Parkinsonian-pyramidal syndrome

Summary

Parkinsonian-pyramidal syndrome (MONDO:0009830) is a disease caused by FBXO7 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: FBXO7 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 356
• Phenotypes (HPO): 25

Clinical features

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0001300	Parkinsonism	Obligate (100%)
HP:0007256	Abnormal pyramidal sign	Obligate (100%)
HP:0000011	Neurogenic bladder	Frequent (30-79%)
HP:0000338	Hypomimic face	Frequent (30-79%)
HP:0000514	Slow saccadic eye movements	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001336	Myoclonus	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0001762	Talipes equinovarus	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002063	Rigidity	Frequent (30-79%)
HP:0002067	Bradykinesia	Frequent (30-79%)
HP:0002080	Intention tremor	Frequent (30-79%)
HP:0002172	Postural instability	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0002362	Shuffling gait	Frequent (30-79%)
HP:0002367	Visual hallucinations	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0011960	Substantia nigra gliosis	Frequent (30-79%)
HP:0012332	Abnormal autonomic nervous system physiology	Frequent (30-79%)
HP:0031435	Monotonic speech	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0100315	Lewy bodies	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	parkinsonian-pyramidal syndrome
Mondo ID	MONDO:0009830
MeSH	C538104
OMIM	260300
Orphanet	171695
DOID	DOID:0060372
ICD-11	1128311778
UMLS	C1850100
MedGen	337969
GARD	0009175
Is cancer (heuristic)	no

Also known as: autosomal recessive early-onset Parkinson disease type 15 · pallido-pyramidal disease · Pallidopyramidal syndrome · pallidopyramidal syndrome · PARK15 · Parkinson disease 15, autosomal recessive · Parkinson disease 15, autosomal recessive early-onset · parkinsonian-pyramidal syndrome

Data availability: 356 ClinVar variants · 5 GenCC gene-disease records · 7 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

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 › Parkinson disease › parkinsonian-pyramidal syndrome

Related subtypes (5): late-onset Parkinson disease, Parkinson disease, mitochondrial, Parkinson disease 16, young-onset Parkinson disease, Parkinson disease 25, autosomal recessive early-onset, with impaired intellectual development

Subtypes (1): paralysis agitans, juvenile, of Hunt

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

356 retrieved; paginated sample, class counts are floors:

202 likely benign, 83 uncertain significance, 31 pathogenic, 11 pathogenic/likely pathogenic, 11 conflicting classifications of pathogenicity, 10 benign, 6 likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1455741	NM_012179.4(FBXO7):c.1213G>T (p.Glu405Ter)	FBXO7	Pathogenic	criteria provided, single submitter
1678355	NM_012179.4(FBXO7):c.961C>T (p.Arg321Ter)	FBXO7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2032126	NM_012179.4(FBXO7):c.521C>A (p.Ser174Ter)	FBXO7	Pathogenic	criteria provided, single submitter
2150213	NM_012179.4(FBXO7):c.269_270del (p.Ser90fs)	FBXO7	Pathogenic	criteria provided, single submitter
2429049	NM_012179.4(FBXO7):c.1033C>T (p.Arg345Ter)	FBXO7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2661902	NM_012179.4(FBXO7):c.133C>T (p.Arg45Ter)	FBXO7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2699868	NM_012179.4(FBXO7):c.575_576del (p.Cys192fs)	FBXO7	Pathogenic	criteria provided, single submitter
2715290	NM_012179.4(FBXO7):c.1220del (p.Pro407fs)	FBXO7	Pathogenic	criteria provided, single submitter
2725775	NM_012179.4(FBXO7):c.156C>G (p.Tyr52Ter)	FBXO7	Pathogenic	criteria provided, single submitter
2732774	NM_012179.4(FBXO7):c.915_916del (p.Arg306fs)	FBXO7	Pathogenic	criteria provided, single submitter
2733394	NM_012179.4(FBXO7):c.709C>T (p.Gln237Ter)	FBXO7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2751170	NM_012179.4(FBXO7):c.1A>G (p.Met1Val)	FBXO7	Pathogenic	criteria provided, single submitter
2751184	NM_012179.4(FBXO7):c.497C>G (p.Ser166Ter)	FBXO7	Pathogenic	criteria provided, single submitter
2752709	NM_012179.4(FBXO7):c.1188C>A (p.Tyr396Ter)	FBXO7	Pathogenic	criteria provided, single submitter
2757154	NM_012179.4(FBXO7):c.544dup (p.Ser182fs)	FBXO7	Pathogenic	criteria provided, single submitter
2765341	NM_012179.4(FBXO7):c.564_567del (p.Ser189fs)	FBXO7	Pathogenic	criteria provided, single submitter
2796908	NM_012179.4(FBXO7):c.1344T>A (p.Tyr448Ter)	FBXO7	Pathogenic	criteria provided, single submitter
2830552	NM_012179.4(FBXO7):c.316_317del (p.Leu106fs)	FBXO7	Pathogenic	criteria provided, single submitter
2842805	NM_012179.4(FBXO7):c.925A>T (p.Lys309Ter)	FBXO7	Pathogenic	criteria provided, single submitter
2884317	NM_012179.4(FBXO7):c.377del (p.Gly126fs)	FBXO7	Pathogenic	criteria provided, single submitter
2887235	NM_012179.4(FBXO7):c.1A>C (p.Met1Leu)	FBXO7	Pathogenic	criteria provided, single submitter
2900056	NM_012179.4(FBXO7):c.821_822del (p.Val274fs)	FBXO7	Pathogenic	criteria provided, single submitter
2909762	NM_012179.4(FBXO7):c.917_918del (p.Arg306fs)	FBXO7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2911981	NM_012179.4(FBXO7):c.1141C>T (p.Arg381Ter)	FBXO7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2915527	NM_012179.4(FBXO7):c.1408G>T (p.Glu470Ter)	FBXO7	Pathogenic	criteria provided, single submitter
2916108	NM_012179.4(FBXO7):c.2T>G (p.Met1Arg)	FBXO7	Pathogenic	criteria provided, single submitter
2960440	NM_012179.4(FBXO7):c.893_894insT (p.Lys299fs)	FBXO7	Pathogenic	criteria provided, single submitter
2960687	NM_012179.4(FBXO7):c.2T>A (p.Met1Lys)	FBXO7	Pathogenic	criteria provided, single submitter
2977139	NM_012179.4(FBXO7):c.1451del (p.Pro484fs)	FBXO7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3247732	NC_000022.10:g.(?32894111)(32894517_?)del	FBXO7	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
FBXO7	Strong	Autosomal recessive	parkinsonian-pyramidal syndrome	4
SNCA	Supportive	Autosomal recessive	parkinsonian-pyramidal syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FBXO7	Orphanet:171695	Parkinsonian-pyramidal syndrome
SNCA	Orphanet:171695	Parkinsonian-pyramidal syndrome
SNCA	Orphanet:2828	Young-onset Parkinson disease
SNCA	Orphanet:411602	Hereditary late-onset Parkinson disease

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FBXO7	HGNC:13586	ENSG00000100225	Q9Y3I1	F-box only protein 7	gencc,clinvar
SNCA	HGNC:11138	ENSG00000145335	P37840	Alpha-synuclein	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FBXO7	F-box only protein 7	Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins and plays a role in several biological proce…
SNCA	Alpha-synuclein	Neuronal protein that plays several roles in synaptic activity such as regulation of synaptic vesicle trafficking and subsequent neurotransmitter release.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FBXO7	Other/Unknown	no		F-box_dom, PI31_Prot_N, Ubiquitin-like_domsf
SNCA	Other/Unknown	no		Synuclein, Synuclein_alpha

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
trabecular bone tissue	2
blood	1
sperm	1
orbitofrontal cortex	1
pons	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FBXO7	299	ubiquitous	marker	trabecular bone tissue, blood, sperm
SNCA	280	ubiquitous	marker	trabecular bone tissue, orbitofrontal cortex, pons

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SNCA	7,615
FBXO7	3,407

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SNCA	P37840	232
FBXO7	Q9Y3I1	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Antimicrobial mechanism of IFN-stimulated genes	1	98.5×	0.044	SNCA
PKR-mediated signaling	1	70.5×	0.044	SNCA
Interferon Signaling	1	60.1×	0.044	SNCA
Amyloid fiber formation	1	51.4×	0.044	SNCA
Neddylation	1	23.7×	0.068	FBXO7
Cytokine Signaling in Immune system	1	20.4×	0.068	SNCA
Antigen processing: Ubiquitination & Proteasome degradation	1	18.6×	0.068	FBXO7
Immune System	1	6.5×	0.155	SNCA
Metabolism of proteins	1	6.2×	0.155	SNCA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of locomotion	2	2808.7×	9e-06	FBXO7, SNCA
neutral lipid metabolic process	1	8426.0×	0.001	SNCA
positive regulation of SNARE complex assembly	1	8426.0×	0.001	SNCA
negative regulation of lymphocyte differentiation	1	8426.0×	0.001	FBXO7
regulation of acyl-CoA biosynthetic process	1	8426.0×	0.001	SNCA
negative regulation of dopamine uptake involved in synaptic transmission	1	8426.0×	0.001	SNCA
negative regulation of norepinephrine uptake	1	8426.0×	0.001	SNCA
response to desipramine	1	8426.0×	0.001	SNCA
regulation of glutamate secretion	1	4213.0×	0.002	SNCA
regulation of norepinephrine uptake	1	4213.0×	0.002	SNCA
positive regulation of hydrogen peroxide catabolic process	1	4213.0×	0.002	SNCA
regulation of synaptic vesicle recycling	1	4213.0×	0.002	SNCA
negative regulation of dopamine metabolic process	1	2808.7×	0.002	SNCA
negative regulation of serotonin uptake	1	2808.7×	0.002	SNCA
negative regulation of thrombin-activated receptor signaling pathway	1	2808.7×	0.002	SNCA
negative regulation of mitochondrial electron transport, NADH to ubiquinone	1	2808.7×	0.002	SNCA
negative regulation of chaperone-mediated autophagy	1	2808.7×	0.002	SNCA
positive regulation of autophagy of mitochondrion	1	2106.5×	0.002	FBXO7
positive regulation of protein localization to cell periphery	1	1685.2×	0.003	SNCA
lymphocyte differentiation	1	1404.3×	0.003	FBXO7
mitochondrial membrane organization	1	1203.7×	0.003	SNCA
response to iron(II) ion	1	1203.7×	0.003	SNCA
negative regulation of exocytosis	1	1203.7×	0.003	SNCA
positive regulation of inositol phosphate biosynthetic process	1	1203.7×	0.003	SNCA
positive regulation of neurotransmitter secretion	1	936.2×	0.003	SNCA
negative regulation of platelet-derived growth factor receptor signaling pathway	1	936.2×	0.003	SNCA
dopamine biosynthetic process	1	936.2×	0.003	SNCA
mitochondrial ATP synthesis coupled electron transport	1	936.2×	0.003	SNCA
dopamine uptake involved in synaptic transmission	1	936.2×	0.003	SNCA
regulation of reactive oxygen species biosynthetic process	1	936.2×	0.003	SNCA

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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.

Symbol	Example approved molecule
SNCA	ESTRADIOL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SNCA	31	4
FBXO7	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ESTRADIOL	4	SNCA
ESTRONE	4	SNCA
TETRACYCLINE	4	SNCA
PHYTONADIONE	4	SNCA
CEFTRIAXONE	4	SNCA
FLORBETAPIR	4	SNCA
ESTRIOL	4	SNCA
RIFAMPIN	4	SNCA
TRETINOIN	4	SNCA
TESTOSTERONE	4	SNCA
BRILLIANT BLUE G	4	SNCA
BROMOCRIPTINE	4	SNCA
PERGOLIDE	4	SNCA
DOPAMINE	4	SNCA
MENADIONE	4	SNCA
GENTIAN VIOLET	4	SNCA
SELEGILINE	4	SNCA
RETINOL	4	SNCA
CURCUMIN	3	SNCA
MENATETRENONE	3	SNCA
HYPERICIN	3	SNCA
EPIGALOCATECHIN GALLATE	3	SNCA
QUERCETIN	3	SNCA
PARAROSANILINE	2	SNCA
LUTEOLIN	2	SNCA
GALLIC ACID	2	SNCA
EMRUSOLMIN	2	SNCA
MINZASOLMIN	2	SNCA
(-)-EPICATECHIN	2	SNCA
BAICALEIN	2	SNCA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SNCA	459	Binding:458, Functional:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SNCA	459

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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.

Compound	Max phase	Cohort target (bioactivity)
ESTRADIOL	4	SNCA
ESTRONE	4	SNCA
TETRACYCLINE	4	SNCA
PHYTONADIONE	4	SNCA
CEFTRIAXONE	4	SNCA
FLORBETAPIR	4	SNCA
ESTRIOL	4	SNCA
RIFAMPIN	4	SNCA
TRETINOIN	4	SNCA
TESTOSTERONE	4	SNCA
BRILLIANT BLUE G	4	SNCA
BROMOCRIPTINE	4	SNCA
PERGOLIDE	4	SNCA
DOPAMINE	4	SNCA
MENADIONE	4	SNCA
GENTIAN VIOLET	4	SNCA
SELEGILINE	4	SNCA
RETINOL	4	SNCA
CURCUMIN	3	SNCA
MENATETRENONE	3	SNCA
HYPERICIN	3	SNCA
EPIGALOCATECHIN GALLATE	3	SNCA
QUERCETIN	3	SNCA
PARAROSANILINE	2	SNCA
LUTEOLIN	2	SNCA
GALLIC ACID	2	SNCA
EMRUSOLMIN	2	SNCA
MINZASOLMIN	2	SNCA
(-)-EPICATECHIN	2	SNCA
BAICALEIN	2	SNCA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SNCA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	FBXO7

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FBXO7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.