DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for hypermanganesemia with dystonia 2 — 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 moduleHypermanganesemia with dystonia 2 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 hypermanganesemia with dystonia 2 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
Hypermanganesemia with dystonia type 2 is a rare autosomal recessive neurodegenerative disorder caused by a mutation in the SLC39A14 gene, characterised by loss of previously acquired milestones, dystonia, parkinsonian features, high serum manganese, and bilateral T1 hyperintensity with T2 hypointensity in the basal ganglia on MRI. A 2022 retrospective case series of three unrelated paediatric patients at a tertiary university hospital reported that all three were started on chelation therapy with calcium disodium edetate. Two of the three showed improvement in their clinical course, and the authors concluded that early diagnosis and intervention with chelating agents could alter the disease course and prevent deterioration. The sample is three patients, and two responded.
Other abstracts in this set address dystonia more broadly, not hypermanganesemia specifically. A 1990 study found that 5 of 24 (21%) normal men given the catecholamine-depleting agent alpha-methyl-para-tyrosine developed acute dystonic reactions, suggesting catecholamine depletion alone can cause acute dystonia. A 1997 case report described one patient with tardive dystonia who improved substantially on 1200 mg/day of vitamin E. A 2022 case report described new-onset cervical dystonia in pregnancy that persisted after delivery, adding to the concept of dystonia gravidarum. A 2017 report described a 27-year-old man with functional right lower limb focal dystonia who developed axonal sensorimotor neuropathy from repeated Entonox (nitrous oxide) use, which caused functional B12 deficiency despite normal serum B12 levels; symptoms resolved after stopping nitrous oxide, B12 injections, and cognitive behavioural therapy.
No abstract in this set reports a controlled trial for hypermanganesemia with dystonia type 2. The chelation therapy evidence rests on three patients, two of whom improved. What is still missing is any randomised or larger prospective study, standardised dosing and monitoring protocols for chelation, and understanding of why one patient did not respond — possibly due to delayed diagnosis, genetic heterogeneity, or irreversible damage by the time treatment began.
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 · 2013 · 214 citations
The focal dystonias: Current views and challenges for future research
AbstractThe most common forms of dystonia are those that develop in adults and affect a relatively isolated region of the body. Although these adult-onset focal dystonias are most prevalent, knowledge of their etiologies and pathogenesis has lagged behind some of the rarer generalized dystonias, in which the identification of genetic defects has facilitated both basic and clinical research. This summary provides a brief review of the clinical manifestations of the adult-onset focal dystonias, focusing attention on less well understood clinical manifestations that need further study. It also provides a simple conceptual model for the similarities and differences among the different adult-onset focal dystonias as a rationale for lumping them together as a class of disorders while at the same time splitting them into subtypes. The concluding section outlines some of the most important research questions for the future. Answers to these questions are critical for advancing our understanding of this group of disorders and for developing novel therapeutics.
Acute Dystonic Reaction in Normal Humans Caused by Catecholamine Depletion
AbstractFive of 24 (21%) normal men (volunteers) administered alpha-methyl-para-tyrosine (AMPT), a catecholamine-depleting agent, developed acute dystonic reactions. The finding that catecholamine depletion without receptor blockade is sufficient to cause acute dystonia suggests that a variety of neurotransmitter imbalances may lead to idiopathic primary dystonia.
Hypermanganesemia with Dystonia Type 2: A Potentially Treatable Neurodegenerative Disorder: A Case Series in a Tertiary University Hospital
AbstractImportance: Hypermanganesemia with dystonia type 2 is a rare autosomal recessive neurodegenerative disorder characterized by the loss of previously acquired milestones, dystonia, parkinsonian features, a high serum manganese level, and characteristic neuroimaging findings such as bilateral and symmetrically increased T1 and decreased T2/fluid-attenuated inversion recovery signal intensity in the basal ganglia. This condition is secondary to a mutation in the SLC39A14 gene. Objective: To present a series of three cases of hypermanganesemia with dystonia type 2, which was genetically confirmed secondary to a mutation in the SLC39A14 gene, and to describe the treatment and clinical course in these cases. Design: A retrospective case series. Setting: University, Tertiary hospital. Participants: Three unrelated pediatric patients with hypermanganesemia with dystonia type 2, genetically confirmed to be secondary to a mutation in the SLC39A14 gene. Exposures: Chelation therapy using calcium disodium edetate. Main outcome(s) and measure(s): The response to chelation therapy based on clinical improvements in motor and cognition developments. Results: All three patients were started on chelation therapy using calcium disodium edetate, and two of them showed an improvement in their clinical course. The chelation therapy could alter the course of the disease and prevent deterioration in the clinical setting. Conclusions and Relevance: Early diagnosis and intervention with chelating agents, such as calcium disodium edetate, will help change the outcome in patients with hypermanganesemia with dystonia type 2. This finding highlights the importance of early diagnosis and treatment in improving the outcomes of patients with treatable neurodegenerative disorders.
AbstractTardive dystonia is a disorder characterized by abnormally sustained posturing associated with the use of dopamine-receptor blocking agents such as antipsychotic drugs. However, the structural pathologic and pathophysiologic features of this disorder are unknown, and no consistently effective pharmacologic treatment is available. Patients with tardive dystonia mostly are young men. We present the case of one substantially improved with treatment by 1200 mg/d (IU) of vitamin E.
Brain and Behavior · 2023 · 5 citations · open access
Neuroimaging findings in DYT1 dystonia and the pathophysiological implication: A systematic review
AbstractBACKGROUND: Primary generalized dystonia due to the DYT1 gene is an autosomal dominant disorder caused by a GAG deletion on chromosome 9q34. It is a well-defined, genetically proven, isolated dystonia syndrome. However, its pathophysiology remains unclear. OBJECTIVES: This study was aimed at profiling the functional neuroimaging findings in DYT1 dystonia and harmonizing the pathophysiological implications for DYT1 dystonia from the standpoint of different neuroimaging techniques. METHODS: A systematic review was conducted using identified studies published in English from Medline, PsycINFO, Embase, CINAHL, and the Cochrane Database of Systematic Reviews (CDSR), between 1985 and December 2019 (PROSPERO protocol CRD42018111211). RESULTS: All DYT1 gene carriers irrespective of clinical penetrance have reduced striatal GABA, dopamine receptors and increased metabolic activity in the lentiform nucleus, supplementary motor area, and cerebellum in addition to an abnormal cerebellothalamocortical pathway. Nonmanifesting carriers on the other hand have a disruption of the distal (thalamocortical) segment and have larger putaminal volumes than manifesting carriers and healthy controls. Activation of the midbrain, thalamus, and sensorimotor cortex was only found in the manifesting carriers. CONCLUSIONS: Therefore, we propose that DYT1 dystonia is a cerebellostriatothalamocortical network disorder affecting either the structure or function of the different structures or nodes in the network.
Tremor and Other Hyperkinetic Movements · 2022 · 2 citations · open access
A Case of New Onset Cervical Dystonia in Pregnancy
AbstractBackground: Though uncommon, primary movement disorders can occur in pregnancy, the most common being restless legs syndrome and chorea gravidarum [1]. New onset dystonia in pregnancy has been reported four times previously with a resolution of symptoms within six months of delivery [2345]. Exacerbation of pre-existing movement disorders and the onset of de novo movement disorders during pregnancy support the hypothesis that female sex hormones play an important role in the regulation of basal ganglia circuitry. Case Report: Here we describe a case of new-onset cervical dystonia during pregnancy with persistence of symptoms after delivery. Discussion: The phenotypic overlap between this case and previously reported cases further establishes dystonia gravidarum as a distinct clinical entity.
Abstract<h3>To the Editor.—</h3> Torsion dystonia (dystonia muscularum deformans) is a rare condition that is generally difficult to diagnose and more difficult to treat. Our limited understanding of this condition suggests that its mechanism involves abnormalities in one or more neurotransmitter substances in the basal ganglia of the brain. Development of a variety of drugs that modify central neurotransmission has offered considerable therapeutic advance in the treatment of a variety of neurological and psychiatric conditions. Because of the rarity of torsion dystonia, few controlled studies of therapeutic agents have been accomplished in this condition. On the other hand, a variety of clinicians have had experience with one or more patients whose conditions responded or even worsened with one or another pharmacologic approach. I am presently reviewing the pharmacologic treatment of this condition in an attempt to consolidate published and unpublished information regarding potential treatment and mechanisms involved in torsion dystonia. I
PO080 The two faces of a functional neurological disorder
Abstract<h3></h3> Vitamin B12 (Cobalamin) deficiency is a well-known cause of central and peripheral nervous system dysfunction, including sensorimotor peripheral neuropathy. Methylmalonate CoA mutase and homocysteine methyltransferase are cobalamin dependent enzymes. In cobalamin deficiency, the metabolic reactions catalysed by these enzymes are inhibited, resulting in the accumulation of methylmalonic acid (MMA) and homocysteine in the blood. High plasma levels of MMA and homocysteine indicate functional (organic) B12 deficiency in individuals with normal renal function and normal or low B12 level. Nitrous oxide (N<sub>2</sub>O) is a poorly recognised cause of vitamin B12 deficiency and subsequent neuropathy/myelopathy. We present a case of 27 year old male who was diagnosed with a functional (psychogenic) right lower limb focal dystonia. His severely painful right leg paroxysmal spasms were treated on more than fifty occasions with Entonox (50:50 n<sub>2</sub>O and oxygen mixture) over the five years. He developed an axonal sensorimotor neuropathy and was diagnosed with a functional (organic) B12 deficiency related to N<sub>2</sub>O administration. His pre-treatment vitamin B12 levels were normal. However, levels of MMA and homocysteine were high. He was advised complete cessation of N<sub>2</sub>O, B12 injections and cognitive behavioural therapy for the functional limb dystonia. Post-treatment, his sensory symptoms resolved and MMA and homocysteine levels normalised.
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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