DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for pontocerebellar hypoplasia type 7 — 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 modulePontocerebellar hypoplasia type 7 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
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 pontocerebellar hypoplasia type 7 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
mutY DNA glycosylase (MUTYH) — MUTYH 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 sf4drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8FAY · 1.91 Å · ligand IRON/SULFUR CLUSTER (SF4). Experimental structure, not a prediction.
What the evidence adds up to
Pontocerebellar hypoplasia type 7 is not mentioned in any of the provided abstracts. The 2025 review covering literature from 1912 to 2022 states that very few cases are described for all pontocerebellar hypoplasia types other than 1, 2, 3, 4, 6, and 9, and that the most reported types are 1, 2, and 6. No abstract gives a case count, survival statistic, or genetic finding specific to type 7.
The 2011 cohort study of 169 patients from 141 families tested for mutations in TSEN54, TSEN2, TSEN34, and RARS2 found that 106 patients had mutations in one of those genes. That study reported a strong correlation between TSEN54 mutations and a dragonfly-like cerebellar pattern on MRI, and associated those mutations with dyskinesia, dystonia, and variable spasticity. Nonsense or splice site mutations in TSEN54 were linked to perinatal symptoms, ventilator dependency, and early death. No patient in that cohort is identified as having pontocerebellar hypoplasia type 7.
The 2025 clinical and genetic analysis of six children with RARS2 gene variants describes infantile onset, severe psychomotor retardation, drug-resistant epilepsy, and feeding difficulties. Seizures were controlled in only two of the six children, and one of those later relapsed. Pontocerebellar hypoplasia was seen on neuroimaging in two of the six. The authors conclude that most affected children have a poor prognosis. Again, none of these children are classified as type 7.
What is still missing for pontocerebellar hypoplasia type 7 specifically is any published case series, any identified causal gene, any neuroimaging pattern, and any natural history data. Without a molecular diagnosis or a clinical definition that distinguishes type 7 from other subtypes, no trial design, patient stratification, or funding target can be proposed.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Child Neurology · 2011 · 28 citations
Pontocerebellar Hypoplasia: Review of Classification and Genetics, and Exclusion of Several Genes Known to Be Important for Cerebellar Development
AbstractThe pontocerebellar hypoplasias are a heterogeneous group of rare and devastating conditions characterized by multiple structural abnormalities of the ventral pons, inferior olive, and cerebellum. Here, we briefly review these conditions and discuss genes recently discovered to be involved in pontocerebellar hypoplasia pathogenesis. We then present data that exclude several genes important for cerebellar development as causes of pontocerebellar hypoplasia-4 and pontocerebellar hypoplasia-5, and we demonstrate that not all cases of clinically defined pontocerebellar hypoplasia-4 result from mutations in TSEN54. We conclude that classification based on clinical, imaging, and neuropathological findings does not differentiate between pontocerebellar hypoplasia subtypes with different genetic causes.
Developmental Medicine & Child Neurology · 1997 · 10 citations · open access
Pontocerebellar hypoplasia with microcephaly and dyskinesia: report of two cases
AbstractWe present two clinically diagnosed cases of pontocerebellar hypoplasia with microcephaly and dyskinesia (pontocerebellar hypoplasia type 2) from two different Portuguese families. Both children presented neurological involvement from birth, progressive microcephaly, exuberant chorea and dystonia, myoclonic jerks, pontocerebellar hypoplasia, and progressive cerebral cortical atrophy. One child had consanguineous parents.
Brain Communications · 2025 · 4 citations · open access
Pontocerebellar hypoplasia: a review from 1912 to 2022
AbstractAbstract Pontocerebellar hypoplasia is a rare neurodevelopmental disorder that results from differences in formation and function of the pons, cerebellum and cerebrum. It can be diagnosed prenatally or postnatally with a combination of clinical, neuroimaging and genetic data obtained over time. The diagnosis of pontocerebellar hypoplasia usually portends severe developmental delay, epilepsy and/or neurodegeneration in childhood. Here we perform a comprehensive review with the primary goal of evaluating published evidence addressing the clinical and genetic features of pontocerebellar hypoplasia by type and subtype. Secondly, we summarize neurodiagnostic patterns of pontocerebellar hypoplasia and demonstrate its spectrum. Finally, we provide recommendations in diagnosis, prognosis and management for the neurologist. To address these goals, we performed an extensive review of published literature from 1912 to 2022. We identified 191 publications by combining search results from PubMed, OMIM and cross-referenced bibliographies. Publications on developmental neuroanatomy, not pertaining to pontocerebellar hypoplasia or published in a foreign language were excluded. We performed both qualitative (1912–1993) and quantitative (1993–2022) analyses to understand the current classification of this disease as it pertains to genetic and neurodiagnostic features of pontocerebellar hypoplasia by type and subtype. Our review shows that the most reported types of pontocerebellar hypoplasia are 1, 2 and 6; less frequently described are 3, 4 and 9. Very few cases are described for all other subsequent pontocerebellar hypoplasia types. Mutations in TSEN54, RARS2, EXOSC3 and AMPD2 (genes that regulate RNA processing and basic cellular metabolism) are the most frequently reported pathological mutations in pontocerebellar hypoplasia. The neuroradiographic features of pontocerebellar hypoplasia are complex and evolve over time, affecting the pons, cerebellum, vermis, cortex and cerebral white matter. In conclusion, pontocerebellar hypoplasia is a rare neurodevelopmental disorder, often the result of genetic dysfunction in basic neural metabolism. The diagnosis conveys significant implications for the affected individual and their families and requires a combination of clinical, neuroradiographic, and genetic testing to best inform type/subtype categorization of pontocerebellar hypoplasia.
[Clinical and genetic analysis of six children with RARS2-related pontocerebellar hypoplasia].
AbstractOBJECTIVE: To analyze the clinical characteristics and genotypic changes of six children with RARS2 gene variants. METHODS: The clinical data of 6 children with RARS2 gene variants diagnosed at the Third Affiliated Hospital of Zhengzhou University from January 2017 to August 2024 were collected. Genetic variants were detected using trio-whole exome sequencing. Genomic DNA was extracted from samples and subjected to high-throughput sequencing. Variants were detected and analyzed using relevant databases and software. Pathogenic variants were validated by Sanger sequencing. The protein structure encoded by a previously unreported variant was predicted using a SWISS-MODEL online server. This study was approved by the Medical Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethics No.: 2024-373-01). RESULTS: Among the six children, four were males and two were females, with the most recent follow-up age ranging from 1-year-and-1-month to 7 years old. The age of onset was under 1 year in all cases. All six children exhibited seizures, including infantile spasms in three, spasms and tonic spasms in one, and focal seizures in two. One child became seizure-free for 4 ~ 5 years following Valproic acid combined with topiramate and adrenocorticotropic hormone (ACTH) pulse therapy, but subsequently experienced a relapse. Another child has remained seizure-free for nearly one year with oral sodium valproate, levetiracetam, and a "cocktail" therapy. Seizures were not controlled in the remaining four children. Pontocerebellar hypoplasia was observed on neuroimaging in two children. All six patients exhibited severe psychomotor retardation. A total of 10 RARS2 gene variants were identified, three of which were previously unreported. CONCLUSION: The predominant clinical features of Pontocerebellar hypoplasia associated with RARS2 gene variants include infantile onset, severe psychomotor retardation or regression, drug-resistant epilepsy, and feeding difficulties. The characteristic neuroimaging finding is pontocerebellar hypoplasia. However, its appearance may vary widely with time. The majority of affected children have a poor prognosis.
Zurich Open Repository and Archive (University of Zurich) · 2011 · 0 citations · open access
Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia
AbstractPontocerebellar hypoplasia is a group of autosomal recessive neurodegenerative disorders with prenatal onset. The common characteristics are cerebellar hypoplasia with variable atrophy of the cerebellum and the ventral pons. Supratentorial involvement is reflected by variable neocortical atrophy, ventriculomegaly and microcephaly. Mutations in the transfer RNA splicing endonuclease subunit genes (TSEN54, TSEN2, TSEN34) were found to be associated with pontocerebellar hypoplasia types 2 and 4. Mutations in the mitochondrial transfer RNA arginyl synthetase gene (RARS2) were associated with pontocerebellar hypoplasia type 6. We studied a cohort of 169 patients from 141 families for mutations in these genes, of whom 106 patients tested positive for mutations in one of the TSEN genes or the RARS2 gene. In order to delineate the neuroradiological and clinical phenotype of patients with mutations in these genes, we compared this group with 63 patients suspected of pontocerebellar hypoplasia who were negative on mutation analysis. We found a strong correlation (P < 0.0005) between TSEN54 mutations and a dragonfly-like cerebellar pattern on magnetic resonance imaging, in which the cerebellar hemispheres are flat and severely reduced in size and the vermis is relatively spared. Mutations in TSEN54 are clinically associated with dyskinesia and/or dystonia and variable degrees of spasticity, in some cases with pure generalized spasticity. Nonsense or splice site mutations in TSEN54 are associated with a more severe phenotype of more perinatal symptoms, ventilator dependency and early death. In addition, we present ten new mutations in TSEN54, TSEN2 and RARS2. Furthermore, we show that pontocerebellar hypoplasia type 1 together with elevated cerebrospinal fluid lactate may be caused by RARS2 mutations.
AbstractCase Study: Pontocerebellar hypoplasia (PCH) comprises a group of autosomal recessive neurodegenerative disorders with mostly prenatal onset. Clinical hallmarks are severe global developmental delay as well as specific neurologic symptoms depending on the subtype of PCH. Treatment is symptomatic and affected individuals often die during the neonatal period or infancy.
Supra- and Infratentorial Atrophy with Cortical Blindness Caused by Mutations in SEPSECS: Case Report
AbstractBackground/Purpose: Mutations in SEPSECS (encoding O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase) have been reported in 11 patients with pontocerebellar hypoplasia type II, progressive cerebellocerebral atrophy, and progressive encephalopathy. The phenotypic spectrum involves severe retardation, muscular hypotony, and early abnormalities of cerebellum, vermis, and cortex in MRI. A milder clinical course with slow progression of cerebellar atrophy has been described only recently.
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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