DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for myoclonic dystonia 26 — 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 moduleMyoclonic dystonia 26 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 myoclonic dystonia 26 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
potassium channel tetramerization domain containing 17 (KCTD17) — KCTD17 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 5A6R · 2.85 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Myoclonus-dystonia (M-D) is a heritable movement disorder characterised by myoclonic jerks and dystonia, primarily of the upper extremities. Pharmacological treatment remains poorly effective. A systematic review of 17 publications covering 40 unique cases of deep brain stimulation (DBS) reported a mean follow-up of 27.2 months. All patients showed improvements in myoclonus scores, with 93.5% achieving at least a 50% improvement on the Unified Myoclonus Rating Scale (UMRS), and a mean improvement of 72.6%. Dystonia scores improved in 87.9% of patients, with 72.7% reporting at least a 50% improvement on the Burke-Fahn-Marsden dystonia rating scale (BFMDRS), and a mean improvement of 52.6%. Improvements in myoclonus were similar for stimulation of the internal globus pallidus (GPi, 75.7%) and the ventral intermediate nucleus of the thalamus (VIM, 70.4%; P = 0.27). However, dystonia improvements were greater with GPi stimulation (60.2%) than with VIM stimulation (33.3%; P = 0.03).
Mutations in the epsilon-sarcoglycan gene (SGCE) are associated with M-D in most families. In a Dutch cohort of 31 patients with the M-D phenotype, only 7 carried an SGCE mutation. Positive family history and truncal myoclonus were independent predictors of mutation carrier status. Early disease onset, onset with both myoclonus and dystonia, and axial dystonia were significantly more frequent in mutation carriers. In two single families where mutations in DRD2 or DYT1 were reported, a concurrent SGCE mutation was also found. The molecular mechanisms by which these mutations contribute to the disorder remain undetermined.
The genetic landscape of dystonia is heterogeneous. Isolated dystonia can be caused by mutations in TOR1A (DYT1), TUBB4 (DYT4), THAP1 (DYT6), CIZ1 (DYT23), ANO3 (DYT24), and GNAL (DYT25). Combined dystonias with myoclonus or parkinsonism are further subdivided into persistent forms (including SGCE for DYT11) and paroxysmal forms. New dystonia genes continue to be identified through next-generation sequencing, though independent confirmation is still needed. The genetic contribution to dystonia ranges from small-effect susceptibility factors to fully penetrant causative genes, and the pathways involved include dopamine signalling, intracellular transport, cytoskeletal dynamics, transcriptional regulation, and ion channel function.
What is missing is a clear understanding of how the identified mutations produce the clinical phenotype, and why most patients with the M-D phenotype test negative for known mutations. The DBS evidence is limited to 40 uncontrolled cases with no randomised comparison, and the long-term outcomes beyond a mean of 27 months are unknown. No pharmacological trial has shown reliable benefit. Stratification by genotype and target selection in DBS remains based on small numbers, and no prospective trial has been funded to address these gaps.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Movement Disorders · 2009 · 163 citations · open access
Myoclonus‐dystonia: An update
AbstractOur knowledge of the clinical, neurophysiological, and genetic aspects of myoclonus-dystonia (M-D) has improved markedly in the recent years. Basic research has provided new insights into the complex dysfunctions involved in the pathogenesis of M-D. On the basis of a comprehensive literature search, this review summarizes current knowledge on M-D, with a focus on recent findings. We also propose modified diagnostic criteria and recommendations for clinical management.
AbstractMyoclonus dystonia (M-D) syndrome is a heritable movement disorder characterized by myoclonic jerks and dystonia primarily of the upper extremities. M-D remains poorly responsive to pharmacological treatment. Emerging reports suggest good response to DBS of the internal globus pallidus (GPi) and ventral intermediate nucleus (VIM) of the thalamus. This study aimed to appraise the value of these two DBS targets by evaluating reports available in the literature. A systematic search of published case reports and case series was performed on Medline and Embase. Responses to DBS were evaluated. Myoclonus was assessed with the Unified Myoclonus Rating Scale (UMRS) and dystonia by the Burke-Fahn-Marsden dystonia rating scale (BFMDRS). The primary outcome of interest was the relative improvements noted with GPi, compared to VIM stimulation. A total of 17 publications yielded 40 unique cases, with mean follow-up of 27.2 months. All patients demonstrated improvements in myoclonus scores, with 93.5% showing at least a 50% improvement in UMRS. The mean improvement in myoclonus scores was 72.6%. In contrast, dystonia scores were improved in 87.9% of patients, with 72.7% reporting at least a 50% improvement in BFMDRS. The mean improvement in dystonia scores was 52.6%. Improvements in myoclonus scores were similar for both GPi (75.7%) and VIM (70.4%; P = 0.27). However, the improvements in dystonia scores were greater with GPi (60.2%), compared to VIM (33.3%; P = 0.03). Although both targets achieve similar improvements in myoclonus, GPi stimulation may be a preferred target because it may achieve greater improvements in dystonia, compared to VIM stimulation.
ε‐sarcoglycan mutations found in combination with other dystonia gene mutations
AbstractMyoclonus-dystonia is a movement disorder associated with mutations in the epsilon-sarcoglycan gene (SGCE) in most families and in the DRD2 and DYT1 genes in two single families. In both of the latter families, we also found a mutation of SGCE. The molecular mechanisms through which the detected mutations may contribute to myoclonus-dystonia remain to be determined.
A randomized, controlled, double-blind, crossover trial of zonisamide in myoclonus-dystonia
AbstractOBJECTIVE: To evaluate the efficacy and safety of zonisamide in patients with myoclonus-dystonia. METHODS: We conducted a randomized, double-blind, placebo-controlled crossover trial of zonisamide (300 mg/d) in 24 patients with myoclonus-dystonia. Each treatment period consisted of a 6-week titration phase followed by a 3-week fixed-dose phase. The periods were separated by a 5-week washout period. The co-primary outcomes were action myoclonus severity (section 4 of the Unified Myoclonus Rating Scale [UMRS 4]) and myoclonus-related functional disability (UMRS 5). Secondary outcomes included dystonia severity, assessed with the movement and disability subscales of the Burke-Fahn-Marsden-Dystonia Rating Scale (BFM), the Clinical Global Impression-Improvement scale (CGI), and safety measures. Wilcoxon signed-rank tests for paired data were used to analyze treatment effects. RESULTS: Twenty-three patients (11 men, 12 women) were analyzed in the intention-to-treat analysis. Zonisamide significantly improved both action myoclonus (median improvement [95% confidence limits] -5 [-9.25 to -1.44], p = 0.003) and myoclonus-related functional disability (median improvement [95% confidence limits] -2 [-2.58 to -2.46], p = 0.007) compared to placebo. Zonisamide also significantly improved dystonia (BFM movement) compared to placebo (median improvement [95% confidence limits] -3 [-8.46 to 0.03], p = 0.009). No difference was found between zonisamide and placebo with respect to the CGI (median improvement [95% confidence limits] -1 [-1.31 to 0.09], p = 0.1). Zonisamide was well-tolerated. CONCLUSIONS: Zonisamide is well-tolerated and effective on the motor symptoms of myoclonus-dystonia. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that zonisamide improves myoclonus and related disability in patients with myoclonus-dystonia.
Phenotype-genotype correlation in Dutch patients with myoclonus-dystonia
AbstractThe epsilon-sarcoglycan (SGCE) gene is an important cause of myoclonus-dystonia (M-D), although the majority of cases with an M-D phenotype test negative. Seven of 31 patients with the M-D phenotype carried a mutation in the SGCE gene. Positive family history and truncal myoclonus were independent prognostic factors. Early disease onset, onset with both myoclonus and dystonia, and axial dystonia were detected significantly more often in the mutation carriers.
A Case of Myoclonus–Dystonia Responding to Low-frequency Pallidal Stimulation
AbstractBACKGROUND: High-frequency pallidal stimulation has been shown to improve various types of dystonia, including myoclonus-dystonia. CASE REPORT: We report a case of epsilon sarcoglycan mutation-negative myoclonus-dystonia with response to low-frequency bilateral pallidal stimulation. DISCUSSION: Low-frequency pallidal stimulation provides an effective means of treating various dystonias, regardless of genetic status, as in our case, as it provides increased programming options with fewer adverse effects.
Journal of Neurology & Neurophysiology · 2014 · 3 citations · open access
Research Advances on the Treatment of Myoclonus-Dystonia Syndrome
AbstractMyoclonus-Dystonia Syndrome is a movement disorder characterized by the association of myoclonus and dystonia as the sole or prominent symptoms. Non-motor features may include obsessive-compulsive disorder, depression, anxiety, personality disorders, alcohol abuse, and panic attacks. The pathogenesis of MDS is not very clear, and the current opinions are mainly focus on gene mutations. The diagnosis is mainly based on clinical features, and this disorder is confirmed by gene testing. Myoclonus-Dystonia Syndrome can't be cured, and the current therapy is mainly aimed to improve the symptoms, which includes medical and surgical treatment. All in all, MDS remains poorly responsive to medical treatment. Although the surgical treatment develops very quickly in recent years, due to the difficulty in predicting the range of operation and the large expense, surgical treatment is hard to be implemented in clinical practice widely. Currently, medical treatment is still the main method, and the surgery is considered when medication is ineffective.
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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