 studies (including the case presented herein). A review of these cases showed that patients with DYNC1H1-related MCD had higher risks of epilepsy (odds ratio [OR] = 33.67, 95% confidence interval [CI] = 11.59, 97.84) and intellectual disability/developmental delay (OR = 52.64, 95% CI = 16.27, 170.38). Patients with the variants in the regions encoding the protein stalk or microtubule-binding domain had the most prevalence of MCD (95%).</p>Conclusion<p>MCD, particularly pachygyria, is a common neurodevelopmental disorder in patients with DYNC1H1 mutations. Literature searches reveales that most (95%) patients who carried mutations in the protein stalk or microtubule binding domains exhibited DYNC1H1-related MCD, whereas almost two-thirds of patients (63%) who carried mutations in the tail domain did not display MCD. Patients with DYNC1H1 mutations may experience central nervous system (CNS) manifestations due to MCD.</p>
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.
