DeCure for Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for sensory ataxic neuropathy, dysarthria, and ophthalmoparesis — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleSensory ataxic neuropathy, dysarthria, and ophthalmoparesis maps to a 2-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 sensory ataxic neuropathy, dysarthria, and ophthalmoparesis 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
DNA polymerase gamma, catalytic subunit (POLG) — POLG 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 dcpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8D33 · 2.46 Å · ligand 2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE (DCP). Experimental structure, not a prediction.
What the evidence adds up to
Four unrelated patients first described in 1997 presented with severe sensory ataxic neuropathy, dysarthria, and chronic progressive external ophthalmoplegia. Electrophysiologic and pathologic studies showed severe axonal loss disproportionately affecting sensory nerves. Molecular genetic analysis revealed multiple mitochondrial DNA deletions in muscle and peripheral nerve. The triad was named SANDO and proposed as a novel mitochondrial disease associated with multiple mitochondrial DNA deletions.
A 2018 study modelled a novel POLG variant, T599P, that causes the SANDO phenotype. The proband was a 42-year-old woman with a one-year history of progressive gait instability, dysarthria, and foot numbness. Examination showed ataxic dysarthria, restricted eye movements, head and palatal tremors, reduced lower limb reflexes, distal multimodal sensory loss, and a wide ataxic gait. Electromyography indicated a sensory neuropathy. Whole-exome sequencing was pursued after tests for infectious, inflammatory, and paraneoplastic causes were negative. Molecular modelling showed that changes at the T599 residue introduce extra rigidity into the surrounding helix–loop–helix, placing steric pressure on nearby nucleotides.
A 2024 case report described a 52-year-old man with hearing loss since childhood, recurrent foot ulcers and osteomyelitis since his forties, and worsening gait disturbance and dysarthria over four years. Neurological exams revealed cognitive impairment, proximal lower extremity weakness, generalised hyperreflexia, ataxia, sensory disturbances predominant in deep sensation, urinary retention, and gait instability. No sensory nerve action potentials were evoked in upper or lower limbs. Genetic analysis revealed a missense mutation in DNA methyltransferase 1, leading to a diagnosis of hereditary sensory and autonomic neuropathy 1E (HSAN1E). The report notes that increased deep tendon reflex can be observed in HSAN1E.
A 2023 case described a 25-year-old man with dysarthria and limb tremor initially misdiagnosed as spinocerebellar ataxia. Symptoms worsened to include limb weakness, sensory disorders, distal lower limb muscle atrophy, and positional dizziness. Neuroelectrophysiology showed multiple peripheral nerve damage involving both myelin sheath and axons. Anti-CNTN-1 antibody and serum GD1b antibody were positive. After treatment with rituximab, limb weakness and dysarthria were improved at three months of follow-up. No controlled trial data exist for any drug in SANDO itself. What is missing is a dedicated clinical trial for SANDO, any randomised evidence for rituximab in anti-CNTN-1 nodopathy, and patient stratification by genetic subtype.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Neurology · 1997 · 144 citations
Sensory ataxic neuropathy as the presenting feature of a novel mitochondrial disease
AbstractFour unrelated patients presented with a severe sensory ataxic neuropathy in association with dysarthria and chronic progressive external ophthalmoplegia. Electrophysiologic and pathologic studies showed severe axonal loss disproportionately affecting sensory nerves. Molecular genetic analysis revealed multiple mitochondrial DNA deletions in muscle and peripheral nerve. Sensory ataxic neuropathy may be the predominant and presenting manifestation of a mitochondrial disorder, and a mitochondrial etiology should be included in its differential diagnosis. The triad of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) may represent a novel mitochondrial disease associated with multiple mitochondrial DNA deletions.
D-Penicillamine treatment for chronic sensory ataxic neuropathy associated with Sjogren's syndrome
AbstractBeneficial treatment has not been established for chronic sensory ataxic neuropathy associated with Sjögren's syndrome (CSAN-SS). We describe two patients with CSAN-SS who clinically improved in response to D-penicillamine treatment. Their neuropathic symptoms were lessened after D-penicillamine, and the results of electrophysiologic studies support the clinical improvement. D-Penicillamine can be considered a potentially beneficial agent in the treatment of CSAN-SS.
Human Genome Variation · 2018 · 8 citations · open access
Protein molecular modeling shows residue T599 is critical to wild-type function of POLG and description of a novel variant associated with the SANDO phenotype
AbstractAbstract Sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO) is a rare phenotype resulting from pathogenic variants of mitochondrial DNA polymerase gamma ( POLG ). We modeled a novel POLG variant, T599P, that causes the SANDO phenotype and another variant at the same residue, p.T599E, to observe their effect on protein function and confirm the pathogenicity of T599P. Through neoteric molecular modeling techniques, we show that changes at the T599 residue position introduce extra rigidity into the surrounding helix–loop–helix, which places steric pressure on nearby nucleotides. We also provide a clinical description of the T599P variant, which was found in a 42-year-old female proband. The proband presented a 1-year history of progressive gait instability, dysarthria and foot numbness. Her neurologic examination revealed ataxic dysarthria, restricted eye movements, head and palatal tremors, reduced lower limb reflexes, distal multimodal sensory loss and a wide, unsteady ataxic gait. Electromyography studies indicated a sensory neuropathy. Whole-exome sequencing was pursued after tests for infectious, inflammatory and paraneoplastic causes were negative.
Journal of the Peripheral Nervous System · 2019 · 7 citations
Myelin uncompaction and axo‐glial detachment in chronic ataxic neuropathy with monospecific IgM antibody to ganglioside GD1b
AbstractTo describe clinical features, disease course, treatment response, and sural nerve biopsy findings in a patient with chronic sensory ataxic neuropathy, Binet stage A chronic lymphocytic leukemia, and monoclonal IgMλ paraprotein against ganglioside GD1b. During 9 months of hospitalization at two neurologic centers, the patient underwent serial neurologic examinations, neurophysiologic studies, imaging investigations, extensive laboratory work-up, bone marrow, and sural nerve biopsies. The patient had a severe progressive sensory neuropathy accompanied by motor involvement, dysautonomia, and marked bulbar weakness with preserved ocular movements. Conduction studies were characterized by prolonged F-wave minimal latencies, prolonged distal latencies, reduction of compound motor action potentials, and absence of sensory nerve action potentials. Sural nerve biopsy showed endoneurial edema, axonal degeneration, and regeneration, in the absence of cellular inflammation, macrophagic activation, and B-lymphocyte infiltration; no IgM or complement deposition was detected. Myelinated fibers showed redundant/abnormally thickened myelin, myelin vacuolation, and frank intramyelinic edema with condensed axoplasm. Ultrastructural features included axo-glial detachment, disruption of membrane integrity, and myelin uncompaction. This study shows that monospecific anti-GD1b IgM paraprotein is associated with non-inflammatory nerve damage. We suggest that the loss of myelin and axonal integrity reflects antibody-induced disruption of membrane lipid rafts.
Rinsho Shinkeigaku · 2024 · 1 citations · open access
Hereditary sensory and autonomic neuropathy 1E showing hyperreflexia: a case report
AbstractA 52-year-old man had developed hearing loss since childhood, as well as recurrent foot ulcers and osteomyelitis since his forties. He presented with gait disturbance and dysarthria that had worsened over four years and a month, respectively. Neurological exams revealed cognitive impairment, proximal weakness of the lower extremities, generalized hyperrflexia, ataxia, sensory disturbances predominant in deep sensation, urinary retention, and gait instability. On nerve conduction study, no sensory nerve action potentials were evoked in the upper and lower limbs. Since his grandmother suffered from similar symptoms, we investigated genetic analysis, which revealed a missense mutation (c.1483T>C, p.Y495H) in DNA methyltransferase 1 gene. He was subsequently diagnosed with hereditary sensory and autonomic neuropathy 1E (HSAN1E). It is important to recognize that increased deep tendon reflex can be observed in HSAN1E.
Research Square · 2023 · 0 citations · open access
Anti-CNTN-1 autoimmune nodopathies with dysarthria at onset - a case report and literature review
AbstractAbstract BACKGROUND: Anti-CNTN-1 autoimmune nodopathies (AN) is a new and rare diagnosis of peripheral neuropathy proposed by the European Society of Neurology in recent years. Clinical manifestations usually include chronic, subacute or rapidly progressive sensory or motor disorders, sensory ataxia, tremor, and cranial nerve involvement (facial paralysis, eye movement limitation, diplopia, etc. However, anti-CNTN-1 autoimmune nodopathies with dysarthria have rarely been reported. We report a rare young case with dysarthria. Case introduction: This is a case of a 25-year-old male patient with an initial onset of dysarthria and limb tremor. He was initially misdiagnosed withspinocerebellar ataxia (SCA), and the symptoms gradually worsened, including limb weakness, sensory disorders of the limbs, muscle atrophy of the distal lower limbs, and positional dizziness. Neuroelectrophysiological examination showed multiple peripheral nerve damage (motor and sensory damage), and the myelin sheath and axons were involved (mainly the myelin sheath). The blood and cerebrospinal fluid of peripheral neuropathy autoimmune antibody tests indicated that anti-CNTN-1 antibody, the serum GD1b antibody was positive, and a corrected diagnosis of CNTN-1 autoimmune nodopathies. The patient was treated with rituximab, and limb weakness and dysarthria were improved after 3 months of follow-up. Conclusion: Compared with the previously reported cases of anti-CNTN-1 AN, the cases we describe are young patients with dysarthria and limb tremor, highlighting the possibility of this disease presenting as unconventional peripheral nerve onset. We hope this article will improve clinicians' awareness of this kind of disease and reduce the misdiagnosis rate of this disease to help patients diagnose and treat it in time.
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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