DeCure for Autosomal dominant cerebellar ataxia, deafness and narcolepsy
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for autosomal dominant cerebellar ataxia, deafness and narcolepsy — 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 moduleAutosomal dominant cerebellar ataxia, deafness and narcolepsy 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 autosomal dominant cerebellar ataxia, deafness and narcolepsy 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
Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). Exome sequencing in five individuals from three kindreds identified DNMT1 as the only gene with mutations in all five affected individuals. Sanger sequencing confirmed a de novo mutation p.Ala570Val in one family and showed co-segregation of p.Val606Phe and p.Ala570Val with the phenotype in two other kindreds. A fourth kindred with p.Gly605Ala was subsequently identified. All mutations are located in exon 21, in close spatial proximity, whereas mutations in exon 20 of DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Narcolepsy and deafness appear first, followed by ataxia. DNMT1 is a DNA methyltransferase expressed in immune cells and required for CD4+ differentiation into T regulatory cells.
A 1984 report described three members of a family with an autosomal dominant disorder comprising cerebellar ataxia, sensorineural deafness, myoclonus, and peripheral neuropathy. Necropsy of the proband showed loss of cells in the dentate nuclei, reduced cerebellar white matter, and pallor of the gracile tracts in the spinal cord. A 1974 study reported four sibs with adult-onset cerebellar ataxia and neurosensory deafness, slowly progressive over 10 years, with no other neurological signs; this was considered a distinct autosomal recessive entity.
A 2023 review notes that cerebellar ataxias are a heterogeneous group of movement disorders with genetic and sporadic forms. Advances in genetics and molecular pathophysiology have opened avenues for therapeutic strategies aimed at preventing or arresting disease progression. However, the rarity of certain ataxia forms limits insights into etiology and target pathways. Lack of suitable models hampers understanding of molecular pathophysiology and testing of novel interventions. The review describes epidemiology, symptomatology, and pathological progression of hereditary ataxias, and lists molecular pathways and therapeutic approaches under investigation in pre-clinical studies and clinical trials.
What is still missing is sufficient funding and infrastructure to study rare ataxia subtypes, better patient stratification by genotype and phenotype, and validated animal or cellular models that recapitulate the specific DNMT1 mutation effects. Without these, the gap between genetic discovery and any disease-modifying intervention remains wide.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Human Molecular Genetics · 2012 · 264 citations · open access
Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy
AbstractAutosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30-40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy-cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT1 as the only gene with mutations found in all five affected individuals. Sanger sequencing confirmed the de novo mutation p.Ala570Val in one family, and showed co-segregation of p.Val606Phe and p.Ala570Val, with the ADCA-DN phenotype, in two other kindreds. An additional ADCA-DN kindred with a p.GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding to HDAC2. It is also highly expressed in immune cells and required for the differentiation of CD4+ into T regulatory cells. Mutations in exon 20 of this gene were recently reported to cause hereditary sensory neuropathy with dementia and hearing loss (HSAN1). Our mutations are all located in exon 21 and in very close spatial proximity, suggesting distinct phenotypes depending on mutation location within this gene.
Autosomal recessive cerebellar ataxias: the current state of affairs
AbstractAmong the hereditary ataxias, autosomal recessive cerebellar ataxias (ARCAs) encompass a diverse group of rare neurodegenerative disorders in which a cerebellar syndrome is the key clinical feature. The clinical overlap between the different cerebellar ataxias, the occasional atypical phenotypes, and the genetic heterogeneity often complicate the clinical management of such patients. Despite the steady increase in newly discovered ARCA genes, many patients with a putative ARCA cannot be genotyped yet, proving that more genes must be involved. This review presents an updated overview of the various ARCAs. The clinical and genetic characteristics of those forms with a known molecular genetic defect are discussed, along with the emerging insights in the underlying pathophysiological mechanisms.
Hereditary Ataxias: From Bench to Clinic, Where Do We Stand?
AbstractCerebellar ataxias are a wide heterogeneous group of movement disorders. Within this broad umbrella of diseases, there are both genetics and sporadic forms. The clinical presentation of these conditions can exhibit a diverse range of symptoms across different age groups, spanning from pure cerebellar manifestations to sensory ataxia and multisystemic diseases. Over the last few decades, advancements in our understanding of genetics and molecular pathophysiology related to both dominant and recessive ataxias have propelled the field forward, paving the way for innovative therapeutic strategies aimed at preventing and arresting the progression of these diseases. Nevertheless, the rarity of certain forms of ataxia continues to pose challenges, leading to limited insights into the etiology of the disease and the identification of target pathways. Additionally, the lack of suitable models hampers efforts to comprehensively understand the molecular foundations of disease's pathophysiology and test novel therapeutic interventions. In the following review, we describe the epidemiology, symptomatology, and pathological progression of hereditary ataxia, including both the prevalent and less common forms of these diseases. Furthermore, we illustrate the diverse molecular pathways and therapeutic approaches currently undergoing investigation in both pre-clinical studies and clinical trials. Finally, we address the existing and anticipated challenges within this field, encompassing both basic research and clinical endeavors.
Journal of Neurology Neurosurgery & Psychiatry · 1984 · 13 citations · open access
Autosomal dominant late onset cerebellar ataxia with myoclonus, peripheral neuropathy and sensorineural deafness: a clinicopathological report.
AbstractThree members of a family were affected by an autosomal dominant disorder comprising cerebellar ataxia, sensorineural deafness, myoclonus, and peripheral neuropathy. This is the second kindred with this syndrome reported to date. Necropsy of the proband showed loss of cells in the dentate nuclei, a reduced amount of cerebellar white matter, and pallor of the gracile tracts in the spinal cord.
Adult‐onset hereditary cerebellar ataxia and neurosensory deafness
AbstractA family has been studied in which four sibs were affected with an adult‐onset form of cerebellar ataxia and deafness. The ataxia and hearing loss have been slowly progressive over a 10 year follow‐up period, and no other neurological signs have developed in the interim. This variety of hereditary ataxia, which appears to be a distinct autosomal recessive entity, is compared and contrasted with other genetic types, compiled in tabular form. It is emphasized that closer attention to other symptoms, either in the central nervous system or elsewhere, might have considerable use in the differential diagnosis of these conditions and thus provide for more effective genetic counselling.
Hereditary Ataxias: From Bench to Clinic, where Do We Stand?
AbstractCerebellar ataxias are a wide heterogeneous group of movement disorders. Within this broad umbrella of diseases, there are both genetics and sporadic forms. The clinical presentation of these conditions can exhibit a diverse range of symptoms across different age groups, spanning from pure cerebellar manifestations to sensory ataxia and multisystemic diseases. Over the last few decades, advancements in our understanding of genetics and molecular pathophysiology related to both dominant and recessive ataxias have propelled the field forward, paving the way for in-novative therapeutic strategies aimed at preventing and arresting the progression of these diseas-es. Nevertheless, the rarity of certain forms of ataxia continues to pose challenges, leading to lim-ited insights into the etiology of the disease and the identification of target pathways. Addition-ally, the lack of suitable models hampers efforts to comprehensively understand the molecular foundations of disease pathophysiology and test novel therapeutic interventions. In the following review, we describe the epidemiology, symptomatology, and pathological progression of heredi-tary ataxia, including both the prevalent and less common forms of these diseases. Furthermore, we illustrate the diverse molecular pathways and therapeutic approaches currently undergoing investigation in both pre-clinical studies and clinical trials. Finally, we address the existing and anticipated challenges within this field, encompassing both basic research and clinical endeavors.
Laryngo-Rhino-Otologie · 2018 · 0 citations · open access
Auditory neuropathy in CAPOS syndrome
AbstractCAPOS (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy and Sensorineural hearing impairment) syndrome (OMIM 601338) is a rare disorder of autosomal dominant inheritance. The remarkable clinical picture is characterized by sudden acute episodes of cerebellar ataxia triggered by febrile illness during childhood. It is caused by the missense mutation c.2452G>A, p.Glu818Lys, in the gene ATP1A3 which encodes for the neuron specific alpha subunit of Na+/K+-ATPase α3. This ion pump is highly expressed in spiral ganglion neurons and essential for maintaining a low intracellular Na+ concentration.
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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