DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for apraxia — 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 moduleApraxia 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
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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 apraxia 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
SIL1 nucleotide exchange factor (SIL1) — SIL1 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 u9odrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8Q7R · 3.71 Å · ligand 5-azanyl-1-oxidanyl-pentan-2-one (U9O). Experimental structure, not a prediction.
What the evidence adds up to
Apraxia is not a single disease but a symptom that appears in several distinct genetic and neurodegenerative conditions. In ataxia with oculomotor apraxia type 2 (AOA2), a recessive disorder caused by SETX mutations, ten patients from four Italian families all had cerebellar ataxia and slurred speech, but oculomotor apraxia itself was seen in only two of them. All ten had elevated serum alpha-fetoprotein, motor and sensory axonal neuropathy, and marked cerebellar atrophy on MRI. Sural nerve biopsy in two patients showed severe depletion of large myelinated fibres in one and loss of both large and small fibres in the other. Four different homozygous SETX mutations were found, including a missense change outside the helicase domain, suggesting an additional functional region in senataxin.
In a separate genetic syndrome, the c.429_452 duplication of the ARX gene produces a recognisable clinical picture in 27 patients from 12 French families. All had intellectual disability without primary motor impairment, but with a specific upper limb distal motor apraxia and a pathognomonic hand-grip. Kinematic analysis showed loss of preference for the index finger when gripping, major impairment of fourth finger dexterity, and lack of pronation movements — a pattern described as a developmental model of limb kinetic apraxia. A control group of 27 age- and IQ-matched Down syndrome patients did not show these features. The most severely affected patients, fitting the earlier description of Partington syndrome, had major hand dystonia and orolingual apraxia.
Among neurodegenerative dementias, apraxia is common but its pattern varies by diagnosis. In a study of 300 patients meeting DSM-IV criteria for dementia, Alzheimer’s disease showed ideational, ideomotor, dressing and constructional apraxias early, with buccopharyngeal and gait apraxia appearing late. Frontotemporal lobe dementia showed buccopharyngeal and gait apraxia only late in the disease. Cortical basal ganglionic degeneration showed limb apraxias, while diffuse Lewy body disease showed more agnosias and fewer apraxias. In a separate review of primary progressive apraxia covering 31 published cases and four new ones, mean onset age was 60.5 years and mean illness duration was 4.2 years for survivors and 6.8 years for deceased cases. Limb-kinetic apraxia was the most frequent symptom, but apraxia of speech, buccofacial apraxia and dressing apraxia also occurred in isolation. Autopsy findings in four cases showed corticobasal degeneration in one, Alzheimer’s disease in three, and Pick’s disease in one, confirming that primary progressive apraxia is a heterogeneous symptomatic condition.
At the molecular level, aprataxin — the protein mutated in ataxia-oculomotor apraxia syndrome 1 (AOA1) — is an AMP-lysine hydrolase whose activity depends on a histidine triad domain and an N-terminal forkhead-associated domain. Eight disease-associated mutations caused major loss of both protein stability and enzymatic activity; a mutation linked to milder disease showed less severe loss. The authors concluded that loss of aprataxin’s ability to hydrolyse nucleotidylated protein modifications is associated with development of AOA. What remains missing for all these conditions is not a candidate mechanism but the practical infrastructure to test interventions: no randomised trials of any drug for apraxia have been reported, no biomarker that tracks progression in daily function has been validated across syndromes, and patient stratification by genetic subtype or pathological diagnosis is rarely attempted in treatment studies.
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 · 2006 · 122 citations
Ataxia with oculomotor apraxia type 2
AbstractBACKGROUND: Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset between age 10 and 22 years, cerebellar atrophy, peripheral neuropathy, oculomotor apraxia (OMA), and elevated serum alpha-fetoprotein (AFP) levels. Recessive mutations in SETX have been described in AOA2 patients. OBJECTIVE: To describe the clinical features of AOA2 and to identify the SETX mutations in 10 patients from four Italian families. METHODS: The patients underwent clinical examination, routine laboratory tests, nerve conduction studies, sural nerve biopsy, and brain MRI. All were screened for SETX mutations. RESULTS: All the patients had cerebellar features, including limb and truncal ataxia, and slurred speech. OMA was observed in two patients, extrapyramidal symptoms in two, and mental impairment in three. High serum AFP levels, motor and sensory axonal neuropathy, and marked cerebellar atrophy on MRI were detected in all the patients who underwent these examinations. Sural nerve biopsy revealed a severe depletion of large myelinated fibers in one patient, and both large and small myelinated fibers in another. Postmortem findings are also reported in one of the patients. Four different homozygous SETX mutations were found (a large-scale deletion, a missense change, a single-base deletion, and a splice-site mutation). CONCLUSIONS: The clinical phenotype of oculomotor apraxia type 2 is fairly homogeneous, showing only subtle intrafamilial variability. OMA is an inconstant finding. The identification of new mutations expands the array of SETX variants, and the finding of a missense change outside the helicase domain suggests the existence of at least one more functional region in the N-terminus of senataxin.
Indian Journal of Psychological Medicine · 2015 · 31 citations · open access
Apraxias in Neurodegenerative Dementias
AbstractBACKGROUND: Apraxia is a state of inability to carry out a learned motor act in the absence of motor, sensory or cerebellar defect on command processed through the Praxis circuit. Breakdown in default networking is one of the early dysfunction in cortical dementias and result in perplexity, awkwardness, omission, substitution errors, toying behavior and unrecognizable gestures in response to command with voluntary reflex dissociation where, when unobserved patient will carry out reflex movements normally. Awareness into the organicity of these phenomenas will help in early diagnosis, which will help in initiating appropriate treatment and slowing down the progression of the disease. AIMS AND OBJECTIVES: The aim was to look for the various kinds of apraxias in patients with dementia using appropriate simple tests. PATIENTS AND METHODS: Three hundred patients satisfying Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for dementia were evaluated in detail with mandatory investigations for dementia followed by testing for ideational, ideomotor, limb-kinetic, buccopharyngeal, dressing apraxia, constructional apraxia and gait apraxias in addition to recording of rare apraxias when present. RESULTS: Alzheimer's disease showed maximum association with apraxias in all the phases of the disease ideational, ideomotor, dressing and constructional apraxias early and buccopharyngeal and gait apraxia late. Frontotemporal lobe dementia showed buccopharyngeal and gait apraxias late into the disease. Cortical basal ganglionic degeneration showed limb apraxias and diffuse Lewy body disease showed more agnosias and less apraxias common apraxias seen was Ideational and Ideomotor. CONCLUSION: Recognition of the apraxias help in establishing organicity, categorization, caregiver education, early strategies for treatment, avoiding anti-psychotics and introducing disease modifying pharmacotherapeutic agents and also prognosticating.
Neuropathology · 1999 · 18 citations · open access
Primary progressive apraxia
AbstractWe have investigated the clinical symptoms and pathological findings of primary progressive apraxia (PPA) in 31 cases in the literature and four of our own cases. The mean age of onset of the initial symptoms was 60.5 years, with a slight predilection for males. The time between the onset of symptoms and the medical examination was 3.1 years. The mean duration of illness was 4.2 years for the surviving cases and 6.8 years for the four deceased cases. The most frequently encountered apraxia symptom is a limb‐kinetic apraxia. It has become known that other forms of apraxia such as apraxia of speech, buccofacial apraxia and dressing apraxia, which are not established as a symptomatic condition, can manifest themselves in an isolated manner. Neurological examination often reveals extrapyramidal symptoms such as rigidity and myoclonus from the beginning of the illness. As for the higher functional problems, apraxia is often accompanied by a distrubance of calculation. With regard to the radiological findings, computed tomography and magnetic resonance imaging show characteristic atrophy with left–right inequality and diffuse disturbance in single photon emission computed tomography‐positron emission tomography study is seen on the more severely atrophic side. In autopsy and biopsy examinations, one patient was diagnosed with corticobasal degeneration, three cases were diagnosed with Alzheimer's disease and one with Pick's disease. PPA is a heterogeneous symptomatic condition. This paper confirm the existence of apraxias which were not previously recognized as concrete symptomatic conditions; furthermore, it is suggested that the cerebral system of behavioral association might be more subdivided than was formerly considered.
Orphanet Journal of Rare Diseases · 2014 · 17 citations · open access
The c.429_452 duplication of the ARX gene: a unique developmental-model of limb kinetic apraxia
AbstractBACKGROUND: The c.429_452dup24 of the ARX gene is a rare genetic anomaly, leading to X-Linked Intellectual Disability without brain malformation. While in certain cases c.429_452dup24 has been associated with specific clinical patterns such as Partington syndrome, the consequence of this mutation has been also often classified as "non-specific Intellectual Disability". The present work aims at a more precise description of the clinical features linked to the c.429_452dup24 mutation. METHODS: We clinically reviewed all affected patients identified in France over a five-year period, i.e. 27 patients from 12 different families. Detailed cognitive, behavioural, and motor evaluation, as well as standardized videotaped assessments of oro-lingual and gestural praxis, were performed. In a sub-group of 13 ARX patients, kinematic and MRI studies were further accomplished to better characterize the motor impairment prevalent in the ARX patients group. To ensure that data were specific to the ARX gene mutation and did not result from low-cognitive functioning per se, a group of 27 age- and IQ-matched Down syndrome patients served as control. RESULTS: Neuropsychological and motor assessment indicated that the c.429_452dup24 mutation constitutes a recognizable clinical syndrome: ARX patients exhibiting Intellectual Disability, without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip. Patients affected with the so-called Partington syndrome, which involves major hand dystonia and orolingual apraxia, exhibit the most severe symptoms of the disorder. The particular "reach and grip" impairment which was observed in all ARX patients, but not in Down syndrome patients, was further characterized by the kinematic data: (i) loss of preference for the index finger when gripping an object, (ii) major impairment of fourth finger deftness, and (iii) a lack of pronation movements. This lack of distal movement coordination exhibited by ARX patients is associated with the loss of independent digital dexterity and is similar to the distortion of individual finger movements and posture observed in Limb Kinetic Apraxia. CONCLUSION: These findings suggest that the ARX c.429_452dup24 mutation may be a developmental model for Limb Kinetic Apraxia.
S S Korsakov Journal of Neurology and Psychiatry · 2015 · 1 citations
Classification and diagnosis of apraxia
AbstractApraxia is one of the most frequent clinical presentations of vascular, traumatic, infectious, tumor and neurodegenerative diseases of the brain. However neurologists have difficulties with diagnosis. The author presents a review of current classifications of apraxia and methods of its clinical diagnosis.
AbstractAtaxia-oculomotor apraxia syndrome 1 (AOA), a neurological disorder characterized by abnormal movements of the head and eye, is associated with mutation of APTX , the gene that encodes aprataxin (a nuclear protein that mediates protein-protein interactions as part of the DNA damage response). Curiously, though, aptx -mutant cells do not show evidence of a major deficit in this response. Noting that APTX mutations associated with AOA involve either a histidine triad (HIT) domain similar to that of Hint (an AMP-lysine hydrolase) or the HIT domain's immediate C-terminal region, Seidle et al. used fluorigenic substrates to show that aprataxin acted as an AMP-lysine and GMP-lysine hydrolase. Aprataxin contains an N-terminal forkhead-associated (FHA) domain and a C-terminal zinc-finger domain, as well as the HIT domain; its AMP-lysine hydrolase activity depended on the Hint active site and also on the presence of the FHA domain, whereas the zinc-finger domain was necessary for protein stability. The authors used SDS-PAGE and Western analysis, together with analysis of biochemical activity against an adenylylated lysine substrate, to show that eight disease-associated mutations were characterized by a major loss of both protein stability and enzymatic activity. A mutation associated with less severe disease displayed a less dramatic loss of protein stability and enzymatic activity. Thus, the authors conclude that it is the loss of the ability of aprataxin to hydrolyze nucleotidylated protein modifications that is associated with the development of AOA. H. F. Seidle, P. Biegnowski, C. Brenner, Disease-associated mutations inactivate AMP-lysine hydrolase activity of aprataxin. J. Biol. Chem. 280 , 20927-20931 (2005). [Abstract] [Full Text]
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.
