Dyskinesia with orofacial involvement, autosomal dominant

Summary

Dyskinesia with orofacial involvement, autosomal dominant (MONDO:0800028) is a disease caused by ADCY5 (GenCC Strong), with 1 cohort gene and 2 clinical trials. Top therapeutic interventions include caffeine.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ADCY5 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 92
• Phenotypes (HPO): 15
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		18	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0000317	Facial myokymia	Very frequent (80-99%)
HP:0002310	Orofacial dyskinesia	Very frequent (80-99%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001336	Myoclonus	Frequent (30-79%)
HP:0002072	Chorea	Frequent (30-79%)
HP:0002322	Resting tremor	Frequent (30-79%)
HP:0002509	Limb hypertonia	Frequent (30-79%)
HP:0008936	Axial hypotonia	Frequent (30-79%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0001635	Congestive heart failure	Occasional (5-29%)
HP:0001644	Dilated cardiomyopathy	Occasional (5-29%)
HP:0002194	Delayed gross motor development	Occasional (5-29%)
HP:0001249	Intellectual disability	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	dyskinesia with orofacial involvement, autosomal dominant
Mondo ID	MONDO:0800028
MeSH	C564676
OMIM	606703
Orphanet	324588
SNOMED CT	763352005
UMLS	C1847627
MedGen	338280
GARD	0012722
Is cancer (heuristic)	no

Also known as: ADCY5-related dyskinesia · dyskinesia, familial, with facial myokymia · FDFM

Data availability: 92 ClinVar variants · 1 GenCC gene-disease record · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › dyskinesia with orofacial involvement, autosomal dominant

Related subtypes (53): cerebellar ataxia, chronic tic disorder, choreatic disease, extrapyramidal and movement disease, benign shuddering attacks, transient tic disorder, essential tremor, lingual-facial-buccal dyskinesia, kuru, inherited Creutzfeldt-Jakob disease, Tourette syndrome, clonic hemifacial spasm, Huntington disease, multiple system atrophy, spinal muscular atrophy-progressive myoclonic epilepsy syndrome, benign paroxysmal tonic upgaze of childhood with ataxia, hereditary geniospasm, tremor-nystagmus-duodenal ulcer syndrome, arthrogryposis, Lafora disease, Unverricht-Lundborg syndrome, neuronal intranuclear inclusion disease, Huntington disease-like 3, brain-lung-thyroid syndrome, myoclonus, familial, proximal myopathy with extrapyramidal signs, progressive myoclonic epilepsy type 7, progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome, progressive non-fluent aphasia, opsoclonus-myoclonus syndrome, isolated facial myokymia, primary orthostatic tremor, familial congenital mirror movements, neuroacanthocytosis, behavioral variant of frontotemporal dementia, frontotemporal dementia with motor neuron disease, hyperekplexia, intellectual disability-hyperkinetic movement-truncal ataxia syndrome, neurodegeneration with brain iron accumulation, Huntington disease-like syndrome due to C9ORF72 expansions, variably protease-sensitive prionopathy, corticobasal syndrome, sensorineural hearing loss-early graying-essential tremor syndrome, progressive supranuclear palsy, Sandifer syndrome, psychogenic movement disorders, epilepsy with myoclonic absences, infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome, childhood-onset benign chorea with striatal involvement, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, PRRT2-associated paroxysmal movement disorder, SLC6A3-related dopamine transporter deficiency syndrome, complex movement disorder with or without neurodevelopmental features

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

92 retrieved; paginated sample, class counts are floors:

29 uncertain significance, 20 benign, 16 benign/likely benign, 10 pathogenic, 10 likely pathogenic, 6 conflicting classifications of pathogenicity, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1188830	NM_183357.3(ADCY5):c.2080_2088del (p.Lys694_Met696del)	ADCY5	Pathogenic	no assertion criteria provided
1327477	NM_183357.3(ADCY5):c.3045C>A (p.Asp1015Glu)	ADCY5	Pathogenic	no assertion criteria provided
1327478	NM_183357.3(ADCY5):c.697T>C (p.Tyr233His)	ADCY5	Pathogenic	no assertion criteria provided
162090	NM_183357.3(ADCY5):c.1252C>T (p.Arg418Trp)	ADCY5	Pathogenic	criteria provided, multiple submitters, no conflicts
162091	NM_183357.3(ADCY5):c.2176G>A (p.Ala726Thr)	ADCY5	Pathogenic	criteria provided, multiple submitters, no conflicts
162092	NM_183357.3(ADCY5):c.3086T>A (p.Met1029Lys)	ADCY5	Pathogenic	no assertion criteria provided
1685503	NM_183357.3(ADCY5):c.2278C>T (p.Arg760Ter)	ADCY5	Pathogenic	criteria provided, multiple submitters, no conflicts
208485	NM_183357.3(ADCY5):c.2088+1G>T	ADCY5	Pathogenic	no assertion criteria provided
218354	NM_183357.3(ADCY5):c.1253G>A (p.Arg418Gln)	ADCY5	Pathogenic	criteria provided, multiple submitters, no conflicts
218355	NM_183357.3(ADCY5):c.2088+1G>A	ADCY5	Pathogenic	criteria provided, multiple submitters, no conflicts
1685235	NM_183357.3(ADCY5):c.3074A>G (p.Glu1025Gly)	ADCY5	Likely pathogenic	criteria provided, single submitter
1685236	NM_183357.3(ADCY5):c.2072A>T (p.Lys691Met)	ADCY5	Likely pathogenic	criteria provided, single submitter
1803015	NM_183357.3(ADCY5):c.1235G>T (p.Arg412Leu)	ADCY5	Likely pathogenic	criteria provided, single submitter
1804151	NM_183357.3(ADCY5):c.3061C>T (p.Gln1021Ter)	ADCY5	Likely pathogenic	criteria provided, single submitter
801996	NM_183357.3(ADCY5):c.3074A>C (p.Glu1025Ala)	ADCY5	Likely pathogenic	criteria provided, single submitter
801998	NM_183357.3(ADCY5):c.1579C>A (p.Pro527Thr)	ADCY5	Likely pathogenic	criteria provided, single submitter
801999	NM_183357.3(ADCY5):c.459_460del (p.Arg154fs)	ADCY5	Likely pathogenic	criteria provided, single submitter
807532	NM_183357.3(ADCY5):c.2071A>G (p.Lys691Glu)	ADCY5	Likely pathogenic	criteria provided, single submitter
807533	NM_183357.3(ADCY5):c.1378A>T (p.Ile460Phe)	ADCY5	Likely pathogenic	criteria provided, single submitter
807534	NM_183357.3(ADCY5):c.1322C>T (p.Ala441Val)	ADCY5	Likely pathogenic	criteria provided, single submitter
1031781	NM_183357.3(ADCY5):c.400G>A (p.Gly134Ser)	ADCY5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1165864	NM_183357.3(ADCY5):c.242C>T (p.Pro81Leu)	ADCY5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1453013	NM_183357.3(ADCY5):c.2272GAC[1] (p.Asp759del)	ADCY5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
381222	NM_183357.3(ADCY5):c.1902G>C (p.Glu634Asp)	ADCY5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
390053	NM_183357.3(ADCY5):c.304G>A (p.Ala102Thr)	ADCY5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
706217	NM_183357.3(ADCY5):c.2866G>A (p.Asp956Asn)	ADCY5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030392	NM_183357.3(ADCY5):c.2443-14T>A	ADCY5	Uncertain significance	criteria provided, single submitter
1030446	NM_183357.3(ADCY5):c.503G>A (p.Arg168His)	ADCY5	Uncertain significance	criteria provided, single submitter
1031780	NM_183357.3(ADCY5):c.395C>G (p.Pro132Arg)	ADCY5	Uncertain significance	criteria provided, single submitter
1303516	NM_183357.3(ADCY5):c.2707A>G (p.Asn903Asp)	ADCY5	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
ADCY5	Strong	Autosomal dominant	dyskinesia with orofacial involvement, autosomal dominant	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADCY5	Orphanet:1429	Benign hereditary chorea
ADCY5	Orphanet:324588	Familial dyskinesia and facial myokymia

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
ADCY5	HGNC:236	ENSG00000173175	O95622	Adenylate cyclase type 5	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADCY5	Adenylate cyclase type 5	Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling.

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADCY5	Enzyme (other)	yes	4.6.1.1	A/G_cyclase, Adcy_conserved_dom, A/G_cyclase_CS

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
apex of heart	1
lower esophagus	1
lower esophagus muscularis layer	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADCY5	193	broad	marker	apex of heart, lower esophagus muscularis layer, lower esophagus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ADCY5	1,992

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ADCY5	O95622	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 49. 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
Adenylate cyclase activating pathway	1	1142.0×	0.007	ADCY5
Adenylate cyclase inhibitory pathway	1	761.3×	0.007	ADCY5
PKA activation in glucagon signalling	1	671.8×	0.007	ADCY5
PKA activation	1	634.4×	0.007	ADCY5
Activation of GABAB receptors	1	601.0×	0.007	ADCY5
PKA-mediated phosphorylation of CREB	1	571.0×	0.007	ADCY5
GABA B receptor activation	1	543.8×	0.007	ADCY5
Adrenaline,noradrenaline inhibits insulin secretion	1	393.8×	0.007	ADCY5
Anti-inflammatory response favouring Leishmania parasite infection	1	393.8×	0.007	ADCY5
Leishmania parasite growth and survival	1	393.8×	0.007	ADCY5
Calmodulin induced events	1	380.7×	0.007	ADCY5
CaM pathway	1	380.7×	0.007	ADCY5
Ca-dependent events	1	368.4×	0.007	ADCY5
Aquaporin-mediated transport	1	368.4×	0.007	ADCY5
Glucagon signaling in metabolic regulation	1	346.1×	0.007	ADCY5
G-protein mediated events	1	326.3×	0.007	ADCY5
DAG and IP3 signaling	1	317.2×	0.007	ADCY5
GABA receptor activation	1	317.2×	0.007	ADCY5
Response of endothelial cells to shear stress	1	300.5×	0.007	ADCY5
FCGR3A-mediated IL10 synthesis	1	292.8×	0.007	ADCY5
Opioid Signalling	1	265.6×	0.007	ADCY5
PLC beta mediated events	1	265.6×	0.007	ADCY5
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	265.6×	0.007	ADCY5
Vasopressin regulates renal water homeostasis via Aquaporins	1	265.6×	0.007	ADCY5
Cellular responses to mechanical stimuli	1	259.6×	0.007	ADCY5
ADORA2B mediated anti-inflammatory cytokines production	1	253.8×	0.007	ADCY5
GPER1 signaling	1	248.3×	0.007	ADCY5
G alpha (z) signalling events	1	233.1×	0.008	ADCY5
Regulation of insulin secretion	1	219.6×	0.008	ADCY5
Signaling by Hedgehog	1	184.2×	0.009	ADCY5

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
adenylate cyclase-inhibiting dopamine receptor signaling pathway	1	3370.4×	0.002	ADCY5
G protein-coupled adenosine receptor signaling pathway	1	2407.4×	0.002	ADCY5
adenylate cyclase-activating dopamine receptor signaling pathway	1	1532.0×	0.002	ADCY5
cAMP biosynthetic process	1	1404.3×	0.002	ADCY5
cellular response to forskolin	1	1123.5×	0.002	ADCY5
regulation of insulin secretion involved in cellular response to glucose stimulus	1	936.2×	0.002	ADCY5
cellular response to glucagon stimulus	1	842.6×	0.002	ADCY5
vascular endothelial cell response to laminar fluid shear stress	1	732.7×	0.002	ADCY5
renal water homeostasis	1	510.7×	0.003	ADCY5
neuromuscular process controlling balance	1	330.4×	0.004	ADCY5
locomotory behavior	1	179.3×	0.007	ADCY5
positive regulation of cytosolic calcium ion concentration	1	117.0×	0.010	ADCY5
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	113.1×	0.010	ADCY5
intracellular signal transduction	1	38.1×	0.026	ADCY5

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ADCY5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ADCY5	43	Binding:33, Functional:9, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADCY5	4.6.1.1	adenylate cyclase

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	1	ADCY5
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
ADCY5	43	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04469283	Not specified	UNKNOWN	Caffeine Efficacy in ADCY5-related Dyskinesia
NCT05136495	Not specified	COMPLETED	Assessment of ADCY5-related Movement Disorders With Motion SENSors

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CAFFEINE	4	1