An ultra-rare autosomal recessive dystonia caused by biallelic loss-of-function variants in TSPOAP1, which encodes RIM-binding protein 1 (RIMBP1), a multidomain scaffold of the presynaptic active zone that binds RIM proteins and voltage-gated calcium channels. Affected individuals develop progressive generalized dystonia in late childhood or adolescence, predominantly affecting the upper body and spreading cranio-caudally, together with intellectual disability and cerebellar atrophy; eye movement abnormalities have also been reported. The disorder was defined in an Indian family and an Estonian individual carrying homozygous frameshift and nonsense variants, and later reports from India have added unrelated patients with further truncating variants. The mechanism is inferred from mouse work rather than measured in patients. RIM-binding proteins are required for tight coupling of action-potential-evoked calcium influx to synaptic vesicle exocytosis, and Tspoap1-knockout mice show dystonia-like motor abnormalities, reduced Purkinje cell dendritic arborization and fewer cerebellar synapses. Whether the cerebellar changes cause the dystonia, and how the mouse findings relate to the progressive cerebellar atrophy seen on patient MRI, has not been established.
Ask a research question about Dystonia 22, Juvenile-Onset. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
name: Dystonia 22, Juvenile-Onset
creation_date: "2026-10-11T00:00:00Z"
category: Mendelian
synonyms:
- DYT22JO
- juvenile-onset dystonia 22
- juvenile-onset TSPOAP1-related dystonia
- DYT-TSPOAP1, juvenile-onset form
description: >-
An ultra-rare autosomal recessive dystonia caused by biallelic loss-of-function
variants in TSPOAP1, which encodes RIM-binding protein 1 (RIMBP1), a
multidomain scaffold of the presynaptic active zone that binds RIM proteins and
voltage-gated calcium channels. Affected individuals develop progressive
generalized dystonia in late childhood or adolescence, predominantly affecting
the upper body and spreading cranio-caudally, together with intellectual
disability and cerebellar atrophy; eye movement abnormalities have also been
reported. The disorder was defined in an Indian family and an Estonian
individual carrying homozygous frameshift and nonsense variants, and later
reports from India have added unrelated patients with further truncating
variants.
The mechanism is inferred from mouse work rather than measured in patients.
RIM-binding proteins are required for tight coupling of action-potential-evoked
calcium influx to synaptic vesicle exocytosis, and Tspoap1-knockout mice show
dystonia-like motor abnormalities, reduced Purkinje cell dendritic arborization
and fewer cerebellar synapses. Whether the cerebellar changes cause the dystonia,
and how the mouse findings relate to the progressive cerebellar atrophy seen on
patient MRI, has not been established.
disease_term:
preferred_term: dystonia 22, juvenile-onset
term:
id: MONDO:0957539
label: dystonia 22, juvenile-onset
parents:
- Inherited dystonia
categories:
- Movement Disorder
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Affected individuals are homozygous for truncating TSPOAP1 variants, with
heterozygous parents. Consanguinity was present in one of the original
families but not reported in the other.
evidence:
- reference: PMID:33539324
reference_title: "Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we describe homozygous frameshift, nonsense, and missense variants in TSPOAP1, which encodes the active-zone RIM-binding protein 1 (RIMBP1), as a genetic cause of autosomal recessive dystonia in 7 subjects from 3 unrelated families."
explanation: >-
The gene-identification study reports homozygous variants as a cause of
autosomal recessive dystonia. The 7 subjects include the 3 adult-onset
missense carriers of the separate adult-onset entity; the recessive mode
holds for both.
- reference: PMID:41371074
reference_title: "Expanding the genotypic and phenotypic spectrum of DYT-TSPOAP1: First report from India."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Pathogenic variants in TSPOAP1, encoding RIMBP1, cause ultra-rare autosomal recessive dystonia (DYT-TSPOAP1/DYT-22), with only two reports worldwide."
explanation: >-
Independent later report restating the recessive inheritance as established
background before describing two new patients.
pathophysiology:
- name: Biallelic TSPOAP1 Loss of Function
biological_scale: MOLECULAR
conforms_to: "synaptic_vesicle_cycle#Synaptic Vesicle Cycle Protein Deficiency"
description: >-
Homozygous truncating TSPOAP1 variants (a frameshift and a nonsense variant in
the original families; further truncating variants in later reports) are
predicted to abolish RIMBP1, an active-zone protein of the presynaptic release
machinery. Loss of RIMBP1 protein has not been measured in patient neurons;
the loss-of-function reading rests on variant class and on the knockout mouse.
genetic_context:
variant_origin: GERMLINE
zygosity: HOMOZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
genes:
- preferred_term: TSPOAP1
term:
id: hgnc:16831
label: TSPOAP1
molecular_functions:
- preferred_term: RIM and voltage-gated calcium channel adaptor activity
term:
id: GO:0030674
label: protein-macromolecule adaptor activity
modifier: DECREASED
cellular_components:
- preferred_term: presynaptic active zone
term:
id: GO:0048786
label: presynaptic active zone
downstream:
- target: Impaired Coupling of Calcium Influx to Synaptic Vesicle Release
description: >-
RIM-binding proteins tie voltage-gated calcium channels to release-ready
vesicles, so their loss is expected to make action-potential-evoked release
slower and less reliable.
evidence:
- reference: PMID:26402606
reference_title: "RIM-BPs Mediate Tight Coupling of Action Potentials to Ca(2+)-Triggered Neurotransmitter Release."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "Deletion of RIM-BPs decelerated action-potential-triggered neurotransmitter release and rendered it unreliable, thereby impairing the fidelity of synaptic transmission."
explanation: >-
Measured in synapses lacking both RIM-BP1 and RIM-BP2, not RIMBP1 alone
and not in patient cells, so the edge is inferred for this disease.
- target: Cerebellar Purkinje Cell Dendritic and Synaptic Deficit
description: >-
Complete loss of RIMBP1 in mice reduces Purkinje cell dendritic arborization
and cerebellar synapse number.
evidence:
- reference: PMID:33539324
reference_title: "Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses."
explanation: >-
Knockout mouse result linking RIMBP1 loss to the cerebellar cellular
deficit.
evidence:
- reference: PMID:33539324
reference_title: "Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Subjects carrying loss-of-function variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy."
explanation: >-
Identifies the juvenile-onset phenotype with the loss-of-function
genotype class.
- reference: PMID:41371074
reference_title: "Expanding the genotypic and phenotypic spectrum of DYT-TSPOAP1: First report from India."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We describe two unrelated patients with adolescent-onset generalized dystonia showing cranio-caudal progression due to novel truncating variants in the TSPOAP1 gene."
explanation: >-
Two further unrelated patients with truncating variants, extending the
loss-of-function genotype class beyond the original families.
- reference: PMID:26402606
reference_title: "RIM-BPs Mediate Tight Coupling of Action Potentials to Ca(2+)-Triggered Neurotransmitter Release."
supports: SUPPORT
directness: INDIRECT
quote_role: BACKGROUND
evidence_source: IN_VITRO
snippet: "RIM-binding proteins (RIM-BPs) are multidomain active zone proteins that bind to RIMs and to Ca(2+) channels."
explanation: >-
Supports the molecular function bound on this node: RIM-BPs bridge RIM
proteins and voltage-gated calcium channels, which is adaptor activity.
GO's own TSPOAP1 annotations (benzodiazepine receptor binding, and an
electronically inferred calcium channel activity) do not describe this
scaffolding role. The sentence covers the RIM-BP family, not RIMBP1 alone.
- name: Impaired Coupling of Calcium Influx to Synaptic Vesicle Release
biological_scale: CELLULAR
conforms_to: "synaptic_vesicle_cycle#Neurotransmitter Release Failure and Synaptic Transmission Deficit"
description: >-
Without RIM-binding proteins, release is not abolished but becomes slower and
less reliable because calcium channels are not held close to primed vesicles.
The single-protein (RIMBP1-only) effect and its magnitude in human motor
circuits are inferred, and which neuronal population carries the defect that
produces dystonia is unknown.
biological_processes:
- preferred_term: action-potential-evoked synaptic vesicle exocytosis
modifier: ABNORMAL
term:
id: GO:0016079
label: synaptic vesicle exocytosis
downstream:
- target: Generalized dystonia
description: >-
The authors conclude that presynaptic active-zone dysfunction causes the
dystonia; the circuit through which it acts is not identified.
evidence:
- reference: PMID:33539324
reference_title: "Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Our findings establish a direct link between dysfunction of the presynaptic active zone and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis."
explanation: >-
The authors' synthesis of human genetics, mouse and in vitro data. Marked
INDIRECT because the release defect was not measured in patient neurons.
evidence:
- reference: PMID:26402606
reference_title: "RIM-BPs Mediate Tight Coupling of Action Potentials to Ca(2+)-Triggered Neurotransmitter Release."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Surprisingly, we find that in murine synapses, RIM-BPs are not essential for neurotransmitter release as such, but are selectively required for high-fidelity coupling of action potential-induced Ca(2+) influx to Ca(2+)-stimulated synaptic vesicle exocytosis."
explanation: >-
Defines the normal role of RIM-BPs from RIM-BP1/RIM-BP2 double conditional
knockout synapses in cultured neurons and calyx of Held.
- name: Cerebellar Purkinje Cell Dendritic and Synaptic Deficit
biological_scale: CELLULAR
description: >-
Tspoap1-knockout mice show reduced Purkinje cell dendritic arborization and
fewer cerebellar synapses. This is a mouse cellular finding. It is not linked
here to patient cerebellar atrophy or to dystonia by an edge, because the
source does not show that the cerebellar change causes either; nor is this
node conformed to the cerebellar Purkinje degeneration module, since Purkinje
neuron loss and cerebellar ataxia are not what the source reports.
cell_types:
- preferred_term: Purkinje cell
term:
id: CL:0000121
label: Purkinje cell
biological_processes:
- preferred_term: Purkinje cell dendrite morphogenesis
modifier: DECREASED
term:
id: GO:0048813
label: dendrite morphogenesis
- preferred_term: cerebellar synapse organization
modifier: DECREASED
term:
id: GO:0050808
label: synapse organization
locations:
- preferred_term: cerebellum
term:
id: UBERON:0002037
label: cerebellum
evidence:
- reference: PMID:33539324
reference_title: "Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses."
explanation: Knockout mouse evidence for the cerebellar cellular deficit.
phenotypes:
- category: Neurological
name: Generalized dystonia
description: >-
Progressive generalized dystonia beginning in late childhood or adolescence,
predominantly affecting the upper body (craniocervical and upper-limb
involvement) and spreading cranio-caudally.
phenotype_term:
preferred_term: progressive generalized dystonia
term:
id: HP:0007325
label: Generalized dystonia
clinical_course: PROGRESSIVE
onset:
onset_category: JUVENILE
evidence:
- reference: PMID:33539324
reference_title: "Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Subjects carrying loss-of-function variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy."
explanation: Defines juvenile-onset progressive generalized dystonia as the core feature.
- reference: PMID:41371074
reference_title: "Expanding the genotypic and phenotypic spectrum of DYT-TSPOAP1: First report from India."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We describe two unrelated patients with adolescent-onset generalized dystonia showing cranio-caudal progression due to novel truncating variants in the TSPOAP1 gene."
explanation: Replicates adolescent onset and progression in two unrelated patients.
- reference: PMID:41371074
reference_title: "Expanding the genotypic and phenotypic spectrum of DYT-TSPOAP1: First report from India."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Clinical features include upper-segment-predominant dystonia, intellectual disability, eye movement abnormalities, and cerebellar atrophy."
explanation: Summarizes the upper-segment predominance from the earlier reports.
- category: Neurological
name: Intellectual disability
description: >-
Intellectual disability accompanies the dystonia in carriers of
loss-of-function variants.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:33539324
reference_title: "Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Subjects carrying loss-of-function variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy."
explanation: Reports intellectual disability with the loss-of-function genotype.
- reference: PMID:41371074
reference_title: "Expanding the genotypic and phenotypic spectrum of DYT-TSPOAP1: First report from India."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Clinical features include upper-segment-predominant dystonia, intellectual disability, eye movement abnormalities, and cerebellar atrophy."
explanation: Restates intellectual disability as a recognized feature.
- category: Neurological
name: Cerebellar atrophy
description: >-
Cerebellar atrophy on brain MRI. Whether it reflects the Purkinje dendritic
and synaptic deficit seen in knockout mice is not established.
phenotype_term:
preferred_term: Cerebellar atrophy
term:
id: HP:0001272
label: Cerebellar atrophy
evidence:
- reference: PMID:33539324
reference_title: "Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Subjects carrying loss-of-function variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy."
explanation: Reports cerebellar atrophy with the loss-of-function genotype.
- reference: PMID:41371074
reference_title: "Expanding the genotypic and phenotypic spectrum of DYT-TSPOAP1: First report from India."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Clinical features include upper-segment-predominant dystonia, intellectual disability, eye movement abnormalities, and cerebellar atrophy."
explanation: Restates cerebellar atrophy as a recognized feature.
- category: Neurological
name: Eye movement abnormalities
description: >-
Eye movement abnormalities are listed among the clinical features of the
disorder. The source abstract does not say which type, so the binding stays
at the general term.
phenotype_term:
preferred_term: Eye movement abnormalities
term:
id: HP:0000496
label: Abnormality of eye movement
evidence:
- reference: PMID:41371074
reference_title: "Expanding the genotypic and phenotypic spectrum of DYT-TSPOAP1: First report from India."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Clinical features include upper-segment-predominant dystonia, intellectual disability, eye movement abnormalities, and cerebellar atrophy."
explanation: Lists eye movement abnormalities among the recognized features.
genetic:
- name: TSPOAP1
gene_term:
preferred_term: TSPOAP1
term:
id: hgnc:16831
label: TSPOAP1
relationship_type: CAUSATIVE
notes: >-
TSPOAP1 (previous symbol BZRAP1; OMIM gene entry 610764) encodes RIMBP1. This
entry covers only biallelic truncating, loss-of-function variants. The
homozygous missense variant p.Gly1808Ser, reported in the same discovery study
with isolated adult-onset focal dystonia and enhanced neurotransmission in
vitro, defines the separate entity dystonia 22, adult-onset (MONDO:0957542,
OMIM 620456) and is not recorded here. No ClinGen gene-disease validity
record for TSPOAP1 is in references_cache, so no validity tier is recorded.
evidence:
- reference: PMID:33539324
reference_title: "Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Subjects carrying loss-of-function variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy."
explanation: Gene-identification study for the juvenile-onset loss-of-function form.
- reference: PMID:41371074
reference_title: "Expanding the genotypic and phenotypic spectrum of DYT-TSPOAP1: First report from India."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We describe two unrelated patients with adolescent-onset generalized dystonia showing cranio-caudal progression due to novel truncating variants in the TSPOAP1 gene."
explanation: Independent replication with novel truncating variants.
animal_models:
- name: Tspoap1 knockout mouse
species: Mouse
genotype: Tspoap1(-/-) (complete RIMBP1 loss)
publication: PMID:33539324
description: >-
Constitutive loss of RIMBP1 in mice, studied in the gene-identification paper
to test whether loss of the protein produces motor and cerebellar
abnormalities.
modeled_mechanisms:
- target: Cerebellar Purkinje Cell Dendritic and Synaptic Deficit
relationship: RECAPITULATES
fidelity: UNKNOWN
model_scale: CELLULAR
description: >-
The knockout is the source of the cerebellar cellular node; whether patients
have the same Purkinje dendritic and synaptic deficit is unknown.
limitations: >-
The mouse shows motor abnormalities described only as reminiscent of
dystonia, and the human cerebellar findings are MRI atrophy rather than
histology, so correspondence between the mouse cellular deficit and the
human phenotype is assumed rather than shown.
divergences:
- divergence_type: SPECIES_MISMATCH
materiality: QUALIFYING
description: >-
Mouse cerebellar and motor circuits differ from human ones, and
dystonia-like behaviour in mice is not the same clinical sign as
progressive generalized dystonia in patients.
readouts:
- name: Purkinje cell dendritic arborization and cerebellar synapse number
target: Cerebellar Purkinje Cell Dendritic and Synaptic Deficit
direction: DECREASED
interpretation: Structural readout behind the cerebellar node.
evidence:
- reference: PMID:33539324
reference_title: "Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses."
explanation: Reports the decreased dendritic arborization and synapse number.
evidence:
- reference: PMID:33539324
reference_title: "Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses."
explanation: Supports the knockout as informative for the cerebellar node.
mappings:
mondo_mappings:
- term:
id: MONDO:0957539
label: dystonia 22, juvenile-onset
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: >-
The entry and the MONDO class denote the same entity, the juvenile-onset
loss-of-function form; MONDO cross-references OMIM 620453 and DOID:0060966.
notes: >-
Identifiers. MONDO:0957539 cross-references OMIM 620453 (phenotype) and
DOID:0060966. OMIM 610764 is the TSPOAP1 gene entry, not a phenotype. OMIM
620456 is dystonia 22, adult-onset (MONDO:0957542), the isolated adult-onset
focal dystonia of homozygous p.Gly1808Ser carriers; it is also recessive, so the
two entities differ by allele class and phenotype rather than by inheritance,
and it is not curated in this entry.
Relationship to dopa-responsive dystonia entries. Orphanet attaches TSPOAP1 to
ORPHA:101150 (autosomal recessive dopa-responsive dystonia), and
Dopa_Responsive_Dystonia lists rarer biallelic TSPOAP1 variants as a cause of
AR-DRD. The sources cited here describe progressive generalized dystonia with
intellectual disability and cerebellar atrophy and report no levodopa
response, and no levodopa-response data for TSPOAP1 were found in the
abstracts read. Autosomal_Recessive_Dopa_Responsive_Dystonia already excludes
TSPOAP1 for this reason; the Dopa_Responsive_Dystonia wording disagrees with
this entry and is left for that entry's curators to review.
Treatment. No disease-specific treatment evidence is quotable. A single case of
deep brain stimulation in a TSPOAP1-biallelic patient is reported in
PMID:37850637, and a further homozygous case with childhood-onset generalized
dystonia and cerebellar atrophy in PMID:42027086; neither PubMed record carries
an abstract and no quotable text was retrieved on two fetches, so neither is
used as evidence and no treatment is recorded. Features described only in the
discovery paper's full text (dysarthria, dysphagia, seizures and spasticity in
single patients, vermis-predominant atrophy, learning difficulty preceding
motor onset) are not recorded, because the abstract does not state them.
No GeneReviews chapter names this disease or its synonyms (Bookshelf index
snapshot 2026-09-10 plus a live PubMed title search, 2026-10-11).
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.
Review round 1: bind TSPOAP1 molecular function; drop unsourced family origin · 2026-10-11T20:48:19Z · View source
Bound GO:0030674 protein-macromolecule adaptor activity (modifier DECREASED) on the Biallelic TSPOAP1 Loss of Function node, supported by the PMID:26402606 abstract sentence that RIM-binding proteins bind both RIMs and Ca(2+) channels. GO's own TSPOAP1 molecular-function annotations were not used: benzodiazepine receptor binding (GO:0030156) is the TSPO interaction that names the gene and is unrelated to the release-coupling mechanism, and the electronically inferred calcium channel activity (GO:0099626) describes a channel, which RIMBP1 is not. The description no longer calls the original family Gujarati, because no cited abstract states it; the detail came from the deep-research report only. Validation after the change: validate, validate-terms, 22/22 snippets, entity refs, snippet grading, and check_gene_activity_grounding against origin/main all pass.
Create: Dystonia 22, Juvenile-Onset · 2026-10-11T20:23:55Z · View source
New entry for the juvenile-onset, loss-of-function form of TSPOAP1 dystonia (MONDO:0957539). Deep-research input was a single Perplexity report (research/Dystonia_22_Juvenile_Onset-deep-research-perplexity.md). preflight-dr returned WARN because the report cites OMIM 610764 and 620456 while MONDO xrefs OMIM 620453; resolved by lookup in the local MONDO build: 610764 is the TSPOAP1 gene entry and 620456 is dystonia 22, adult-onset (MONDO:0957542), the homozygous p.Gly1808Ser focal adult-onset form, which is excluded here and recorded in notes. Evidence is quoted from abstracts only: the discovery paper (PMID:33539324), the 2025 Indian report (PMID:41371074) and the RIM-BP coupling study (PMID:26402606). Two TSPOAP1 case reports (PMID:37850637, DBS; PMID:42027086) have no abstract, returned no quotable text on two fetches, and are mentioned in notes only; no treatment is recorded. Pathophysiology is a three-node chain conforming to synaptic_vesicle_cycle at its first and release nodes; only generalized dystonia is causally wired, intellectual disability, cerebellar atrophy and eye movement abnormalities are left unconnected because no source links them to a mechanism node. Disagreement with Dopa_Responsive_Dystonia (which lists TSPOAP1 under AR-DRD) is recorded in notes, not edited. check-genereviews --online: NO_CHAPTER. Validation: just validate passed (21 snippets, 21 titles, 0 issues), validate-terms passed, count-verified-snippets 21/21, entity refs, causal targets, duplicate keys and block-scalar checks clean.
Dystonia 22, juvenile-onset (DYT22JO) is an ultra-rare, autosomal-recessive disorder caused by biallelic loss-of-function variants in TSPOAP1. It typically presents in the early teenage years with progressive, predominantly craniocervical dystonia that becomes generalized, cognitive deterioration, and cerebellar—especially vermian—atrophy. The most detailed clinical and experimental evidence remains the original study of four affected people in two families; later reports have added patients but have not established population rates or a standardized treatment response. TSPOAP1 missense-associated adult-onset focal dystonia is a distinct DYT22 phenotype and should not be pooled with DYT22JO. [46][1][77]
Evidence notation: “Human” means observation in affected people; “mouse” and “in vitro” identify experimental evidence. Fractions below describe reported individuals, not population prevalence or reliable penetrance estimates.
| Identifier or name | Disease-specific information |
|---|---|
| Preferred name and synonyms | Dystonia 22, juvenile-onset; juvenile-onset dystonia-22; DYT22JO; juvenile-onset TSPOAP1-related dystonia. The broader label DYT-TSPOAP1/DYT-22 may also encompass the distinct adult-onset phenotype. [1][77] |
| OMIM phenotype | 620453; causal-gene OMIM entry 610764 (TSPOAP1). Adult-onset dystonia-22 is separately OMIM:620456. [1] |
| Disease Ontology | DOID:0060966. [1] |
| MONDO | MONDO:0957539 was supplied in the request but could not be independently verified against the retrieved disease records; retain it as a provisional mapping pending ontology validation, rather than treating it as confirmed. [1][185] |
| Orphanet | A disease-specific ORPHA number was not verified. Do not substitute an ORPHA number for another juvenile dystonia. |
| ICD | ICD-10 G24 describes dystonia; G24.9 is an unspecified-dystonia code, not a DYT22JO-specific code. A disease-specific ICD-11 code was not verified. [152][154] |
| MeSH | Dystonic Disorders: D020821; Dystonia: D004421. “Juvenile-onset dystonia,” C537704, is a broader supplementary concept, not a unique identifier for TSPOAP1 disease. [151][158][153] |
| Evidence provenance | This entry synthesizes published, aggregated disease-level descriptions derived primarily from individually examined research participants, pedigrees, imaging, and laboratory experiments. It is not an EHR-derived cohort or a patient-level clinical record. [46][1] |
Primary abstract, exact quotation: “Subjects carrying loss-of-function variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy.” — Mencacci et al., Journal of Clinical Investigation, 1 April 2021, PMID 33539324, DOI 10.1172/JCI140625; article URL. [46]
The established cause is homozygous truncating TSPOAP1 variation, predicted to remove functional RIM-binding protein 1 (RIMBP1) through early truncation or nonsense-mediated decay. The original families were of Gujarati Indian and Estonian origin. First-cousin parentage in the Gujarati family increased the opportunity for homozygosity; consanguinity is not required, as it was not reported for the Estonian family. These are germline inherited findings, not somatic mutations. [46][1]
| Factor | DYT22JO-specific conclusion |
|---|---|
| Causal genetic risk | Biallelic loss-of-function TSPOAP1 variants; see Section 4. [46] |
| Family history and consanguinity | An affected sibling or known carrier parents raise individual risk under autosomal-recessive inheritance. Consanguinity occurred in one original family; its population-attributable contribution is unknown. [46] |
| Age and sex | Age in the early teenage years describes observed onset, not a demonstrated exposure-related risk. No sex-specific risk estimate is available. [46] |
| Toxins, occupation, diet, smoking, alcohol, infection, radiation | No DYT22JO-specific causal association established in the cited clinical series. |
| Protective alleles, modifier genes, diet, lifestyle | None established. Absence of disease in a carrier is consistent with recessive inheritance, not evidence of a protective allele. [46] |
| Gene–environment interaction | Not demonstrated in humans. Oxotremorine provoked more dystonia-like events in Tspoap1-knockout mice; this is an experimental pharmacological challenge, not evidence that environmental oxotremorine exposure causes human DYT22JO. [46] |
The following frequencies are original-series observations, at most four people, and should be stored with that denominator and source rather than as generalizable disease frequencies. Onset of dystonia was in the early teenage years; school-age learning difficulties could precede it. “All four” applies only where explicitly reported. [46][1]
| Phenotype and type | Onset, course, severity, frequency in original series | Functional or quality-of-life implication | Suggested HPO term |
|---|---|---|---|
| Generalized dystonia; clinical sign | Early teenage onset; progressive, severe, craniocervical-predominant; 4/4. [46] | Increasing difficulty with movement and independence; no DYT22JO-specific EQ-5D or SF-36 score reported. | HP:0007325 generalized dystonia; HP:0001332 dystonia. [166][107] |
| Craniocervical dystonia and abnormal voice; sign/symptom | Prominent cranial involvement, including dysphonia; described across the four loss-of-function cases, without a separately published per-feature percentage. [46] | Impaired spoken communication. | HP:0001618 dysphonia; HP:0001332 dystonia. [106] |
| Dysarthria; sign | Prominent and progressive; separate numerical frequency unavailable. [46] | Reduced speech intelligibility. | HP:0001260 dysarthria. [109] |
| Dysphagia; symptom/sign | Progressive swallowing difficulty; separate numerical frequency unavailable. [46] | Eating and swallowing become harder; aspiration risk warrants clinical assessment, but a DYT22JO-specific aspiration rate has not been measured. | HP:0002015 dysphagia. [46][113] |
| Upper-limb dystonic posturing, overflow, writhing; signs | Ongoing and progressive; separate numerical frequency unavailable. [46] | Impaired dexterity and severe handwriting difficulty. | HP:0001332 dystonia; HP:0007010 poor fine motor coordination is a functional descriptor, not proof of primary coordination disease. [168] |
| Abnormal gait and lower-limb dystonic posturing; signs | Progressive inward foot turning, tiptoeing and leg stiffening; reported in the original juvenile group. [46] | Progressive loss of independent walking was described. | HP:0001332 dystonia; document observed gait pattern individually rather than automatically coding gait ataxia. |
| School-age learning difficulty, then cognitive deterioration; behavioral/cognitive findings | Early motor and language development initially normal; mild primary-school learning difficulty followed by deterioration in 4/4. Formal assessments documented worsening in two individuals. [46] | Educational and later daily-living support needs; no disease-specific patient-reported outcome score. | HP:0001249 intellectual disability when clinically established; HP:0001256 mild intellectual disability where assessed. [175][167] |
| Cerebellar, predominantly vermian, atrophy; imaging sign | 4/4 on MRI; progressive on serial imaging in reported individuals. Classic nystagmus, limb dysmetria and gait ataxia were not prominent in the original group. [46] | An important diagnostic clue; an independent contribution to disability is unproven. | HP:0001272 cerebellar atrophy; HP:0006855 cerebellar vermis atrophy. [106][169] |
| Generalized tonic–clonic seizures and interictal EEG activity; signs/test finding | 1/4 for seizures in the original series. [46] | Potential episodic safety and treatment burden. | HP:0001250 seizure; describe EEG finding separately. [175] |
| Movement-triggered painful episodic limb/truncal dystonia; symptom/sign | Reported in one original individual, superimposed on progressive dystonia. [46] | Episodic pain and interruption of activity. | HP:0001332 dystonia; document the trigger and episodic pattern in free text. |
| Lower-limb spasticity and brisk reflexes; signs | Reported in one original individual. [46] | May further impair walking. | Use clinically verified spasticity/brisk-reflex HPO terms in that patient; do not assign to all DYT22JO cases. |
Later phenotype evidence: A 2025 report of two unrelated patients described adolescent-onset generalized dystonia with craniocaudal progression and noted eye-movement abnormalities within the broader reported spectrum. A 2026 case report identifies childhood-onset generalized dystonia with cerebellar atrophy; its PubMed record has no abstract, so an exact variant or further phenotype cannot responsibly be extracted from that record. Holla et al., Parkinsonism & Related Disorders, online 2 December 2025, PMID 41371074, DOI 10.1016/j.parkreldis.2025.108139, URL; Dutta et al., Movement Disorders Clinical Practice, 24 April 2026, PMID 42027086, DOI 10.1002/mdc3.70622, URL. [77][78]
TSPOAP1, formerly BZRAP1, is at 17q22: HGNC:16831; NCBI Gene:9256; Ensembl:ENSG00000005379; UniProt:O95153; OMIM:610764. It encodes the presynaptic active-zone scaffolding protein RIMBP1. Transcript versions must be preserved when recording variants: the original study used NM_004758.3, while a later ClinVar representation of the second variant uses NM_004758.4 and the equivalent inversion description. [72][65][46][131]
| Variant and original transcript | Class, original evidence, and population observation | Interpretation for this entry |
|---|---|---|
| NM_004758.3:c.538delG; p.(Ala180Profs*8) | Homozygous frameshift in three affected siblings; each parent heterozygous; unaffected sibling reference homozygous. Absent among >120,000 gnomAD individuals examined in the original analysis, including >15,000 South Asian individuals. Human segregation and computationally predicted loss of function; no patient-cell functional test reported. [46] | Original authors identified it as pathogenic/causal for DYT22JO. An observed database absence is not a measured carrier frequency. [46] |
| NM_004758.3:c.2449_2450delinsTG; p.(Gln817Ter) | Homozygous stop-gain in one affected Estonian individual; mother heterozygous; father unavailable. Absent from the gnomAD data examined, which included 2,418 Estonian individuals. Also recorded as NM_004758.4:c.2449_2450inv in ClinVar. [46][131] | ClinVar records a germline pathogenic submission for juvenile-onset dystonia-22; ClinVar notes no variant-specific functional evidence. [131] |
| NM_004758.3:c.5422G>A; p.(Gly1808Ser) | Homozygous missense in three relatives with adult-onset focal dystonia, not the juvenile loss-of-function syndrome. In neuronal rescue assays it increased calcium transients and evoked transmission. [46] | Exclude from DYT22JO-specific pathogenic-variant counts. It illustrates a different variant class and phenotype, OMIM:620456. [1][46] |
| Additional truncating variants reported in 2025; novel homozygous variant reported in 2026 | The retrieved 2025 abstract does not give HGVS nomenclature; the retrieved 2026 record has no abstract. [77][78] | Record the case reports as supporting evidence, but do not invent variant strings, allele frequencies, or ACMG classifications. |
The original study found no additional confirmed biallelic cases among approximately 700 other dystonia exomes it screened. No DYT22JO-specific modifier gene, protective variant, repeat expansion, pathogenic structural chromosome rearrangement, or epigenetic signature was established. The Estonian case’s chromosomal microarray found no explanatory copy-number variant. [46]
No infectious agent, toxin, radiation exposure, occupation, smoking pattern, diet, or exercise pattern has been established as a cause or preventive factor for this Mendelian syndrome. In particular, the mouse oxotremorine result concerns experimentally induced sensitivity after gene knockout, not a documented human exposure pathway. CHEBI annotation: enter chemical identifiers only after verifying a specific compound and its context; do not enter oxotremorine as a human disease cause. [46]
Experimental detail. At about six months, knockout mice showed approximately 30% less distal Purkinje dendritic calbindin-covered area, roughly 20% less vGluT1 signal, and approximately 15–30% fewer vGluT2-labelled clusters, depending on dendritic region. These changes were not evident at two months. Purkinje-cell number and gross cerebellar volume were not significantly reduced in that mouse analysis; therefore, do not equate the mouse histology with proven Purkinje-cell death in patients. After muscarinic challenge, knockout mice had approximately 300% greater motor-dysfunction scores than controls. These are mouse experimental measurements, not human disease biomarkers. [46]
Mechanistic boundary: the original paper explicitly cautions that it does not establish a causal link between cerebellar structural changes and dystonia. The adult-onset p.Gly1808Ser in-vitro findings—larger spike-evoked calcium transients and enhanced release—must not be described as the demonstrated effect of juvenile truncating alleles. No DYT22JO-specific Wnt, MAPK, mTOR, immune, apoptosis, metabolic, methylation, patient single-cell, spatial-transcriptomic, proteomic, lipidomic, or metabolomic disease signature was established by these studies. A mitochondrial-suspected Estonian case later attributed to TSPOAP1 does not establish primary mitochondrial DYT22JO. [46][48][234][238]
| Suggested mechanistic annotation | Term and evidence boundary |
|---|---|
| Biological process | GO:0007269, neurotransmitter secretion; annotate as relevant protein/pathway biology, not as an experimentally quantified process in patient neurons. [243][46] |
| Cellular component | GO:0048786, presynaptic active zone; GO:0045202, synapse. [239][240] |
| Cell type | CL:0000121, Purkinje cell, for the mouse morphological findings; presynaptic neurons supplying excitatory Purkinje inputs were assessed through markers, not conclusively assigned a single affected human cell type. [246][46] |
| Pathway description | Calcium-dependent, action-potential-evoked synaptic-vesicle release and excitatory synapse maintenance are supported descriptions; a DYT22JO-specific KEGG signaling cascade has not been established. [46] |
The nervous system is primary. MRI directly implicates the cerebellum, predominantly its vermis. Mouse findings locate abnormalities in cerebellar Purkinje dendrites and their excitatory synaptic inputs, with the presynaptic active zone as the relevant subcellular site. Speech, swallowing, upper-limb and gait effects involve muscles as downstream effectors; primary muscle disease has not been shown. The original MRIs did not show characteristic basal-ganglia volume loss or signal abnormality, despite the potential involvement of wider motor circuits. [46]
Suggested anatomy: UBERON:0002037, cerebellum; use HP:0006855 for the directly observed vermian atrophy. Suggested cells/components: CL:0000121, Purkinje cell, and GO:0048786, presynaptic active zone. Disease-defining unilateral or bilateral anatomical lateralization has not been established; lower-limb gait posturing could be bilateral. [248][169][246][239][46]
Early motor and language milestones were generally normal in the original four patients; mild learning problems emerged at primary-school age, followed by insidious early-teenage motor onset and progressive generalization. Serial MRI showed increasing cerebellar atrophy in individuals scanned at ages 5, 8 and 14, and 15 and 17, respectively. The course appears chronic, but there is no validated stage system, median progression rate, remission rate, or established intervention window. The published movement-triggered paroxysms in one person should not be mistaken for remission of the underlying progressive disorder. [46]
Inheritance is autosomal recessive, supported by homozygous affected individuals and segregation in the reported families. If both parents are confirmed heterozygous carriers of the same pathogenic allele, the standard Mendelian risk for each pregnancy is 25% affected, 50% carrier, 25% inheriting neither parental variant; that calculation is a genetic expectation, not a measured DYT22JO penetrance. Neither penetrance nor carrier frequency has been estimated. There is no evidence establishing anticipation or germline mosaicism as characteristic. [46][1]
The original four juvenile cases came from two families; a later 2025 report added two unrelated adolescent-onset patients, and a 2026 publication reports one childhood-onset case. These are publication counts, not an exhaustive worldwide case registry: overlapping earlier reports must not be double-counted. No defensible prevalence per 100,000, annual incidence, sex ratio, founder-variant frequency, ethnic risk ratio, or geographic distribution estimate is available. The 2018 Estonian exome study reported the individual later included in the 2021 genetic characterization; its cohort’s 57% WES diagnostic yield is not a DYT22JO prevalence statistic. [46][77][78][228][238]
Clinical suspicion should rise with adolescent progressive, upper-segment-predominant generalized dystonia plus cognitive deterioration and vermis-predominant cerebellar atrophy. A movement-disorder examination, developmental and family history, cognitive assessment, swallowing assessment when indicated, and brain MRI establish the phenotype and identify competing explanations; MRI is supportive, not molecular confirmation. EEG is indicated by seizures, not an obligatory disease biomarker. No specific blood, urine, enzyme, biopsy, PET, EMG, or circulating assay diagnoses DYT22JO. [46][1]
| Test or diagnostic approach | DYT22JO-specific use and limitation |
|---|---|
| Early-onset dystonia/movement-disorder gene panel | Include TSPOAP1 alongside genes for clinically overlapping dystonias; Genomics England lists TSPOAP1 as a green/high-evidence childhood-onset movement-disorder gene. A panel’s actual coverage and deletion/duplication detection must be checked. [65] |
| WES with segregation testing | Directly demonstrated: homozygosity mapping and WES identified the original causal variants; Sanger sequencing confirmed segregation. Assess both alleles and transcript-specific HGVS nomenclature. [46] |
| WGS | Reasonable escalation if panel/WES is unrevealing or structural/noncoding variation is suspected, but a disease-specific incremental diagnostic yield has not been established. |
| Single-gene TSPOAP1 testing | Efficient when a familial pathogenic variant is known; consider targeted testing of relatives with appropriate counseling. [46] |
| CMA; karyotype; FISH | Not first-line confirmation of the reported sequence-variant mechanism. CMA excluded a copy-number explanation in one original patient; use cytogenetic tests when findings independently suggest a chromosome disorder. [46] |
| mtDNA, repeat-expansion, or omics testing | Not tests for known DYT22JO alleles; pursue only for a broader differential. The historically mitochondrial-suspected Estonian patient was diagnosed through a nuclear-gene finding. [238][46] |
Differential diagnosis: other genetically determined generalized or combined dystonias, particularly when there is developmental or cognitive involvement, and treatable causes of childhood dystonia should be assessed through phenotype-guided evaluation. A structurally normal basal ganglia does not exclude DYT22JO. Do not use the adult-onset TSPOAP1 p.Gly1808Ser phenotype as the expected course for juvenile truncating variants. No validated DYT22JO-specific clinical diagnostic criteria or population/newborn screening program was identified. [46][1][65]
The best-supported prognosis is progressive motor and cognitive morbidity, with reported deterioration in walking, speech, swallowing and independent functioning; progressive cerebellar atrophy can accompany it. Five- or ten-year survival, life expectancy, disease-specific mortality, recovery probability, quantitative quality-of-life scores, and validated molecular prognostic biomarkers have not been established. Swallowing and mobility complications merit assessment, but their DYT22JO-specific incidence cannot be calculated from these reports. [46][1]
No treatment has been shown to correct the TSPOAP1 lesion or halt DYT22JO progression. Care is individualized and symptomatic; evidence for general dystonia treatments must not be reported as a DYT22JO response rate. A 2023 TSPOAP1-biallelic DBS case report exists, but its accessible PubMed record supplies no abstract or quantitative outcome. Hasani et al., Movement Disorders, 18 October 2023 online, PMID 37850637, DOI 10.1002/mds.29618, URL. [76][46]
| Treatment or intervention | Role, evidence and important qualification | Suggested NCIT intervention annotation |
|---|---|---|
| Botulinum neurotoxin injections | An established focal-dystonia intervention that may be considered for selected troublesome neck or other focal components. This is extrapolation, not a measured DYT22JO outcome; localized weakness or worsened swallowing requires particular consideration when bulbar symptoms exist. [253][46] | Botulinum toxin injection—candidate NCIT label; code not verified. |
| Trihexyphenidyl or other symptom-directed oral therapy | Anticholinergic therapy is used in broader dystonia practice; benefit, tolerability, and dose for DYT22JO are unestablished. Cognitive vulnerability makes adverse-effect review important. [253][46] | Drug therapy—candidate label; code not verified. |
| Baclofen or clonazepam | Possible symptom-directed choices based on clinical presentation, without DYT22JO-specific trial evidence. Assess sedation and functional trade-offs. [253] | Drug therapy—candidate label; code not verified. |
| Levodopa trial during evaluation | May help evaluate an alternative treatable dystonia diagnosis; no demonstrated disease-modifying effect for confirmed DYT22JO. [253][46] | Drug therapy—candidate label; code not verified. |
| Phenytoin for superimposed paroxysms | Movement-triggered painful dystonic episodes were controlled in one original patient. This is a single-person symptomatic observation, not a generalized-DYT22JO treatment response. [46] | Anticonvulsant drug therapy—candidate label; code not verified. |
| Deep brain stimulation, considered for severe refractory dystonia | One TSPOAP1-biallelic case report documents its use, but a reliable genotype-specific percentage benefit and long-term safety estimate are unavailable from the retrieved report. Broader dystonia DBS outcomes must not be imputed to DYT22JO. [76][253] | Deep brain stimulation—candidate label; code not verified. |
| Physical, occupational, speech and swallowing rehabilitation | Individualized support for mobility, hand use, communication, nutrition and safety; broadly supported as multidisciplinary dystonia care, not proven to stop DYT22JO neurodegeneration. [253][46] | Physical therapy; occupational therapy; speech-language therapy—candidate labels; codes not verified. |
| Gene, RNA, cell, targeted molecular or immunotherapy | No DYT22JO-specific approved therapy or identified interventional trial in the retrieved evidence. These should be marked investigational/not established, not offered as existing treatments. [253] | No disease-specific NCIT intervention assignment warranted. |
No NCT identifier, TSPOAP1-specific pharmacogenomic rule, comparative treatment-response rate, or verified NCIT code was found; the suggested labels above require terminology-service validation before knowledge-base ingestion.
Primary prevention of the inherited mutation through lifestyle, vaccination, or environmental control is not established. Secondary prevention centers on timely recognition, molecular diagnosis, testing of at-risk relatives for a known family variant, and counseling before reproductive decisions. Where a pathogenic familial variant is known, prenatal or preimplantation genetic testing can be discussed according to patient preferences and applicable clinical practice. Tertiary prevention means monitoring and treating swallowing difficulty, falls, communication limitations and other functional consequences. There is no DYT22JO-specific newborn screening, vaccine, chemoprophylaxis, or public-health exposure-control program. [46][1]
The genetically characterized natural disease is human (Homo sapiens, NCBI Taxon:9606). Mouse (Mus musculus, Taxon:10090) Tspoap1 is an experimental ortholog and model, not evidence of an established naturally occurring veterinary DYT22JO syndrome. Zebrafish (Danio rerio, Taxon:7955) has an annotated tspoap1 ortholog, but that annotation alone does not demonstrate natural disease or phenotype recapitulation. No affected breed, OMIA-defined natural counterpart, zoonotic transmission, or cross-species infectious susceptibility applies to the established Mendelian condition. [266][254][67][46]
| Model and resource | Demonstrated phenotype or application | Limitation |
|---|---|---|
| Tspoap1/RIMBP1 knockout mouse; Mus musculus, Taxon:10090, mouse-gene resource MGI:2450877 | Increased open-field activity (~30%), nearly doubled beam-walk slips, limb clasping, and heightened dystonia-like postures after oxotremorine; progressively abnormal Purkinje dendrites and reduced excitatory synaptic markers. Tests motor-network and cerebellar consequences of complete loss. Mouse evidence. [46][130][254] | Provoked mouse movements are not identical to spontaneous progressive human dystonia; gross mouse cerebellar volume and Purkinje-cell counts were not significantly reduced in the reported analysis. [46] |
| Mouse-derived cultured hippocampal autaptic neurons with conditional presynaptic-protein deletion and RIMBP1 rescue | Patch clamp and synaptic calcium imaging test active-zone function; the adult-associated p.Gly1808Ser, not a juvenile allele, produced nearly 100% larger evoked EPSCs and >100% larger calcium transients than wild-type RIMBP1 rescue. In-vitro evidence. [46] | Demonstrates a possible adult-variant functional mechanism; not a patient-derived DYT22JO neuron or direct measurement of juvenile truncating variants. |
| HEK293T interaction assay | Adult-associated mutant RIMBP1 co-immunoprecipitated >3-fold more CaV2.1 than wild type in the reported experiment. In-vitro evidence. [46] | Overexpression/interaction assay, not proof of increased calcium-channel recruitment in juvenile patients. |
| Other organisms and advanced models | A zebrafish tspoap1 ortholog is catalogued. [67] | No disease-recapitulating zebrafish, naturally affected animal, patient iPSC/organoid, single-cell, spatial-transcriptomic, or CRISPR-screen result was established in the retrieved DYT22JO evidence. |
Knowledge-base interpretation: attach PMID:33539324 to the original human phenotypes, two named juvenile variants, mouse findings, and their explicitly qualified mechanistic connection. Attach PMID:41371074 and PMID:42027086 to later case observations without inferring unpublished HGVS strings; attach PMID:37850637 to the existence of a DBS case report without inventing its outcome. [46][77][78][76]
Checked with linkml-reference-validator 0.3.0.
| Outcome | Count |
|---|---|
| References checked | 16 |
| Resolved | 16 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 16 |
| On topic | 3 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 28 |
| Resolved | 19 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 9 |
Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM, Gene, UniProt, Taxon, MGI.
19 of 28 terms resolved to a current term; the rest could not be looked up either way.