Atypical juvenile parkinsonism

Summary

Atypical juvenile parkinsonism (MONDO:0018321) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• Phenotypes (HPO): 27

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0002540	Inability to walk	Very frequent (80-99%)
HP:0007164	Slowed slurred speech	Very frequent (80-99%)
HP:0000338	Hypomimic face	Very frequent (80-99%)
HP:0001332	Dystonia	Very frequent (80-99%)
HP:0002063	Rigidity	Very frequent (80-99%)
HP:0002067	Bradykinesia	Very frequent (80-99%)
HP:0002172	Postural instability	Very frequent (80-99%)
HP:0002322	Resting tremor	Very frequent (80-99%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0001621	Weak voice	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002304	Akinesia	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0004305	Involuntary movements	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Frequent (30-79%)
HP:0007311	Short stepped shuffling gait	Frequent (30-79%)
HP:0008969	Leg muscle stiffness	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0012444	Brain atrophy	Frequent (30-79%)
HP:0012638	Abnormality of nervous system physiology	Frequent (30-79%)
HP:0100022	Abnormality of movement	Frequent (30-79%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0002362	Shuffling gait	Occasional (5-29%)
HP:0002425	Anarthria	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	atypical juvenile parkinsonism
Mondo ID	MONDO:0018321
Orphanet	391411
SNOMED CT	725146001
UMLS	C4510873
MedGen	1380105
GARD	0017621
Is cancer (heuristic)	no

Data availability: 3 GenCC gene-disease records.

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 › atypical juvenile 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, primary progressive freezing gait, encephalitis lethargica, parkinsonism with dementia of Guadeloupe, multiple system atrophy, parkinsonian type, parkinsonism with polyneuropathy, vascular parkinsonism

Subtypes (1): juvenile onset Parkinson disease 19A

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 22 · Orphanet: 7 · 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
DNAJC6	Strong	Autosomal recessive	juvenile onset Parkinson disease 19A	7
PODXL	Supportive	Autosomal recessive	atypical juvenile parkinsonism	5
SYNJ1	Supportive	Autosomal recessive	atypical juvenile parkinsonism	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SYNJ1	Orphanet:2828	Young-onset Parkinson disease
SYNJ1	Orphanet:391411	Atypical juvenile parkinsonism
SYNJ1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
DNAJC6	Orphanet:2828	Young-onset Parkinson disease
DNAJC6	Orphanet:391411	Atypical juvenile parkinsonism
PODXL	Orphanet:2828	Young-onset Parkinson disease
PODXL	Orphanet:391411	Atypical juvenile parkinsonism

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SYNJ1	HGNC:11503	ENSG00000159082	O43426	Synaptojanin-1	gencc
DNAJC6	HGNC:15469	ENSG00000116675	O75061	Auxilin	gencc
PODXL	HGNC:9171	ENSG00000128567	O00592	Podocalyxin	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SYNJ1	Synaptojanin-1	Phosphatase that acts on various phosphoinositides, including phosphatidylinositol 4-phosphate, phosphatidylinositol (4,5)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate.
DNAJC6	Auxilin	May act as a protein phosphatase and/or a lipid phosphatase.
PODXL	Podocalyxin	Involved in the regulation of both adhesion and cell morphology and cancer progression.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Phosphatase	1	28.0×	0.071
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SYNJ1	Other/Unknown	no		IPPc, RRM_dom, SAC_dom
DNAJC6	Phosphatase	yes		Tyr_Pase_dom, DnaJ_domain, Tensin_C2-dom
PODXL	Other/Unknown	no		CD34/Podocalyxin, PODXL

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	2
lateral nuclear group of thalamus	1
pons	1
endothelial cell	1
substantia nigra pars compacta	1
germinal epithelium of ovary	1
metanephric glomerulus	1
renal glomerulus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SYNJ1	278	ubiquitous	yes	Brodmann (1909) area 23, lateral nuclear group of thalamus, pons
DNAJC6	227	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, substantia nigra pars compacta
PODXL	276	ubiquitous	marker	renal glomerulus, metanephric glomerulus, germinal epithelium of ovary

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNAJC6	3,784
PODXL	2,741
SYNJ1	2,177

Intra-cohort edges

A	B	Sources
DNAJC6	SYNJ1	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SYNJ1	O43426	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNAJC6	O75061	64.29
PODXL	O00592	53.66

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 3 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
Clathrin-mediated endocytosis	2	85.2×	0.002	SYNJ1, DNAJC6
Membrane Trafficking	2	37.1×	0.004	SYNJ1, DNAJC6
Vesicle-mediated transport	2	34.8×	0.004	SYNJ1, DNAJC6
Synthesis of IP2, IP, and Ins in the cytosol	1	380.7×	0.009	SYNJ1
Inositol phosphate metabolism	1	237.9×	0.011	SYNJ1
Synthesis of IP3 and IP4 in the cytosol	1	211.5×	0.011	SYNJ1
PI Metabolism	1	178.4×	0.011	SYNJ1
Lysosome Vesicle Biogenesis	1	163.1×	0.011	DNAJC6
trans-Golgi Network Vesicle Budding	1	126.9×	0.012	DNAJC6
Synthesis of PIPs at the plasma membrane	1	105.7×	0.012	SYNJ1
Phospholipid metabolism	1	100.2×	0.012	SYNJ1
Golgi Associated Vesicle Biogenesis	1	100.2×	0.012	DNAJC6
Metabolism of lipids	1	15.8×	0.067	SYNJ1
Metabolism	1	5.8×	0.165	SYNJ1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
synaptic vesicle uncoating	2	3744.9×	2e-06	SYNJ1, DNAJC6
positive regulation of endosome organization	1	5617.3×	0.002	SYNJ1
epithelial tube formation	1	2808.7×	0.002	PODXL
regulation of clathrin coat assembly	1	2808.7×	0.002	DNAJC6
clathrin coat disassembly	1	1404.3×	0.004	DNAJC6
regulation of microvillus assembly	1	802.5×	0.005	PODXL
positive regulation of cell-cell adhesion mediated by integrin	1	702.2×	0.005	PODXL
regulation of clathrin-dependent endocytosis	1	561.7×	0.005	DNAJC6
intracellular transport	1	510.7×	0.005	DNAJC6
podocyte development	1	510.7×	0.005	PODXL
synaptic vesicle recycling	1	401.2×	0.006	DNAJC6
negative regulation of cell-cell adhesion	1	330.4×	0.006	PODXL
inositol phosphate metabolic process	1	330.4×	0.006	SYNJ1
phosphatidylinositol metabolic process	1	295.6×	0.006	SYNJ1
synaptic vesicle transport	1	280.9×	0.006	SYNJ1
synaptic vesicle priming	1	267.5×	0.006	SYNJ1
phosphatidylinositol dephosphorylation	1	216.1×	0.007	SYNJ1
clathrin-dependent endocytosis	1	193.7×	0.008	DNAJC6
membrane organization	1	170.2×	0.008	SYNJ1
synaptic vesicle endocytosis	1	144.0×	0.009	SYNJ1
neurotransmitter transport	1	140.4×	0.009	SYNJ1
negative regulation of cell adhesion	1	127.7×	0.010	PODXL
phosphatidylinositol biosynthetic process	1	122.1×	0.010	SYNJ1
learning	1	93.6×	0.012	SYNJ1
positive regulation of cell migration	1	20.6×	0.050	PODXL
cell migration	1	20.5×	0.050	PODXL
cell adhesion	1	12.5×	0.078	PODXL

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
SYNJ1	PYRVINIUM

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SYNJ1	1	4
DNAJC6	0	0
PODXL	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PYRVINIUM	4	SYNJ1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SYNJ1	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
PYRVINIUM	4	SYNJ1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SYNJ1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	DNAJC6
E	Difficult family or no structure, no drug	1	PODXL

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DNAJC6	0	SYNJ1
PODXL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.