DeCure for Classic dopamine transporter deficiency syndrome
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for classic dopamine transporter deficiency syndrome — 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 moduleClassic dopamine transporter deficiency syndrome 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 classic dopamine transporter deficiency syndrome 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
solute carrier family 6 member 3 (SLC6A3) — SLC6A3 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 clrdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9EO4 · 2.66 Å · ligand CHOLESTEROL (CLR). Experimental structure, not a prediction.
What the evidence adds up to
The 2010 study of 11 children with dopamine transporter deficiency syndrome found that all had raised ratios of homovanillic acid to 5-hydroxyindoleacetic acid in cerebrospinal fluid, ranging from 5.0 to 13.2 (normal 1.3–4.0). All carried homozygous or compound heterozygous SLC6A3 mutations. In-vitro functional studies showed loss of function in all missense variants. Single photon emission CT DaTSCAN imaging in one patient showed complete loss of dopamine transporter activity in the basal nuclei. Children presented in infancy (median age 2.5 months, range 0.5–7) with hyperkinesia (n=5), parkinsonism (n=4), or a mixed hyperkinetic and hypokinetic movement disorder (n=2). Seven of the 11 had been initially misdiagnosed with cerebral palsy. During childhood, patients developed severe parkinsonism-dystonia with an eye movement disorder and pyramidal tract features.
The 2004 study of 164 older subjects used FP-CIT SPECT to measure dopamine transporter loss in dementia with Lewy bodies, Alzheimer disease, Parkinson disease, and Parkinson disease with dementia. Significant reductions in FP-CIT binding occurred in the caudate and putamen in DLB compared with AD and controls. Transporter loss in DLB was of similar magnitude to that in PD but with a flatter rostrocaudal gradient. Region of interest analysis gave 78% sensitivity and 94% specificity for separating DLB from AD. The study did not include patients with dopamine transporter deficiency syndrome.
The 2013 study of 18 never-medicated adult ADHD subjects found that 12 months of methylphenidate treatment increased striatal dopamine transporter availability by 24% (caudate, putamen, ventral striatum; p<0.01). No changes occurred in 11 controls scanned twice at a 12-month interval. Before treatment there was no significant difference in dopamine transporter availability between ADHD and control groups; after treatment, ADHD participants had higher availability than controls (caudate p<0.007, putamen p<0.005). The authors note that upregulation of dopamine transporter availability during long-term treatment may decrease treatment efficacy and exacerbate symptoms when not under medication.
The 2016 review discusses mice with genetically altered DAT function but provides no new human data for dopamine transporter deficiency syndrome. The 2017 report of two siblings with identical compound heterozygous PARK2 mutations describes discordant phenotypes: the older brother had marked parkinsonism by his mid-20s, the younger brother had exercise-induced dystonia in his mid-30s with no progression. The younger sibling had a clearly abnormal DaT-SPECT scan despite not meeting clinical criteria for Parkinson disease. This is not a study of dopamine transporter deficiency syndrome.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Archives of Neurology · 2004 · 332 citations
Dopamine Transporter Loss Visualized With FP-CIT SPECT in the Differential Diagnosis of Dementia With Lewy Bodies
AbstractBACKGROUND: Dementia with Lewy bodies (DLB) is a common form of late-life dementia that can be difficult to differentiate from other disorders, especially Alzheimer disease (AD), during life. At autopsy the striatal dopaminergic transporter is reduced. OBJECTIVES: To examine the extent and pattern of dopamine transporter loss using iodine I 123-radiolabeled 2beta-carbomethoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (FP-CIT) with single-photon emission computed tomography (SPECT) in DLBs compared with other dementias and to assess its potential to enhance a differential diagnosis. DESIGN: Cohort study comparing FP-CIT with criterion standard of consensus clinical diagnosis. SETTING: General hospital. PARTICIPANTS: One hundred sixty-four older subjects (33 healthy older control subjects, 34 with NINCDS/ADRDA [National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association]-confirmed AD, 23 with consensus guideline-confirmed DLB, 38 with United Kingdom's Parkinson Disease Society Brain Bank-confirmed Parkinson disease [PD], and 36 with PD and dementia). INTERVENTIONS: Injection of (123)I-2beta-carbomethoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane with SPECT scan performed at 4 hours. MAIN OUTCOME MEASURES: Visual ratings of scans and region of interest analysis. RESULTS: Significant reductions (P<.001) in FP-CIT binding occurred in the caudate and anterior and posterior putamens in subjects with DLB compared with subjects with AD and controls. Transporter loss in DLBs was of similar magnitude to that seen in PD, but with a flatter rostrocaudal (caudate-putamen) gradient (P =.001), while the greatest loss in all 3 areas was seen in those who had PD and dementia. Both region of interest analysis and visual ratings provided good separation between DLBs and AD (region of interest: sensitivity, 78%; specificity, 94%; positive predictive value, 90%) but not among subjects with DLB, PD, and PD with dementia. CONCLUSIONS: Dopamine transporter loss can be detected in vivo using FP-CIT SPECT in DLB. Further studies, especially of subjects with DLB without PD, are required to fully establish use in clinical practice.
The Lancet Neurology · 2010 · 209 citations · open access
Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study
AbstractBACKGROUND: dopamine transporter deficiency syndrome is the first identified parkinsonian disorder caused by genetic alterations of the dopamine transporter. We describe a cohort of children with mutations in the gene encoding the dopamine transporter (SLC6A3) with the aim to improve clinical and molecular characterisation, reduce diagnostic delay and misdiagnosis, and provide insights into the pathophysiological mechanisms. METHODS: 11 children with a biochemical profile suggestive of dopamine transporter deficiency syndrome were enrolled from seven paediatric neurology centres in the UK, Germany, and the USA from February, 2009, and studied until June, 2010. The syndrome was characterised by detailed clinical phenotyping, biochemical and neuroradiological studies, and SLC6A3 mutation analysis. Mutant constructs of human dopamine transporter were used for in-vitro functional analysis of dopamine uptake and cocaine-analogue binding. FINDINGS: children presented in infancy (median age 2·5 months, range 0·5-7) with either hyperkinesia (n=5), parkinsonism (n=4), or a mixed hyperkinetic and hypokinetic movement disorder (n=2). Seven children had been initially misdiagnosed with cerebral palsy. During childhood, patients developed severe parkinsonism-dystonia associated with an eye movement disorder and pyramidal tract features. All children had raised ratios of homovanillic acid to 5-hydroxyindoleacetic acid in cerebrospinal fluid, of range 5·0-13·2 (normal range 1·3-4·0). Homozygous or compound heterozygous SLC6A3 mutations were detected in all cases. Loss of function in all missense variants was recorded from in-vitro functional studies, and was supported by the findings of single photon emission CT DaTSCAN imaging in one patient, which showed complete loss of dopamine transporter activity in the basal nuclei. INTERPRETATION: dopamine transporter deficiency syndrome is a newly recognised, autosomal recessive disorder related to impaired dopamine transporter function. Careful characterisation of patients with this disorder should provide novel insights into the complex role of dopamine homoeostasis in human disease, and understanding of the pathophysiology could help to drive drug development.
Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood
AbstractDopamine transporter deficiency syndrome due to SLC6A3 mutations is the first inherited dopamine 'transportopathy' to be described, with a classical presentation of early infantile-onset progressive parkinsonism dystonia. In this study we have identified a new cohort of patients with dopamine transporter deficiency syndrome, including, most significantly, atypical presentation later in childhood with a milder disease course. We report the detailed clinical features, molecular genetic findings and in vitro functional investigations undertaken for adult and paediatric cases. Patients presenting with parkinsonism dystonia or a neurotransmitter profile characteristic of dopamine transporter deficiency syndrome were recruited for study. SLC6A3 mutational analysis was undertaken in all patients. The functional consequences of missense variants on the dopamine transporter were evaluated by determining the effect of mutant dopamine transporter on dopamine uptake, protein expression and amphetamine-mediated dopamine efflux using an in vitro cellular heterologous expression system. We identified eight new patients from five unrelated families with dopamine transporter deficiency syndrome. The median age at diagnosis was 13 years (range 1.5-34 years). Most significantly, the case series included three adolescent males with atypical dopamine transporter deficiency syndrome of juvenile onset (outside infancy) and progressive parkinsonism dystonia. The other five patients in the cohort presented with classical infantile-onset parkinsonism dystonia, with one surviving into adulthood (currently aged 34 years) and labelled as having 'juvenile parkinsonism'. All eight patients harboured homozygous or compound heterozygous mutations in SLC6A3, of which the majority are previously unreported variants. In vitro studies of mutant dopamine transporter demonstrated multifaceted loss of dopamine transporter function. Impaired dopamine uptake was universally present, and more severely impacted in dopamine transporter mutants causing infantile-onset rather than juvenile-onset disease. Dopamine transporter mutants also showed diminished dopamine binding affinity, reduced cell surface transporter, loss of post-translational dopamine transporter glycosylation and failure of amphetamine-mediated dopamine efflux. Our data series expands the clinical phenotypic continuum of dopamine transporter deficiency syndrome and indicates that there is a phenotypic spectrum from infancy (early onset, rapidly progressive disease) to childhood/adolescence and adulthood (later onset, slower disease progression). Genotype-phenotype analysis in this cohort suggests that higher residual dopamine transporter activity is likely to contribute to postponing disease presentation in these later-onset adult cases. Dopamine transporter deficiency syndrome remains under-recognized and our data highlights that dopamine transporter deficiency syndrome should be considered as a differential diagnosis for both infantile- and juvenile-onset movement disorders, including cerebral palsy and juvenile parkinsonism.
Long-Term Stimulant Treatment Affects Brain Dopamine Transporter Level in Patients with Attention Deficit Hyperactive Disorder
AbstractOBJECTIVE: Brain dopamine dysfunction in attention deficit/hyperactivity disorder (ADHD) could explain why stimulant medications, which increase dopamine signaling, are therapeutically beneficial. However while the acute increases in dopamine induced by stimulant medications have been associated with symptom improvement in ADHD the chronic effects have not been investigated. METHOD: We used positron emission tomography and [(11)C]cocaine (dopamine transporter radioligand) to measure dopamine transporter availability in the brains of 18 never-medicated adult ADHD subjects prior to and after 12 months of treatment with methylphenidate and in 11 controls who were also scanned twice at 12 months interval but without stimulant medication. Dopamine transporter availability was quantified as non-displaceable binding potential using a kinetic model for reversible ligands. RESULTS: Twelve months of methylphenidate treatment increased striatal dopamine transporter availability in ADHD (caudate, putamen and ventral striatum: +24%, p<0.01); whereas there were no changes in control subjects retested at 12-month interval. Comparisons between controls and ADHD participants revealed no significant difference in dopamine transporter availability prior to treatment but showed higher dopamine transporter availability in ADHD participants than control after long-term treatment (caudate: p<0.007; putamen: p<0.005). CONCLUSION: Upregulation of dopamine transporter availability during long-term treatment with methylphenidate may decrease treatment efficacy and exacerbate symptoms while not under the effects of the medication. Our findings also suggest that the discrepancies in the literature regarding dopamine transporter availability in ADHD participants (some studies reporting increases, other no changes and other decreases) may reflect, in part, differences in treatment histories.
Journal of Neurogenetics · 2016 · 81 citations · open access
Dopamine transporter mutant animals: a translational perspective
AbstractThe dopamine transporter (DAT) plays an important homeostatic role in the control of both the extracellular and intraneuronal concentrations of dopamine, thereby providing effective control over activity of dopaminergic transmission. Since brain dopamine is known to be involved in numerous neuropsychiatric disorders, investigations using mice with genetically altered DAT function and thus intensity of dopamine-mediated signaling have provided numerous insights into the pathology of these disorders and novel pathological mechanisms that could be targeted to provide new therapeutic approaches for these disorders. In this brief overview, we discuss recent investigations involving animals with genetically altered DAT function, particularly focusing on translational studies providing new insights into pathology and pharmacology of dopamine-related disorders. Perspective applications of these and newly developed models of DAT dysfunction are also discussed.
Brain Sciences · 2017 · 10 citations · open access
Phenotypic Discordance in Siblings with Identical Compound Heterozygous PARK2 Mutations
AbstractPARK2 mutations are the most common cause of early-onset Parkinson’s disease. No genotype-phenotype correlation exists, and phenotypic variability is quite common. We report two siblings with confirmed identical compound heterozygous mutations in the PARK2 gene manifesting strikingly different phenotypes. The older brother demonstrated marked parkinsonism by his mid-20’s, whereas the younger brother developed exercise-induced dystonia in his mid-30’s with no subsequent clinical progression, highlighting the clinical heterogeneity of the disease and implying the role of other genetic and/or environmental factors in disease progression. The younger sibling, despite his mild symptoms, had a clearly abnormal dopamine transporter (DaT)-SPECT scan. To our knowledge, this is the first such reported case of an abnormal DaT-SPECT scan in a patient with biallelic PARK2 mutations who does not meet the clinical criteria for Parkinson’s disease.
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.
