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Vascular parkinsonism

disease
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Summary

Vascular parkinsonism (MONDO:0956980) is a disease with 7 cohort genes and 12 clinical trials. Top therapeutic interventions include zoledronic acid anhydrous and florbenazine f 18.

At a glance

  • Cohort genes: 7
  • ClinVar variants: 10
  • Clinical trials: 12

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

FieldValue
Canonical namevascular parkinsonism
Mondo IDMONDO:0956980
DOIDDOID:0080856
ICD-10-CMG21.4
ICD-111852145464
UMLSC0393568
MedGen581453
Is cancer (heuristic)no

Data availability: 10 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › basal ganglia disorder › parkinsonian disorder › vascular parkinsonism

Related subtypes (20): postencephalitic Parkinson disease, Parkinson disease, dystonia 12, Perry syndrome, X-linked parkinsonism-spasticity syndrome, early-onset parkinsonism-intellectual disability syndrome, X-linked dystonia-parkinsonism, autosomal dominant striatal neurodegeneration type 1, dystonia 16, parkinsonism-dystonia, infantile, cirrhosis - dystonia - polycythemia - hypermanganesemia syndrome, hemiparkinsonism-hemiatrophy syndrome, carbon monoxide-induced parkinsonism, cyanide-induced parkinsonism, atypical juvenile parkinsonism, primary progressive freezing gait, encephalitis lethargica, parkinsonism with dementia of Guadeloupe, multiple system atrophy, parkinsonian type, parkinsonism with polyneuropathy

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

10 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 4 benign/likely benign, 2 conflicting classifications of pathogenicity

ClinVarVariant (HGVS)GeneClassificationReview
18398NM_181840.1(KCNK18):c.414_415del (p.Phe139fs)KCNK18Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
3571549NM_198578.4(LRRK2):c.2300G>A (p.Arg767His)LRRK2Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
4075748NM_003458.4(BSN):c.9862G>A (p.Glu3288Lys)BSNUncertain significancecriteria provided, single submitter
2150544NM_003560.4(PLA2G6):c.1028C>T (p.Ala343Val)PLA2G6Uncertain significancecriteria provided, multiple submitters, no conflicts
1434096NM_032242.4(PLXNA1):c.3368C>T (p.Pro1123Leu)PLXNA1Uncertain significancecriteria provided, multiple submitters, no conflicts
3015387NM_198994.3(TGM6):c.1076C>T (p.Pro359Leu)TGM6Uncertain significancecriteria provided, multiple submitters, no conflicts
39221NM_198578.4(LRRK2):c.6241A>G (p.Asn2081Asp)LRRK2Benign/Likely benigncriteria provided, multiple submitters, no conflicts
256121NM_000435.3(NOTCH3):c.1490C>T (p.Ser497Leu)NOTCH3Benign/Likely benigncriteria provided, multiple submitters, no conflicts
159725NM_003560.4(PLA2G6):c.1027G>A (p.Ala343Thr)PLA2G6Benign/Likely benigncriteria provided, multiple submitters, no conflicts
337926NM_198994.3(TGM6):c.1342C>T (p.Arg448Trp)TGM6Benign/Likely benigncriteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

GeneOrphanet IDRare disease
TGM6Orphanet:276193Spinocerebellar ataxia type 35
TGM6Orphanet:319465Inherited acute myeloid leukemia
LRRK2Orphanet:2828Young-onset Parkinson disease
LRRK2Orphanet:411602Hereditary late-onset Parkinson disease
NOTCH3Orphanet:136Cerebral autosomal dominant arteriopathy-subcortical infarcts-leukoencephalopathy
NOTCH3Orphanet:2591Infantile myofibromatosis
NOTCH3Orphanet:2789Lateral meningocele syndrome
PLA2G6Orphanet:199351Adult-onset dystonia-parkinsonism
PLA2G6Orphanet:35069Infantile neuroaxonal dystrophy
PLXNA1Orphanet:528084Non-specific syndromic intellectual disability

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

SubsetGenes
multi_evidence7

Cohort genes (full)

SymbolHGNCEnsemblUniProtNameEvidence
BSNHGNC:1117ENSG00000164061Q9UPA5Protein bassoonclinvar
TGM6HGNC:16255ENSG00000166948O95932Protein-glutamine gamma-glutamyltransferase 6clinvar
LRRK2HGNC:18618ENSG00000188906Q5S007Leucine-rich repeat serine/threonine-protein kinase 2clinvar
KCNK18HGNC:19439ENSG00000186795Q7Z418Potassium channel subfamily K member 18clinvar
NOTCH3HGNC:7883ENSG00000074181Q9UM47Neurogenic locus notch homolog protein 3clinvar
PLA2G6HGNC:9039ENSG00000184381O6073385/88 kDa calcium-independent phospholipase A2clinvar
PLXNA1HGNC:9099ENSG00000114554Q9UIW2Plexin-A1clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

SymbolProtein nameFunction (lead sentence)
BSNProtein bassoonScaffold protein of the presynaptic cytomatrix at the active zone (CAZ) which is the place in the synapse where neurotransmitter is released.
TGM6Protein-glutamine gamma-glutamyltransferase 6Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins.
LRRK2Leucine-rich repeat serine/threonine-protein kinase 2Serine/threonine-protein kinase which phosphorylates a broad range of proteins involved in multiple processes such as neuronal plasticity, innate immunity, autophagy, and vesicle trafficking.
KCNK18Potassium channel subfamily K member 18K(+) channel that conducts outward and inward rectifying currents at depolarized and hyperpolarized membrane potentials, respectively.
NOTCH3Neurogenic locus notch homolog protein 3Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination.
PLA2G685/88 kDa calcium-independent phospholipase A2Calcium-independent phospholipase involved in phospholipid remodeling with implications in cellular membrane homeostasis, mitochondrial integrity and signal transduction.
PLXNA1Plexin-A1Coreceptor for SEMA3A, SEMA3C, SEMA3F and SEMA6D.

Protein-family classification

Druggable: 4 · Difficult: 3 · Unknown: 0 · Druggable fraction: 0.57

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

FamilyGenesFoldFDR
Ion channel115.9×0.102
Antibody/Immunoglobulin28.3×0.102
Scaffold/PPI24.9×0.102
Kinase14.0×0.283
Transcription factor11.2×0.595

Per-gene assignment

SymbolFamilyDruggable?ECInterPro (top 3)
BSNTranscription factornoZnf_piccolo, Znf_FYVE_PHD, Znf_RING/FYVE/PHD
TGM6Antibody/Immunoglobulinyes2.3.2.13Transglutaminase_N, Transglutaminase-like, Transglutaminase_C
LRRK2KinaseyesProt_kinase_dom, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp
KCNK18Ion channelyes2pore_dom_K_chnl, K_chnl_dom
NOTCH3Scaffold/PPInoEGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom
PLA2G6Scaffold/PPIno3.1.1.4Ankyrin_rpt, PNPLA_dom, Acyl_Trfase/lysoPLipase
PLXNA1Antibody/ImmunoglobulinyesSemap_dom, Plexin_repeat, IPT_dom

Expression context

Cohort genes with no expression data: 0.

6 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

BucketGenes
narrow (1-5 tissues)0
moderate (6-20)1
broad (>20)6
unknown0

Top tissues across cohort

TissueCohort genes
middle temporal gyrus2
colonic epithelium2
frontal pole1
paraflocculus1
bone marrow cell1
kidney epithelium1
buccal mucosa cell1
leukocyte1
monocyte1
caudate nucleus1
nucleus accumbens1
popliteal artery1
right coronary artery1
tibial artery1
left lobe of thyroid gland1
right lobe of thyroid gland1
right uterine tube1
cortical plate1
stromal cell of endometrium1

Per-gene tissue summary (top 30)

SymbolBgee breadthFANTOM5 breadthSCXATop tissues
BSN156broadmarkerfrontal pole, paraflocculus, middle temporal gyrus
TGM639tissue_specificmarkercolonic epithelium, bone marrow cell, kidney epithelium
LRRK2220broadmarkerbuccal mucosa cell, monocyte, leukocyte
KCNK1811yesnucleus accumbens, caudate nucleus, colonic epithelium
NOTCH3273ubiquitousmarkerpopliteal artery, tibial artery, right coronary artery
PLA2G6232ubiquitousmarkerright uterine tube, right lobe of thyroid gland, left lobe of thyroid gland
PLXNA1279tissue_specificmarkermiddle temporal gyrus, cortical plate, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

SymbolInteractor count
LRRK27,628
NOTCH34,403
BSN2,060
PLA2G61,769
PLXNA11,574
KCNK18711
TGM6385

Intra-cohort edges

ABSources
KCNK18NOTCH3biogrid_interaction

Structural data

PDB: 3 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

SymbolUniProtPDB entries
LRRK2Q5S00744
NOTCH3Q9UM476
PLXNA1Q9UIW23

AlphaFold-only cohort genes (top 30 by pLDDT)

SymbolUniProtpLDDT
TGM6O9593290.95
PLA2G6O6073386.16
KCNK18Q7Z41870.04
BSNQ9UPA5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 33. Enrichment computed across 7 evidence-associated genes (6 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

PathwayCohort genesFoldFDRSample cohort genes
TWIK-related spinal cord K+ channel (TRESK)11903.3×0.017KCNK18
Defective LFNG causes SCDO31380.7×0.023NOTCH3
Acyl chain remodeling of CL1317.2×0.023PLA2G6
Pre-NOTCH Processing in the Endoplasmic Reticulum1317.2×0.023NOTCH3
PTK6 promotes HIF1A stabilization1271.9×0.023LRRK2
Noncanonical activation of NOTCH31237.9×0.023NOTCH3
Tandem pore domain potassium channels1158.6×0.024KCNK18
SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion1126.9×0.024PLXNA1
Sema3A PAK dependent Axon repulsion1112.0×0.024PLXNA1
Pre-NOTCH Processing in Golgi1105.7×0.024NOTCH3
CRMPs in Sema3A signaling1105.7×0.024PLXNA1
Other semaphorin interactions1100.2×0.024PLXNA1
Phase 4 - resting membrane potential1100.2×0.024KCNK18
Signaling by PTK6190.6×0.024LRRK2
Signaling by Non-Receptor Tyrosine Kinases190.6×0.024LRRK2
NOTCH3 Activation and Transmission of Signal to the Nucleus179.3×0.024NOTCH3
Role of phospholipids in phagocytosis176.1×0.024PLA2G6
NOTCH3 Intracellular Domain Regulates Transcription173.2×0.024NOTCH3
Acyl chain remodelling of PC170.5×0.024PLA2G6
Notch-HLH transcription pathway168.0×0.024NOTCH3
Acyl chain remodelling of PE165.6×0.024PLA2G6
Sensory processing of sound151.4×0.029BSN
RND1 GTPase cycle144.3×0.032PLXNA1
COPI-independent Golgi-to-ER retrograde traffic134.6×0.038PLA2G6
RHOD GTPase cycle134.0×0.038PLXNA1
Sensory processing of sound by inner hair cells of the cochlea127.2×0.046BSN
Potassium Channels122.4×0.054KCNK18
Pre-NOTCH Transcription and Translation120.5×0.056NOTCH3
Cardiac conduction118.1×0.061KCNK18
Sensory Perception115.9×0.068BSN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO termCohort genesFoldFDRSample cohort genes
regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation12808.7×0.008KCNK18
cellular response to curcumin12808.7×0.008LRRK2
Wnt signalosome assembly12808.7×0.008LRRK2
olfactory nerve formation11404.3×0.008PLXNA1
regulation of kidney size11404.3×0.008LRRK2
negative regulation of late endosome to lysosome transport11404.3×0.008LRRK2
obsolete negative regulation of protein processing involved in protein targeting to mitochondrion11404.3×0.008LRRK2
regulation of neuron maturation1936.2×0.008LRRK2
platelet activating factor metabolic process1936.2×0.008PLA2G6
glomerular capillary formation1936.2×0.008NOTCH3
regulation of cAMP/PKA signal transduction1936.2×0.008LRRK2
positive regulation of protein autoubiquitination1936.2×0.008LRRK2
regulation of synaptic vesicle transport1936.2×0.008LRRK2
presynaptic active zone assembly1936.2×0.008BSN
negative regulation of motile cilium assembly1936.2×0.008LRRK2
regulation of branching morphogenesis of a nerve1936.2×0.008LRRK2
cardiolipin acyl-chain remodeling1702.2×0.008PLA2G6
phosphatidylethanolamine catabolic process1702.2×0.008PLA2G6
regulation of dopamine receptor signaling pathway1702.2×0.008LRRK2
positive regulation of dopamine receptor signaling pathway1702.2×0.008LRRK2
dichotomous subdivision of terminal units involved in salivary gland branching1702.2×0.008PLXNA1
neuron projection guidance1702.2×0.008PLXNA1
regulation of retrograde transport, endosome to Golgi1702.2×0.008LRRK2
regulation of CAMKK-AMPK signaling cascade1702.2×0.008LRRK2
tangential migration from the subventricular zone to the olfactory bulb1561.7×0.008LRRK2
regulation of cell projection organization1561.7×0.008LRRK2
regulation of neuroblast proliferation1561.7×0.008LRRK2
gonadotrophin-releasing hormone neuronal migration to the hypothalamus1468.1×0.008PLXNA1
regulation of locomotion1468.1×0.008LRRK2
phosphatidic acid metabolic process1468.1×0.008PLA2G6

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 3 · Undrugged: 4

Druggability breadth: 5 of 7 evidence-associated genes (71%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

SymbolExample approved molecule
LRRK2PONATINIB

Top cohort targets by molecule count

SymbolMoleculesMax phase
LRRK2424
NOTCH312
PLA2G612
BSN00
TGM600
KCNK1800
PLXNA100

Drugs targeting cohort genes (top 30)

MoleculeMax phaseTargets in cohort
PONATINIB4LRRK2
FEDRATINIB4LRRK2
AXITINIB4LRRK2
RUXOLITINIB4LRRK2
PALBOCICLIB4LRRK2
ENTRECTINIB4LRRK2
TOFACITINIB CITRATE4LRRK2
TOFACITINIB4LRRK2
VANDETANIB4LRRK2
BOSUTINIB4LRRK2
BRIGATINIB4LRRK2
NINTEDANIB4LRRK2
SUNITINIB4LRRK2
ERLOTINIB4LRRK2
MIDOSTAURIN4LRRK2
DACTOLISIB3LRRK2
ADENINE3LRRK2
OLVEREMBATINIB3LRRK2
CANERTINIB3LRRK2
FASUDIL3LRRK2
ALVOCIDIB3LRRK2
ABIVERTINIB3LRRK2
ALISERTIB3LRRK2
DOVITINIB3LRRK2
LESTAURTINIB3LRRK2
RUBOXISTAURIN3LRRK2
SU-0148132LRRK2
REBASTINIB2LRRK2
CENISERTIB2LRRK2
ADAVOSERTIB2LRRK2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

SymbolAssaysType breakdown
LRRK2809Binding:799, ADMET:7, Functional:3
PLA2G647Binding:47
KCNK189Binding:7, ADMET:2
TGM68Binding:8
NOTCH33Binding:3

Cohort enzymes (BRENDA EC)

SymbolEC numbersNames
TGM62.3.2.13protein-glutamine gamma-glutamyltransferase
PLA2G63.1.1.4phospholipase A2

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

SymbolChEMBL assays
LRRK2809

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

CompoundMax phaseCohort target (bioactivity)
PONATINIB4LRRK2
FEDRATINIB4LRRK2
AXITINIB4LRRK2
RUXOLITINIB4LRRK2
PALBOCICLIB4LRRK2
ENTRECTINIB4LRRK2
TOFACITINIB CITRATE4LRRK2
TOFACITINIB4LRRK2
VANDETANIB4LRRK2
BOSUTINIB4LRRK2
BRIGATINIB4LRRK2
NINTEDANIB4LRRK2
SUNITINIB4LRRK2
ERLOTINIB4LRRK2
MIDOSTAURIN4LRRK2
DACTOLISIB3LRRK2
ADENINE3LRRK2
OLVEREMBATINIB3LRRK2
CANERTINIB3LRRK2
FASUDIL3LRRK2
ALVOCIDIB3LRRK2
ABIVERTINIB3LRRK2
ALISERTIB3LRRK2
DOVITINIB3LRRK2
LESTAURTINIB3LRRK2
RUBOXISTAURIN3LRRK2
SU-0148132LRRK2
REBASTINIB2LRRK2
CENISERTIB2LRRK2
ADAVOSERTIB2LRRK2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

TierDefinitionGenesSymbols
AApproved (phase 4 drug)1LRRK2
BPhased (≥1) drug, not yet approved2NOTCH3, PLA2G6
CDruggable family + PDB, no drug1PLXNA1
DDruggable family + AlphaFold only, no drug2TGM6, KCNK18
EDifficult family or no structure, no drug1BSN

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

SymbolChEMBL assaysDrugged partners (top 3)
BSN0—
TGM68—
KCNK189—
PLXNA10—

Clinical trials & evidence

Clinical trials

Clinical trials: 12.

Phase distribution (across all retrieved trials)

PhaseTrials
Not specified10
PHASE41
PHASE21

Top trials by phase / activity

NCTPhaseStatusTitle
NCT03924414PHASE4ACTIVE_NOT_RECRUITINGTrial of Parkinson’s And Zoledronic Acid
NCT02195154PHASE2COMPLETED18F-DTBZ PET and Multi-modal MRI in the Patients With Vascular Parkinsonism
NCT05222386Not specifiedACTIVE_NOT_RECRUITINGCommunity Outreach for Palliative Engagement – Parkinson Disease
NCT06174948Not specifiedRECRUITINGThe Use of the CUE1/CUE1+ in People With Parkinson’s Disease and Related Disorders
NCT06949865Not specifiedRECRUITINGAI-Enhanced Optimization of Acute Levodopa Challenge Test
NCT07386015Not specifiedRECRUITINGEtiology-Phenotype-Outcome Pathway Study on Freezing of Gait (FOG)
NCT00368199Not specifiedCOMPLETEDTranscranial Duplex Scanning and Single Photon Emission Computer Tomography (SPECT) in Parkinsonian Syndromes
NCT02445469Not specifiedTERMINATEDMagnetic Resonance Imaging in the Diagnosis of Parkinsonian Syndromes
NCT03076671Not specifiedCOMPLETEDMore Than a Movement Disorder: Applying Palliative Care to Parkinson’s Disease
NCT03720691Not specifiedUNKNOWNrTMS Treatment in Vascular Parkinsonism
NCT04308135Not specifiedCOMPLETEDDifferences Between Patients With Vascular Parkinsonism and Parkinson’s Disease
NCT04925622Not specifiedCOMPLETEDComplex Eye Movements in Parkinson’s Disease and Related Movement Disorders

Drugs tested across these trials (top 30)

MoleculeMax phaseTrials referencing
ZOLEDRONIC ACID ANHYDROUS43
FLORBENAZINE F 1821

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
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This page pulls from 70 datasets indexed by BioBTree:

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