Brain dopamine-serotonin vesicular transport disease

Summary

Brain dopamine-serotonin vesicular transport disease (MONDO:0018130) is a disease caused by SLC18A2 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC18A2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 16
• Phenotypes (HPO): 31
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

31 HPO clinical features (Orphanet curated; top 31 by frequency):

HPO ID	Term	Frequency
HP:0000338	Hypomimic face	Very frequent (80-99%)
HP:0000496	Abnormality of eye movement	Very frequent (80-99%)
HP:0000508	Ptosis	Very frequent (80-99%)
HP:0000975	Hyperhidrosis	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001260	Dysarthria	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001276	Hypertonia	Very frequent (80-99%)
HP:0001285	Spastic tetraparesis	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001290	Generalized hypotonia	Very frequent (80-99%)
HP:0001300	Parkinsonism	Very frequent (80-99%)
HP:0001332	Dystonia	Very frequent (80-99%)
HP:0001337	Tremor	Very frequent (80-99%)
HP:0001611	Hypernasal speech	Very frequent (80-99%)
HP:0001760	Abnormal foot morphology	Very frequent (80-99%)
HP:0002075	Dysdiadochokinesis	Very frequent (80-99%)
HP:0002310	Orofacial dyskinesia	Very frequent (80-99%)
HP:0002360	Sleep abnormality	Very frequent (80-99%)
HP:0002362	Shuffling gait	Very frequent (80-99%)
HP:0002421	Poor head control	Very frequent (80-99%)
HP:0002451	Limb dystonia	Very frequent (80-99%)
HP:0002597	Abnormality of the vasculature	Very frequent (80-99%)
HP:0005484	Secondary microcephaly	Very frequent (80-99%)
HP:0008936	Axial hypotonia	Very frequent (80-99%)
HP:0010307	Stridor	Very frequent (80-99%)
HP:0010553	Oculogyric crisis	Very frequent (80-99%)
HP:0011443	Abnormality of coordination	Very frequent (80-99%)
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0030215	Inappropriate crying	Very frequent (80-99%)
HP:0100543	Cognitive impairment	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	brain dopamine-serotonin vesicular transport disease
Mondo ID	MONDO:0018130
OMIM	618049
Orphanet	352649
DOID	DOID:0070490
SNOMED CT	717942003
UMLS	C4303546
MedGen	929215
GARD	0013594
Is cancer (heuristic)	no

Also known as: parkinsonism-dystonia, infantile, 2 · PKDYS2

Data availability: 16 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › parkinsonism-dystonia, infantile › brain dopamine-serotonin vesicular transport disease

Related subtypes (2): parkinsonism-dystonia 3, childhood-onset, classic dopamine transporter deficiency syndrome

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

16 retrieved; paginated sample, class counts are floors:

4 benign, 4 uncertain significance, 4 likely pathogenic, 2 pathogenic, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1919082	NM_003054.6(SLC18A2):c.216dup (p.Asp73fs)	SLC18A2	Pathogenic	criteria provided, single submitter
2664950	NM_003054.6(SLC18A2):c.240_244del (p.Ser80_Tyr81insTer)	SLC18A2	Pathogenic	no assertion criteria provided
812731	NM_003054.6(SLC18A2):c.946C>G (p.Pro316Ala)	SLC18A2	Pathogenic/Likely pathogenic	no assertion criteria provided
3897717	NM_003054.6(SLC18A2):c.700+2T>G	SLC18A2	Likely pathogenic	criteria provided, single submitter
4077515	NM_003054.6(SLC18A2):c.464+2T>C	SLC18A2	Likely pathogenic	criteria provided, single submitter
4278092	NM_003054.6(SLC18A2):c.1184T>C (p.Ile395Thr)	SLC18A2	Likely pathogenic	criteria provided, single submitter
548130	NM_003054.6(SLC18A2):c.1160C>T (p.Pro387Leu)	SLC18A2	Likely pathogenic	criteria provided, single submitter
666409	NM_003054.6(SLC18A2):c.710C>A (p.Pro237His)	SLC18A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1310746	NM_003054.6(SLC18A2):c.33G>A (p.Trp11Ter)	SLC18A2	Uncertain significance	criteria provided, single submitter
1805448	NM_003054.6(SLC18A2):c.1196A>C (p.Asp399Ala)	SLC18A2	Uncertain significance	criteria provided, single submitter
2689997	NM_003054.6(SLC18A2):c.590C>T (p.Ser197Phe)	SLC18A2	Uncertain significance	criteria provided, single submitter
3775279	NM_003054.6(SLC18A2):c.596C>T (p.Ser199Phe)	SLC18A2	Uncertain significance	criteria provided, single submitter
1165075	NM_003054.6(SLC18A2):c.700+15C>T	SLC18A2	Benign	criteria provided, multiple submitters, no conflicts
1227431	NM_003054.6(SLC18A2):c.-15-39A>C	SLC18A2	Benign	criteria provided, multiple submitters, no conflicts
1236472	NM_003054.6(SLC18A2):c.1306+43G>A	SLC18A2	Benign	criteria provided, multiple submitters, no conflicts
1238275	NM_003054.6(SLC18A2):c.791-42C>A	SLC18A2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
SLC18A2	Strong	Autosomal recessive	brain dopamine-serotonin vesicular transport disease	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC18A2	Orphanet:352649	Brain dopamine-serotonin vesicular transport disease

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
SLC18A2	HGNC:10935	ENSG00000165646	Q05940	Synaptic vesicular amine transporter	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC18A2	Synaptic vesicular amine transporter	Electrogenic antiporter that exchanges one cationic monoamine with two intravesicular protons across the membrane of secretory and synaptic vesicles.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Transporter	1	77.8×	0.013

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC18A2	Transporter	yes		MFS, MFS_dom, MFS_trans_sf

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
secondary oocyte	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC18A2	191	broad	marker	substantia nigra pars reticulata, substantia nigra pars compacta, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC18A2	1,579

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC18A2	Q05940	32

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
Serotonin Neurotransmitter Release Cycle	1	634.4×	0.002	SLC18A2
Norepinephrine Neurotransmitter Release Cycle	1	634.4×	0.002	SLC18A2
Dopamine Neurotransmitter Release Cycle	1	496.5×	0.002	SLC18A2

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
serotonin secretion by mast cell	1	16852.0×	5e-04	SLC18A2
somato-dendritic dopamine secretion	1	16852.0×	5e-04	SLC18A2
aminergic neurotransmitter loading into synaptic vesicle	1	5617.3×	9e-04	SLC18A2
histamine uptake	1	4213.0×	9e-04	SLC18A2
histamine secretion by mast cell	1	3370.4×	9e-04	SLC18A2
neurotransmitter loading into synaptic vesicle	1	2808.7×	9e-04	SLC18A2
obsolete dopamine transport	1	1532.0×	0.001	SLC18A2
serotonin uptake	1	1532.0×	0.001	SLC18A2
obsolete monoamine transport	1	1203.7×	0.001	SLC18A2
negative regulation of reactive oxygen species biosynthetic process	1	991.3×	0.002	SLC18A2
response to amphetamine	1	495.6×	0.003	SLC18A2
neurotransmitter transport	1	421.3×	0.003	SLC18A2
response to toxic substance	1	210.7×	0.006	SLC18A2
post-embryonic development	1	205.5×	0.006	SLC18A2
locomotory behavior	1	179.3×	0.006	SLC18A2
chemical synaptic transmission	1	77.3×	0.013	SLC18A2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
SLC18A2	TETRABENAZINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC18A2	6	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TETRABENAZINE	4	SLC18A2
KETANSERIN	4	SLC18A2
RESERPINE	4	SLC18A2
SEROTONIN	3	SLC18A2
LOBELINE	2	SLC18A2
FLORBENAZINE	2	SLC18A2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC18A2	28	Binding:26, ADMET:1, Functional:1

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

6 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)
TETRABENAZINE	4	SLC18A2
KETANSERIN	4	SLC18A2
RESERPINE	4	SLC18A2
SEROTONIN	3	SLC18A2
LOBELINE	2	SLC18A2
FLORBENAZINE	2	SLC18A2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SLC18A2
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening