Dystonia 22, juvenile-onset: disease-characteristics research report
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.
1. Disease information and identifiers
Table (click to expand)
| 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]
2. Etiology: causal, risk, protective, and environmental factors
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]
Table (click to expand)
| 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] |
3. Phenotypes and effects on functioning
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]
Table (click to expand)
| 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]
4. Genetic and molecular information
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]
Table (click to expand)
| 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]
5. Environmental information
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]
6. Mechanism and pathophysiology
Ordered causal chain
- Biallelic truncating TSPOAP1 variants lead to predicted loss of functional presynaptic RIMBP1. Human genetic evidence supports the initiating lesion; the exact effect of each patient allele on patient-neuron protein abundance was not directly measured. [46]
- RIMBP1 deficiency leads to impaired presynaptic active-zone organization and less effectively coupled calcium-channel activity and vesicle release. This step draws on established RIMBP1 biology and knockout experiments; its precise magnitude in affected human neurons is inferred. [46]
- Altered synaptic transmission leads to, or accompanies, reduced excitatory synaptic markers and shortened Purkinje-cell dendritic arbors in older knockout mice. Whether one abnormality causes the other has not been demonstrated. [46]
- Abnormal cerebellar development or maintenance is consistent with progressive human cerebellar atrophy. A direct mouse-to-human structural causal link, and the extent to which cerebellar changes themselves cause dystonia, remain inferred rather than established. [46]
- Disrupted motor-network signaling plausibly leads to progressive dystonia and impaired movement, speech, swallowing, and gait; a possible parallel branch through other RIMBP1-expressing motor circuits may contribute. Circuit-specific necessity in patients has not been demonstrated. [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]
Table (click to expand)
| 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] |
7. Anatomical structures affected
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]
8. Temporal development
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]
9. Inheritance, epidemiology, and population
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]
10. Diagnostics
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]
Table (click to expand)
| 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]
11. Outcomes and prognosis
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]
12. Treatment and implementation
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]
Table (click to expand)
| 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.
13. Prevention and counseling
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]
14. Other species and naturally occurring disease
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]
15. Model organisms and experimental systems
Table (click to expand)
| 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]
Reference Validation
Checked with linkml-reference-validator 0.3.0.
Table (click to expand)
| 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.
Term Validation
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
Table (click to expand)
| Outcome | Count |
|---|---|
| Terms checked | 28 |
| Resolved | 19 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 9 |
Prefixes with no resolver
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.