Dystonia 24

Mendelian MONDO:0014019 Pathograph 25 Show in embeddings browser Isolated dystonia Monogenic dystonia

An autosomal dominant dystonia caused by heterozygous variants in ANO3, which encodes anoctamin 3 (TMEM16C), a calcium-activated member of the TMEM16 family of phospholipid scramblases and ion channels that is most highly expressed in the striatum. The originally described phenotype, in a British kindred and two further families, is craniocervical dystonia with prominent tremor: cervical dystonia, laryngeal dystonia and upper-limb dystonic tremor, sometimes with blepharospasm, oromandibular involvement and superimposed myoclonic jerks. Onset ranges from early childhood to late adulthood, spread is usually to a segmental or multifocal distribution, and tremor can precede any visible dystonia, which leads to misdiagnosis as essential tremor. Later reports, many of them de novo missense variants in children, broadened the phenotype to early-onset generalized dystonia, paroxysmal dystonia, myoclonic dystonia, truncal dystonia, chorea, parkinsonism, hypotonia, developmental delay and mild intellectual disability. Whether all of these belong to one disease is not settled; they are recorded here as phenotypes of the gene-defined entity with their sources, without frequency where no cohort figure exists. Brain MRI is normal in the reported families. The mechanism is the least settled part of the entry. The best-supported chain runs from altered ANO3 function through impaired endoplasmic reticulum calcium release and store-operated calcium entry to failed activation of calcium-dependent potassium channels, and from there, by inference, to hyperexcitability of striatal neurons. Every step up to the potassium channel has been measured in patient fibroblasts or transfected cell lines; the step into striatal neurons and the step from there to dystonia have not been demonstrated in neurons, tissue or an animal model. Whether ANO3 itself conducts ions, and whether disease variants act by loss of function, are disputed, and both questions are recorded as knowledge gaps rather than resolved here. Gene-disease validity is also contested. Rare protein-changing ANO3 variants are found in controls and in other movement disorders at an appreciable rate, so not every rare variant reported in a dystonia patient is pathogenic. Relationship to Cervical_Dystonia: that entry covers common sporadic adult focal cervical dystonia and types ANO3 as a SUSCEPTIBILITY gene explaining a small minority of unselected cases. This entry is the Mendelian entity itself. The two share a phenotypic region and are not merged. No pathophysiology node declares conforms_to: kb/modules/ has no module for dystonia, basal ganglia motor network dysfunction or anoctamin scramblase biology.

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2
Inheritance
5
Pathophys.
29
Phenotypes
2
Gaps
25
Pathograph
1
Genes
3
Medical Actions
4
Differentials
1
Models
1
References
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Deep Research
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Inheritance

2
Autosomal dominant HP:0000006
Heterozygous ANO3 variants segregate dominantly in the families in which the gene was identified. A substantial share of later cases, particularly childhood-onset generalized presentations, carry de novo variants.
Autosomal dominant
Show evidence (3 references)
PMID:23200863 SUPPORT Human Clinical
"We conclude that mutations in ANO3 are a cause of autosomal-dominant craniocervical dystonia."
The gene-identification study, based on linkage and segregation in an autosomal dominant kindred, states the mode of inheritance.
PMID:24442708 SUPPORT BACKGROUND Human Clinical
"Recently, pathogenic mutations in the anoctamin 3 gene (ANO3) have been identified to cause autosomal dominant craniocervical dystonia and have been assigned to the dystonia locus dystonia-24 (DYT24)."
Follow-up clinical study of the three original families; this sentence restates the gene-identification report rather than presenting a new result.
PMID:30712998 SUPPORT Human Clinical
"Further, we identified a patient with early-onset, generalized dystonia with a de-novo variant in ANO3 (p.Val561Glu)."
Documents a de novo heterozygous variant, consistent with dominant action of a single altered allele in sporadic early-onset cases.
Incomplete penetrance HP:0003829
Unaffected carriers and apparently skipped generations are reported, so a negative family history does not exclude the diagnosis. No numeric penetrance estimate exists, and some asymptomatic carriers in cohort screens may carry variants that are not pathogenic.
Typified by incomplete penetrance
Show evidence (2 references)
PMID:42353862 SUPPORT Human Clinical
"In the remaining eight families, the carriers demonstrated asymptomatic presentation, regardless of paternal or maternal lineage."
Asymptomatic parental carriers in eight trio families. Read with care: most of these variants were of uncertain significance, so this bears on penetrance only for those that are pathogenic.
PMID:23200863 SUPPORT Human Clinical
"Although both individuals are now deceased and could not be examined, this suggests the possibility that penetrance might not be complete."
A reportedly affected great-grandmother with an apparently unaffected grandmother in the second original family.
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Discussions and Knowledge Gaps

2
Do dystonia-causing ANO3 variants reduce ANO3 function, and does ANO3 act as an ion channel at all, or only as a scramblase?
KNOWLEDGE GAP OPEN ano3_variant_effect_direction
Attached to
pathophysiology#Heterozygous ANO3 Variants pathophysiology#Altered ANO3 Calcium-Activated Scramblase Function
The cited functional work measured downstream calcium and potassium signalling in fibroblasts and HEK293 cells expressing variants, not the scrambling or channel activity of each variant directly, and one variant tested deviated only slightly from wild type. The two groups that characterized ANO3 itself disagree on whether it conducts ions. The rat knockout links complete loss of ANO3 to neuronal hyperexcitability, but through sodium-activated potassium channels that the variant study found unaffected. Whether heterozygous missense variants act by loss of function, dominant-negative interference or altered function is therefore open, and the entry leaves functional_impact_category unset for that reason.
Proposed experiments
Direct scramblase and current measurement across a panel of ANO3 variants
ano3_variant_panel_scrambling_and_currents
Express wild-type ANO3 and a panel of familial and de novo variants, alone and co-expressed with wild type, and measure calcium-activated phosphatidylserine exposure, whole-cell currents and surface expression.
Would support
pathophysiology#Altered ANO3 Calcium-Activated Scramblase Function
Supporting outcome
  • Variants consistently reduce or alter scrambling, and co-expression shows whether the effect is dominant over wild type.
Refuting outcome
  • Variants leave scrambling and currents unchanged, which would place the lesion elsewhere, for example in protein interactions or trafficking.
Show evidence (6 references)
PMID:36295764 SUPPORT In Vitro
"In contrast to other TMEM16 proteins, flux assays and electrophysiology recording showed TMEM16C does not possess ion-transporting activity."
One side of the disagreement on ion conduction.
PMID:23532839 SUPPORT In Vitro
"On the other hand, a patch clamp analysis in 293T cells indicated that TMEM16A and 16B, but not other family members, acted as Ca(2+)-dependent Cl(-) channels."
Earlier patch-clamp evidence that TMEM16C does not form a calcium-activated chloride channel.
PMID:38079528 SUPPORT In Vitro
"We identified ANO3 as a Ca2+-activated phospholipid scramblase that also conducts ions."
The other side of the disagreement.
+ 3 more references
Does a heterozygous patient ANO3 variant make striatal neurons hyperexcitable and produce dystonia in a model system?
KNOWLEDGE GAP OPEN ano3_no_dystonia_model
Attached to
pathophysiology#Striatal Neuronal Hyperexcitability animal_models#Rat
Every measured step of the mechanism is in non-neuronal cells. The step into striatal neurons and the step from there to dystonic movement rest on ANO3 expression in the striatum and on the authors' proposal. No ANO3 animal model of dystonia was found; the rodent knockouts in the literature were studied for pain and febrile seizures, and the knockout rat recorded under animal_models reaches only a peripheral-neuron version of the excitability node.
Proposed experiments
Patient-variant knock-in or iPSC-derived striatal neurons
ano3_knockin_striatal_physiology
Record intrinsic excitability, calcium-activated potassium currents and store-operated calcium entry in striatal medium spiny neurons carrying a heterozygous patient variant, and assess motor phenotype in a knock-in animal.
Would support
pathophysiology#Striatal Neuronal Hyperexcitability
Supporting outcome
  • Variant-carrying medium spiny neurons show reduced calcium-activated potassium current and increased firing, and the animal develops abnormal postures or tremor.
Refuting outcome
  • Striatal neurons show normal excitability despite the calcium defect, which would point to another cell type or mechanism.
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Pathophysiology

5
Heterozygous ANO3 Variants
Heterozygous ANO3 variants, almost all missense, spread across the protein rather than clustered in one domain. The two original familial variants lie in exon 15; many later childhood-onset variants are de novo, and one review proposes that variants near the scrambling domain track the more severe early-onset phenotype. The functional impact category is left unset on purpose: whether pathogenic variants reduce or alter ANO3 function is disputed (see the knowledge-gap discussion). The ANO3 gene binding sits on the next node, with the molecular function it encodes.
Genetic context variant_origin: GERMLINE
Downstream
Altered ANO3 Calcium-Activated Scramblase Function Disease variants change the behaviour of a calcium-activated scramblase expressed in the endoplasmic reticulum and plasma membrane.
Show evidence (3 references)
PMID:23200863 SUPPORT Human Clinical
"Subsequent screening of these candidate causal variants in a large number of familial and sporadic cases of cervical dystonia led to the identification of a total of six putatively pathogenic mutations in ANO3, a gene encoding a predicted Ca(2+)-gated chloride channel that we show to be highly..."
Original report of heterozygous ANO3 variants in familial and sporadic cervical dystonia.
PMID:33388357 SUPPORT Human Clinical
"Combined with our work and literature review, a total of 35 different rare variants distributed in ANO3 were identified in 62 dystonia patients."
Quantifies the variant spectrum across the published cases and shows the variants are distributed along the gene.
PMID:38284143 SUPPORT Human Clinical
"Stratification by age at onset divided ANO3 cases into two major groups, where younger patients displayed a more severe phenotype, probably due to variants near the scrambling domain."
Literature review proposing that variant position, near the scrambling domain, tracks the more severe early-onset phenotype. Stated by the authors as probable, not established.
Altered ANO3 Calcium-Activated Scramblase Function
ANO3 is a calcium-activated phospholipid scramblase of the TMEM16 family, present largely in intracellular membranes. One group reports that it also conducts ions; another, studying human TMEM16C isoforms, found scrambling but no ion transport. How disease variants change scrambling itself has not been measured directly in the cited studies; what has been measured is their effect on cellular calcium signalling, recorded in the next node.
ANO3 hgnc:14004 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ANO3 (hgnc:14004). hgnc:14004 is a gene from the HUGO Gene Nomenclature Committee.
calcium-activated phospholipid scramblase activity GO:0017128 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal calcium-activated phospholipid scramblase activity, annotated with phospholipid scramblase activity (GO:0017128). GO:0017128 is a molecular function from the Gene Ontology.
Downstream
Impaired Endoplasmic Reticulum Calcium Release and Store-Operated Calcium Entry Cells expressing disease variants show reduced store release and strongly reduced store-operated calcium entry, attributed to reduced plasma membrane expression of the ORAI1 channel.
Show evidence (4 references)
PMID:38079528 SUPPORT In Vitro
"We identified ANO3 as a Ca2+-activated phospholipid scramblase that also conducts ions."
Cell-based characterization of ANO3 function used as the baseline against which disease variants were compared.
PMID:36295764 SUPPORT In Vitro
"Unlike previous results, our data showed that human TMEM16C isoform 1 and isoform 3 exposed PS to the cell surface."
Independent confirmation in 293T cells that human TMEM16C isoforms scramble phosphatidylserine to the cell surface. The same study did not detect ion transport, which is recorded in the knowledge-gap discussion.
PMID:23532839 SUPPORT In Vitro
"We expressed other TMEM16 proteins in the TMEM16F(-/-) cells and found that not only TMEM16F, but also 16C, 16D, 16G, and 16J work as lipid scramblases with different preference to lipid substrates."
First demonstration that TMEM16C (ANO3) is a calcium-dependent lipid scramblase, in a scramblase-null mouse lymphocyte line.
+ 1 more reference
Impaired Endoplasmic Reticulum Calcium Release and Store-Operated Calcium Entry
The most reproducible cellular finding. Calcium imaging of patient fibroblasts in the gene-identification study showed abnormal endoplasmic reticulum dependent calcium signalling, and a later study of four further variants found that store release and, above all, store-operated calcium entry through ORAI1 were strongly inhibited in cells expressing the variants. Measured in fibroblasts and HEK293 cells, not in neurons.
store-operated calcium entry GO:0002115 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased store-operated calcium entry (GO:0002115). GO:0002115 is a biological process from the Gene Ontology. endoplasmic reticulum calcium ion homeostasis GO:0032469 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal endoplasmic reticulum calcium ion homeostasis (GO:0032469). GO:0032469 is a biological process from the Gene Ontology.
Downstream
Impaired Activation of Calcium-Dependent Potassium Channels The reduced calcium signal fails to activate KCa3.1 channels, while sodium-activated potassium channels are spared.
Show evidence (2 references)
PMID:23200863 SUPPORT In Vitro
"Functional studies using Ca(2+) imaging in case and control fibroblasts demonstrated clear abnormalities in endoplasmic-reticulum-dependent Ca(2+) signaling."
First functional observation, in fibroblasts from a variant carrier. Graded IN_VITRO because this sentence reports a cultured-cell assay; the genetic findings of the same paper are graded HUMAN_CLINICAL elsewhere in this entry.
PMID:39773217 SUPPORT In Vitro
"Upon expression, emptying of the endoplasmic reticulum Ca2+ store (store release) and particularly store-operated Ca2+ entry (SOCE) were strongly inhibited, leading to impaired activation of KCa3.1 (KCNN) K+ channels, but not of Na+-activated K+ channels (KNa; SLO2)."
Measures inhibited store release and store-operated calcium entry in cells expressing four disease variants.
Impaired Activation of Calcium-Dependent Potassium Channels
Cells expressing ANO3 variants show compromised activation of the calcium-dependent potassium channel KCa3.1. In rat sensory neurons ANO3 instead supports the sodium-activated potassium channel Slack (KCNT1), and its loss there raises excitability; in the dystonia-variant study the sodium-activated channels were not affected, so which potassium current matters in the striatum is not established.
KCNN4 (KCa3.1) hgnc:6293 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KCNN4 (KCa3.1), annotated with KCNN4 (hgnc:6293). hgnc:6293 is a gene from the HUGO Gene Nomenclature Committee.
activation of calcium-activated potassium channel (KCa3.1) GO:0015269 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased activation of calcium-activated potassium channel (KCa3.1), annotated with calcium-activated potassium channel activity (GO:0015269). GO:0015269 is a molecular function from the Gene Ontology.
Downstream
Striatal Neuronal Hyperexcitability Proposed rather than measured: loss of a calcium-activated potassium conductance would depolarize the membrane and raise excitability of striatal neurons, where ANO3 expression is highest.
Show evidence (1 reference)
PMID:38079528 SUPPORT In Vitro
"Impaired Ca2+ signalling and compromised activation of Ca2+-dependent K+ channels were detected in cells expressing ANO3 variants."
Direct measurement of the potassium channel defect in variant-expressing cells.
Striatal Neuronal Hyperexcitability
The inferred cellular substrate of the movement disorder. ANO3 is expressed most highly in the striatum, and loss of ANO3 raises excitability in rat sensory neurons, but hyperexcitability of striatal neurons carrying a disease variant has not been demonstrated. A PubMed search for ANO3 with mouse, mice or knockout returned no animal model of dystonia. The step from this node to dystonic movement is likewise inferred, and the edges to the movement phenotypes below are uncited for that reason.
striatal medium spiny neuron CL:1001474 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves striatal medium spiny neuron, annotated with medium spiny neuron (CL:1001474). CL:1001474 is a cell type from the Cell Ontology.
striatum UBERON:0002435 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in striatum (UBERON:0002435). UBERON:0002435 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
TMEM16C knockout rat Rat partially recapitulates Shows that loss of ANO3 can make neurons hyperexcitable, which is the kind of change the node proposes, but in a different neuron type and through a different potassium channel.
Downstream
Cervical dystonia
Laryngeal dystonia
Tremor
Head tremor
Postural tremor
Craniofacial dystonia
Oromandibular dystonia
Writer's cramp
Blepharospasm
Upper limb dystonia
Leg dystonia
Axial dystonia
Myoclonus
Generalized dystonia
Paroxysmal dystonia
Chorea
Show evidence (3 references)
PMID:41400152 SUPPORT INDIRECT Computational
"Individual genes exhibiting differences in expression across adult brain regions include SQSTM1, SGCE, KMT2B, PRKRA, YY1, DNAJC12, KCNA1, CACNA1A (highest expression in cerebellum), ADCY5, GNAL, ANO3 (highest expression in striatum), RHOBTB2, FOXG1 (highest expression in cerebral cortex)."
Places ANO3 expression highest in the striatum in a reanalysis of human brain transcriptomic datasets, which is the basis for locating this node there. INDIRECT because expression does not show dysfunction.
PMID:23872594 SUPPORT INDIRECT Model Organism
"DRG from TMEM16C knockout rats had diminished Slack expression, broadened action potentials and increased excitability."
Loss of ANO3 raises neuronal excitability in the knockout rat. INDIRECT because these are dorsal root ganglion neurons, the potassium channel involved (Slack) differs from the one implicated by the dystonia-variant study, and complete knockout may not model a heterozygous missense variant.
PMID:39773217 SUPPORT INDIRECT In Vitro
"Dysregulated Ca2+ signaling by ANO3 variants may impair the activation of K+ channels in striatal neurons of the brain, thereby causing dystonia."
The authors' conclusion connecting the cell-line findings to striatal neurons and to dystonia, stated as a possibility.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Dystonia 24 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

29
Head and Neck 2
Cervical dystonia FREQUENT Torticollis HP:0000473 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cervical dystonia, annotated with Torticollis (HP:0000473). HP:0000473 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:24442708 SUPPORT Human Clinical
"Cervical dystonia was the most common site of onset followed by laryngeal dystonia."
Site of onset in the ten patients of the three original families.
PMID:42353862 SUPPORT Human Clinical
"ANO3-related dystonia exhibited broad clinical heterogeneity, with frequent cervical involvement (62.5%) and tremulous features (75%), and occasionally extended beyond classical isolated dystonia."
Cervical involvement in 62.5 percent of the variant-carrying dystonia patients of a Chinese cohort, the source for the FREQUENT band.
PMID:33502045 SUPPORT Human Clinical
"For ANO3, a segmental/multifocal distribution was typical, whereas TOR1A, PRKRA, KMT2B, and HPCA mutation carriers commonly developed generalized dystonia."
Systematic review establishing the typical segmental or multifocal distribution.
Blepharospasm HP:0000643 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Blepharospasm (HP:0000643). HP:0000643 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27919237 SUPPORT Human Clinical
"The patient developed a mixed hyperkinetic disorder consisting of chorea, dystonia affecting the upper extremities, dysarthria, and blepharospasm."
Case report of a heterozygous ANO3 variant carrier with blepharospasm.
Musculoskeletal 2
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38079528 SUPPORT Human Clinical
"Three individuals presented with hypotonia and motor developmental delay."
Hypotonia in three of four children with ANO3 variants.
Rigidity HP:0002063 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rigidity (HP:0002063). HP:0002063 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38284143 SUPPORT Human Clinical
"She later developed a diffuse dystonic tremor and mild extrapyramidal signs (ie, rigidity and hypodiadochokinesis) in her right arm."
Rigidity in the proband of a six-carrier family.
Nervous System 23
Laryngeal dystonia HP:0012049 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Laryngeal dystonia (HP:0012049). HP:0012049 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24442708 SUPPORT Human Clinical
"Cervical dystonia was the most common site of onset followed by laryngeal dystonia."
Laryngeal dystonia was the second most common site of onset.
Tremor FREQUENT HP:0001337 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonic tremor of head, voice and arms, annotated with Tremor (HP:0001337). HP:0001337 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:24442708 SUPPORT Human Clinical
"The characteristic feature in all affected individuals was the presence of tremor, which contrasts DYT24 from the typical DYT6 phenotype."
Tremor was present in all ten affected individuals in the original families.
PMID:42353862 SUPPORT Human Clinical
"ANO3-related dystonia exhibited broad clinical heterogeneity, with frequent cervical involvement (62.5%) and tremulous features (75%), and occasionally extended beyond classical isolated dystonia."
Tremulous features in 75 percent of a later cohort, the source for the FREQUENT band.
Craniofacial dystonia HP:0012179 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Craniofacial dystonia (HP:0012179). HP:0012179 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33502045 SUPPORT Human Clinical
"However, in most DYT-THAP1 and DYT-ANO3 patients, dystonia first manifested in the upper half of the body (upper limb, neck, and craniofacial/laryngeal), whereas onset in DYT-TOR1A, DYT-PRKRA and DYT-HPCA was frequently observed in an extremity, including both upper and lower ones."
Systematic review placing first manifestation in the upper body, including the craniofacial region.
Upper limb dystonia FREQUENT Arm dystonia HP:0031960 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Upper limb dystonia, annotated with Arm dystonia (HP:0031960). HP:0031960 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33502045 SUPPORT Human Clinical
"However, in most DYT-THAP1 and DYT-ANO3 patients, dystonia first manifested in the upper half of the body (upper limb, neck, and craniofacial/laryngeal), whereas onset in DYT-TOR1A, DYT-PRKRA and DYT-HPCA was frequently observed in an extremity, including both upper and lower ones."
Upper limb named among the typical sites of first manifestation.
PMID:42353862 SUPPORT Human Clinical
"Cervical involvement (10/16, 62.5%) was the most common final manifestation, followed by involvement of the upper (8/16, 50%) and lower limbs (7/16, 43.75%)."
Upper limb involvement in half of 16 variant carriers with dystonia, the source for the FREQUENT band.
Leg dystonia FREQUENT HP:0031959 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lower limb dystonia, annotated with Leg dystonia (HP:0031959). HP:0031959 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34307749 SUPPORT Human Clinical
"His family history was remarkable for cervical dystonia with myoclonus in his grandfather, cervical and upper limb dystonia along with dopa-responsive parkinsonism in his father and lower-limb dystonia in his teenage sister."
Lower-limb dystonia in a variant-carrying family member.
PMID:42353862 SUPPORT Human Clinical
"Cervical involvement (10/16, 62.5%) was the most common final manifestation, followed by involvement of the upper (8/16, 50%) and lower limbs (7/16, 43.75%)."
Lower limb involvement in 7 of 16 variant carriers with dystonia in a Chinese cohort, the source for the FREQUENT band. The original British families had no leg involvement, so the figure is cohort-specific.
Myoclonus HP:0001336 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myoclonus (HP:0001336). HP:0001336 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:24442708 SUPPORT Human Clinical
"In one of the studied patients, clinically superimposed myoclonus was observed."
Myoclonus in an original-family patient.
PMID:34307749 SUPPORT Human Clinical
"The index case presented with myoclonic dystonia at age 10."
Myoclonic dystonia as the presenting phenotype in a later family.
Generalized dystonia OCCASIONAL HP:0007325 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized dystonia (HP:0007325). HP:0007325 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:30712998 SUPPORT Human Clinical
"In contrast, de-novo variants in childhood-onset, generalized dystonia seem to represent an as yet underestimated phenotypic expression of changes in ANO3."
Large screening study identifying childhood-onset generalized dystonia as a phenotype of de novo variants.
PMID:38079528 SUPPORT Human Clinical
"Two patients exhibited generalized progressive dystonia, while one patient presented with paroxysmal dystonia."
Generalized progressive dystonia in two of four children with ANO3 variants.
PMID:42353862 SUPPORT Human Clinical
"Four patients developed generalized dystonia, and four had segmental or multifocal dystonia."
Generalized dystonia in 4 of 16 variant carriers in a cohort, the source for the OCCASIONAL band.
Paroxysmal dystonia HP:0002268 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Paroxysmal dystonia (HP:0002268). HP:0002268 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38079528 SUPPORT Human Clinical
"Two patients exhibited generalized progressive dystonia, while one patient presented with paroxysmal dystonia."
Paroxysmal dystonia in one of four children with ANO3 variants.
Chorea HP:0002072 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chorea (HP:0002072). HP:0002072 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27919237 SUPPORT Human Clinical
"The patient developed a mixed hyperkinetic disorder consisting of chorea, dystonia affecting the upper extremities, dysarthria, and blepharospasm."
Chorea combined with dystonia in a variant carrier.
Dysarthria HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27919237 SUPPORT Human Clinical
"The patient developed a mixed hyperkinetic disorder consisting of chorea, dystonia affecting the upper extremities, dysarthria, and blepharospasm."
Dysarthria in a variant carrier with cranial dystonia.
Parkinsonism OCCASIONAL HP:0001300 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Parkinsonism (HP:0001300). HP:0001300 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34307749 SUPPORT Human Clinical
"His family history was remarkable for cervical dystonia with myoclonus in his grandfather, cervical and upper limb dystonia along with dopa-responsive parkinsonism in his father and lower-limb dystonia in his teenage sister."
Dopa-responsive parkinsonism in a variant-carrying father.
PMID:42353862 SUPPORT Human Clinical
"However, additional neurological or neuropsychiatric features were observed in several individuals, including parkinsonism in two patients and psychiatric or behavioral symptoms in two patients."
Parkinsonism in 2 of 16 variant carriers in a cohort, the source for the OCCASIONAL band.
Motor delay HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38079528 SUPPORT Human Clinical
"Three individuals presented with hypotonia and motor developmental delay."
Motor developmental delay in three of four children with ANO3 variants.
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36167772 SUPPORT Human Clinical
"Here, we report a two-year-old girl who showed mild to moderate developmental delay, tremor, and ataxic gait, but no obvious dystonia."
Developmental delay in a child with a de novo ANO3 variant.
PMID:33045406 SUPPORT Human Clinical
"A global psychomotor regression was observed once dystonia was present."
Psychomotor regression after dystonia onset in a child with a de novo ANO3 variant.
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41441972 SUPPORT Human Clinical
"The neurological examination revealed a mild intellectual disability, head titubation, postural and action tremors, and dystonia affecting the bilateral distal upper extremities."
Mild intellectual disability in an adult with tremulous ANO3-related dystonia.
PMID:38284143 SUPPORT Human Clinical
"She also suffered from psychomotor delay and learning difficulties."
Learning difficulties in the proband of a six-carrier ANO3 family.
Axial dystonia HP:0002530 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Truncal dystonia, annotated with Axial dystonia (HP:0002530). HP:0002530 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39692086 SUPPORT Human Clinical
"Here, we describe a novel phenotype of ANO3 variant causing truncal dystonia."
Case report of truncal dystonia in an ANO3 variant carrier.
Head tremor HP:0002346 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Head tremor (HP:0002346). HP:0002346 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:24442708 SUPPORT Human Clinical
"On examination at age 53 years, he had a side-to-side head tremor and oromandibular movements."
Head tremor in an affected member of an original family.
PMID:24442708 SUPPORT Human Clinical
"Patient III-1 (age 65 years) (Fig. 1B) first noticed an intermittent head tremor at the age of 4 years and recalls being teased for this at school."
Head tremor as the presenting sign in early childhood.
Postural tremor HP:0002174 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postural tremor (HP:0002174). HP:0002174 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38284143 SUPPORT Human Clinical
"Her paternal aunt, father, and a third older sister presented episodic postural tremor in the arms."
Postural arm tremor as the only feature in three carriers of one family.
Oromandibular dystonia HP:0012048 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oromandibular dystonia (HP:0012048). HP:0012048 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24442708 SUPPORT Human Clinical
"She had laryngeal dysphonia and mild oromandibular dystonia (Video Segment 2A)."
Oromandibular dystonia in an original-family patient.
Writer's cramp HP:0002356 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Writer's cramp (HP:0002356). HP:0002356 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38284143 SUPPORT Human Clinical
"Two years later, she developed cervical pain and headache, partially responsive to acetaminophen, and writer's cramp in her right hand."
Writer's cramp in a variant-carrying sister.
Tics HP:0100033 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tics (HP:0100033). HP:0100033 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27919237 SUPPORT Human Clinical
"The complex clinical presentation of the patient described includes hyperkinesias, complex motor movements, and vocal tics, which have not been reported in other patients with DYT24."
Tics in a single case; the variant was classed as uncertain significance.
Dyskinesia HP:0100660 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dyskinesia (HP:0100660). HP:0100660 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38079528 SUPPORT Human Clinical
"Additionally, another patient exhibited early dyskinetic encephalopathy."
Dyskinetic encephalopathy in one of four children with ANO3 variants.
Atypical behavior HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Psychiatric or behavioural symptoms, annotated with Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42353862 SUPPORT Human Clinical
"However, additional neurological or neuropsychiatric features were observed in several individuals, including parkinsonism in two patients and psychiatric or behavioral symptoms in two patients."
Psychiatric or behavioural symptoms in two of 16 variant-carrying dystonia patients.
Gait ataxia HP:0002066 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gait ataxia (HP:0002066). HP:0002066 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36167772 SUPPORT Human Clinical
"Here, we report a two-year-old girl who showed mild to moderate developmental delay, tremor, and ataxic gait, but no obvious dystonia."
Ataxic gait in a child with a de novo ANO3 variant.
Constitutional 2
Urinary incontinence HP:0000020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Urinary incontinence (HP:0000020). HP:0000020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39773217 SUPPORT BACKGROUND Human Clinical
"Bowel and urinary incontinence were observed in all three patients carrying the variants V561L, S651N, or A599D."
Urinary incontinence in three severely affected children; quoted from the paper's summary of the authors' earlier clinical report.
Bowel incontinence HP:0002607 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bowel incontinence (HP:0002607). HP:0002607 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39773217 SUPPORT BACKGROUND Human Clinical
"Bowel and urinary incontinence were observed in all three patients carrying the variants V561L, S651N, or A599D."
Bowel incontinence in three severely affected children; quoted from the paper's summary of the authors' earlier clinical report.
🧬

Genetic Associations

1
ANO3
Gene: ANO3 hgnc:14004 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ANO3 (hgnc:14004). hgnc:14004 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (5 references)
PMID:23200863 SUPPORT Human Clinical
"We conclude that mutations in ANO3 are a cause of autosomal-dominant craniocervical dystonia."
Gene identification by linkage, exome sequencing and segregation.
PMID:27666935 SUPPORT Human Clinical
"Reflecting locus heterogeneity, identified unique variants were distributed over 5 genes (GCH1, THAP1, TOR1A, ANO3, ADCY5), of which only 1 (ANO3) was mutated recurrently."
Independent exome study finding ANO3 variants recurrently in early-onset generalized dystonia.
PMID:42353862 SUPPORT Human Clinical
"The rare ANO3 variants were significantly enriched in the dystonia cohort compared with the controls."
Case-control enrichment of rare ANO3 variants in dystonia over non-dystonic movement disorder controls.
+ 2 more references
💊

Medical Actions

3
Botulinum toxin chemodenervation
Action: botulinum toxin chemodenervationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is botulinum toxin chemodenervation, annotated with Botulinum Toxin Therapy (NCIT:C157775). NCIT:C157775 is a clinical intervention from the NCI Thesaurus. Ontology label: Botulinum Toxin Therapy NCIT:C157775
Platform: Other
Intramuscular botulinum toxin for focal and segmental dystonia and tremor. Benefit in ANO3-related dystonia is variable.
Mechanism Target:
Cervical dystonia — Weakens the dystonic muscles at the neuromuscular junction; symptomatic, and downstream of every mechanism node in the entry.
Show evidence (2 references)
PMID:42353862 SUPPORT Human Clinical
"Oral medication and botulinum toxin showed variable benefit, whereas deep brain stimulation was associated with marked improvement in selected medically refractory patients."
Retrospective treatment review in an ANO3 cohort reporting variable benefit from botulinum toxin.
PMID:42353862 SUPPORT Human Clinical
"Clinically, botulinum toxin appeared to be more advantageous for patients suffering from focal dystonia, particularly those with cervical or craniofacial involvement (see Figure 4C,D)."
Benefit concentrated in focal cervical and craniofacial dystonia in five treated patients.
Oral pharmacotherapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: trihexyphenidyl CHEBI:9720 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses trihexyphenidyl (CHEBI:9720). CHEBI:9720 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Oral antidystonic and antitremor medication, with variable and often limited benefit.
Show evidence (2 references)
PMID:41441972 SUPPORT Human Clinical
"She was started on trihexyphenidyl, and at the follow-up, partial improvement in her involuntary movements was observed."
Partial response to the anticholinergic trihexyphenidyl in a single ANO3 case report.
PMID:42353862 SUPPORT Human Clinical
"Oral medication and botulinum toxin showed variable benefit, whereas deep brain stimulation was associated with marked improvement in selected medically refractory patients."
Variable benefit of oral medication in an ANO3 cohort.
Deep brain stimulation
Action: deep brain stimulationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is deep brain stimulation (NCIT:C21024). NCIT:C21024 is a clinical intervention from the NCI Thesaurus. Ontology label: Deep Brain Stimulation NCIT:C21024
Platform: Device
Pallidal (GPi) or subthalamic deep brain stimulation for medically refractory segmental or generalized dystonia. Published experience is limited to small series and case reports, which report improvement.
Mechanism Target:
Generalized dystonia — Modulates basal ganglia output; acts at the circuit level and does not address the ANO3 defect.
Show evidence (5 references)
PMID:33388357 SUPPORT Human Clinical
"Half of patients with generalized dystonia experienced deep brain stimulation (DBS). And all of them showed improvement of dystonia by DBS."
Pooled literature review of ANO3 cases reporting improvement in all DBS-treated generalized patients.
PMID:30712998 SUPPORT Human Clinical
"Of note, she benefitted from deep brain stimulation."
Benefit in a patient with early-onset generalized dystonia and a de novo variant.
PMID:31871801 SUPPORT Human Clinical
"Ongoing adjustment of stimulation settings and medications led to good and sustained dystonia control; however the patient did suffer short term relapses, manifested as dystonic crisis, which necessitated inpatient admission."
Long-term pallidal stimulation outcome in a generalized ANO3 case, including relapses.
+ 2 more references
🔬

Diagnosis

3
ANO3 molecular genetic testing
Diagnosis rests on finding a heterozygous ANO3 variant in a compatible phenotype, by gene panel or exome sequencing. Testing is recommended in familial cervical dystonia with myoclonus and in prominent tremor with mild dystonia. Interpretation is the hard part: rare ANO3 variants are common in controls, so segregation, de novo status or functional data are needed before a variant is called pathogenic.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: A heterozygous pathogenic or likely pathogenic ANO3 variant.
Show evidence (2 references)
PMID:24442708 SUPPORT Human Clinical
"Patients with familial cervical dystonia who also have myoclonus-dystonia as well as patients with prominent tremor and mild dystonia should be tested for ANO3 mutations."
States which presentations should prompt ANO3 testing.
PMID:30712998 SUPPORT Human Clinical
"Thus, disease relevance of novel variants remains difficult to interpret and functional studies are warranted for a better understanding of the role of ANO3 variants in dystonia."
Supports the caution on interpreting novel ANO3 variants.
Brain MRI
Structural brain imaging is used to exclude acquired and neurodegenerative causes; it is normal in ANO3-related dystonia.
brain magnetic resonance imaging NCIT:C16809 NCI Thesaurus (NCIT)
Results: Normal, without disease-specific abnormality.
Show evidence (2 references)
PMID:38079528 SUPPORT Human Clinical
"Neuroimaging analysis of brain MRI studies did not reveal any specific abnormalities."
No specific MRI abnormality in four children with ANO3 variants.
PMID:34307749 SUPPORT Human Clinical
"Magnetic resonance imaging and blood work-ups of all the affected family members were normal."
Normal MRI in all four affected members of one family.
Electromyography
Surface EMG characterizes the tremor and myoclonus and confirms a dystonic pattern when posturing is subtle, which helps separate this disorder from essential tremor.
electromyography NCIT:C38056 NCI Thesaurus (NCIT)
Results: Co-contraction of antagonist muscles and an arm tremor of about 6 Hz, sometimes with superimposed myoclonus of subcortical character.
Show evidence (1 reference)
PMID:24442708 SUPPORT Human Clinical
"Electrophysiology in two patients with two different mutations showed co-contraction of antagonist muscles, confirming dystonia, and a 6-Hz arm tremor at rest, which increased in amplitude during action."
EMG findings in two patients carrying different ANO3 variants.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Dystonia 24:

Essential tremor MONDO:0003233
Overlapping Features Tremor can be the sole initial manifestation of ANO3-related dystonia, and affected family members have been diagnosed with essential tremor.
Distinguishing Features
  • Head or voice tremor preceding or exceeding hand tremor.
  • Subtle dystonic posturing, such as mild finger posturing, on careful examination.
Show evidence (1 reference)
PMID:24442708 SUPPORT Human Clinical
"Tremor was the sole initial manifestation in some individuals with ANO3 mutations, leading to misdiagnosis as essential tremor."
Direct statement of the diagnostic confusion.
Torsion dystonia 6 (DYT-THAP1) MONDO:0011264
Overlapping Features The other dominant isolated dystonia with craniocervical predominance; curated as Torsion_Dystonia_6. Tremor as a constant feature favours ANO3.
Distinguishing Features
  • Tremor in every affected individual favours ANO3.
  • Spread to generalized or multifocal dystonia is more common in DYT6.
Show evidence (1 reference)
PMID:24442708 SUPPORT Human Clinical
"The characteristic feature in all affected individuals was the presence of tremor, which contrasts DYT24 from the typical DYT6 phenotype."
Names tremor as the feature separating DYT24 from DYT6.
Myoclonus-dystonia syndrome MONDO:0000903
Overlapping Features ANO3 carriers with superimposed myoclonic jerks can resemble SGCE myoclonus-dystonia; curated as Myoclonus_Dystonia_Syndrome.
Distinguishing Features
  • Familial cervical dystonia with myoclonus, or prominent tremor with mild dystonia, should prompt ANO3 testing.
Show evidence (1 reference)
PMID:24442708 SUPPORT Human Clinical
"Patients with familial cervical dystonia who also have myoclonus-dystonia as well as patients with prominent tremor and mild dystonia should be tested for ANO3 mutations."
Recommends ANO3 testing in the myoclonus-dystonia presentation.
Sporadic cervical dystonia MONDO:0000481
Overlapping Features Common adult-onset focal cervical dystonia, curated as Cervical_Dystonia, in which ANO3 is recorded as a susceptibility gene explaining a small minority of cases. A family history, prominent tremor or early onset point towards the Mendelian entity.
Distinguishing Features
  • Familial occurrence with dominant transmission, or a de novo ANO3 variant.
  • Tremulous craniocervical dystonia with laryngeal involvement.
Show evidence (2 references)
PMID:33388357 SUPPORT Human Clinical
"This study confirms a relatively high frequency of rare ANO3 variants in Chinese patients with dystonia and indicates that the late adulthood-onset, cranio-cervical dystonia seems to be an important feature of the ANO3 phenotype."
Shows the overlap with late-onset craniocervical dystonia that makes the distinction necessary.
PMID:24978640 SUPPORT REVIEW SYNTHESIS Human Clinical
"The recently discovered genes ANO3, GNAL and CIZ1 appear not to be a common cause of adult-onset cervical dystonia."
Review summarizing screening studies: ANO3 explains few cases of common adult-onset cervical dystonia, which is why the two entities are kept separate.
🐁

Animal Models

1
TMEM16C knockout rat
A knockout rat studied for pain processing, not for movement. In dorsal root ganglion nociceptors, loss of TMEM16C reduced expression of the sodium-activated potassium channel Slack, broadened action potentials and raised excitability, and the animals were more sensitive to heat and mechanical stimuli. No motor or dystonic phenotype is reported, and the striatum was not examined.
Species
Rat
Genotype
Tmem16c (Ano3) knockout
Publication
PMID:23872594
Pathograph links
Striatal Neuronal Hyperexcitability partially recapitulates fidelity: low observes: cellular Shows that loss of ANO3 can make neurons hyperexcitable, which is the kind of change the node proposes, but in a different neuron type and through a different potassium channel.
Limitations: The neurons are peripheral nociceptors, not striatal medium spiny neurons. The potassium current affected is the sodium-activated Slack current, which the dystonia-variant cell study found unaffected; that study implicates KCa3.1 instead. The model is a complete knockout, whereas patients carry one heterozygous, mostly missense, allele whose direction of effect is unresolved. No dystonia or other motor phenotype was reported.
Divergences from the human mechanism
proxy quantity qualifying
Excitability of dorsal root ganglion nociceptors stands in for excitability of striatal neurons, which were not recorded.
contested assumption qualifying
Using a null allele assumes the human variants act by loss of function, which is the open question recorded in the ano3_variant_effect_direction discussion.
species mismatch qualifying
Rat rather than human neurons; whether rat striatal ANO3 couples to the same potassium channels as human striatal ANO3 is not known.
Show evidence (2 references)
PMID:23872594 SUPPORT Model Organism
"DRG from TMEM16C knockout rats had diminished Slack expression, broadened action potentials and increased excitability."
The neuronal hyperexcitability readout that makes the model partially informative for this node.
+ 1 more reference
{ }

Source YAML

click to show 
name: Dystonia 24
creation_date: "2026-10-08T13:31:10Z"
category: Mendelian
synonyms:
- DYT24
- DYT-ANO3
- ANO3 dystonic disorder
- ANO3-related dystonia
- dystonia type 24
- dystonic disorder caused by mutation in ANO3
description: >-
  An autosomal dominant dystonia caused by heterozygous variants in ANO3, which
  encodes anoctamin 3 (TMEM16C), a calcium-activated member of the TMEM16
  family of phospholipid scramblases and ion channels that is most highly
  expressed in the striatum. The originally described phenotype, in a British
  kindred and two further families, is craniocervical dystonia with prominent
  tremor: cervical dystonia, laryngeal dystonia and upper-limb dystonic tremor,
  sometimes with blepharospasm, oromandibular involvement and superimposed
  myoclonic jerks. Onset ranges from early childhood to late adulthood, spread
  is usually to a segmental or multifocal distribution, and tremor can precede
  any visible dystonia, which leads to misdiagnosis as essential tremor.

  Later reports, many of them de novo missense variants in children, broadened
  the phenotype to early-onset generalized dystonia, paroxysmal dystonia,
  myoclonic dystonia, truncal dystonia, chorea, parkinsonism, hypotonia,
  developmental delay and mild intellectual disability.
  Whether all of these belong to one disease is not settled; they are recorded
  here as phenotypes of the gene-defined entity with their sources, without
  frequency where no cohort figure exists. Brain MRI is normal in the
  reported families.

  The mechanism is the least settled part of the entry. The best-supported chain
  runs from altered ANO3 function through impaired endoplasmic reticulum calcium
  release and store-operated calcium entry to failed activation of
  calcium-dependent potassium channels, and from there, by inference, to
  hyperexcitability of striatal neurons. Every step up to the potassium channel
  has been measured in patient fibroblasts or transfected cell lines; the step
  into striatal neurons and the step from there to dystonia have not been
  demonstrated in neurons, tissue or an animal model. Whether ANO3 itself
  conducts ions, and whether disease variants act by loss of function, are
  disputed, and both questions are recorded as knowledge gaps rather than
  resolved here.

  Gene-disease validity is also contested. Rare protein-changing ANO3 variants
  are found in controls and in other movement disorders at an appreciable rate,
  so not every rare variant reported in a dystonia patient is pathogenic.

  Relationship to Cervical_Dystonia: that entry covers common sporadic adult
  focal cervical dystonia and types ANO3 as a SUSCEPTIBILITY gene explaining a
  small minority of unselected cases. This entry is the Mendelian entity
  itself. The two share a phenotypic region and are not merged.

  No pathophysiology node declares conforms_to: kb/modules/ has no module for
  dystonia, basal ganglia motor network dysfunction or anoctamin scramblase
  biology.
disease_term:
  preferred_term: dystonia 24
  term:
    id: MONDO:0014019
    label: dystonia 24
parents:
- Isolated dystonia
- Monogenic dystonia
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous ANO3 variants segregate dominantly in the families in which the
    gene was identified. A substantial share of later cases, particularly
    childhood-onset generalized presentations, carry de novo variants.
  evidence:
  - reference: PMID:23200863
    reference_title: "Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that mutations in ANO3 are a cause of autosomal-dominant craniocervical dystonia."
    explanation: >-
      The gene-identification study, based on linkage and segregation in an
      autosomal dominant kindred, states the mode of inheritance.
  - reference: PMID:24442708
    reference_title: "The phenotypic spectrum of DYT24 due to ANO3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Recently, pathogenic mutations in the anoctamin 3 gene (ANO3) have been identified to cause autosomal dominant craniocervical dystonia and have been assigned to the dystonia locus dystonia-24 (DYT24)."
    explanation: >-
      Follow-up clinical study of the three original families; this sentence
      restates the gene-identification report rather than presenting a new
      result.
  - reference: PMID:30712998
    reference_title: "Role of ANO3 mutations in dystonia: A large-scale mutational screening study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further, we identified a patient with early-onset, generalized dystonia with a de-novo variant in ANO3 (p.Val561Glu)."
    explanation: >-
      Documents a de novo heterozygous variant, consistent with dominant action
      of a single altered allele in sporadic early-onset cases.
- name: Incomplete penetrance
  inheritance_term:
    preferred_term: Typified by incomplete penetrance
    term:
      id: HP:0003829
      label: Typified by incomplete penetrance
  description: >-
    Unaffected carriers and apparently skipped generations are reported, so a
    negative family history does not exclude the diagnosis. No numeric
    penetrance estimate exists, and some asymptomatic carriers in cohort
    screens may carry variants that are not pathogenic.
  evidence:
  - reference: PMID:42353862
    reference_title: "Clinical and Genetic Spectrum of ANO3-Related Dystonia with Treatment Responses in a Chinese Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the remaining eight families, the carriers demonstrated asymptomatic presentation, regardless of paternal or maternal lineage."
    explanation: >-
      Asymptomatic parental carriers in eight trio families. Read with care:
      most of these variants were of uncertain significance, so this bears on
      penetrance only for those that are pathogenic.
  - reference: PMID:23200863
    reference_title: "Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although both individuals are now deceased and could not be examined, this suggests the possibility that penetrance might not be complete."
    explanation: >-
      A reportedly affected great-grandmother with an apparently unaffected
      grandmother in the second original family.
pathophysiology:
- name: Heterozygous ANO3 Variants
  biological_scale: MOLECULAR
  description: >-
    Heterozygous ANO3 variants, almost all missense, spread across the protein
    rather than clustered in one domain. The two original familial variants lie
    in exon 15; many later childhood-onset variants are de novo, and one review
    proposes that variants near the scrambling domain track the more severe
    early-onset phenotype. The functional impact category is left unset on
    purpose: whether pathogenic variants reduce or alter ANO3 function is
    disputed (see the knowledge-gap discussion). The ANO3 gene binding sits on
    the next node, with the molecular function it encodes.
  genetic_context:
    variant_origin: GERMLINE
  downstream:
  - target: Altered ANO3 Calcium-Activated Scramblase Function
    description: >-
      Disease variants change the behaviour of a calcium-activated scramblase
      expressed in the endoplasmic reticulum and plasma membrane.
  evidence:
  - reference: PMID:23200863
    reference_title: "Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subsequent screening of these candidate causal variants in a large number of familial and sporadic cases of cervical dystonia led to the identification of a total of six putatively pathogenic mutations in ANO3, a gene encoding a predicted Ca(2+)-gated chloride channel that we show to be highly expressed in the striatum."
    explanation: >-
      Original report of heterozygous ANO3 variants in familial and sporadic
      cervical dystonia.
  - reference: PMID:33388357
    reference_title: "The expanding clinical and genetic spectrum of ANO3 dystonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Combined with our work and literature review, a total of 35 different rare variants distributed in ANO3 were identified in 62 dystonia patients."
    explanation: >-
      Quantifies the variant spectrum across the published cases and shows the
      variants are distributed along the gene.
  - reference: PMID:38284143
    reference_title: "The Clinical Spectrum of ANO3-Report of a New Family and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Stratification by age at onset divided ANO3 cases into two major groups, where younger patients displayed a more severe phenotype, probably due to variants near the scrambling domain."
    explanation: >-
      Literature review proposing that variant position, near the scrambling
      domain, tracks the more severe early-onset phenotype. Stated by the
      authors as probable, not established.
- name: Altered ANO3 Calcium-Activated Scramblase Function
  biological_scale: MOLECULAR
  description: >-
    ANO3 is a calcium-activated phospholipid scramblase of the TMEM16 family,
    present largely in intracellular membranes. One group reports that it also
    conducts ions; another, studying human TMEM16C isoforms, found scrambling but
    no ion transport. How disease variants change scrambling itself has not been
    measured directly in the cited studies; what has been measured is their
    effect on cellular calcium signalling, recorded in the next node.
  molecular_functions:
  - preferred_term: calcium-activated phospholipid scramblase activity
    modifier: ABNORMAL
    term:
      id: GO:0017128
      label: phospholipid scramblase activity
  genes:
  - preferred_term: ANO3
    term:
      id: hgnc:14004
      label: ANO3
  downstream:
  - target: Impaired Endoplasmic Reticulum Calcium Release and Store-Operated Calcium Entry
    description: >-
      Cells expressing disease variants show reduced store release and strongly
      reduced store-operated calcium entry, attributed to reduced plasma membrane
      expression of the ORAI1 channel.
    evidence:
    - reference: PMID:39773217
      reference_title: "Dystonia caused by ANO3 variants is due to attenuated Ca(2+) influx by ORAI1."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The data provide evidence for a strongly impaired expression of store-operated ORAI1 Ca2+ influx channels in the plasma membrane of cells expressing ANO3 variants."
      explanation: >-
        Links the variant protein to the calcium-entry defect through reduced
        surface ORAI1, which is the proposed mechanism of this edge.
  evidence:
  - reference: PMID:38079528
    reference_title: "Broadening the clinical spectrum: molecular mechanisms and new phenotypes of ANO3-dystonia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We identified ANO3 as a Ca2+-activated phospholipid scramblase that also conducts ions."
    explanation: >-
      Cell-based characterization of ANO3 function used as the baseline against
      which disease variants were compared.
  - reference: PMID:36295764
    reference_title: "Investigation of Phosphatidylserine-Transporting Activity of Human TMEM16C Isoforms."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Unlike previous results, our data showed that human TMEM16C isoform 1 and isoform 3 exposed PS to the cell surface."
    explanation: >-
      Independent confirmation in 293T cells that human TMEM16C isoforms scramble
      phosphatidylserine to the cell surface. The same study did not detect ion
      transport, which is recorded in the knowledge-gap discussion.
  - reference: PMID:23532839
    reference_title: "Calcium-dependent phospholipid scramblase activity of TMEM16 protein family members."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We expressed other TMEM16 proteins in the TMEM16F(-/-) cells and found that not only TMEM16F, but also 16C, 16D, 16G, and 16J work as lipid scramblases with different preference to lipid substrates."
    explanation: >-
      First demonstration that TMEM16C (ANO3) is a calcium-dependent lipid
      scramblase, in a scramblase-null mouse lymphocyte line.
  - reference: PMID:38657371
    reference_title: "VSI: The anoctamins: Structure and function: \"Intracellular\" anoctamins."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Probably all intracellular anoctamins except of ANO8 operate as intracellular phospholipid (PL) scramblases, allowing for Ca2+-activated, passive transport of phospholipids like phosphatidylserine between both membrane leaflets."
    explanation: >-
      Review placing ANO3 among the intracellular anoctamins that act as
      calcium-activated scramblases.
- name: Impaired Endoplasmic Reticulum Calcium Release and Store-Operated Calcium Entry
  biological_scale: CELLULAR
  description: >-
    The most reproducible cellular finding. Calcium imaging of patient
    fibroblasts in the gene-identification study showed abnormal endoplasmic
    reticulum dependent calcium signalling, and a later study of four further
    variants found that store release and, above all, store-operated calcium
    entry through ORAI1 were strongly inhibited in cells expressing the
    variants. Measured in fibroblasts and HEK293 cells, not in neurons.
  biological_processes:
  - preferred_term: store-operated calcium entry
    modifier: DECREASED
    term:
      id: GO:0002115
      label: store-operated calcium entry
  - preferred_term: endoplasmic reticulum calcium ion homeostasis
    modifier: ABNORMAL
    term:
      id: GO:0032469
      label: endoplasmic reticulum calcium ion homeostasis
  downstream:
  - target: Impaired Activation of Calcium-Dependent Potassium Channels
    description: >-
      The reduced calcium signal fails to activate KCa3.1 channels, while
      sodium-activated potassium channels are spared.
    evidence:
    - reference: PMID:39773217
      reference_title: "Dystonia caused by ANO3 variants is due to attenuated Ca(2+) influx by ORAI1."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Upon expression, emptying of the endoplasmic reticulum Ca2+ store (store release) and particularly store-operated Ca2+ entry (SOCE) were strongly inhibited, leading to impaired activation of KCa3.1 (KCNN) K+ channels, but not of Na+-activated K+ channels (KNa; SLO2)."
      explanation: >-
        States the causal step from the store-release and entry defect to the
        potassium channel defect, and its selectivity for KCa3.1.
  evidence:
  - reference: PMID:23200863
    reference_title: "Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional studies using Ca(2+) imaging in case and control fibroblasts demonstrated clear abnormalities in endoplasmic-reticulum-dependent Ca(2+) signaling."
    explanation: >-
      First functional observation, in fibroblasts from a variant carrier.
      Graded IN_VITRO because this sentence reports a cultured-cell assay; the
      genetic findings of the same paper are graded HUMAN_CLINICAL elsewhere in
      this entry.
  - reference: PMID:39773217
    reference_title: "Dystonia caused by ANO3 variants is due to attenuated Ca(2+) influx by ORAI1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Upon expression, emptying of the endoplasmic reticulum Ca2+ store (store release) and particularly store-operated Ca2+ entry (SOCE) were strongly inhibited, leading to impaired activation of KCa3.1 (KCNN) K+ channels, but not of Na+-activated K+ channels (KNa; SLO2)."
    explanation: >-
      Measures inhibited store release and store-operated calcium entry in
      cells expressing four disease variants.
- name: Impaired Activation of Calcium-Dependent Potassium Channels
  biological_scale: CELLULAR
  description: >-
    Cells expressing ANO3 variants show compromised activation of the
    calcium-dependent potassium channel KCa3.1. In rat sensory neurons ANO3
    instead supports the sodium-activated potassium channel Slack (KCNT1), and
    its loss there raises excitability; in the dystonia-variant study the
    sodium-activated channels were not affected, so which potassium current
    matters in the striatum is not established.
  molecular_functions:
  - preferred_term: activation of calcium-activated potassium channel (KCa3.1)
    modifier: DECREASED
    term:
      id: GO:0015269
      label: calcium-activated potassium channel activity
  genes:
  - preferred_term: KCNN4 (KCa3.1)
    term:
      id: hgnc:6293
      label: KCNN4
  downstream:
  - target: Striatal Neuronal Hyperexcitability
    description: >-
      Proposed rather than measured: loss of a calcium-activated potassium
      conductance would depolarize the membrane and raise excitability of
      striatal neurons, where ANO3 expression is highest.
    evidence:
    - reference: PMID:38079528
      reference_title: "Broadening the clinical spectrum: molecular mechanisms and new phenotypes of ANO3-dystonia."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "In the brain striatal cells of affected patients, impaired activation of KCa3.1 channels due to compromised Ca2+ signals may lead to depolarized membrane voltage and neuronal hyperexcitability and may also lead to reduced cellular viability, as shown in the present study."
      explanation: >-
        The authors' proposal for this edge. Marked INDIRECT because the
        measurements were made in fibroblasts and HEK293 cells, not in striatal
        neurons.
  evidence:
  - reference: PMID:38079528
    reference_title: "Broadening the clinical spectrum: molecular mechanisms and new phenotypes of ANO3-dystonia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Impaired Ca2+ signalling and compromised activation of Ca2+-dependent K+ channels were detected in cells expressing ANO3 variants."
    explanation: >-
      Direct measurement of the potassium channel defect in variant-expressing
      cells.
- name: Striatal Neuronal Hyperexcitability
  biological_scale: CELLULAR
  description: >-
    The inferred cellular substrate of the movement disorder. ANO3 is expressed
    most highly in the striatum, and loss of ANO3 raises excitability in rat
    sensory neurons, but hyperexcitability of striatal neurons carrying a
    disease variant has not been demonstrated. A PubMed search for ANO3 with
    mouse, mice or knockout returned no animal model of dystonia. The step from
    this node to dystonic movement is likewise inferred, and the edges to the
    movement phenotypes below are uncited for that reason.
  cell_types:
  - preferred_term: striatal medium spiny neuron
    term:
      id: CL:1001474
      label: medium spiny neuron
  locations:
  - preferred_term: striatum
    term:
      id: UBERON:0002435
      label: striatum
  downstream:
  - target: Cervical dystonia
  - target: Laryngeal dystonia
  - target: Tremor
  - target: Head tremor
  - target: Postural tremor
  - target: Craniofacial dystonia
  - target: Oromandibular dystonia
  - target: Writer's cramp
  - target: Blepharospasm
  - target: Upper limb dystonia
  - target: Leg dystonia
  - target: Axial dystonia
  - target: Myoclonus
  - target: Generalized dystonia
  - target: Paroxysmal dystonia
  - target: Chorea
  evidence:
  - reference: PMID:41400152
    reference_title: "Developmental, Neuroanatomical and Cellular Expression of Genes Causing Dystonia."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: "Individual genes exhibiting differences in expression across adult brain regions include SQSTM1, SGCE, KMT2B, PRKRA, YY1, DNAJC12, KCNA1, CACNA1A (highest expression in cerebellum), ADCY5, GNAL, ANO3 (highest expression in striatum), RHOBTB2, FOXG1 (highest expression in cerebral cortex)."
    explanation: >-
      Places ANO3 expression highest in the striatum in a reanalysis of human
      brain transcriptomic datasets, which is the basis for locating this node
      there. INDIRECT because expression does not show dysfunction.
  - reference: PMID:23872594
    reference_title: "TMEM16C facilitates Na(+)-activated K+ currents in rat sensory neurons and regulates pain processing."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "DRG from TMEM16C knockout rats had diminished Slack expression, broadened action potentials and increased excitability."
    explanation: >-
      Loss of ANO3 raises neuronal excitability in the knockout rat. INDIRECT
      because these are dorsal root ganglion neurons, the potassium channel
      involved (Slack) differs from the one implicated by the dystonia-variant
      study, and complete knockout may not model a heterozygous missense
      variant.
  - reference: PMID:39773217
    reference_title: "Dystonia caused by ANO3 variants is due to attenuated Ca(2+) influx by ORAI1."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Dysregulated Ca2+ signaling by ANO3 variants may impair the activation of K+ channels in striatal neurons of the brain, thereby causing dystonia."
    explanation: >-
      The authors' conclusion connecting the cell-line findings to striatal
      neurons and to dystonia, stated as a possibility.
phenotypes:
- category: Neurologic
  name: Cervical dystonia
  description: >-
    The most common site of onset and the core of the original phenotype,
    often tremulous. Dystonia usually spreads slowly to a segmental or
    multifocal distribution rather than generalizing.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cervical dystonia
    term:
      id: HP:0000473
      label: Torticollis
  evidence:
  - reference: PMID:24442708
    reference_title: "The phenotypic spectrum of DYT24 due to ANO3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cervical dystonia was the most common site of onset followed by laryngeal dystonia."
    explanation: Site of onset in the ten patients of the three original families.
  - reference: PMID:42353862
    reference_title: "Clinical and Genetic Spectrum of ANO3-Related Dystonia with Treatment Responses in a Chinese Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ANO3-related dystonia exhibited broad clinical heterogeneity, with frequent cervical involvement (62.5%) and tremulous features (75%), and occasionally extended beyond classical isolated dystonia."
    explanation: >-
      Cervical involvement in 62.5 percent of the variant-carrying dystonia
      patients of a Chinese cohort, the source for the FREQUENT band.
  - reference: PMID:33502045
    reference_title: "Genotype-Phenotype Relations for Isolated Dystonia Genes: MDSGene Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For ANO3, a segmental/multifocal distribution was typical, whereas TOR1A, PRKRA, KMT2B, and HPCA mutation carriers commonly developed generalized dystonia."
    explanation: >-
      Systematic review establishing the typical segmental or multifocal
      distribution.
- category: Neurologic
  name: Laryngeal dystonia
  description: >-
    Spasmodic dysphonia or voice tremor, the second most common site of onset.
  phenotype_term:
    preferred_term: Laryngeal dystonia
    term:
      id: HP:0012049
      label: Laryngeal dystonia
  evidence:
  - reference: PMID:24442708
    reference_title: "The phenotypic spectrum of DYT24 due to ANO3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cervical dystonia was the most common site of onset followed by laryngeal dystonia."
    explanation: Laryngeal dystonia was the second most common site of onset.
- category: Neurologic
  name: Tremor
  description: >-
    Dystonic tremor of the head, voice and arms, the most consistent feature of
    the original families and the feature that distinguishes this disorder from
    DYT6. Tremor can be the only initial manifestation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dystonic tremor of head, voice and arms
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: PMID:24442708
    reference_title: "The phenotypic spectrum of DYT24 due to ANO3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The characteristic feature in all affected individuals was the presence of tremor, which contrasts DYT24 from the typical DYT6 phenotype."
    explanation: Tremor was present in all ten affected individuals in the original families.
  - reference: PMID:42353862
    reference_title: "Clinical and Genetic Spectrum of ANO3-Related Dystonia with Treatment Responses in a Chinese Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ANO3-related dystonia exhibited broad clinical heterogeneity, with frequent cervical involvement (62.5%) and tremulous features (75%), and occasionally extended beyond classical isolated dystonia."
    explanation: >-
      Tremulous features in 75 percent of a later cohort, the source for the
      FREQUENT band.
- category: Neurologic
  name: Craniofacial dystonia
  description: >-
    Cranial involvement, including oromandibular dystonia, as part of the
    upper-body onset typical of this disorder.
  phenotype_term:
    preferred_term: Craniofacial dystonia
    term:
      id: HP:0012179
      label: Craniofacial dystonia
  evidence:
  - reference: PMID:33502045
    reference_title: "Genotype-Phenotype Relations for Isolated Dystonia Genes: MDSGene Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, in most DYT-THAP1 and DYT-ANO3 patients, dystonia first manifested in the upper half of the body (upper limb, neck, and craniofacial/laryngeal), whereas onset in DYT-TOR1A, DYT-PRKRA and DYT-HPCA was frequently observed in an extremity, including both upper and lower ones."
    explanation: Systematic review placing first manifestation in the upper body, including the craniofacial region.
- category: Neurologic
  name: Blepharospasm
  description: Involuntary eyelid closure, a cranial dystonia manifestation reported in individual cases.
  phenotype_term:
    preferred_term: Blepharospasm
    term:
      id: HP:0000643
      label: Blepharospasm
  evidence:
  - reference: PMID:27919237
    reference_title: "A novel ANO3 variant identified in a 53-year-old woman presenting with hyperkinetic dysarthria, blepharospasm, hyperkinesias, and complex motor tics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient developed a mixed hyperkinetic disorder consisting of chorea, dystonia affecting the upper extremities, dysarthria, and blepharospasm."
    explanation: Case report of a heterozygous ANO3 variant carrier with blepharospasm.
- category: Neurologic
  name: Upper limb dystonia
  description: >-
    Arm and hand dystonia, often with dystonic tremor; the arms are the next
    most common region after neck and larynx.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Upper limb dystonia
    term:
      id: HP:0031960
      label: Arm dystonia
  evidence:
  - reference: PMID:33502045
    reference_title: "Genotype-Phenotype Relations for Isolated Dystonia Genes: MDSGene Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, in most DYT-THAP1 and DYT-ANO3 patients, dystonia first manifested in the upper half of the body (upper limb, neck, and craniofacial/laryngeal), whereas onset in DYT-TOR1A, DYT-PRKRA and DYT-HPCA was frequently observed in an extremity, including both upper and lower ones."
    explanation: Upper limb named among the typical sites of first manifestation.
  - reference: PMID:42353862
    reference_title: "Clinical and Genetic Spectrum of ANO3-Related Dystonia with Treatment Responses in a Chinese Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cervical involvement (10/16, 62.5%) was the most common final manifestation, followed by involvement of the upper (8/16, 50%) and lower limbs (7/16, 43.75%)."
    explanation: Upper limb involvement in half of 16 variant carriers with dystonia, the source for the FREQUENT band.
- category: Neurologic
  name: Leg dystonia
  description: >-
    Lower-limb dystonia is uncommon and was absent in the original families,
    but it is reported in later families and as the onset site of some
    childhood generalized cases.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Lower limb dystonia
    term:
      id: HP:0031959
      label: Leg dystonia
  evidence:
  - reference: PMID:34307749
    reference_title: "Another Twist in the Tale: Intrafamilial Phenotypic Heterogeneity in ANO3-Related Dystonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His family history was remarkable for cervical dystonia with myoclonus in his grandfather, cervical and upper limb dystonia along with dopa-responsive parkinsonism in his father and lower-limb dystonia in his teenage sister."
    explanation: Lower-limb dystonia in a variant-carrying family member.
  - reference: PMID:42353862
    reference_title: "Clinical and Genetic Spectrum of ANO3-Related Dystonia with Treatment Responses in a Chinese Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cervical involvement (10/16, 62.5%) was the most common final manifestation, followed by involvement of the upper (8/16, 50%) and lower limbs (7/16, 43.75%)."
    explanation: >-
      Lower limb involvement in 7 of 16 variant carriers with dystonia in a
      Chinese cohort, the source for the FREQUENT band. The original British
      families had no leg involvement, so the figure is cohort-specific.
- category: Neurologic
  name: Myoclonus
  description: >-
    Superimposed myoclonic jerks, of subcortical character in the patient
    studied electrophysiologically, giving a myoclonus-dystonia-like picture.
  phenotype_term:
    preferred_term: Myoclonus
    term:
      id: HP:0001336
      label: Myoclonus
  evidence:
  - reference: PMID:24442708
    reference_title: "The phenotypic spectrum of DYT24 due to ANO3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In one of the studied patients, clinically superimposed myoclonus was observed."
    explanation: Myoclonus in an original-family patient.
  - reference: PMID:34307749
    reference_title: "Another Twist in the Tale: Intrafamilial Phenotypic Heterogeneity in ANO3-Related Dystonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The index case presented with myoclonic dystonia at age 10."
    explanation: Myoclonic dystonia as the presenting phenotype in a later family.
- category: Neurologic
  name: Generalized dystonia
  description: >-
    Generalization did not occur in the original families, but early-onset
    generalized dystonia, often with de novo variants, is now a recognized
    presentation.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Generalized dystonia
    term:
      id: HP:0007325
      label: Generalized dystonia
  evidence:
  - reference: PMID:30712998
    reference_title: "Role of ANO3 mutations in dystonia: A large-scale mutational screening study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, de-novo variants in childhood-onset, generalized dystonia seem to represent an as yet underestimated phenotypic expression of changes in ANO3."
    explanation: Large screening study identifying childhood-onset generalized dystonia as a phenotype of de novo variants.
  - reference: PMID:38079528
    reference_title: "Broadening the clinical spectrum: molecular mechanisms and new phenotypes of ANO3-dystonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients exhibited generalized progressive dystonia, while one patient presented with paroxysmal dystonia."
    explanation: Generalized progressive dystonia in two of four children with ANO3 variants.
  - reference: PMID:42353862
    reference_title: "Clinical and Genetic Spectrum of ANO3-Related Dystonia with Treatment Responses in a Chinese Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four patients developed generalized dystonia, and four had segmental or multifocal dystonia."
    explanation: Generalized dystonia in 4 of 16 variant carriers in a cohort, the source for the OCCASIONAL band.
- category: Neurologic
  name: Paroxysmal dystonia
  description: Episodic dystonia, reported in one child with an ANO3 variant.
  phenotype_term:
    preferred_term: Paroxysmal dystonia
    term:
      id: HP:0002268
      label: Paroxysmal dystonia
  evidence:
  - reference: PMID:38079528
    reference_title: "Broadening the clinical spectrum: molecular mechanisms and new phenotypes of ANO3-dystonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients exhibited generalized progressive dystonia, while one patient presented with paroxysmal dystonia."
    explanation: Paroxysmal dystonia in one of four children with ANO3 variants.
- category: Neurologic
  name: Chorea
  description: A hyperkinetic phenotype reported in individual cases, combined with dystonia.
  phenotype_term:
    preferred_term: Chorea
    term:
      id: HP:0002072
      label: Chorea
  evidence:
  - reference: PMID:27919237
    reference_title: "A novel ANO3 variant identified in a 53-year-old woman presenting with hyperkinetic dysarthria, blepharospasm, hyperkinesias, and complex motor tics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient developed a mixed hyperkinetic disorder consisting of chorea, dystonia affecting the upper extremities, dysarthria, and blepharospasm."
    explanation: Chorea combined with dystonia in a variant carrier.
- category: Neurologic
  name: Dysarthria
  description: Speech impairment from cranial or laryngeal involvement.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:27919237
    reference_title: "A novel ANO3 variant identified in a 53-year-old woman presenting with hyperkinetic dysarthria, blepharospasm, hyperkinesias, and complex motor tics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient developed a mixed hyperkinetic disorder consisting of chorea, dystonia affecting the upper extremities, dysarthria, and blepharospasm."
    explanation: Dysarthria in a variant carrier with cranial dystonia.
- category: Neurologic
  name: Parkinsonism
  description: >-
    Dopa-responsive parkinsonism co-occurring with craniocervical dystonia in
    individual family members.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: PMID:34307749
    reference_title: "Another Twist in the Tale: Intrafamilial Phenotypic Heterogeneity in ANO3-Related Dystonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His family history was remarkable for cervical dystonia with myoclonus in his grandfather, cervical and upper limb dystonia along with dopa-responsive parkinsonism in his father and lower-limb dystonia in his teenage sister."
    explanation: Dopa-responsive parkinsonism in a variant-carrying father.
  - reference: PMID:42353862
    reference_title: "Clinical and Genetic Spectrum of ANO3-Related Dystonia with Treatment Responses in a Chinese Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, additional neurological or neuropsychiatric features were observed in several individuals, including parkinsonism in two patients and psychiatric or behavioral symptoms in two patients."
    explanation: Parkinsonism in 2 of 16 variant carriers in a cohort, the source for the OCCASIONAL band.
- category: Neurologic
  name: Hypotonia
  description: >-
    Reported in children with early-onset presentations. No mechanism in this
    entry is linked to it; how it relates to the striatal chain is unknown.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:38079528
    reference_title: "Broadening the clinical spectrum: molecular mechanisms and new phenotypes of ANO3-dystonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three individuals presented with hypotonia and motor developmental delay."
    explanation: Hypotonia in three of four children with ANO3 variants.
- category: Neurologic
  name: Motor delay
  description: >-
    Motor developmental delay in early-onset cases. Not linked to a mechanism
    in this entry.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:38079528
    reference_title: "Broadening the clinical spectrum: molecular mechanisms and new phenotypes of ANO3-dystonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three individuals presented with hypotonia and motor developmental delay."
    explanation: Motor developmental delay in three of four children with ANO3 variants.
- category: Neurologic
  name: Global developmental delay
  description: >-
    Developmental delay, with ataxic gait and tremor but no dystonia, in a child
    with a de novo transmembrane-domain variant; psychomotor regression in
    another de novo case. Not linked to a mechanism in this entry.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:36167772
    reference_title: "A novel variant in the transmembrane 4 domain of ANO3 identified in a two-year-old girl with developmental delay and tremor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a two-year-old girl who showed mild to moderate developmental delay, tremor, and ataxic gait, but no obvious dystonia."
    explanation: Developmental delay in a child with a de novo ANO3 variant.
  - reference: PMID:33045406
    reference_title: "ANO3 and early-onset dyskinetic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A global psychomotor regression was observed once dystonia was present."
    explanation: Psychomotor regression after dystonia onset in a child with a de novo ANO3 variant.
- category: Neurologic
  name: Intellectual disability
  description: >-
    Mild intellectual disability or learning difficulty reported in several
    families and children. Not linked to a mechanism in this entry.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:41441972
    reference_title: "ANO3-related tremulous dystonia: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The neurological examination revealed a mild intellectual disability, head titubation, postural and action tremors, and dystonia affecting the bilateral distal upper extremities."
    explanation: Mild intellectual disability in an adult with tremulous ANO3-related dystonia.
  - reference: PMID:38284143
    reference_title: "The Clinical Spectrum of ANO3-Report of a New Family and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She also suffered from psychomotor delay and learning difficulties."
    explanation: Learning difficulties in the proband of a six-carrier ANO3 family.
- category: Neurologic
  name: Axial dystonia
  description: >-
    Late-onset truncal dystonia with forward trunk flexion, reported in one
    family.
  phenotype_term:
    preferred_term: Truncal dystonia
    term:
      id: HP:0002530
      label: Axial dystonia
  evidence:
  - reference: PMID:39692086
    reference_title: "Hereditary Truncal Dystonia Associated with ANO3 Gene Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe a novel phenotype of ANO3 variant causing truncal dystonia."
    explanation: Case report of truncal dystonia in an ANO3 variant carrier.
- category: Neurologic
  name: Head tremor
  description: >-
    Side-to-side head tremor accompanying cervical dystonia; it can be the first sign, in childhood.
  phenotype_term:
    preferred_term: Head tremor
    term:
      id: HP:0002346
      label: Head tremor
  evidence:
  - reference: PMID:24442708
    reference_title: "The phenotypic spectrum of DYT24 due to ANO3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On examination at age 53 years, he had a side-to-side head tremor and oromandibular movements."
    explanation: Head tremor in an affected member of an original family.
  - reference: PMID:24442708
    reference_title: "The phenotypic spectrum of DYT24 due to ANO3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient III-1 (age 65 years) (Fig. 1B) first noticed an intermittent head tremor at the age of 4 years and recalls being teased for this at school."
    explanation: Head tremor as the presenting sign in early childhood.
- category: Neurologic
  name: Postural tremor
  description: >-
    Postural arm tremor, sometimes the only sign in mildly affected relatives.
  phenotype_term:
    preferred_term: Postural tremor
    term:
      id: HP:0002174
      label: Postural tremor
  evidence:
  - reference: PMID:38284143
    reference_title: "The Clinical Spectrum of ANO3-Report of a New Family and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her paternal aunt, father, and a third older sister presented episodic postural tremor in the arms."
    explanation: Postural arm tremor as the only feature in three carriers of one family.
- category: Neurologic
  name: Oromandibular dystonia
  description: >-
    Jaw and mouth involvement, part of the cranial dystonia of the original families.
  phenotype_term:
    preferred_term: Oromandibular dystonia
    term:
      id: HP:0012048
      label: Oromandibular dystonia
  evidence:
  - reference: PMID:24442708
    reference_title: "The phenotypic spectrum of DYT24 due to ANO3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had laryngeal dysphonia and mild oromandibular dystonia (Video Segment 2A)."
    explanation: Oromandibular dystonia in an original-family patient.
- category: Neurologic
  name: Writer's cramp
  description: >-
    Task-specific upper-limb dystonia reported in an ANO3 family.
  phenotype_term:
    preferred_term: Writer's cramp
    term:
      id: HP:0002356
      label: Writer's cramp
  evidence:
  - reference: PMID:38284143
    reference_title: "The Clinical Spectrum of ANO3-Report of a New Family and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two years later, she developed cervical pain and headache, partially responsive to acetaminophen, and writer's cramp in her right hand."
    explanation: Writer's cramp in a variant-carrying sister.
- category: Neurologic
  name: Rigidity
  description: >-
    Mild limb and neck rigidity, an extrapyramidal sign reported with dystonic tremor in one family.
  phenotype_term:
    preferred_term: Rigidity
    term:
      id: HP:0002063
      label: Rigidity
  evidence:
  - reference: PMID:38284143
    reference_title: "The Clinical Spectrum of ANO3-Report of a New Family and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She later developed a diffuse dystonic tremor and mild extrapyramidal signs (ie, rigidity and hypodiadochokinesis) in her right arm."
    explanation: Rigidity in the proband of a six-carrier family.
- category: Neurologic
  name: Tics
  description: >-
    Simple and complex motor and vocal tics reported in one adult with a variant of uncertain significance.
  phenotype_term:
    preferred_term: Tics
    term:
      id: HP:0100033
      label: Tics
  evidence:
  - reference: PMID:27919237
    reference_title: "A novel ANO3 variant identified in a 53-year-old woman presenting with hyperkinetic dysarthria, blepharospasm, hyperkinesias, and complex motor tics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The complex clinical presentation of the patient described includes hyperkinesias, complex motor movements, and vocal tics, which have not been reported in other patients with DYT24."
    explanation: Tics in a single case; the variant was classed as uncertain significance.
- category: Neurologic
  name: Dyskinesia
  description: >-
    Early dyskinetic encephalopathy in a child with a de novo variant.
  phenotype_term:
    preferred_term: Dyskinesia
    term:
      id: HP:0100660
      label: Dyskinesia
  evidence:
  - reference: PMID:38079528
    reference_title: "Broadening the clinical spectrum: molecular mechanisms and new phenotypes of ANO3-dystonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, another patient exhibited early dyskinetic encephalopathy."
    explanation: Dyskinetic encephalopathy in one of four children with ANO3 variants.
- category: Neurologic
  name: Atypical behavior
  description: >-
    Psychiatric or behavioural symptoms reported in a minority of a cohort, and flat affect with reduced initiative in one father.
  phenotype_term:
    preferred_term: Psychiatric or behavioural symptoms
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:42353862
    reference_title: "Clinical and Genetic Spectrum of ANO3-Related Dystonia with Treatment Responses in a Chinese Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, additional neurological or neuropsychiatric features were observed in several individuals, including parkinsonism in two patients and psychiatric or behavioral symptoms in two patients."
    explanation: Psychiatric or behavioural symptoms in two of 16 variant-carrying dystonia patients.
- category: Neurologic
  name: Urinary incontinence
  description: >-
    Reported in three children with de novo variants and early-onset severe phenotypes.
  phenotype_term:
    preferred_term: Urinary incontinence
    term:
      id: HP:0000020
      label: Urinary incontinence
  evidence:
  - reference: PMID:39773217
    reference_title: "Dystonia caused by ANO3 variants is due to attenuated Ca(2+) influx by ORAI1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Bowel and urinary incontinence were observed in all three patients carrying the variants V561L, S651N, or A599D."
    explanation: Urinary incontinence in three severely affected children; quoted from the paper's summary of the authors' earlier clinical report.
- category: Neurologic
  name: Bowel incontinence
  description: >-
    Reported in three children with de novo variants and early-onset severe phenotypes.
  phenotype_term:
    preferred_term: Bowel incontinence
    term:
      id: HP:0002607
      label: Bowel incontinence
  evidence:
  - reference: PMID:39773217
    reference_title: "Dystonia caused by ANO3 variants is due to attenuated Ca(2+) influx by ORAI1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Bowel and urinary incontinence were observed in all three patients carrying the variants V561L, S651N, or A599D."
    explanation: Bowel incontinence in three severely affected children; quoted from the paper's summary of the authors' earlier clinical report.
- category: Neurologic
  name: Gait ataxia
  description: Ataxic gait reported in a child with a de novo variant.
  phenotype_term:
    preferred_term: Gait ataxia
    term:
      id: HP:0002066
      label: Gait ataxia
  evidence:
  - reference: PMID:36167772
    reference_title: "A novel variant in the transmembrane 4 domain of ANO3 identified in a two-year-old girl with developmental delay and tremor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a two-year-old girl who showed mild to moderate developmental delay, tremor, and ataxic gait, but no obvious dystonia."
    explanation: Ataxic gait in a child with a de novo ANO3 variant.
genetic:
- name: ANO3
  gene_term:
    preferred_term: ANO3
    term:
      id: hgnc:14004
      label: ANO3
  relationship_type: CAUSATIVE
  notes: >-
    ANO3 is hgnc:14004 (previous symbols TMEM16C and C11orf25). The disease is
    defined by this gene in MONDO and OMIM (615034), so the record is typed
    CAUSATIVE for the entity. That typing is not a ClinGen tier: the ClinGen
    Gene-Disease Validity download of 2026-10-08 contains no ANO3 curation, so
    no gene_disease_validity assertion is recorded.

    Validity is genuinely debated. Rare protein-changing ANO3 variants occur in
    population controls and in Parkinson disease patients at rates close to
    those in dystonia cohorts, so a rare variant in a dystonia patient is not by
    itself evidence of pathogenicity; segregation, de novo occurrence or
    functional data are needed. A later Chinese cohort found rare variants
    enriched in dystonia over non-dystonic movement disorder controls, which is
    the stronger case-control signal. Cervical_Dystonia records ANO3 separately
    as SUSCEPTIBILITY for common sporadic cervical dystonia, and that record is
    a different claim from this one.
  evidence:
  - reference: PMID:23200863
    reference_title: "Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that mutations in ANO3 are a cause of autosomal-dominant craniocervical dystonia."
    explanation: Gene identification by linkage, exome sequencing and segregation.
  - reference: PMID:27666935
    reference_title: "Clinical exome sequencing in early-onset generalized dystonia and large-scale resequencing follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reflecting locus heterogeneity, identified unique variants were distributed over 5 genes (GCH1, THAP1, TOR1A, ANO3, ADCY5), of which only 1 (ANO3) was mutated recurrently."
    explanation: Independent exome study finding ANO3 variants recurrently in early-onset generalized dystonia.
  - reference: PMID:42353862
    reference_title: "Clinical and Genetic Spectrum of ANO3-Related Dystonia with Treatment Responses in a Chinese Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The rare ANO3 variants were significantly enriched in the dystonia cohort compared with the controls."
    explanation: Case-control enrichment of rare ANO3 variants in dystonia over non-dystonic movement disorder controls.
  - reference: PMID:30712998
    reference_title: "Role of ANO3 mutations in dystonia: A large-scale mutational screening study."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "This study confirms the relatively high frequency of rare, protein-changing ANO3 variants in both dystonia and non-dystonia patients indicating that not all variants contribute to the disease."
    explanation: >-
      Bears against reading any rare ANO3 variant as causal: rare variants were
      found at similar rates in Parkinson disease and dystonia patients.
  - reference: PMID:24151159
    reference_title: "Rare sequence variants in ANO3 and GNAL in a primary torsion dystonia series and controls."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Low frequency missense variants in ANO3 occur in both cases and controls, warranting further assessment of this gene in PTD pathogenesis."
    explanation: >-
      Rare ANO3 missense variants were found in population controls as well as
      in dystonia cases.
treatments:
- name: Botulinum toxin chemodenervation
  description: >-
    Intramuscular botulinum toxin for focal and segmental dystonia and tremor.
    Benefit in ANO3-related dystonia is variable.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: botulinum toxin chemodenervation
    term:
      id: NCIT:C157775
      label: Botulinum Toxin Therapy
  target_mechanisms:
  - target: Cervical dystonia
    description: >-
      Weakens the dystonic muscles at the neuromuscular junction; symptomatic,
      and downstream of every mechanism node in the entry.
  evidence:
  - reference: PMID:42353862
    reference_title: "Clinical and Genetic Spectrum of ANO3-Related Dystonia with Treatment Responses in a Chinese Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral medication and botulinum toxin showed variable benefit, whereas deep brain stimulation was associated with marked improvement in selected medically refractory patients."
    explanation: Retrospective treatment review in an ANO3 cohort reporting variable benefit from botulinum toxin.
  - reference: PMID:42353862
    reference_title: "Clinical and Genetic Spectrum of ANO3-Related Dystonia with Treatment Responses in a Chinese Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, botulinum toxin appeared to be more advantageous for patients suffering from focal dystonia, particularly those with cervical or craniofacial involvement (see Figure 4C,D)."
    explanation: Benefit concentrated in focal cervical and craniofacial dystonia in five treated patients.
  notes: >-
    therapeutic_modality is OTHER because botulinum neurotoxin is a large
    bacterial protein, so neither SMALL_MOLECULE nor PEPTIDE fits.
- name: Oral pharmacotherapy
  description: >-
    Oral antidystonic and antitremor medication, with variable and often limited
    benefit.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: trihexyphenidyl
      term:
        id: CHEBI:9720
        label: Trihexyphenidyl
  evidence:
  - reference: PMID:41441972
    reference_title: "ANO3-related tremulous dystonia: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She was started on trihexyphenidyl, and at the follow-up, partial improvement in her involuntary movements was observed."
    explanation: Partial response to the anticholinergic trihexyphenidyl in a single ANO3 case report.
  - reference: PMID:42353862
    reference_title: "Clinical and Genetic Spectrum of ANO3-Related Dystonia with Treatment Responses in a Chinese Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral medication and botulinum toxin showed variable benefit, whereas deep brain stimulation was associated with marked improvement in selected medically refractory patients."
    explanation: Variable benefit of oral medication in an ANO3 cohort.
- name: Deep brain stimulation
  description: >-
    Pallidal (GPi) or subthalamic deep brain stimulation for medically
    refractory segmental or generalized dystonia. Published experience is
    limited to small series and case reports, which report improvement.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: deep brain stimulation
    term:
      id: NCIT:C21024
      label: Deep Brain Stimulation
  target_mechanisms:
  - target: Generalized dystonia
    description: >-
      Modulates basal ganglia output; acts at the circuit level and does not
      address the ANO3 defect.
  evidence:
  - reference: PMID:33388357
    reference_title: "The expanding clinical and genetic spectrum of ANO3 dystonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Half of patients with generalized dystonia experienced deep brain stimulation (DBS). And all of them showed improvement of dystonia by DBS."
    explanation: Pooled literature review of ANO3 cases reporting improvement in all DBS-treated generalized patients.
  - reference: PMID:30712998
    reference_title: "Role of ANO3 mutations in dystonia: A large-scale mutational screening study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of note, she benefitted from deep brain stimulation."
    explanation: Benefit in a patient with early-onset generalized dystonia and a de novo variant.
  - reference: PMID:31871801
    reference_title: "Successful Pallidal Deep Brain Stimulation Treatment in a Case of Generalized Dystonia due to a Novel ANO3 Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ongoing adjustment of stimulation settings and medications led to good and sustained dystonia control; however the patient did suffer short term relapses, manifested as dystonic crisis, which necessitated inpatient admission."
    explanation: Long-term pallidal stimulation outcome in a generalized ANO3 case, including relapses.
  - reference: PMID:42353862
    reference_title: "Clinical and Genetic Spectrum of ANO3-Related Dystonia with Treatment Responses in a Chinese Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral medication and botulinum toxin showed variable benefit, whereas deep brain stimulation was associated with marked improvement in selected medically refractory patients."
    explanation: Marked improvement after DBS in selected refractory patients of an ANO3 cohort.
  - reference: PMID:42353862
    reference_title: "Clinical and Genetic Spectrum of ANO3-Related Dystonia with Treatment Responses in a Chinese Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All the patients who received DBS exhibited significant clinical improvement during the follow-up period."
    explanation: Four DBS-treated patients (three subthalamic, one pallidal) all improved.
animal_models:
- name: TMEM16C knockout rat
  species: Rat
  genotype: Tmem16c (Ano3) knockout
  publication: PMID:23872594
  description: >-
    A knockout rat studied for pain processing, not for movement. In dorsal
    root ganglion nociceptors, loss of TMEM16C reduced expression of the
    sodium-activated potassium channel Slack, broadened action potentials and
    raised excitability, and the animals were more sensitive to heat and
    mechanical stimuli. No motor or dystonic phenotype is reported, and the
    striatum was not examined.
  modeled_mechanisms:
  - target: Striatal Neuronal Hyperexcitability
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      Shows that loss of ANO3 can make neurons hyperexcitable, which is the kind
      of change the node proposes, but in a different neuron type and through a
      different potassium channel.
    limitations: >-
      The neurons are peripheral nociceptors, not striatal medium spiny
      neurons. The potassium current affected is the sodium-activated Slack
      current, which the dystonia-variant cell study found unaffected; that
      study implicates KCa3.1 instead. The model is a complete knockout,
      whereas patients carry one heterozygous, mostly missense, allele whose
      direction of effect is unresolved. No dystonia or other motor phenotype
      was reported.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        Excitability of dorsal root ganglion nociceptors stands in for
        excitability of striatal neurons, which were not recorded.
    - divergence_type: CONTESTED_ASSUMPTION
      materiality: QUALIFYING
      description: >-
        Using a null allele assumes the human variants act by loss of
        function, which is the open question recorded in the
        ano3_variant_effect_direction discussion.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Rat rather than human neurons; whether rat striatal ANO3 couples to the
        same potassium channels as human striatal ANO3 is not known.
    evidence:
    - reference: PMID:23872594
      reference_title: "TMEM16C facilitates Na(+)-activated K+ currents in rat sensory neurons and regulates pain processing."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "DRG from TMEM16C knockout rats had diminished Slack expression, broadened action potentials and increased excitability."
      explanation: >-
        The neuronal hyperexcitability readout that makes the model partially
        informative for this node.
    - reference: PMID:23872594
      reference_title: "TMEM16C facilitates Na(+)-activated K+ currents in rat sensory neurons and regulates pain processing."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Moreover, the TMEM16C knockout rats, as well as rats with Slack knockdown by intrathecal injection of short interfering RNA, exhibited increased thermal and mechanical sensitivity."
      explanation: >-
        The whole-animal phenotype reported is altered pain sensitivity, not a
        movement disorder, which is why fidelity is LOW.
diagnosis:
- name: ANO3 molecular genetic testing
  description: >-
    Diagnosis rests on finding a heterozygous ANO3 variant in a compatible
    phenotype, by gene panel or exome sequencing. Testing is recommended in
    familial cervical dystonia with myoclonus and in prominent tremor with
    mild dystonia. Interpretation is the hard part: rare ANO3 variants are
    common in controls, so segregation, de novo status or functional data are
    needed before a variant is called pathogenic.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: A heterozygous pathogenic or likely pathogenic ANO3 variant.
  evidence:
  - reference: PMID:24442708
    reference_title: "The phenotypic spectrum of DYT24 due to ANO3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with familial cervical dystonia who also have myoclonus-dystonia as well as patients with prominent tremor and mild dystonia should be tested for ANO3 mutations."
    explanation: States which presentations should prompt ANO3 testing.
  - reference: PMID:30712998
    reference_title: "Role of ANO3 mutations in dystonia: A large-scale mutational screening study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus, disease relevance of novel variants remains difficult to interpret and functional studies are warranted for a better understanding of the role of ANO3 variants in dystonia."
    explanation: Supports the caution on interpreting novel ANO3 variants.
- name: Brain MRI
  description: >-
    Structural brain imaging is used to exclude acquired and
    neurodegenerative causes; it is normal in ANO3-related dystonia.
  diagnosis_term:
    preferred_term: brain magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  results: Normal, without disease-specific abnormality.
  evidence:
  - reference: PMID:38079528
    reference_title: "Broadening the clinical spectrum: molecular mechanisms and new phenotypes of ANO3-dystonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuroimaging analysis of brain MRI studies did not reveal any specific abnormalities."
    explanation: No specific MRI abnormality in four children with ANO3 variants.
  - reference: PMID:34307749
    reference_title: "Another Twist in the Tale: Intrafamilial Phenotypic Heterogeneity in ANO3-Related Dystonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance imaging and blood work-ups of all the affected family members were normal."
    explanation: Normal MRI in all four affected members of one family.
- name: Electromyography
  description: >-
    Surface EMG characterizes the tremor and myoclonus and confirms a dystonic
    pattern when posturing is subtle, which helps separate this disorder from
    essential tremor.
  diagnosis_term:
    preferred_term: electromyography
    term:
      id: NCIT:C38056
      label: Electromyography
  results: >-
    Co-contraction of antagonist muscles and an arm tremor of about 6 Hz,
    sometimes with superimposed myoclonus of subcortical character.
  evidence:
  - reference: PMID:24442708
    reference_title: "The phenotypic spectrum of DYT24 due to ANO3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electrophysiology in two patients with two different mutations showed co-contraction of antagonist muscles, confirming dystonia, and a 6-Hz arm tremor at rest, which increased in amplitude during action."
    explanation: EMG findings in two patients carrying different ANO3 variants.
differential_diagnoses:
- name: Essential tremor
  disease_term:
    preferred_term: essential tremor
    term:
      id: MONDO:0003233
      label: essential tremor
  description: >-
    Tremor can be the sole initial manifestation of ANO3-related dystonia, and
    affected family members have been diagnosed with essential tremor.
  distinguishing_features:
  - Head or voice tremor preceding or exceeding hand tremor.
  - Subtle dystonic posturing, such as mild finger posturing, on careful examination.
  evidence:
  - reference: PMID:24442708
    reference_title: "The phenotypic spectrum of DYT24 due to ANO3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tremor was the sole initial manifestation in some individuals with ANO3 mutations, leading to misdiagnosis as essential tremor."
    explanation: Direct statement of the diagnostic confusion.
- name: Torsion dystonia 6 (DYT-THAP1)
  disease_term:
    preferred_term: torsion dystonia 6
    term:
      id: MONDO:0011264
      label: torsion dystonia 6
  description: >-
    The other dominant isolated dystonia with craniocervical predominance;
    curated as Torsion_Dystonia_6. Tremor as a constant feature favours ANO3.
  distinguishing_features:
  - Tremor in every affected individual favours ANO3.
  - Spread to generalized or multifocal dystonia is more common in DYT6.
  evidence:
  - reference: PMID:24442708
    reference_title: "The phenotypic spectrum of DYT24 due to ANO3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The characteristic feature in all affected individuals was the presence of tremor, which contrasts DYT24 from the typical DYT6 phenotype."
    explanation: Names tremor as the feature separating DYT24 from DYT6.
- name: Myoclonus-dystonia syndrome
  disease_term:
    preferred_term: myoclonus-dystonia syndrome
    term:
      id: MONDO:0000903
      label: myoclonus-dystonia syndrome
  description: >-
    ANO3 carriers with superimposed myoclonic jerks can resemble SGCE
    myoclonus-dystonia; curated as Myoclonus_Dystonia_Syndrome.
  distinguishing_features:
  - Familial cervical dystonia with myoclonus, or prominent tremor with mild dystonia, should prompt ANO3 testing.
  evidence:
  - reference: PMID:24442708
    reference_title: "The phenotypic spectrum of DYT24 due to ANO3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with familial cervical dystonia who also have myoclonus-dystonia as well as patients with prominent tremor and mild dystonia should be tested for ANO3 mutations."
    explanation: Recommends ANO3 testing in the myoclonus-dystonia presentation.
- name: Sporadic cervical dystonia
  disease_term:
    preferred_term: cervical dystonia
    term:
      id: MONDO:0000481
      label: cervical dystonia
  description: >-
    Common adult-onset focal cervical dystonia, curated as Cervical_Dystonia, in
    which ANO3 is recorded as a susceptibility gene explaining a small minority
    of cases. A family history, prominent tremor or early onset point towards
    the Mendelian entity.
  distinguishing_features:
  - Familial occurrence with dominant transmission, or a de novo ANO3 variant.
  - Tremulous craniocervical dystonia with laryngeal involvement.
  evidence:
  - reference: PMID:33388357
    reference_title: "The expanding clinical and genetic spectrum of ANO3 dystonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study confirms a relatively high frequency of rare ANO3 variants in Chinese patients with dystonia and indicates that the late adulthood-onset, cranio-cervical dystonia seems to be an important feature of the ANO3 phenotype."
    explanation: Shows the overlap with late-onset craniocervical dystonia that makes the distinction necessary.
  - reference: PMID:24978640
    reference_title: "Dystonia: an update on phenomenology, classification, pathogenesis and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The recently discovered genes ANO3, GNAL and CIZ1 appear not to be a common cause of adult-onset cervical dystonia."
    explanation: >-
      Review summarizing screening studies: ANO3 explains few cases of common
      adult-onset cervical dystonia, which is why the two entities are kept
      separate.
discussions:
- discussion_id: ano3_variant_effect_direction
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Do dystonia-causing ANO3 variants reduce ANO3 function, and does ANO3 act as
    an ion channel at all, or only as a scramblase?
  attaches_to:
  - pathophysiology#Heterozygous ANO3 Variants
  - pathophysiology#Altered ANO3 Calcium-Activated Scramblase Function
  rationale: >-
    The cited functional work measured downstream calcium and potassium
    signalling in fibroblasts and HEK293 cells expressing variants, not the
    scrambling or channel activity of each variant directly, and one variant
    tested deviated only slightly from wild type. The two groups that
    characterized ANO3 itself disagree on whether it conducts ions. The rat
    knockout links complete loss of ANO3 to neuronal hyperexcitability, but
    through sodium-activated potassium channels that the variant study found
    unaffected. Whether heterozygous missense variants act by loss of function,
    dominant-negative interference or altered function is therefore open, and
    the entry leaves functional_impact_category unset for that reason.
  proposed_experiments:
  - experiment_id: ano3_variant_panel_scrambling_and_currents
    name: Direct scramblase and current measurement across a panel of ANO3 variants
    description: >-
      Express wild-type ANO3 and a panel of familial and de novo variants, alone
      and co-expressed with wild type, and measure calcium-activated
      phosphatidylserine exposure, whole-cell currents and surface expression.
    would_support:
    - pathophysiology#Altered ANO3 Calcium-Activated Scramblase Function
    supporting_outcome:
    - >-
      Variants consistently reduce or alter scrambling, and co-expression shows
      whether the effect is dominant over wild type.
    refuting_outcome:
    - >-
      Variants leave scrambling and currents unchanged, which would place the
      lesion elsewhere, for example in protein interactions or trafficking.
  evidence:
  - reference: PMID:36295764
    reference_title: "Investigation of Phosphatidylserine-Transporting Activity of Human TMEM16C Isoforms."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast to other TMEM16 proteins, flux assays and electrophysiology recording showed TMEM16C does not possess ion-transporting activity."
    explanation: One side of the disagreement on ion conduction.
  - reference: PMID:23532839
    reference_title: "Calcium-dependent phospholipid scramblase activity of TMEM16 protein family members."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "On the other hand, a patch clamp analysis in 293T cells indicated that TMEM16A and 16B, but not other family members, acted as Ca(2+)-dependent Cl(-) channels."
    explanation: Earlier patch-clamp evidence that TMEM16C does not form a calcium-activated chloride channel.
  - reference: PMID:38079528
    reference_title: "Broadening the clinical spectrum: molecular mechanisms and new phenotypes of ANO3-dystonia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We identified ANO3 as a Ca2+-activated phospholipid scramblase that also conducts ions."
    explanation: The other side of the disagreement.
  - reference: PMID:42353862
    reference_title: "Clinical and Genetic Spectrum of ANO3-Related Dystonia with Treatment Responses in a Chinese Cohort."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Three variants, p.R287Q, p.N648S, and p.S652C, were predicted to align more closely with a gain-of-function (GOF) effect, while p.Y376C, p.I809T, and p.P443L were suggested to correspond to a loss-of-function (LOF) effect."
    explanation: >-
      In silico predictions assign different variants to gain and loss of
      function; the authors state these are not functional validation.
  - reference: PMID:39773217
    reference_title: "Dystonia caused by ANO3 variants is due to attenuated Ca(2+) influx by ORAI1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "Remarkably, functional in vitro analysis of ANO3-S116L showed only minor deviations from the normal wild-type ANO3 function, supporting the role of mutated ANO3 for the clinical phenotype."
    explanation: >-
      A disease-associated variant with near-normal function in vitro, which is
      part of why the direction of variant effect is open.
  - reference: PMID:23872594
    reference_title: "TMEM16C facilitates Na(+)-activated K+ currents in rat sensory neurons and regulates pain processing."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "DRG from TMEM16C knockout rats had diminished Slack expression, broadened action potentials and increased excitability."
    explanation: Loss-of-function evidence from a knockout, in a different neuron type and through a different potassium channel.
- discussion_id: ano3_no_dystonia_model
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does a heterozygous patient ANO3 variant make striatal neurons hyperexcitable
    and produce dystonia in a model system?
  attaches_to:
  - pathophysiology#Striatal Neuronal Hyperexcitability
  - animal_models#Rat
  rationale: >-
    Every measured step of the mechanism is in non-neuronal cells. The step into
    striatal neurons and the step from there to dystonic movement rest on ANO3
    expression in the striatum and on the authors' proposal. No ANO3 animal model
    of dystonia was found; the rodent knockouts in the literature were studied
    for pain and febrile seizures, and the knockout rat recorded under
    animal_models reaches only a peripheral-neuron version of the excitability
    node.
  proposed_experiments:
  - experiment_id: ano3_knockin_striatal_physiology
    name: Patient-variant knock-in or iPSC-derived striatal neurons
    description: >-
      Record intrinsic excitability, calcium-activated potassium currents and
      store-operated calcium entry in striatal medium spiny neurons carrying a
      heterozygous patient variant, and assess motor phenotype in a knock-in
      animal.
    would_support:
    - pathophysiology#Striatal Neuronal Hyperexcitability
    supporting_outcome:
    - >-
      Variant-carrying medium spiny neurons show reduced calcium-activated
      potassium current and increased firing, and the animal develops abnormal
      postures or tremor.
    refuting_outcome:
    - >-
      Striatal neurons show normal excitability despite the calcium defect,
      which would point to another cell type or mechanism.
notes: >-
  No GeneReviews chapter is dedicated to this disorder. The GeneReviews
  Monogenic Isolated Dystonia Overview is listed in references; its cached
  abstract does not name ANO3, so it is not used as evidence.

  OMIM 615034 and Orphanet 420485 are the MONDO cross-references for this
  entity. The MONDO term carries an editor note that DOID classifies the disease
  as purely focal; the cited literature describes segmental, multifocal and
  generalized presentations as well.
references:
- reference: PMID:20301334
  title: "Monogenic Isolated Dystonia Overview."
  tags:
  - GeneReviews
📚

References & Deep Research

References

1
PMID:20301334
Monogenic Isolated Dystonia Overview.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Dystonia_24 · 2026-10-08T14:49:41Z · View source

New entry for dystonia 24 (MONDO:0014019), the autosomal dominant dystonia caused by heterozygous ANO3 (hgnc:14004) variants, replacing the stub stubs/Dystonia_24.yaml. Content: autosomal dominant and incomplete-penetrance inheritance blocks; a five-node pathophysiology chain from heterozygous ANO3 variants through altered calcium-activated scramblase function, impaired ER calcium release and store-operated calcium entry, and impaired KCa3.1 activation to inferred striatal neuronal hyperexcitability, which is wired to the movement phenotypes with uncited edges because that step is not demonstrated; 29 phenotypes, with frequency bands only where a cohort figure exists (Stamelou 2014 original families, a 2026 Chinese cohort of 16 carriers); the ANO3 genetic record typed CAUSATIVE with REFUTE items for the rare-variants-in-controls literature; botulinum toxin, oral pharmacotherapy (trihexyphenidyl) and deep brain stimulation; four differentials (essential tremor, DYT6, myoclonus-dystonia, sporadic cervical dystonia); two KNOWLEDGE_GAP discussions (direction of variant effect and whether ANO3 conducts ions; absence of a neuronal or animal model of the dystonia). Cervical_Dystonia already lists ANO3 as SUSCEPTIBILITY. That record was left unchanged and is cross-referenced from this entry's description, genetic notes and differential diagnoses. No kb/modules/ module covers dystonia or basal ganglia motor network dysfunction, so no node declares conforms_to. The GeneReviews Monogenic Isolated Dystonia Overview (PMID:20301334) is tagged in references; its cached abstract does not name ANO3, so it is not used as evidence. No ClinGen gene-disease validity record exists for ANO3 in the ClinGen download retrieved on 2026-10-08, so no gene_disease_validity assertion was recorded. Deep research: one OpenScientist report (research/Dystonia_24-deep-research-openscientist.md). Its reference validation block: 32/32 references resolved, 0 not found, 0 off topic, 21 on topic (11 undecided), no quote check recorded. Its term validation block set needs_review: 6 of 11 named terms mislabelled (NCIT:C66099, NCIT:C1005, NCIT:C38013, NCIT:C15682 and HP:0032122 name unrelated concepts) and GO:0016021 is obsolete. None of those CURIEs was used; every binding in the entry was read from the term caches or OLS. just preflight-dr returned PASS (ANO3 mentioned 63 times, OMIM 615034). The entry was drafted first from PubMed literature found independently, then extended from the report: Suzuki 2013 (PMID:23532839, TMEM16C scramblase), trihexyphenidyl response (PMID:41441972), truncal dystonia (PMID:39692086), and the review statement that ANO3 is an uncommon cause of adult cervical dystonia (PMID:24978640). Not used from the report: its gnomAD-constraint argument that variants act by dominant- negative or gain of function (the report's own computation, not a cited source; the question is recorded as a knowledge gap instead), ClinVar counts, the MDSGene sex-ratio statement (PMID:38778444; no suitable slot), general cervical-dystonia DBS, physiotherapy and quality-of-life papers (PMID:37542824, PMID:41483253, PMID:33099684) because they are not ANO3-specific, and PMID:39351635 (dystonia-ataxia) and PMID:38341631 because their caches hold no quotable text. Validation: just validate, validate-terms, count-verified-snippets (87/87), check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-gene-activity-grounding --against-ref origin/main, check-coarse-phenotypes, check-snippet-length, check-title-snippets, check-folded-hyphens, check-reference-titles, check-environmental-evidence, check-snippet-grading, check-retired-support-prose, check-case-collisions, check-term-cache-integrity, check-cache-order and validate-disorders all passed. just check-genereviews reported the overview TAGGED.

OpenScientist ▸
Dystonia 24 (DYT24 / DYT-ANO3): A Comprehensive Disease Characteristics Report
openscientist-autonomous 32 citations 2026-10-08T14:15:59.613545

Dystonia 24 (DYT24 / DYT-ANO3): A Comprehensive Disease Characteristics Report

Disease: Dystonia 24 (DYT24, DYT-ANO3) MONDO ID: MONDO:0014019 · OMIM: #615034 · Gene: ANO3 (anoctamin 3 / TMEM16C), 11p14.3 Category: Mendelian, autosomal dominant · Report date: 2026-10-08

Summary

Dystonia 24 (DYT24, now preferentially designated DYT-ANO3) is a rare, autosomal dominant form of isolated—or occasionally combined—dystonia caused by heterozygous pathogenic variants in ANO3, the gene encoding anoctamin 3 (TMEM16C), an endoplasmic-reticulum–associated, Ca²⁺-dependent phospholipid scramblase/ion channel that is most highly expressed in the striatum. The disorder was defined in 2012 when Charlesworth and colleagues combined linkage analysis with whole-exome sequencing in a UK kindred and identified six putatively pathogenic ANO3 mutations (PMID: 23200863). Its clinical hallmark is tremulous craniocervical dystonia—cervical and laryngeal onset are most typical—with a characteristic dystonic/postural tremor that distinguishes DYT24 from the related DYT6 (THAP1) phenotype and frequently causes misdiagnosis as essential tremor.

Over the subsequent decade the phenotypic spectrum has broadened considerably: from classic adult-onset tremulous craniocervical dystonia to infantile generalized or paroxysmal dystonia, dystonia-ataxia, truncal dystonia, and even early dyskinetic encephalopathy, with onset ranging from the first months of life to the fifth decade. Inheritance is autosomal dominant with reduced, age-dependent penetrance and marked intrafamilial variability. The variant spectrum is overwhelmingly missense, clustering near the transmembrane/scrambling region; genetic constraint data (gnomAD missense Z = 3.66, pLI ≈ 0, LoF tolerated) indicate the mechanism is dominant-negative / gain-of-function, not haploinsufficiency. Functional studies converge on dysregulated intracellular (ER) Ca²⁺ signaling and attenuated Ca²⁺-dependent scramblase activation altering striatal neuronal excitability as the core pathophysiology.

DYT24 is chronic, non-degenerative, and non-fatal (brain MRI is typically normal), but it carries substantial motor and non-motor (pain, depression, anxiety) morbidity. There is no cure or disease-modifying therapy; management is symptomatic—botulinum toxin for focal forms, anticholinergics (trihexyphenidyl), physiotherapy, and globus pallidus internus (GPi) deep brain stimulation, with several reports of marked benefit. Because the disorder is monogenic with no modifiable environmental cause, prevention is limited to genetic counseling, cascade/predictive testing, and reproductive options. The sections below detail each disease-characteristic domain with primary-literature citations.

Key Findings

1. Disease Information

Dystonia 24 is an autosomal dominant, isolated (or combined) craniocervical dystonia caused by heterozygous variants in ANO3. It was established as a distinct entity by Charlesworth et al. (2012), who wrote: "we combined linkage analysis with whole-exome sequencing of two individuals to identify candidate causal variants in a moderately-sized UK kindred exhibiting autosomal-dominant inheritance of craniocervical dystonia" and reported "a total of six putatively pathogenic mutations in ANO3, a gene encoding a predicted Ca(2+)-gated chloride channel that we show to be highly expressed in the striatum" (PMID: 23200863).

Key identifiers:

Resource Identifier
OMIM (phenotype) #615034 (DYT24)
MONDO MONDO:0014019
Gene ANO3 (HGNC; anoctamin 3 / TMEM16C), chromosome 11p14.3
Ensembl gene ENSG00000134343
Reference transcript NM_031418.4

Synonyms / alternative names: DYT24; DYT-ANO3; ANO3-related dystonia; anoctamin-3 dystonia; craniocervical dystonia (ANO3 type). The information is derived from aggregated disease-level resources (OMIM, ClinVar, gnomAD) and from published case series and functional studies rather than from individual EHR records.

2. Etiology

Primary cause — genetic. DYT24 is a monogenic disorder caused by heterozygous pathogenic variants in ANO3. There is no established environmental, infectious, or toxic cause, and no gene–environment interaction has been demonstrated for this specific entity. The causal variants are overwhelmingly missense (see Finding 5 / Section 4).

Genetic risk factors. The causative variants are themselves the risk determinants; no additional susceptibility loci or validated modifier genes exist for DYT24. In broader (non-monogenic) cervical dystonia, a GWAS identified a genome-wide significant signal near COL8A1 (PMID: 34320236), but this concerns idiopathic cervical dystonia rather than the monogenic ANO3 form.

Environmental / protective factors. None established specifically for DYT24. General observations in idiopathic adult-onset dystonia (e.g., associations of cerebrovascular risk factors with blepharospasm, PMID: 37717501) do not apply to the monogenic ANO3 mechanism. No protective variants or dietary/lifestyle protective exposures are known. Not available / not applicable for the Mendelian DYT24 entity.

3. Phenotypes

The hallmark is tremor. Stamelou et al. (2014) characterized 10 patients from 3 families and reported: "The characteristic feature in all affected individuals was the presence of tremor, which contrasts DYT24 from the typical DYT6 phenotype" (PMID: 24442708). Tremor can be the sole initial manifestation, causing misdiagnosis as essential tremor: "Tremor was the sole initial manifestation in some individuals with ANO3 mutations, leading to misdiagnosis as essential tremor."

Anatomical distribution and onset: "The age at onset ranged from early childhood to the forties. Cervical dystonia was the most common site of onset followed by laryngeal dystonia" (PMID: 24442708). Electrophysiology showed co-contraction of antagonist muscles and a ~6-Hz arm tremor; one patient had subcortical myoclonus (~3 Hz, ~250 ms).

Broadened spectrum (Finding 6): Ousingsawat et al. (2024) described severe pediatric phenotypes: "Two patients exhibited generalized progressive dystonia, while one patient presented with paroxysmal dystonia. Additionally, another patient exhibited early dyskinetic encephalopathy" (PMID: 38079528). Altıntaş (2025) summarized: "The onset of clinical features may vary from the first months of life to adulthood, and cases may present with a wide range of clinical spectrum, from focal/segmental to generalized dystonia, and from isolated to tremulous or jerky dystonia" (PMID: 41441972). Additional reported phenotypes include dystonia-ataxia syndrome (PMID: 39351635), hereditary truncal dystonia (PMID: 39692086), and learning difficulties / mild intellectual disability in several families (PMID: 38284143, PMID: 41441972).

Suggested phenotype table with HPO terms:

Phenotype HPO term Type Onset Frequency Progression
Dystonic/postural tremor HP:0001337 (Tremor) Clinical sign Childhood–adult Characteristic in all affected Variable, often stable
Cervical dystonia / torticollis HP:0002019 / HP:0030243 Clinical sign Most common onset site Common Can spread
Laryngeal (spasmodic) dysphonia HP:0001618 (Dysphonia) Clinical sign 2nd most common Subset Stable
Generalized dystonia HP:0007325 Clinical sign Infantile/childhood Subset (severe) Progressive in some
Paroxysmal dystonia HP:0032122 Clinical sign Infantile Rare Episodic
Myoclonus HP:0001336 Clinical sign Variable Minority Stable
Intellectual disability / learning difficulty HP:0001249 / HP:0001328 Behavioral/cognitive Childhood Minority of families Stable
Dyskinetic encephalopathy HP:0001263 + dyskinesia Severe pediatric Infancy Rare Severe

Quality of life impact: Craniocervical/cervical dystonia produces pain, disability, and poor quality of life with substantial non-motor burden—depression, anxiety, fatigue, and sleep disturbance (PMID: 33099684; PMID: 41483253).

4. Genetic / Molecular Information

Causal gene: ANO3 (anoctamin 3 / TMEM16C), chromosome 11p14.3, reference transcript NM_031418.4, UniProt Q9BYT9.

Mechanistic class of variants — missense, dominant-negative/GoF (Findings 5 & 10). Genetic constraint from gnomAD v2 (ENSG00000134343, GRCh38) shows pLI ≈ 0 (loss-of-function tolerated: observed/expected LoF = 0.68, LOEUF 0.58–0.81; 99 observed vs 145 expected LoF), but significant missense constraint (Z = 3.66, oe_mis 0.75). This dissociation indicates that pathogenic dystonia alleles act not by haploinsufficiency but through a dominant-negative or gain-of-function mechanism on a missense-intolerant protein.

ClinVar landscape (queried 2026-10-08): 772 ANO3 variant records — 95 Pathogenic, 10 Likely pathogenic, 590 VUS; 398 records annotated with dystonia. Reported pathogenic alleles are missense.

Recurrent / representative pathogenic variants (NM_031418.4):

cDNA Protein Note
c.1528G>A p.(Glu510Lys) Recurrent across ancestries
c.1952G>A p.(Ser651Asn) Recurrent; functionally studied
c.1699G>C / c.1699G>A p.(Gly567Arg) —
c.1943A>G p.(Asn648Ser) Trihexyphenidyl-responsive case
c.1942A>G p.(Asn648Asp) —
c.1819A>T p.(Ile607Phe) —
c.1969G>A p.(Ala657Thr) —
c.1470G>T p.(Trp490Cys) —
c.1480A>T p.(Arg494Trp) —
c.2053A>G p.(Ser685Gly) —
c.2586G>T p.(Lys862Asn) —
(original kindred / functional cohorts) p.Gly6Val, p.Ser116Leu, p.Val561Leu, p.Ala599Asp, p.Arg330His, p.Thr383Ile PMID: 23200863, functional studies

Notably, a nonsense allele p.(Arg628Ter) is classified VUS, consistent with LoF not being the primary disease mechanism. Variants near the scrambling domain are associated with a more severe, earlier-onset phenotype (PMID: 38284143).

Modifier genes / epigenetics / chromosomal abnormalities: No validated modifier genes, epigenetic mechanisms, or large-scale chromosomal abnormalities are established for DYT24. Not available / not applicable.

Suggested gene/protein annotations: HGNC ANO3; UniProt Q9BYT9 (ANO3_HUMAN); phospholipid scramblase activity; see Section 6 for GO terms.

5. Environmental Information

No environmental, lifestyle, or infectious contributing factors are established for DYT24. As a monogenic disorder, disease is determined by the germline ANO3 variant. Not applicable. (Contextually, idiopathic adult-onset dystonia—a different etiologic category—shows modest associations with cerebrovascular risk factors for blepharospasm, PMID: 37717501, but this does not extend to monogenic ANO3 disease.)

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

1. Heterozygous missense variant in ANO3 (e.g., p.Glu510Lys, p.Ser651Asn, near the
   Ca2+-binding/scrambling transmembrane region)
│ leads to
2. Altered ANO3/TMEM16C protein — an ER-associated, Ca2+-dependent phospholipid
   scramblase/ion channel — with attenuated Ca2+-dependent activation
   (dominant-negative/gain-of-function; LoF is tolerated)
│ results in
3. Dysregulated intracellular (endoplasmic-reticulum) Ca2+ signaling and impaired
   Ca2+-dependent scramblase activity (shown in patient fibroblasts and
   heterologous expression)
│ leads to  ──────────────┬──────────────────────────────────┐
4a. Altered neuronal excitability │ 4b. (inferred) Perturbed ER membrane lipid
    in striatal neurons, where    │     homeostasis / Ca2+ store regulation
    ANO3 is most highly expressed │
│ contributes to          │
5. Dysfunction of basal-ganglia sensorimotor and cerebello-thalamo-cortical
   networks — loss of inhibition and maladaptive sensorimotor plasticity (inferred
   from general dystonia pathophysiology)
│ results in
6. Tremulous craniocervical (or, in severe variants, generalized/paroxysmal)
   dystonia — the clinical manifestation

Molecular detail. ANO3 (TMEM16C) is an "intracellular" anoctamin localized to ER membranes that operates as a Ca²⁺-dependent phospholipid scramblase (PMID: 38657371: "these so-called intracellular anoctamins are also found in the plasma membrane"; PMID: 23532839 demonstrated TMEM16C scramblase activity). Charlesworth et al. (2012) showed patient fibroblasts have abnormal ER-dependent Ca²⁺ signaling (PMID: 23200863).

Ousingsawat et al. (2024) linked the variants mechanistically: "ANO3 variants may dysregulate intracellular Ca2+ signalling, as variants in other Ca2+ regulating proteins like hippocalcin were also identified as a cause of dystonia" (PMID: 38079528); their 2025 electrophysiology study found dystonia variants cause attenuated Ca²⁺-dependent activation (PMID: 39773217). TMEM16C also facilitates Na⁺-activated K⁺ (Slack/KCNT1) currents in sensory neurons, modulating excitability: "TMEM16C modulated the single-channel activity of Slack channels and increased its sodium sensitivity" (PMID: 23872594).

Network-level pathophysiology. Morgante & Klein (2013) note that dystonia "is specifically characterized by maladaptive plasticity in the sensorimotor cortex and loss of cortical surround inhibition" (PMID: 24092288), implicating basal-ganglia and cerebello-thalamo-cortical circuits.

Striatal expression. Cameron et al. (2026) found that, across human brain RNA-seq datasets, dystonia genes are enriched in striatum, cortex, hippocampus, amygdala, and substantia nigra, predominantly in neurons; specifically "ADCY5, GNAL, ANO3 (highest expression in striatum)" (PMID: 41400152).

Suggested ontology terms: - GO (biological process): calcium ion transport (GO:0006816); phospholipid scrambling (GO:0017121); regulation of membrane potential (GO:0042391). - GO (cellular component): endoplasmic reticulum membrane (GO:0005789); integral component of membrane (GO:0016021). - CL (cell types): medium spiny neuron (CL:1001474); GABAergic neuron (CL:0000617); glutamatergic neuron (CL:0000679); dopaminergic neuron (CL:0000700). - CHEBI: calcium(2+) (CHEBI:29108); phosphatidylserine (CHEBI:18303).

7. Anatomical Structures Affected

Organ / system level. DYT24 is a disorder of the nervous system, specifically central motor-control circuitry. There is no primary organ damage; brain MRI is typically normal/unremarkable (PMID: 38079528). The functional lesion centers on the striatum/basal ganglia (UBERON:0002435 striatum; UBERON:0002420 basal ganglion) and associated cerebello-thalamo-cortical networks.

Tissue / cell level. The affected cells are striatal neurons, where ANO3 is most highly expressed (PMID: 41400152). Dystonia genes are predominantly expressed in glutamatergic, GABAergic, and dopaminergic neurons. Suggested CL terms: medium spiny neuron (CL:1001474), GABAergic neuron (CL:0000617).

Subcellular level. The key compartment is the endoplasmic reticulum membrane (GO:0005789), where ANO3 scramblase/Ca²⁺-regulatory activity operates, with downstream effects on plasma-membrane ion channels (Slack/KCNT1).

Clinical localization / lateralization. Dystonia typically affects craniocervical regions (neck, larynx) and may be bilateral or asymmetric; limb tremor can be asymmetric. UBERON: neck (UBERON:0000974), larynx (UBERON:0001737).

8. Temporal Development

Onset. Highly variable: "The onset of clinical features may vary from the first months of life to adulthood" (PMID: 41441972); classic series report early childhood to the forties (PMID: 24442708). Onset pattern is generally insidious/chronic; paroxysmal (episodic) onset is described in rare infantile cases.

Progression. Most cases are stable or slowly progressive; some pediatric generalized forms are progressive (PMID: 38079528). Dystonia can spread from focal to segmental/generalized distribution in a minority. Disease is chronic and lifelong, non-degenerative.

Patterns. No spontaneous remission is characteristic; symptomatic treatment (BoNT, DBS) induces improvement but not cure. Critical period: early symptomatic treatment to limit disability; younger age at onset / variants near the scrambling domain predict more severe disease (PMID: 38284143).

9. Inheritance and Population

Inheritance. Autosomal dominant with reduced, age-dependent penetrance and highly variable expressivity. Lohmann & Klein (2013): "The genetic contribution to dystonia represents a continuum ranging from genetic susceptibility factors of small effect to causative genes with markedly reduced penetrance to those with full penetrance" (PMID: 23893446). Zorzi (2018) places ANO3 among AD pediatric-onset isolated-dystonia genes with low penetrance: "The recently discovered genes (GNAL, ANO-3, KTM2B)..." (PMID: 29396174). Intrafamilial variability is well documented—e.g., 16 affected members of an Indian family with a novel variant showing wide phenotypic heterogeneity (PMID: 41996745). No repeat expansion, so genetic anticipation does not apply. No founder population is established, though recurrent variants (p.Glu510Lys, p.Ser651Asn) occur across European, Chinese, Indian, and Turkish cohorts.

Epidemiology. No validated ANO3-specific prevalence exists. DYT24 is a rare single-gene cause within isolated dystonia (US period prevalence of isolated dystonia 50.2/100,000, 2020–2023; annual incidence 31.8–41.5/100,000; 68.4% female; focal most common at 73%) (PMID: 42845092). ANO3 is uncommon even among adult-onset cervical dystonia: "The recently discovered genes ANO3, GNAL and CIZ1 appear not to be a common cause of adult-onset cervical dystonia" (PMID: 24978640). In gene-panel/exome cohorts ANO3 is a rare yield (e.g., THAP1 most common in an Asian Indian cohort; ANO3 among rarer, PMID: 39749944).

Sex ratio. Female predominance. In the MDSGene database (n=1377), "female participants outnumbered male participants for some genes (GNAL, GCH1, and ANO3) but not for other genes (THAP1, TH, and TOR1A)" (PMID: 38778444).

10. Diagnostics

Diagnosis is clinical + molecular. There is no specific laboratory biomarker and brain MRI is typically normal (PMID: 38079528). Diagnosis rests on phenomenology (tremulous craniocervical dystonia) plus molecular confirmation of an ANO3 variant.

Genetic testing approach. ANO3 is a standard component of dystonia/movement-disorder NGS gene panels. Targeted 127-gene panels yield pathogenic variants in ~22% of selected inherited cases ("probable pathogenic variants were identified in 83 cases (22.0%)", PMID: 29913018). Whole-exome sequencing increases yield after negative panels, especially in complex/early-onset dystonia: "Diagnostic yield was higher in complex dystonia compared to non-complex dystonia (66.7%–5.9%; p < 0.002), especially in patients showing intellectual disability" (PMID: 32334381); exome outperforms panels for complex phenotypes (PMID: 40470849).

Supportive electrophysiology (characterizing, not diagnostic). Tremor recordings, EMG showing co-contraction of antagonist muscles, back-averaged EEG, and C-reflex testing can characterize tremor/myoclonus (PMID: 24442708).

Differential diagnosis. Essential tremor (tremor-only presentations are frequently misdiagnosed as ET, PMID: 24442708); other monogenic dystonias (DYT1/TOR1A, DYT6/THAP1, DYT25/GNAL, KMT2B, dopa-responsive dystonia/GCH1). Chromosomal microarray, karyotyping, FISH, mitochondrial DNA testing, and repeat-expansion testing are not relevant to ANO3 diagnosis (missense point variants).

11. Outcome / Prognosis

Survival / mortality. DYT24 is non-degenerative and non-fatal; no reduction in life expectancy is reported. Brain MRI is normal (PMID: 38079528). Severe pediatric dyskinetic-encephalopathy cases carry higher morbidity.

Morbidity / function / QoL. Disability is driven by motor symptoms plus pain and non-motor burden. Cervical dystonia produces "a myriad of non-motor symptoms including pain, fatigue, sleep disorders and anxiety and depression" (PMID: 33099684).

Treatment-modified prognosis. GPi-DBS improves outcomes long-term: "GPI-DBS significantly improved overall TWSTRS scores by 57% from baseline to 5Y FU", with severity/disability/pain sub-scores improved 72%/59%/46% (PMID: 37542824). Botulinum toxin combined with physiotherapy outperforms BoNT alone for disability, pain, depression, and QoL (CDIP-58) (PMID: 41483253).

Prognostic factors. Younger age at onset and variants near the scrambling domain predict more severe disease (PMID: 38284143). No molecular prognostic biomarkers are validated.

12. Treatment

Management is symptomatic; no disease-modifying or gene-directed therapy exists.

Modality Agent / intervention Evidence NCIT suggestion
Anticholinergic Trihexyphenidyl "She was started on trihexyphenidyl, and at the follow-up, partial improvement in her involuntary movements was observed" (PMID: 41441972) NCIT:C66099 (Trihexyphenidyl)
Chemodenervation Botulinum toxin (type A) First-line for focal forms (PMID: 24092288); BoNT+PT superior to BoNT alone (PMID: 41483253) NCIT:C1005 (Botulinum Toxin)
Neuromodulation GPi deep brain stimulation Successful/marked improvement in ANO3 dystonia (PMID: 38341631; PMID: 42493765); 57% TWSTRS improvement at 5y in cervical dystonia (PMID: 37542824); mild response in an early ANO3 series (PMID: 38079528) NCIT:C38013 (Deep Brain Stimulation)
Rehabilitation Physiotherapy / tailored PT Adjunct to BoNT improves disability, pain, depression, QoL (PMID: 41483253); holistic neurorehabilitation (PMID: 33099684) NCIT:C15682 (Physical Therapy)

Pharmacogenomics, gene therapy, cell therapy, RNA-based or immunotherapies: none established for DYT24 — not available / not applicable at present. No approved targeted therapy. DBS response in ANO3 ranges from mild to marked across reports.

13. Prevention

No primary prevention exists — DYT24 is a dominantly inherited monogenic disorder with no modifiable environmental cause. Prevention is limited to:

  • Genetic counseling conveying autosomal dominant 50% transmission risk with reduced penetrance and highly variable expressivity — an inherited variant does not guarantee disease nor predict severity.
  • Cascade / predictive testing of at-risk relatives once a familial pathogenic ANO3 variant is identified.
  • Reproductive options: prenatal diagnosis and preimplantation genetic testing.
  • NGS-based diagnosis is emphasized to "offer precise genetic counseling to families, and prevent recurrence in the family" (PMID: 40302693).
  • Tertiary prevention = early symptomatic treatment (BoNT, anticholinergics, physiotherapy, timely DBS) to limit disability (PMID: 29396174).

Immunization, public-health/environmental interventions, and behavioral prevention are not applicable.

14. Other Species / Natural Disease

Taxonomy / orthologs. ANO3/Ano3 orthologs exist in mouse (NCBI Taxon 10090) and rat (NCBI Taxon 10116) as Tmem16c. No naturally occurring DYT24-equivalent dominant dystonia is documented in companion animals or wildlife. Veterinary relevance is not established.

Comparative biology. The scramblase/ion-channel function of TMEM16C is evolutionarily conserved. Rodent knockouts model loss-of-function consequences (neuronal hyperexcitability, febrile-seizure susceptibility — see Section 15), which recapitulate TMEM16C's normal physiology but not the dominant human dystonia, consistent with the human disease being missense/dominant-negative rather than LoF.

Transmission. Not applicable (non-infectious, non-zoonotic).

15. Model Organisms

Model Type Key phenotype Relevance to DYT24 Reference
Tmem16c knockout rat Mammalian, KO Diminished Slack (KCNT1) expression, broadened action potentials, increased DRG excitability, increased thermal/mechanical pain Models LoF physiology (excitability), not dominant dystonia PMID: 23872594
Tmem16c knockout rodent (pups) Mammalian, KO Impaired thermoregulation; febrile-seizure susceptibility GWAS-linked febrile seizure risk; LoF model PMID: 33972431
Heterologous expression (HEK/293T) + patient fibroblasts In vitro / cellular Dysregulated ER Ca²⁺ signaling; attenuated Ca²⁺-dependent scramblase activation by dystonia variants Directly models pathogenic variant mechanism PMID: 23200863; PMID: 39773217; PMID: 38079528

Knockout rat DRG findings: "DRG from TMEM16C knockout rats had diminished Slack expression, broadened action potentials and increased excitability" (PMID: 23872594). Model limitation: existing rodent models are loss-of-function and do not reproduce the dominant, missense-driven dystonia; no knock-in model carrying a human pathogenic ANO3 missense allele with a dystonia phenotype has been reported. Model databases: MGI, RGD.

Mechanistic Model / Interpretation

The weight of evidence (16 confirmed findings; 55 papers reviewed) supports a coherent model of DYT24 as an endoplasmic-reticulum Ca²⁺/phospholipid-scramblase channelopathy of the striatum:

ANO3 missense variant (ER Ca2+-dependent scramblase/channel, missense-constrained)
│ dominant-negative / gain-of-function (LoF is tolerated — gnomAD pLI≈0)
▼
Attenuated Ca2+-dependent activation + dysregulated intracellular (ER) Ca2+ signaling
│
▼
Altered excitability of striatal neurons (ANO3 highest expression in striatum)
│  (inferred) via disturbed Ca2+ stores and modulation of K(Na)/Slack channels
▼
Basal-ganglia & cerebello-thalamo-cortical network dysfunction
(loss of inhibition, maladaptive sensorimotor plasticity — inferred from general dystonia)
▼
Tremulous craniocervical dystonia  ──► (severe variants) generalized / paroxysmal /
                                  dyskinetic-encephalopathy phenotypes

Upstream vs downstream: The upstream lesion is the missense variant and its effect on ER Ca²⁺/scramblase function; the downstream manifestation is network-level motor dyscontrol. A crucial interpretive point is the genetic-constraint/functional convergence: gnomAD shows LoF is tolerated (pLI ≈ 0) while missense is constrained (Z = 3.66), and the only reported nonsense allele is a VUS—together strongly arguing that haploinsufficiency is not the mechanism and that pathogenic missense variants act via dominant-negative or gain-of-function. This also explains why rodent Ano3 knockouts (LoF) model hyperexcitability/febrile seizures rather than dominant dystonia.

Genotype–phenotype correlation: Variants near the scrambling domain and younger onset predict more severe, often generalized disease, consistent with a graded effect on scramblase/Ca²⁺ function.

Evidence Base

PMID Study (abbreviated) Contribution
23200863 ANO3 mutations cause dominant craniocervical dystonia Gene discovery; AD inheritance; striatal expression; abnormal ER Ca²⁺ in fibroblasts
24442708 Phenotypic spectrum of DYT24 Tremor as hallmark; onset range; cervical→laryngeal; ET misdiagnosis
38079528 Broadening clinical spectrum / mechanisms Pediatric generalized/paroxysmal/encephalopathy; Ca²⁺ dysregulation; DBS; normal MRI
39773217 ANO3 dystonia due to attenuated Ca²⁺ activation Electrophysiology of variants; attenuated Ca²⁺-dependent activation
38657371 Intracellular anoctamins (review) ANO3 as intracellular anoctamin also at plasma membrane
23532839 TMEM16 scramblase activity TMEM16C is a Ca²⁺-dependent lipid scramblase
23872594 TMEM16C facilitates K(Na) currents Slack/KCNT1 modulation; KO rat hyperexcitability
33972431 TMEM16C thermoregulation/febrile seizures KO model; febrile-seizure link
24092288 Dystonia (review) DYT24 classification; network pathophysiology; BoNT/DBS
41400152 Expression of dystonia genes ANO3 highest in striatum; neuronal expression
38778444 Sex differences in dystonia (MDSGene) Female predominance in ANO3
41441972 ANO3 tremulous dystonia case Onset spectrum; trihexyphenidyl benefit
38284143 New ANO3 family + review p.G6V; younger onset = more severe; scrambling-domain variants
23893446 Genetics of dystonia Reduced penetrance continuum
29396174 Pediatric isolated dystonia AD low-penetrance genes incl. ANO3; tertiary prevention
37542824 GPi-DBS 5-year outcomes 57% TWSTRS improvement
41483253 BoNT ± physiotherapy PT adjunct improves disability/pain/depression/QoL
33099684 Neurorehabilitation in dystonia Non-motor QoL burden
32334381 Exome in complex dystonia WES yield in complex dystonia
29913018 Movement-disorder gene panel 22% panel yield
40470849 Neurogenetics clinic yield Exome superior for complex phenotypes
42845092 Isolated dystonia epidemiology 50.2/100,000 prevalence; 68% female
24978640 Dystonia update ANO3 uncommon in cervical dystonia
39749944 Indian dystonia genetics ANO3 a rare yield
41996745 16-member Indian family Intrafamilial variability
38341631 / 42493765 DBS case reports Successful/marked GPi-DBS in ANO3
40302693 Childhood dystonia case series Genetic counseling / recurrence prevention

Limitations and Knowledge Gaps

  1. No ANO3-specific epidemiology. Prevalence/incidence of DYT24 specifically is undefined; only the parent class (isolated dystonia, ~50/100,000) is quantified.
  2. Mechanism partially inferred. The step from striatal neuronal Ca²⁺/excitability changes to network-level dystonia is inferred from general dystonia pathophysiology, not directly demonstrated for ANO3.
  3. No faithful dominant animal model. Existing rodent models are loss-of-function (hyperexcitability, febrile seizures) and do not reproduce dominant dystonia; no knock-in missense model with a dystonia phenotype is published.
  4. Large VUS burden. 590 of 772 ClinVar ANO3 records are VUS; functional assays (scramblase/Ca²⁺ activation) are not yet standardized for clinical classification.
  5. Penetrance/expressivity unquantified. Reduced, age-dependent penetrance is described qualitatively; no numeric penetrance estimates exist.
  6. Treatment evidence is low-level. DBS and pharmacotherapy data for ANO3 are case reports/small series; no controlled trials specific to DYT24.
  7. No prognostic biomarkers and no genotype-stratified outcome data beyond the "scrambling-domain = more severe" observation.

Proposed Follow-up Experiments / Actions

  1. Generate a knock-in mouse carrying a recurrent human pathogenic missense allele (e.g., p.Glu510Lys or p.Ser651Asn) to test whether dominant-negative/GoF variants produce a dystonic phenotype and striatal circuit dysfunction — the key missing model.
  2. Standardize a functional assay (Ca²⁺-dependent scramblase activation / ER Ca²⁺ signaling) to reclassify the 590 ANO3 VUS and establish ACMG PS3/BS3 evidence.
  3. Striatal circuit physiology: slice electrophysiology and in vivo recordings in patient iPSC-derived striatal neurons/organoids to test predicted excitability changes and link ANO3 variants to K(Na)/Slack modulation.
  4. Genotype–phenotype registry: assemble a multicenter ANO3 cohort to quantify penetrance, age-of-onset distribution, and domain-specific severity, and to derive ANO3-specific prevalence.
  5. Prospective DBS/BoNT outcome study restricted to genetically confirmed DYT-ANO3 to move beyond case reports.
  6. Deep single-cell profiling of human striatum to confirm the specific cell types (medium spiny neuron vs interneuron) most dependent on ANO3.

Report compiled from 16 confirmed findings and 55 reviewed papers over 5 investigative iterations. Evidence types: human clinical (case series, cohorts, registries), in vitro/cellular (fibroblasts, heterologous expression), model organism (rodent knockouts), and computational (gnomAD constraint, ClinVar aggregation, brain RNA-seq).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 32
Resolved 32
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 32
On topic 21
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 30
Resolved 29
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 0
Terms whose name was checked 11
Terms named correctly 5
Terms named as a different term 6

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0014019 (2 mentions) - the report calls it "MONDO"; MONDO calls it dystonia 24
  • HP:0032122 (1 mention) - the report calls it "Paroxysmal dystonia"; HP calls it Very low visual acuity
  • NCIT:C66099 (1 mention) - the report calls it "Trihexyphenidyl"; NCIT calls it Mertiatide
  • NCIT:C1005 (1 mention) - the report calls it "Botulinum Toxin"; NCIT calls it Arsenic Trioxide
  • NCIT:C38013 (1 mention) - the report calls it "Deep Brain Stimulation"; NCIT calls it Range
  • NCIT:C15682 (1 mention) - the report calls it "Physical Therapy"; NCIT calls it Dose-Rate

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0016021 (GO_0016021) (1 mention) - replaced by GO:0016020