X-linked parkinsonism-spasticity syndrome

Summary

X-linked parkinsonism-spasticity syndrome (MONDO:0010482) is a disease caused by ATP6AP2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ATP6AP2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 5
• Phenotypes (HPO): 14

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0002322	Resting tremor	Very frequent (80-99%)
HP:0002396	Cogwheel rigidity	Very frequent (80-99%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0002067	Bradykinesia	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0006801	Hyperactive deep tendon reflexes	Frequent (30-79%)
HP:0000298	Mask-like facies	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0002313	Spastic paraparesis	Occasional (5-29%)
HP:0002506	Diffuse cerebral atrophy	Occasional (5-29%)
HP:0006956	Dilation of lateral ventricles	Occasional (5-29%)
HP:0007082	Dilated third ventricle	Occasional (5-29%)
HP:0011448	Ankle clonus	Occasional (5-29%)
HP:0012407	Scissor gait	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked parkinsonism-spasticity syndrome
Mondo ID	MONDO:0010482
OMIM	300911
Orphanet	363654
DOID	DOID:0112105
UMLS	C3806722
MedGen	813052
GARD	0017567
Is cancer (heuristic)	no

Also known as: PARKINSONISM with spasticity, X-linked · Parkinsonism with spasticity, X-linked, X-linked recessive · XPDS

Data availability: 5 ClinVar variants · 5 GenCC gene-disease records.

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 › X-linked parkinsonism-spasticity syndrome

Related subtypes (20): postencephalitic Parkinson disease, Parkinson disease, dystonia 12, Perry 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, vascular parkinsonism

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

5 retrieved; paginated sample, class counts are floors:

2 benign/likely benign, 2 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
88756	NM_005765.3(ATP6AP2):c.345C>T (p.Ser115=)	ATP6AP2	Pathogenic	no assertion criteria provided
204912	NM_005765.3(ATP6AP2):c.490G>A (p.Val164Ile)	ATP6AP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
533691	NM_005765.3(ATP6AP2):c.858G>A (p.Ala286=)	ATP6AP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
136465	NM_005765.3(ATP6AP2):c.38-5T>C	ATP6AP2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
199113	NM_005765.3(ATP6AP2):c.1050T>C (p.Asp350=)	ATP6AP2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 2 · 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
ATP6AP2	Strong	X-linked	syndromic X-linked intellectual disability Hedera type	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP6AP2	Orphanet:363654	X-linked parkinsonism-spasticity syndrome
ATP6AP2	Orphanet:93952	X-linked intellectual disability, Hedera type

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATP6AP2	HGNC:18305	ENSG00000182220	O75787	Renin receptor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP6AP2	Renin receptor	Multifunctional protein which functions as a renin, prorenin cellular receptor and is involved in the assembly of the lysosomal proton-transporting V-type ATPase (V-ATPase) and the acidification of the endo-lysosomal system.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP6AP2	Other/Unknown	no		Renin_rcpt, Renin_r_C, RENR_N

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
germinal epithelium of ovary	1
tibia	1
visceral pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP6AP2	295	ubiquitous	marker	visceral pleura, tibia, germinal epithelium of ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP6AP2	2,236

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP6AP2	O75787	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	1	671.8×	0.002	ATP6AP2
Metabolism of Angiotensinogen to Angiotensins	1	634.4×	0.002	ATP6AP2
Neutrophil degranulation	1	23.1×	0.043	ATP6AP2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
eye pigmentation	1	16852.0×	9e-04	ATP6AP2
central nervous system maturation	1	8426.0×	9e-04	ATP6AP2
rostrocaudal neural tube patterning	1	5617.3×	9e-04	ATP6AP2
positive regulation of transforming growth factor beta1 production	1	2808.7×	0.001	ATP6AP2
head morphogenesis	1	2106.5×	0.001	ATP6AP2
Golgi lumen acidification	1	1685.2×	0.001	ATP6AP2
angiotensin maturation	1	1296.3×	0.001	ATP6AP2
endosomal lumen acidification	1	1203.7×	0.001	ATP6AP2
intracellular pH reduction	1	1203.7×	0.001	ATP6AP2
synaptic vesicle lumen acidification	1	936.2×	0.002	ATP6AP2
vacuolar acidification	1	732.7×	0.002	ATP6AP2
lysosomal lumen acidification	1	674.1×	0.002	ATP6AP2
regulation of MAPK cascade	1	455.5×	0.003	ATP6AP2
positive regulation of Wnt signaling pathway	1	383.0×	0.003	ATP6AP2
proton transmembrane transport	1	312.1×	0.003	ATP6AP2
positive regulation of canonical Wnt signaling pathway	1	154.6×	0.006	ATP6AP2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP6AP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	ATP6AP2

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)
ATP6AP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.