DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for pontocerebellar hypoplasia type 2C — 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 modulePontocerebellar hypoplasia type 2C 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 pontocerebellar hypoplasia type 2c 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
tRNA splicing endonuclease subunit 34 (TSEN34) — TSEN34 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 8HMZ · 2.9 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Pontocerebellar hypoplasia type 2C is an autosomal recessive neurodegenerative disorder with prenatal onset. The common characteristics are cerebellar hypoplasia with variable atrophy of the cerebellum and the ventral pons, along with supratentorial involvement reflected by variable neocortical atrophy, ventriculomegaly and microcephaly. In a cohort of 169 patients from 141 families, 106 tested positive for mutations in TSEN genes or RARS2. A strong correlation (P < 0.0005) was found between TSEN54 mutations and a dragonfly-like cerebellar pattern on MRI, where the cerebellar hemispheres are flat and severely reduced in size while the vermis is relatively spared. Clinically, TSEN54 mutations are associated with dyskinesia and/or dystonia and variable degrees of spasticity, sometimes pure generalised spasticity. Nonsense or splice site mutations in TSEN54 are associated with a more severe phenotype including perinatal symptoms, ventilator dependency and early death.
Two unrelated patients with pontocerebellar hypoplasia type 2 were found to have novel mutations in TSEN54: a missense mutation c.355T>G/p.Y119D in compound heterozygosity with the common c.919G>T/p.A307S, and a novel homozygous c.7ins6(CCGGAG)/p.E2-P3insPE variant. An expanded array of mutations may contribute to defining differences in severity and phenotype-genotype correlations. Two clinically diagnosed cases from Portuguese families 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.
A comprehensive review of literature from 1912 to 2022 found that the most reported types of pontocerebellar hypoplasia are 1, 2 and 6, with fewer cases described for types 3, 4 and 9. Mutations in TSEN54, RARS2, EXOSC3 and AMPD2 are the most frequently reported pathological mutations. The neuroradiographic features are complex and evolve over time, affecting the pons, cerebellum, vermis, cortex and cerebral white matter. Classification based on clinical, imaging, and neuropathological findings does not differentiate between subtypes with different genetic causes, and not all cases of clinically defined pontocerebellar hypoplasia type 4 result from mutations in TSEN54.
What is still missing is a clear understanding of the full genetic spectrum, as many patients remain mutation-negative, and the lack of prospective natural history studies that could inform trial design. No disease-modifying therapies have been tested in controlled trials, and patient stratification by genotype and phenotype remains imprecise. Funding for systematic longitudinal studies and for developing functional outcome measures in this ultra-rare population is absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Brain · 2010 · 225 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.
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.
Journal of Child Neurology · 2013 · 19 citations · open access
Novel Mutations in <i>TSEN54</i> in Pontocerebellar Hypoplasia Type 2
AbstractPontocerebellar hypoplasias represent a group of neurodegenerative autosomal recessive disorders characterized by hypoplasia/atrophy of the cerebellum, hypoplastic ventral pons, and microcephaly and associated with various clinical features. Pontocerebellar hypolasia type 2 is the most common form, and different mutations in genes encoding subunits of the transfer ribonucleic acid (RNA)-splicing endonuclease (TSEN) complex were identified in patients. The authors report clinical, imaging, and molecular studies in 2 unrelated patients with different clinical pictures of the pontocerebellar hypoplasia type 2 spectrum and novel mutations in TSEN54, aiming to further define the clinical spectrum of the disease and possible indicators of more favorable progression. They identified a novel missense mutation c.355T>G/p.Y119D in compound heterozygosity with the "common" c.919G>T/p.A307S (patient 1) and a novel homozygous c.7ins6(CCGGAG)/p.E2-P3insPE variant (patient 2). An expanded array of mutations might contribute in defining possible differences in severity and phenotype-genotype correlations.
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.
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.
Arquivos de Neuro-Psiquiatria · 2023 · 0 citations · open access
Case report: pontocerebellar hypoplasia type 1D
AbstractCase presentation: This report aims to describe the case of a patient with a rare diagnosis of type 1D pontocerebellar hypoplasia (PCH1D), resulting from the alteration of the EXOSC9 gene. G. T. S. D. S., male, 1 year and 2 months old, fruit of unplanned pregnancy of non-consanguineous parents. Prenatal care was complete. The patient was born by vaginal delivery without complications, with 36 weeks and 6 days of gestational age, and with the following measurements: height = 44.5 cm; weight = 2,660 kg; head circumference = 33.8 cm.
Ultraschall in der Medizin - European Journal of Ultrasound · 2006 · 0 citations
Ponto-cerebelläre Hypoplasie Typ II: Sonographische Charakteristika einer seltenen Ursache für ein „stiff-baby“-Syndrom beim Neugeborenen
AbstractProblemstellung: Ausgeprägte muskuläre Hypertonie und Hyperekplexie beim Neugeborenen sind selten, meist jedoch Ausdruck einer schweren cerebralen Erkrankung mit ungünstiger Prognose. Zur Vermeidung irreversibeler Schäden oder auch belastender und oft unnötiger Untersu-chungen ist rasche Diagnosestellung dringend indiziert. Differenzialdiagnostisch ist auch an eine pontocerebelläre Hypoplasie Typ II (PCH II) zu denken.
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.
