Spinocerebellar ataxia type 17

Mendelian MONDO:0011781 Pathograph 14 Hereditary cerebellar ataxia Neurodegenerative Disease Movement Disorder

Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominant polyglutamine neurodegenerative disorder caused by CAG/CAA repeat expansion in TBP. The syndrome combines progressive cerebellar ataxia with cognitive decline, psychiatric symptoms, and extrapyramidal movement disorders including chorea, dystonia, and parkinsonism. Disease expression is highly variable, with onset ranging from childhood to late adulthood, reduced penetrance at borderline repeat lengths, and relatively uncommon anticipation because the TBP repeat tract is partly stabilized by CAA interruptions. No disease-modifying therapy is established; current management is symptomatic and supportive.

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Mappings

MONDO

MONDO:0011781 spinocerebellar ataxia type 17

MONDO provides an exact disease term for spinocerebellar ataxia type 17.

NCIT

NCIT:C179861 Spinocerebellar Ataxia Type 17

NCIT provides an exact term for spinocerebellar ataxia type 17; cross-referenced from MONDO:0011781.

NCIT

NCIT:C179861 Spinocerebellar Ataxia Type 17

NCIT provides an exact term for spinocerebellar ataxia type 17; cross-referenced from MONDO:0011781.

👪

Inheritance

Autosomal dominant HP:0000006

SCA17 is usually transmitted as an autosomal dominant repeat-expansion disorder, but penetrance is incomplete for many lower expanded alleles and can remain reduced even around the traditional full-penetrance threshold.

autosomal dominant inheritance

Show evidence (2 references)

PMID:30532692 SUPPORT Human Clinical

"Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the TATA-box binding protein gene (TBP)."

Establishes SCA17 as an autosomal dominant TBP repeat-expansion disorder.

PMID:15989694 SUPPORT Human Clinical

"Observed pathogenic expansions ranged from 43-63 glutamine (Gln) codons (Gln43-63). Reduced penetrance is known for Gln43-48 alleles."

Supports reduced penetrance for lower expanded alleles within an autosomal dominant pedigree context.

⚙

Pathophysiology

Polyglutamine-expanded TBP disrupts transcriptional programs

Expanded CAG/CAA repeats in exon 3 of TBP lengthen the polyglutamine tract of a general transcription factor. Mutant TBP remains nuclear and perturbs gene expression through abnormal interactions with other transcriptional regulators, linking a ubiquitously expressed protein to selective neuronal dysfunction.

TBP link

regulation of transcription by RNA polymerase II link

Downstream

Cerebellar INPP5A loss drives Purkinje cell vulnerability Mutant TBP represses SP1-dependent transcription of cerebellar INPP5A, linking broad transcriptional dysregulation to selective Purkinje cell vulnerability.

TBP-NFY interference impairs chaperone expression Mutant TBP binds the CCAAT-box transcription factor NFY more tightly, sequestering NFYA and reducing NFY occupancy of chaperone gene promoters, leading to lower Hsp70/Hsp25/HspA5 expression and a blunted heat shock response.

TBP-XBP1s interference reduces MANF expression Mutant TBP shows decreased association with the unfolded protein response transcription factor XBP1s, reducing transcription of the Purkinje-enriched neurotrophic factor MANF and removing a cell-type-specific neuroprotective signal.

Calpain-mediated TBP fragmentation Expanded polyglutamine TBP becomes a substrate for calpain proteolysis, generating C-terminal fragments that mislocalize and seed aggregation. Transcriptome analysis suggests synaptogenesis and calcium-signaling perturbations as a potential cause of elevated calpain activity, but the bridging intermediates are not definitively established.

Astrocyte-mediated NF-kappaB neuroinflammation amplifies neuronal injury Astrocytic mutant TBP activates inflammatory signaling and is required, together with neuronal mutant TBP, for severe neurodegeneration.

Striatal and caudate degeneration Mutant TBP also causes degeneration of the caudate-putamen circuit in parallel with cerebellar pathology. Reduced postsynaptic D2 receptor binding and striatal hypometabolism in presymptomatic mutation carriers indicate that striatal vulnerability is an intrinsic, early consequence of the same polyQ-TBP transcriptional dysfunction rather than a downstream effect of cerebellar disease.

Show evidence (3 references)

PMID:30532692 SUPPORT Human Clinical

"Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the TATA-box binding protein gene (TBP)."

Establishes TBP repeat expansion as the initiating molecular lesion.

PMID:19643914 SUPPORT In Vitro

"We found that the high-affinity nerve growth factor receptor, TrkA, is down-regulated by mutant TBP in cells."

Directly shows transcriptional consequences of mutant TBP in cellular models.

PMID:19643914 SUPPORT In Vitro

"Mutant TBP binds more Sp1, reduces its occupancy of the TrkA promoter and inhibits the activity of the TrkA promoter."

Provides a mechanistic explanation for transcriptional dysregulation caused by mutant TBP.

Cerebellar INPP5A loss drives Purkinje cell vulnerability

Cerebellar neurons are particularly vulnerable to mutant TBP. In the cerebellum, mutant TBP suppresses SP1-dependent INPP5A expression, perturbing IP3-linked calcium signaling in a region enriched for INPP5A and promoting Purkinje cell degeneration.

Purkinje cell link

intracellular calcium ion homeostasis link IP3-linked calcium signaling link

cerebellum link

Downstream

Cerebellar Purkinje cell degeneration Loss of cerebellar INPP5A elevates IP3 levels and disrupts calcium signaling, and is sufficient on its own to cause Purkinje cell degeneration. Restoring INPP5A in SCA17 knock-in mice ameliorates Purkinje cell loss.

Show evidence (3 references)

PMID:32107387 SUPPORT Model Organism

"By expressing mutant TBP in different brain regions in adult wild-type mice via stereotaxic injection of adeno-associated virus, we found that adult cerebellar neurons are particularly vulnerable to mutant TBP."

Demonstrates regional cerebellar vulnerability to mutant TBP in vivo.

PMID:32107387 SUPPORT Model Organism

"In SCA17 knock-in mice, mutant TBP inhibits SP1-mediated gene transcription to down-regulate INPP5A, a protein that is highly abundant in the cerebellum."

Links mutant TBP to cerebellum-specific loss of INPP5A expression.

PMID:32107387 SUPPORT Model Organism

"CRISPR/Cas9-mediated deletion of Inpp5a in the cerebellum of wild-type mice leads to Purkinje cell degeneration, and Inpp5a overexpression decreases inositol 1,4,5-trisphosphate (IP3) levels and ameliorates Purkinje cell degeneration in SCA17 knock-in mice."

Shows that INPP5A loss is mechanistically sufficient and therapeutically reversible in vivo.

Astrocyte-mediated NF-kappaB neuroinflammation amplifies neuronal injury

Astrocytic mutant TBP contributes non-cell-autonomously to neuronal loss. Severe degeneration requires mutant TBP in both neurons and glia, and inflammatory signaling in astrocytes, particularly NF-kappaB pathway activation, augments neurotoxicity. In SCA17 transgenic cerebellum, activation of MAPK/ERK in astrocytes and Bergmann glia precedes Purkinje cell loss, indicating that gliosis-driven signaling is an upstream contributor to neuronal apoptosis rather than a late reactive response.

astrocyte link Bergmann glial cell link neuron link

inflammatory response link canonical NF-kappaB signal transduction link cytokine production link ERK1/ERK2 cascade activation in glia link

Downstream

Cerebellar Purkinje cell degeneration Glial NF-kappaB and ERK activation drive cytokine production and apoptotic signaling that promote Purkinje cell death; blocking astrocytic NF-kappaB ameliorates neurodegeneration in SCA17 models.

Show evidence (2 references)

PMID:28821675 SUPPORT Model Organism

"We found that mutant TBP expression in neuronal cells or astrocytes alone only caused mild neurodegeneration, whereas severe neuronal toxicity requires the expression of mutant TBP in both neuronal and glial cells."

Supports a synergistic neuron-glia mechanism rather than purely cell-autonomous neuronal toxicity.

PMID:28821675 SUPPORT Model Organism

"We identified activated inflammatory signaling pathways in mutant TBP-expressing astrocytes, and blocking nuclear factor κB (NF-κB) signaling in astrocytes ameliorated neurodegeneration."

Directly implicates astrocytic inflammatory signaling as a modifiable contributor to SCA17 neurodegeneration.

Calpain-mediated TBP fragmentation

Calcium-dependent calpain proteolysis cleaves expanded TBP, generating C-terminal fragments that mislocalize to the cytoplasm and create aggregation-prone TBP species.

proteolysis link

Downstream

Impaired proteostasis promotes mutant TBP aggregation Calpain-generated cytoplasmic TBP fragments are aggregation-prone and accumulate when protein-clearance pathways cannot remove them efficiently.

Show evidence (2 references)

PMID:35482253 SUPPORT In Vitro

"Here, we demonstrate that calpains cleave TBP, and emerging C-terminal fragments mislocalize to the cytoplasm."

Shows that proteolytic TBP fragmentation is a direct molecular event in SCA17 models.

PMID:35482253 SUPPORT In Vitro

"Pharmacological or genetic calpain inhibition reduced TBP cleavage and aggregation, consequently improving cell viability."

Shows that blocking calpain activity reduces TBP cleavage and its toxic consequences.

Impaired proteostasis promotes mutant TBP aggregation

Limited chaperone and autophagy capacity permits accumulation of aggregation-prone mutant TBP species, whereas boosting proteostasis pathways enhances aggregate clearance and improves survival.

inclusion body assembly link autophagy link protein folding link

Downstream

Cerebellar Purkinje cell degeneration Accumulating mutant TBP species drive Purkinje cell vacuolation and death. Enhancing chaperone and autophagy pathways reduces insoluble mutant TBP, vacuolation, and Purkinje cell loss in SCA17 mice.

Show evidence (2 references)

PMID:35482253 SUPPORT In Vitro

"Pharmacological or genetic calpain inhibition reduced TBP cleavage and aggregation, consequently improving cell viability."

Supports mutant TBP aggregation as a measurable downstream toxic event that can be reduced when upstream fragment generation is limited.

PMID:26972528 SUPPORT Model Organism

"Upregulation of chaperone and autophagy levels further enhances the clearance of mutant protein aggregation, slowing the progression of pathology in SCA17 mice."

Supports impaired proteostasis as a therapeutically relevant mechanism in vivo.

TBP-NFY interference impairs chaperone expression

Mutant TBP binds the CCAAT-binding transcription factor NFY more tightly, sequestering NFYA into mutant TBP aggregates and blocking NFY occupancy of chaperone gene promoters. The result is reduced Hsp70, Hsp25, and HspA5 expression and a blunted heat shock / unfolded protein response. With age, a constitutive decline in Hsc70 chaperone activity compounds this deficit and contributes to late-onset selective neuronal vulnerability.

neuron link

chaperone-mediated protein folding link response to unfolded protein link regulation of transcription by RNA polymerase II link

Downstream

Impaired proteostasis promotes mutant TBP aggregation Reduced chaperone capacity (lower Hsp70/Hsp25/HspA5 and a blunted heat shock response) limits the cell's ability to refold or clear misfolded mutant TBP, allowing aggregation-prone species to accumulate.

Show evidence (2 references)

PMID:21705419 SUPPORT Model Organism

"Mutant TATA box-binding protein binds more tightly to the transcription factor nuclear factor-Y, inhibits its association with the chaperone protein promoter, as well as the promoter activity and reduces the expression of the chaperones Hsp70, Hsp25 and HspA5, and their response to stress."

Establishes mutant TBP-NFY interference as the molecular cause of chaperone-response failure in SCA17 neurons.

PMID:22530004 SUPPORT In Vitro

"In SCA17 cells, HSPA5 promoter activity was activated as a compensatory response before aggregate formation. NFYA dysfunction was indicated in SCA17 cells as HSPA5 promoter activity reduced along with TBP aggregate formation."

Demonstrates the temporal sequence in which compensatory HSPA5/chaperone activation precedes aggregation and is then lost as NFYA function collapses.

TBP-XBP1s interference reduces MANF expression

Mutant TBP shows decreased association with the unfolded protein response transcription factor XBP1s, reducing transcription of the Purkinje-enriched neurotrophic factor MANF. Loss of this cell-type-specific neuroprotective signal contributes directly to the selective vulnerability of cerebellar Purkinje cells; restoring chaperone (Hsc70) activity or overexpressing MANF rescues Purkinje cell degeneration via PKC-dependent signaling.

Purkinje cell link

endoplasmic reticulum unfolded protein response link regulation of transcription by RNA polymerase II link

cerebellum link

Downstream

Cerebellar Purkinje cell degeneration MANF overexpression rescues mutant TBP-mediated Purkinje cell degeneration via PKC-dependent signaling, demonstrating that the MANF deficit is a proximate, modifiable cause of selective Purkinje cell death in SCA17.

Show evidence (2 references)

PMID:24462098 SUPPORT Model Organism

"Mutant TBP shows decreased association with XBP1s, resulting in the reduced transcription of mesencephalic astrocyte-derived neurotrophic factor (MANF), which is enriched in Purkinje cells."

Establishes the TBP-XBP1s-MANF axis as a distinct transcriptional consequence of mutant TBP, separate from the TBP-NFY chaperone arm.

PMID:24462098 SUPPORT Model Organism

"We find that more mutant TBP accumulates in older mouse and that this accumulation correlates with age-related decreases in Hsc70 and chaperone activity. Consistently, older SCA17 mice experienced earlier neurological symptom onset and more severe Purkinje cell degeneration."

Supports an age-dependent component in which declining Hsc70 chaperone activity further disrupts the TBP-XBP1s interaction and accelerates Purkinje cell loss.

Cerebellar Purkinje cell degeneration

Convergent target of the cerebellar arm of SCA17 pathophysiology. Selective loss of cerebellar Purkinje cells, with accompanying basket and stellate cell pathology and granule layer thinning, produces the cerebellar atrophy seen on imaging and the cerebellar motor syndrome of SCA17 (gait ataxia, appendicular ataxia, and cerebellar dysarthria). Multiple upstream mechanisms - INPP5A loss, MANF/chaperone deficit, glial inflammatory signaling, and impaired proteostasis - converge on intrinsic apoptotic death of Purkinje neurons. Restoring any one upstream node (Inpp5a, chaperone activity, MANF, or NF-kappaB blockade) is partially protective.

Purkinje cell link

apoptotic process link intrinsic apoptotic signaling pathway link neuron apoptotic process link

cerebellum link

Show evidence (3 references)

PMID:23699518 SUPPORT Model Organism

"Neuropathologically, the severe phenotype of SCA17 rats was associated with neuronal loss, particularly in the cerebellum."

Confirms cerebellar neuronal loss as the convergent neuropathologic endpoint in a SCA17 animal model.

PMID:21554323 SUPPORT Model Organism

"Purkinje cell degeneration was identified by immunostaining of calbindin and IP3R1. Reactive gliosis and neuroinflammation occurred in the transgenic cerebellum, accompanied by up-regulation of GFAP and Iba1."

Documents Purkinje cell loss together with reactive gliosis as the shared cerebellar pathology underlying ataxic phenotypes.

PMID:22653791 SUPPORT Human Clinical

"MRI volumetry revealed atrophy of the cerebellum and caudate nucleus in manifesting patients (P = 0.04 and 0.05, respectively) and in presymptomatic mutation carriers (P = 0.04 and 0.01, respectively)."

Human imaging confirms cerebellar atrophy as the structural correlate of the cerebellar Purkinje degeneration described in animal models.

Striatal and caudate degeneration

Parallel to the cerebellar arm, mutant TBP also drives degeneration of the caudate-putamen circuit, which underlies the extrapyramidal and cognitive components of SCA17 (chorea, dystonia, parkinsonism, dementia). Striatal medium spiny neurons show postsynaptic dopaminergic dysfunction with reduced D2 receptor binding and decreased striatal glucose metabolism, and these abnormalities are detectable in presymptomatic mutation carriers, indicating that striatal vulnerability is an early and intrinsic feature rather than a late consequence of cerebellar disease.

medium spiny neuron link

dopamine receptor signaling link neuron apoptotic process link

striatum link caudate nucleus link

Show evidence (2 references)

PMID:22653791 SUPPORT Human Clinical

"(11)C-raclopride PET showed impairment of the postsynaptic dopaminergic compartment of the putamen and caudate nucleus not only in manifest SCA17 patients (P = 0.04 and 0.008, respectively) but also in yet-unaffected mutation carriers (P = 0.05 and 0.05, respectively)."

Demonstrates postsynaptic striatal dopaminergic dysfunction (a marker of medium spiny neuron compromise) even before symptom onset.

PMID:22653791 SUPPORT Human Clinical

"PET demonstrated decreased glucose metabolism in the striatum, as well as in the cuneus, cingulum, and parietal lobe, in all SCA17 patients and presymptomatic mutation carriers."

Supports striatal hypometabolism as the functional correlate of caudate-putamen degeneration.

⬡

Pathograph

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Phenotypes

Progressive gait ataxia VERY_FREQUENT Neurologic HP:0002066

Show evidence (2 references)

PMID:30532692 SUPPORT Human Clinical

"As expected, the majority of subjects were ataxic (21 out of 25, 84%)."

Cohort data support ataxia as the dominant and near-universal phenotype.

PMID:23475385 SUPPORT Human Clinical

"SCA17 is clinically heterogeneous and typically presents with slowly evolving ataxia, dysarthria, dementia, depression, and other movement disorders such as chorea."

Confirms slowly evolving ataxia as a typical presentation.

Cognitive impairment Cognitive HP:0100543

Show evidence (1 reference)

PMID:22653791 SUPPORT Human Clinical

"Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominantly inherited neurodegenerative disorder presenting with a variable phenotype including ataxia, dystonia, chorea, and parkinsonism, as well as cognitive impairment."

Supports cognitive impairment as a common core feature of the clinical phenotype.

Dementia Cognitive HP:0000726

Show evidence (1 reference)

PMID:30532692 SUPPORT Human Clinical

"It is distinct from other SCAs for its association with dementia, psychiatric symptoms, and some patients presenting with chorea."

Identifies dementia as a distinctive feature of SCA17.

Chorea Neurologic HP:0002072

Show evidence (1 reference)

PMID:22653791 SUPPORT Human Clinical

Supports chorea as a characteristic component of the movement disorder spectrum.

Dystonia Neurologic HP:0001332

Show evidence (1 reference)

PMID:22653791 SUPPORT Human Clinical

Supports dystonia as part of the typical variable phenotype.

Parkinsonism Neurologic HP:0001300

Show evidence (1 reference)

PMID:22653791 SUPPORT Human Clinical

Establishes parkinsonism within the core SCA17 movement phenotype spectrum.

Dysarthria Neurologic HP:0001260

Show evidence (1 reference)

PMID:23475385 SUPPORT Human Clinical

"SCA17 is clinically heterogeneous and typically presents with slowly evolving ataxia, dysarthria, dementia, depression, and other movement disorders such as chorea."

Explicitly names dysarthria among typical SCA17 manifestations.

Depression Psychiatric HP:0000716

Show evidence (1 reference)

PMID:23475385 SUPPORT Human Clinical

"SCA17 is clinically heterogeneous and typically presents with slowly evolving ataxia, dysarthria, dementia, depression, and other movement disorders such as chorea."

Supports depression as part of the typical neuropsychiatric presentation.

Psychosis Psychiatric HP:0000709

Show evidence (1 reference)

PMID:30532692 SUPPORT Human Clinical

"SCA17 is characterized by ataxia, pyramidal and extrapyramidal signs, cognitive impairments, psychosis, and seizures as well as involuntary movements including chorea and dystonia."

Explicitly identifies psychosis as part of the SCA17 phenotype.

Seizures OCCASIONAL Neurologic HP:0001250

Show evidence (1 reference)

PMID:30532692 SUPPORT Human Clinical

"SCA17 is characterized by ataxia, pyramidal and extrapyramidal signs, cognitive impairments, psychosis, and seizures as well as involuntary movements including chorea and dystonia."

Explicitly identifies seizures as part of the SCA17 phenotype spectrum.

🧬

Genetic Associations

TBP (CAG/CAA polyglutamine repeat expansion)

Show evidence (7 references)

PMID:30532692 SUPPORT Human Clinical

"We found a negative linear correlation between total CAG repeat length and age at disease onset and, unlike SCA1, there was no correlation between the longest contiguous CAG tract and age at disease onset."

Supports genotype-phenotype correlation between total repeat length and age at onset.

PMID:15989694 SUPPORT Human Clinical

"Observed pathogenic expansions ranged from 43-63 glutamine (Gln) codons (Gln43-63). Reduced penetrance is known for Gln43-48 alleles."

Defines the lower pathogenic range and reduced penetrance interval.

PMID:15989694 SUPPORT Human Clinical

"The 76-year-old father of two SCA17 patients carries the Gln49 TBP allele but presents without obvious neurological symptoms."

Demonstrates that even 49-repeat alleles can remain nonpenetrant late in life.

+ 4 more references

💊

Treatments

Supportive and rehabilitative care

Action: supportive care MAXO:0000950

Multidisciplinary symptomatic management with physical therapy, speech therapy, mobility aids, swallow support, and psychiatric/cognitive care remains the standard of care.

Target Phenotypes: gait ataxia ↗ dysarthria ↗

Show evidence (1 reference)

PMID:39614971 SUPPORT Other

"At present, there is no effective treatment for SCA17, and existing therapies provide only symptomatic relief."

Supports supportive care as the current management paradigm in the absence of disease-modifying therapy.

Granulocyte-colony stimulating factor (preclinical)

Action: hematopoietic growth factor therapy Ontology label: Immunotherapy NCIT:C15262

Agent: filgrastim ↗

Preclinical disease-modifying candidate that improved neurologic function and reduced Purkinje cell pathology in transgenic SCA17 mice. This remains experimental and has not been established as human therapy.

Mechanism Target:

MODULATES Impaired proteostasis promotes mutant TBP aggregation — Enhances chaperone and autophagy pathways to improve clearance of aggregation-prone mutant TBP in preclinical SCA17 models.

Show evidence (1 reference)

PMID:26972528 SUPPORT Model Organism

"Upregulation of chaperone and autophagy levels further enhances the clearance of mutant protein aggregation, slowing the progression of pathology in SCA17 mice."

Connects G-CSF to proteostasis restoration in vivo.

Show evidence (2 references)

PMID:21554323 SUPPORT Model Organism

"Our results suggest that granulocyte-colony stimulating factor has a neuroprotective effect in these transgenic mice, ameliorating their neurological and behavioral deficits."

Demonstrates preclinical neuroprotective benefit of G-CSF in an SCA17 mouse model.

PMID:26972528 SUPPORT Model Organism

"Treatment with G-CSF at the pre-symptomatic stage improved the motor coordination of SCA17 mice and reduced the cell loss, insoluble mutant TBP protein, and vacuole formation in the Purkinje neurons of these mice."

Supports improved motor function and reduced Purkinje pathology with preclinical G-CSF treatment.

{ }

Source YAML

click to show

name: Spinocerebellar ataxia type 17
creation_date: "2026-04-10T00:00:00Z"
updated_date: "2026-05-04T00:00:00Z"
category: Mendelian
synonyms:
- SCA17
- Huntington disease-like 4
- HDL-4
description: >-
  Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominant
  polyglutamine neurodegenerative disorder caused by CAG/CAA repeat expansion
  in TBP. The syndrome combines progressive cerebellar ataxia with cognitive
  decline, psychiatric symptoms, and extrapyramidal movement disorders
  including chorea, dystonia, and parkinsonism. Disease expression is highly
  variable, with onset ranging from childhood to late adulthood, reduced
  penetrance at borderline repeat lengths, and relatively uncommon anticipation
  because the TBP repeat tract is partly stabilized by CAA interruptions. No
  disease-modifying therapy is established; current management is symptomatic
  and supportive.
disease_term:
  preferred_term: Spinocerebellar ataxia type 17
  term:
    id: MONDO:0011781
    label: spinocerebellar ataxia type 17
parents:
- Hereditary cerebellar ataxia
- Neurodegenerative Disease
- Movement Disorder
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    SCA17 is usually transmitted as an autosomal dominant repeat-expansion
    disorder, but penetrance is incomplete for many lower expanded alleles and
    can remain reduced even around the traditional full-penetrance threshold.
  evidence:
  - reference: PMID:30532692
    reference_title: "Complexity of the Genetics and Clinical Presentation of Spinocerebellar Ataxia 17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominant
      neurodegenerative disease caused by a CAG repeat expansion in the
      TATA-box binding protein gene (TBP).
    explanation: Establishes SCA17 as an autosomal dominant TBP repeat-expansion disorder.
  - reference: PMID:15989694
    reference_title: "Spinocerebellar ataxia type 17: report of a family with reduced penetrance of an unstable Gln49 TBP allele, haplotype analysis supporting a founder effect for unstable alleles and comparative analysis of SCA17 genotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Observed pathogenic expansions ranged from 43-63 glutamine (Gln)
      codons (Gln43-63). Reduced penetrance is known for Gln43-48 alleles.
    explanation: Supports reduced penetrance for lower expanded alleles within an autosomal dominant pedigree context.
prevalence:
- population: North East England
  percentage: "0.16/100,000"
  notes: >-
    Minimum observed prevalence in a regional ascertainment study. SCA17 is
    considered globally very rare, and fully penetrant pathogenic alleles were
    also rare in a large United Kingdom diagnostic cohort.
  evidence:
  - reference: PMID:16223509
    reference_title: "Minimum prevalence of spinocerebellar ataxia 17 in the north east of England."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The minimum prevalence of SCA17 in the north east of England was
      0.16/100,000 (upper 95% confidence interval 0.31/100,000).
    explanation: Provides the clearest population-based prevalence estimate identified for SCA17.
progression:
- phase: Prodromal and onset
  age_range: Childhood to late adulthood
  notes: >-
    Age at onset is highly variable and decreases as repeat length increases.
    Presymptomatic mutation carriers can already show cerebellar and caudate
    atrophy with functional imaging abnormalities.
  evidence:
  - reference: PMID:30532692
    reference_title: "Complexity of the Genetics and Clinical Presentation of Spinocerebellar Ataxia 17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease presents with various clinical symptoms at a broad range
      of ages at onset (3–75 years) (Stevanin and Brice, 2008).
    explanation: Supports the exceptionally broad onset window for SCA17.
  - reference: PMID:22653791
    reference_title: "PET and MRI reveal early evidence of neurodegeneration in spinocerebellar ataxia type 17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRI volumetry revealed atrophy of the cerebellum and caudate nucleus
      in manifesting patients (P = 0.04 and 0.05, respectively) and in
      presymptomatic mutation carriers (P = 0.04 and 0.01, respectively).
    explanation: Demonstrates structural neurodegeneration before overt clinical disease.
- phase: Manifest disease
  age_range: Usually adult-onset, but can begin earlier
  notes: >-
    Progressive motor and cognitive decline leads to increasing disability.
    Extrapyramidal and psychiatric manifestations may accompany or follow the
    ataxic syndrome.
  evidence:
  - reference: PMID:39614971
    reference_title: "Molecular Mechanisms of Spinocerebellar Ataxia Type 17."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Spinocerebellar ataxia type 17 (SCA17) is a hereditary
      neurodegenerative disorder characterized by progressive motor and
      cognitive decline, leading to severe disability and death.
    explanation: Summarizes the progressive disabling natural history of manifest SCA17.
pathophysiology:
- name: Polyglutamine-expanded TBP disrupts transcriptional programs
  conforms_to: "polyglutamine_expansion_proteotoxicity#Transcriptional Dysregulation"
  description: >-
    Expanded CAG/CAA repeats in exon 3 of TBP lengthen the polyglutamine tract
    of a general transcription factor. Mutant TBP remains nuclear and
    perturbs gene expression through abnormal interactions with other
    transcriptional regulators, linking a ubiquitously expressed protein to
    selective neuronal dysfunction.
  genes:
  - preferred_term: TBP
    term:
      id: hgnc:11588
      label: TBP
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
  downstream:
  - target: Cerebellar INPP5A loss drives Purkinje cell vulnerability
    description: >-
      Mutant TBP represses SP1-dependent transcription of cerebellar INPP5A,
      linking broad transcriptional dysregulation to selective Purkinje cell
      vulnerability.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32107387
      reference_title: "Cerebellum-enriched protein INPP5A contributes to selective neuropathology in mouse model of spinocerebellar ataxias type 17."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In SCA17 knock-in mice, mutant TBP inhibits SP1-mediated gene
        transcription to down-regulate INPP5A, a protein that is highly
        abundant in the cerebellum.
      explanation: >-
        Directly supports the edge from mutant TBP transcriptional dysfunction
        to cerebellar INPP5A loss.
  - target: TBP-NFY interference impairs chaperone expression
    description: >-
      Mutant TBP binds the CCAAT-box transcription factor NFY more tightly,
      sequestering NFYA and reducing NFY occupancy of chaperone gene
      promoters, leading to lower Hsp70/Hsp25/HspA5 expression and a blunted
      heat shock response.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21705419
      reference_title: "Neuronal expression of TATA box-binding protein containing expanded polyglutamine in knock-in mice reduces chaperone protein response by impairing the function of nuclear factor-Y transcription factor."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mutant TATA box-binding protein binds more tightly to the transcription
        factor nuclear factor-Y, inhibits its association with the chaperone
        protein promoter, as well as the promoter activity and reduces the
        expression of the chaperones Hsp70, Hsp25 and HspA5, and their response
        to stress.
      explanation: >-
        Directly links mutant TBP transcriptional dysregulation to a measurable
        chaperone-response deficit in vivo.
  - target: TBP-XBP1s interference reduces MANF expression
    description: >-
      Mutant TBP shows decreased association with the unfolded protein
      response transcription factor XBP1s, reducing transcription of the
      Purkinje-enriched neurotrophic factor MANF and removing a
      cell-type-specific neuroprotective signal.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24462098
      reference_title: "Age-dependent decrease in chaperone activity impairs MANF expression, leading to Purkinje cell degeneration in inducible SCA17 mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mutant TBP shows decreased association with XBP1s, resulting in the
        reduced transcription of mesencephalic astrocyte-derived neurotrophic
        factor (MANF), which is enriched in Purkinje cells.
      explanation: >-
        Establishes the TBP-XBP1s-MANF axis as a distinct transcriptional
        consequence of mutant TBP, separate from the TBP-NFY chaperone arm.
  - target: Calpain-mediated TBP fragmentation
    description: >-
      Expanded polyglutamine TBP becomes a substrate for calpain proteolysis,
      generating C-terminal fragments that mislocalize and seed aggregation.
      Transcriptome analysis suggests synaptogenesis and calcium-signaling
      perturbations as a potential cause of elevated calpain activity, but
      the bridging intermediates are not definitively established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35482253
      reference_title: "Calpains as novel players in the molecular pathogenesis of spinocerebellar ataxia type 17."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here, we demonstrate that calpains cleave TBP, and emerging
        C-terminal fragments mislocalize to the cytoplasm.
      explanation: >-
        Supports an edge from polyQ-expanded TBP to calpain-mediated
        fragmentation of the same protein.
  - target: Astrocyte-mediated NF-kappaB neuroinflammation amplifies neuronal injury
    description: >-
      Astrocytic mutant TBP activates inflammatory signaling and is required,
      together with neuronal mutant TBP, for severe neurodegeneration.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28821675
      reference_title: "Synergistic Toxicity of Polyglutamine-Expanded TATA-Binding Protein in Glia and Neuronal Cells: Therapeutic Implications for Spinocerebellar Ataxia 17."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We identified activated inflammatory signaling pathways in mutant
        TBP-expressing astrocytes, and blocking nuclear factor κB (NF-κB)
        signaling in astrocytes ameliorated neurodegeneration.
      explanation: >-
        Supports an edge from mutant TBP expression in astrocytes to
        inflammatory signaling that amplifies neuronal injury.
  - target: Striatal and caudate degeneration
    description: >-
      Mutant TBP also causes degeneration of the caudate-putamen circuit in
      parallel with cerebellar pathology. Reduced postsynaptic D2 receptor
      binding and striatal hypometabolism in presymptomatic mutation carriers
      indicate that striatal vulnerability is an intrinsic, early consequence
      of the same polyQ-TBP transcriptional dysfunction rather than a
      downstream effect of cerebellar disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22653791
      reference_title: "PET and MRI reveal early evidence of neurodegeneration in spinocerebellar ataxia type 17."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        (11)C-raclopride PET showed impairment of the postsynaptic dopaminergic
        compartment of the putamen and caudate nucleus not only in manifest
        SCA17 patients (P = 0.04 and 0.008, respectively) but also in
        yet-unaffected mutation carriers (P = 0.05 and 0.05, respectively).
      explanation: >-
        Demonstrates that striatal degeneration is detectable before symptoms,
        consistent with a parallel arm of mutant TBP-driven pathology rather
        than secondary to cerebellar disease.
  evidence:
  - reference: PMID:30532692
    reference_title: "Complexity of the Genetics and Clinical Presentation of Spinocerebellar Ataxia 17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominant
      neurodegenerative disease caused by a CAG repeat expansion in the
      TATA-box binding protein gene (TBP).
    explanation: Establishes TBP repeat expansion as the initiating molecular lesion.
  - reference: PMID:19643914
    reference_title: "Transcriptional dysregulation of TrkA associates with neurodegeneration in spinocerebellar ataxia type 17."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found that the high-affinity nerve growth factor receptor, TrkA, is
      down-regulated by mutant TBP in cells.
    explanation: Directly shows transcriptional consequences of mutant TBP in cellular models.
  - reference: PMID:19643914
    reference_title: "Transcriptional dysregulation of TrkA associates with neurodegeneration in spinocerebellar ataxia type 17."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mutant TBP binds more Sp1, reduces its occupancy of the TrkA promoter
      and inhibits the activity of the TrkA promoter.
    explanation: Provides a mechanistic explanation for transcriptional dysregulation caused by mutant TBP.
- name: Cerebellar INPP5A loss drives Purkinje cell vulnerability
  description: >-
    Cerebellar neurons are particularly vulnerable to mutant TBP. In the
    cerebellum, mutant TBP suppresses SP1-dependent INPP5A expression,
    perturbing IP3-linked calcium signaling in a region enriched for INPP5A
    and promoting Purkinje cell degeneration.
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  biological_processes:
  - preferred_term: intracellular calcium ion homeostasis
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
  - preferred_term: IP3-linked calcium signaling
    term:
      id: GO:0019722
      label: calcium-mediated signaling
  downstream:
  - target: Cerebellar Purkinje cell degeneration
    description: >-
      Loss of cerebellar INPP5A elevates IP3 levels and disrupts calcium
      signaling, and is sufficient on its own to cause Purkinje cell
      degeneration. Restoring INPP5A in SCA17 knock-in mice ameliorates
      Purkinje cell loss.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32107387
      reference_title: "Cerebellum-enriched protein INPP5A contributes to selective neuropathology in mouse model of spinocerebellar ataxias type 17."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        CRISPR/Cas9-mediated deletion of Inpp5a in the cerebellum of
        wild-type mice leads to Purkinje cell degeneration, and Inpp5a
        overexpression decreases inositol 1,4,5-trisphosphate (IP3) levels and
        ameliorates Purkinje cell degeneration in SCA17 knock-in mice.
      explanation: >-
        Directly supports an edge from cerebellar INPP5A loss to Purkinje cell
        degeneration with reciprocal rescue evidence.
  evidence:
  - reference: PMID:32107387
    reference_title: "Cerebellum-enriched protein INPP5A contributes to selective neuropathology in mouse model of spinocerebellar ataxias type 17."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      By expressing mutant TBP in different brain regions in adult
      wild-type mice via stereotaxic injection of adeno-associated virus, we
      found that adult cerebellar neurons are particularly vulnerable to
      mutant TBP.
    explanation: Demonstrates regional cerebellar vulnerability to mutant TBP in vivo.
  - reference: PMID:32107387
    reference_title: "Cerebellum-enriched protein INPP5A contributes to selective neuropathology in mouse model of spinocerebellar ataxias type 17."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In SCA17 knock-in mice, mutant TBP inhibits SP1-mediated gene
      transcription to down-regulate INPP5A, a protein that is highly
      abundant in the cerebellum.
    explanation: Links mutant TBP to cerebellum-specific loss of INPP5A expression.
  - reference: PMID:32107387
    reference_title: "Cerebellum-enriched protein INPP5A contributes to selective neuropathology in mouse model of spinocerebellar ataxias type 17."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      CRISPR/Cas9-mediated deletion of Inpp5a in the cerebellum of
      wild-type mice leads to Purkinje cell degeneration, and Inpp5a
      overexpression decreases inositol 1,4,5-trisphosphate (IP3) levels and
      ameliorates Purkinje cell degeneration in SCA17 knock-in mice.
    explanation: Shows that INPP5A loss is mechanistically sufficient and therapeutically reversible in vivo.
- name: Astrocyte-mediated NF-kappaB neuroinflammation amplifies neuronal injury
  description: >-
    Astrocytic mutant TBP contributes non-cell-autonomously to neuronal loss.
    Severe degeneration requires mutant TBP in both neurons and glia, and
    inflammatory signaling in astrocytes, particularly NF-kappaB pathway
    activation, augments neurotoxicity. In SCA17 transgenic cerebellum,
    activation of MAPK/ERK in astrocytes and Bergmann glia precedes Purkinje
    cell loss, indicating that gliosis-driven signaling is an upstream
    contributor to neuronal apoptosis rather than a late reactive response.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  - preferred_term: Bergmann glial cell
    term:
      id: CL:0000644
      label: Bergmann glial cell
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  - preferred_term: canonical NF-kappaB signal transduction
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
  - preferred_term: cytokine production
    term:
      id: GO:0001816
      label: cytokine production
  - preferred_term: ERK1/ERK2 cascade activation in glia
    term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
  downstream:
  - target: Cerebellar Purkinje cell degeneration
    description: >-
      Glial NF-kappaB and ERK activation drive cytokine production and
      apoptotic signaling that promote Purkinje cell death; blocking
      astrocytic NF-kappaB ameliorates neurodegeneration in SCA17 models.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32877710
      reference_title: "ERK activation precedes Purkinje cell loss in mice with Spinocerebellar ataxia type 17."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our study showed that the activation of ERK in the astrocytes and
        Bergmann glia was identified as preceding motor deficits, which suggest
        the elevated gliosis by ERK activation may contribute to neuronal
        apoptosis in SCA17 mice.
      explanation: >-
        Provides a temporal sequence supporting glial signaling as an upstream
        driver of Purkinje cell loss.
  evidence:
  - reference: PMID:28821675
    reference_title: "Synergistic Toxicity of Polyglutamine-Expanded TATA-Binding Protein in Glia and Neuronal Cells: Therapeutic Implications for Spinocerebellar Ataxia 17."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found that mutant TBP expression in neuronal cells or astrocytes
      alone only caused mild neurodegeneration, whereas severe neuronal
      toxicity requires the expression of mutant TBP in both neuronal and
      glial cells.
    explanation: Supports a synergistic neuron-glia mechanism rather than purely cell-autonomous neuronal toxicity.
  - reference: PMID:28821675
    reference_title: "Synergistic Toxicity of Polyglutamine-Expanded TATA-Binding Protein in Glia and Neuronal Cells: Therapeutic Implications for Spinocerebellar Ataxia 17."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We identified activated inflammatory signaling pathways in mutant
      TBP-expressing astrocytes, and blocking nuclear factor κB (NF-κB)
      signaling in astrocytes ameliorated neurodegeneration.
    explanation: Directly implicates astrocytic inflammatory signaling as a modifiable contributor to SCA17 neurodegeneration.
- name: Calpain-mediated TBP fragmentation
  description: >-
    Calcium-dependent calpain proteolysis cleaves expanded TBP, generating
    C-terminal fragments that mislocalize to the cytoplasm and create
    aggregation-prone TBP species.
  biological_processes:
  - preferred_term: proteolysis
    term:
      id: GO:0006508
      label: proteolysis
  downstream:
  - target: Impaired proteostasis promotes mutant TBP aggregation
    description: >-
      Calpain-generated cytoplasmic TBP fragments are aggregation-prone and
      accumulate when protein-clearance pathways cannot remove them
      efficiently.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35482253
      reference_title: "Calpains as novel players in the molecular pathogenesis of spinocerebellar ataxia type 17."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Pharmacological or genetic calpain inhibition reduced TBP cleavage and
        aggregation, consequently improving cell viability.
      explanation: >-
        Supports a direct mechanistic link between calpain-dependent TBP
        fragmentation and downstream aggregate formation.
  evidence:
  - reference: PMID:35482253
    reference_title: "Calpains as novel players in the molecular pathogenesis of spinocerebellar ataxia type 17."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we demonstrate that calpains cleave TBP, and emerging
      C-terminal fragments mislocalize to the cytoplasm.
    explanation: Shows that proteolytic TBP fragmentation is a direct molecular event in SCA17 models.
  - reference: PMID:35482253
    reference_title: "Calpains as novel players in the molecular pathogenesis of spinocerebellar ataxia type 17."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Pharmacological or genetic calpain inhibition reduced TBP cleavage and
      aggregation, consequently improving cell viability.
    explanation: Shows that blocking calpain activity reduces TBP cleavage and its toxic consequences.
- name: Impaired proteostasis promotes mutant TBP aggregation
  conforms_to: "polyglutamine_expansion_proteotoxicity#Proteostasis Network Overload"
  description: >-
    Limited chaperone and autophagy capacity permits accumulation of
    aggregation-prone mutant TBP species, whereas boosting proteostasis
    pathways enhances aggregate clearance and improves survival.
  biological_processes:
  - preferred_term: inclusion body assembly
    term:
      id: GO:0070841
      label: inclusion body assembly
  - preferred_term: autophagy
    term:
      id: GO:0006914
      label: autophagy
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
  downstream:
  - target: Cerebellar Purkinje cell degeneration
    description: >-
      Accumulating mutant TBP species drive Purkinje cell vacuolation and
      death. Enhancing chaperone and autophagy pathways reduces insoluble
      mutant TBP, vacuolation, and Purkinje cell loss in SCA17 mice.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - mutant TBP aggregation drives cellular dysfunction (transcriptional sequestration, ER stress)
    - cellular dysfunction triggers intrinsic apoptotic signaling in Purkinje neurons
    evidence:
    - reference: PMID:26972528
      reference_title: "Targeting the prodromal stage of spinocerebellar ataxia type 17 mice: G-CSF in the prevention of motor deficits via upregulating chaperone and autophagy levels."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Treatment with G-CSF at the pre-symptomatic stage improved the motor
        coordination of SCA17 mice and reduced the cell loss, insoluble mutant
        TBP protein, and vacuole formation in the Purkinje neurons of these
        mice.
      explanation: >-
        Supports an edge from impaired proteostasis (rescued by enhanced
        chaperone/autophagy) to Purkinje cell loss in vivo.
  evidence:
  - reference: PMID:35482253
    reference_title: "Calpains as novel players in the molecular pathogenesis of spinocerebellar ataxia type 17."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Pharmacological or genetic calpain inhibition reduced TBP cleavage and
      aggregation, consequently improving cell viability.
    explanation: >-
      Supports mutant TBP aggregation as a measurable downstream toxic event
      that can be reduced when upstream fragment generation is limited.
  - reference: PMID:26972528
    reference_title: "Targeting the prodromal stage of spinocerebellar ataxia type 17 mice: G-CSF in the prevention of motor deficits via upregulating chaperone and autophagy levels."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Upregulation of chaperone and autophagy levels further enhances the
      clearance of mutant protein aggregation, slowing the progression of
      pathology in SCA17 mice.
    explanation: Supports impaired proteostasis as a therapeutically relevant mechanism in vivo.
- name: TBP-NFY interference impairs chaperone expression
  description: >-
    Mutant TBP binds the CCAAT-binding transcription factor NFY more tightly,
    sequestering NFYA into mutant TBP aggregates and blocking NFY occupancy of
    chaperone gene promoters. The result is reduced Hsp70, Hsp25, and HspA5
    expression and a blunted heat shock / unfolded protein response. With
    age, a constitutive decline in Hsc70 chaperone activity compounds this
    deficit and contributes to late-onset selective neuronal vulnerability.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: chaperone-mediated protein folding
    term:
      id: GO:0006457
      label: protein folding
  - preferred_term: response to unfolded protein
    term:
      id: GO:0006986
      label: response to unfolded protein
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
  downstream:
  - target: Impaired proteostasis promotes mutant TBP aggregation
    description: >-
      Reduced chaperone capacity (lower Hsp70/Hsp25/HspA5 and a blunted
      heat shock response) limits the cell's ability to refold or clear
      misfolded mutant TBP, allowing aggregation-prone species to accumulate.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21705419
      reference_title: "Neuronal expression of TATA box-binding protein containing expanded polyglutamine in knock-in mice reduces chaperone protein response by impairing the function of nuclear factor-Y transcription factor."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mutant TATA box-binding protein binds more tightly to the transcription
        factor nuclear factor-Y, inhibits its association with the chaperone
        protein promoter, as well as the promoter activity and reduces the
        expression of the chaperones Hsp70, Hsp25 and HspA5, and their response
        to stress.
      explanation: >-
        Supports the edge from chaperone-response failure to impaired
        proteostasis: reduced Hsp70/Hsp25/HspA5 capacity is exactly the deficit
        that permits mutant TBP aggregation.
  evidence:
  - reference: PMID:21705419
    reference_title: "Neuronal expression of TATA box-binding protein containing expanded polyglutamine in knock-in mice reduces chaperone protein response by impairing the function of nuclear factor-Y transcription factor."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mutant TATA box-binding protein binds more tightly to the transcription
      factor nuclear factor-Y, inhibits its association with the chaperone
      protein promoter, as well as the promoter activity and reduces the
      expression of the chaperones Hsp70, Hsp25 and HspA5, and their response
      to stress.
    explanation: >-
      Establishes mutant TBP-NFY interference as the molecular cause of
      chaperone-response failure in SCA17 neurons.
  - reference: PMID:22530004
    reference_title: "Role of the CCAAT-binding protein NFY in SCA17 pathogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In SCA17 cells, HSPA5 promoter activity was activated as a compensatory
      response before aggregate formation. NFYA dysfunction was indicated in
      SCA17 cells as HSPA5 promoter activity reduced along with TBP aggregate
      formation.
    explanation: >-
      Demonstrates the temporal sequence in which compensatory HSPA5/chaperone
      activation precedes aggregation and is then lost as NFYA function
      collapses.
- name: TBP-XBP1s interference reduces MANF expression
  description: >-
    Mutant TBP shows decreased association with the unfolded protein response
    transcription factor XBP1s, reducing transcription of the Purkinje-enriched
    neurotrophic factor MANF. Loss of this cell-type-specific neuroprotective
    signal contributes directly to the selective vulnerability of cerebellar
    Purkinje cells; restoring chaperone (Hsc70) activity or overexpressing
    MANF rescues Purkinje cell degeneration via PKC-dependent signaling.
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  biological_processes:
  - preferred_term: endoplasmic reticulum unfolded protein response
    term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
  downstream:
  - target: Cerebellar Purkinje cell degeneration
    description: >-
      MANF overexpression rescues mutant TBP-mediated Purkinje cell
      degeneration via PKC-dependent signaling, demonstrating that the MANF
      deficit is a proximate, modifiable cause of selective Purkinje cell
      death in SCA17.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24462098
      reference_title: "Age-dependent decrease in chaperone activity impairs MANF expression, leading to Purkinje cell degeneration in inducible SCA17 mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Expression of Hsc70 improves the TBP-XBP1s interaction and MANF
        transcription, and overexpression of MANF ameliorates mutant
        TBP-mediated Purkinje cell degeneration via protein kinase C
        (PKC)-dependent signaling.
      explanation: >-
        Direct rescue evidence supports an edge from the TBP-XBP1s-MANF
        deficit to Purkinje cell degeneration.
  evidence:
  - reference: PMID:24462098
    reference_title: "Age-dependent decrease in chaperone activity impairs MANF expression, leading to Purkinje cell degeneration in inducible SCA17 mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mutant TBP shows decreased association with XBP1s, resulting in the
      reduced transcription of mesencephalic astrocyte-derived neurotrophic
      factor (MANF), which is enriched in Purkinje cells.
    explanation: >-
      Establishes the TBP-XBP1s-MANF axis as a distinct transcriptional
      consequence of mutant TBP, separate from the TBP-NFY chaperone arm.
  - reference: PMID:24462098
    reference_title: "Age-dependent decrease in chaperone activity impairs MANF expression, leading to Purkinje cell degeneration in inducible SCA17 mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We find that more mutant TBP accumulates in older mouse and that this
      accumulation correlates with age-related decreases in Hsc70 and chaperone
      activity. Consistently, older SCA17 mice experienced earlier neurological
      symptom onset and more severe Purkinje cell degeneration.
    explanation: >-
      Supports an age-dependent component in which declining Hsc70 chaperone
      activity further disrupts the TBP-XBP1s interaction and accelerates
      Purkinje cell loss.
- name: Cerebellar Purkinje cell degeneration
  conforms_to: "polyglutamine_expansion_proteotoxicity#Selective Neuronal Dysfunction and Loss"
  description: >-
    Convergent target of the cerebellar arm of SCA17 pathophysiology. Selective
    loss of cerebellar Purkinje cells, with accompanying basket and stellate
    cell pathology and granule layer thinning, produces the cerebellar atrophy
    seen on imaging and the cerebellar motor syndrome of SCA17 (gait ataxia,
    appendicular ataxia, and cerebellar dysarthria). Multiple upstream
    mechanisms - INPP5A loss, MANF/chaperone deficit, glial inflammatory
    signaling, and impaired proteostasis - converge on intrinsic apoptotic
    death of Purkinje neurons. Restoring any one upstream node (Inpp5a,
    chaperone activity, MANF, or NF-kappaB blockade) is partially protective.
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
  - preferred_term: intrinsic apoptotic signaling pathway
    term:
      id: GO:0097193
      label: intrinsic apoptotic signaling pathway
  - preferred_term: neuron apoptotic process
    term:
      id: GO:0051402
      label: neuron apoptotic process
  evidence:
  - reference: PMID:23699518
    reference_title: "A novel transgenic rat model for spinocerebellar ataxia type 17 recapitulates neuropathological changes and supplies in vivo imaging biomarkers."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Neuropathologically, the severe phenotype of SCA17 rats was associated
      with neuronal loss, particularly in the cerebellum.
    explanation: >-
      Confirms cerebellar neuronal loss as the convergent neuropathologic
      endpoint in a SCA17 animal model.
  - reference: PMID:21554323
    reference_title: "Neuroprotective effects of granulocyte-colony stimulating factor in a novel transgenic mouse model of SCA17."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Purkinje cell degeneration was identified by immunostaining of
      calbindin and IP3R1. Reactive gliosis and neuroinflammation occurred
      in the transgenic cerebellum, accompanied by up-regulation of GFAP and
      Iba1.
    explanation: >-
      Documents Purkinje cell loss together with reactive gliosis as the
      shared cerebellar pathology underlying ataxic phenotypes.
  - reference: PMID:22653791
    reference_title: "PET and MRI reveal early evidence of neurodegeneration in spinocerebellar ataxia type 17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRI volumetry revealed atrophy of the cerebellum and caudate nucleus
      in manifesting patients (P = 0.04 and 0.05, respectively) and in
      presymptomatic mutation carriers (P = 0.04 and 0.01, respectively).
    explanation: >-
      Human imaging confirms cerebellar atrophy as the structural correlate
      of the cerebellar Purkinje degeneration described in animal models.
- name: Striatal and caudate degeneration
  description: >-
    Parallel to the cerebellar arm, mutant TBP also drives degeneration of the
    caudate-putamen circuit, which underlies the extrapyramidal and cognitive
    components of SCA17 (chorea, dystonia, parkinsonism, dementia). Striatal
    medium spiny neurons show postsynaptic dopaminergic dysfunction with
    reduced D2 receptor binding and decreased striatal glucose metabolism, and
    these abnormalities are detectable in presymptomatic mutation carriers,
    indicating that striatal vulnerability is an early and intrinsic feature
    rather than a late consequence of cerebellar disease.
  cell_types:
  - preferred_term: medium spiny neuron
    term:
      id: CL:1001474
      label: medium spiny neuron
  locations:
  - preferred_term: striatum
    term:
      id: UBERON:0002435
      label: striatum
  - preferred_term: caudate nucleus
    term:
      id: UBERON:0001873
      label: caudate nucleus
  biological_processes:
  - preferred_term: dopamine receptor signaling
    term:
      id: GO:0007212
      label: G protein-coupled dopamine receptor signaling pathway
  - preferred_term: neuron apoptotic process
    term:
      id: GO:0051402
      label: neuron apoptotic process
  evidence:
  - reference: PMID:22653791
    reference_title: "PET and MRI reveal early evidence of neurodegeneration in spinocerebellar ataxia type 17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      (11)C-raclopride PET showed impairment of the postsynaptic dopaminergic
      compartment of the putamen and caudate nucleus not only in manifest
      SCA17 patients (P = 0.04 and 0.008, respectively) but also in
      yet-unaffected mutation carriers (P = 0.05 and 0.05, respectively).
    explanation: >-
      Demonstrates postsynaptic striatal dopaminergic dysfunction (a marker of
      medium spiny neuron compromise) even before symptom onset.
  - reference: PMID:22653791
    reference_title: "PET and MRI reveal early evidence of neurodegeneration in spinocerebellar ataxia type 17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PET demonstrated decreased glucose metabolism in the striatum, as well
      as in the cuneus, cingulum, and parietal lobe, in all SCA17 patients
      and presymptomatic mutation carriers.
    explanation: >-
      Supports striatal hypometabolism as the functional correlate of
      caudate-putamen degeneration.
phenotypes:
- category: Neurologic
  name: Progressive gait ataxia
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Progressive gait and balance impairment is the core clinical feature and
    may be slowly progressive over years, although more rapid decline can
    occur in some patients with lower expanded alleles.
  phenotype_term:
    preferred_term: gait ataxia
    term:
      id: HP:0002066
      label: Gait ataxia
  evidence:
  - reference: PMID:30532692
    reference_title: "Complexity of the Genetics and Clinical Presentation of Spinocerebellar Ataxia 17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As expected, the majority of subjects were ataxic (21 out of 25,
      84%).
    explanation: Cohort data support ataxia as the dominant and near-universal phenotype.
  - reference: PMID:23475385
    reference_title: "From normal gait to loss of ambulation in 6 months: a novel presentation of SCA17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SCA17 is clinically heterogeneous and typically presents with slowly
      evolving ataxia, dysarthria, dementia, depression, and other movement
      disorders such as chorea.
    explanation: Confirms slowly evolving ataxia as a typical presentation.
- category: Cognitive
  name: Cognitive impairment
  description: >-
    Cognitive decline is a prominent component of the syndrome and may appear
    early, including in patients whose presentation overlaps with
    Huntington-like phenotypes.
  phenotype_term:
    preferred_term: cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:22653791
    reference_title: "PET and MRI reveal early evidence of neurodegeneration in spinocerebellar ataxia type 17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominantly
      inherited neurodegenerative disorder presenting with a variable
      phenotype including ataxia, dystonia, chorea, and parkinsonism, as
      well as cognitive impairment.
    explanation: Supports cognitive impairment as a common core feature of the clinical phenotype.
- category: Cognitive
  name: Dementia
  description: >-
    Progressive dementia is an important distinguishing feature of SCA17
    relative to many other spinocerebellar ataxias and underlies its overlap
    with Huntington disease-like presentations.
  phenotype_term:
    preferred_term: dementia
    term:
      id: HP:0000726
      label: Dementia
  evidence:
  - reference: PMID:30532692
    reference_title: "Complexity of the Genetics and Clinical Presentation of Spinocerebellar Ataxia 17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is distinct from other SCAs for its association with dementia,
      psychiatric symptoms, and some patients presenting with chorea.
    explanation: Identifies dementia as a distinctive feature of SCA17.
- category: Neurologic
  name: Chorea
  description: >-
    Choreiform movements contribute to the Huntington disease-like phenotype
    seen in a subset of SCA17 patients.
  phenotype_term:
    preferred_term: chorea
    term:
      id: HP:0002072
      label: Chorea
  evidence:
  - reference: PMID:22653791
    reference_title: "PET and MRI reveal early evidence of neurodegeneration in spinocerebellar ataxia type 17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominantly
      inherited neurodegenerative disorder presenting with a variable
      phenotype including ataxia, dystonia, chorea, and parkinsonism, as
      well as cognitive impairment.
    explanation: Supports chorea as a characteristic component of the movement disorder spectrum.
- category: Neurologic
  name: Dystonia
  description: >-
    Dystonia is part of the extrapyramidal presentation and may accompany
    ataxia or predominate in selected patients.
  phenotype_term:
    preferred_term: dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:22653791
    reference_title: "PET and MRI reveal early evidence of neurodegeneration in spinocerebellar ataxia type 17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominantly
      inherited neurodegenerative disorder presenting with a variable
      phenotype including ataxia, dystonia, chorea, and parkinsonism, as
      well as cognitive impairment.
    explanation: Supports dystonia as part of the typical variable phenotype.
- category: Neurologic
  name: Parkinsonism
  description: >-
    Parkinsonian presentations occur particularly with smaller expanded
    alleles and can resemble atypical parkinsonian neurodegenerative
    disorders.
  phenotype_term:
    preferred_term: parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: PMID:22653791
    reference_title: "PET and MRI reveal early evidence of neurodegeneration in spinocerebellar ataxia type 17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominantly
      inherited neurodegenerative disorder presenting with a variable
      phenotype including ataxia, dystonia, chorea, and parkinsonism, as
      well as cognitive impairment.
    explanation: Establishes parkinsonism within the core SCA17 movement phenotype spectrum.
- category: Neurologic
  name: Dysarthria
  description: >-
    Progressive cerebellar speech impairment is a typical feature of the
    disorder.
  phenotype_term:
    preferred_term: dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:23475385
    reference_title: "From normal gait to loss of ambulation in 6 months: a novel presentation of SCA17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SCA17 is clinically heterogeneous and typically presents with slowly
      evolving ataxia, dysarthria, dementia, depression, and other movement
      disorders such as chorea.
    explanation: Explicitly names dysarthria among typical SCA17 manifestations.
- category: Psychiatric
  name: Depression
  description: >-
    Depressive symptoms contribute to the psychiatric burden of SCA17 and may
    accompany cognitive decline and motor symptoms.
  phenotype_term:
    preferred_term: depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: PMID:23475385
    reference_title: "From normal gait to loss of ambulation in 6 months: a novel presentation of SCA17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SCA17 is clinically heterogeneous and typically presents with slowly
      evolving ataxia, dysarthria, dementia, depression, and other movement
      disorders such as chorea.
    explanation: Supports depression as part of the typical neuropsychiatric presentation.
- category: Psychiatric
  name: Psychosis
  description: >-
    Psychosis is a recognized psychiatric manifestation and helps distinguish
    SCA17 from more purely cerebellar hereditary ataxias.
  phenotype_term:
    preferred_term: psychosis
    term:
      id: HP:0000709
      label: Psychosis
  evidence:
  - reference: PMID:30532692
    reference_title: "Complexity of the Genetics and Clinical Presentation of Spinocerebellar Ataxia 17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SCA17 is characterized by ataxia, pyramidal and extrapyramidal signs,
      cognitive impairments, psychosis, and seizures as well as involuntary
      movements including chorea and dystonia.
    explanation: Explicitly identifies psychosis as part of the SCA17 phenotype.
- category: Neurologic
  name: Seizures
  frequency: OCCASIONAL
  description: >-
    Epileptic seizures occur in a subset of SCA17 patients (approximately
    20% in some review series) and contribute to the broader neurological
    spectrum of the disorder.
  phenotype_term:
    preferred_term: seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:30532692
    reference_title: "Complexity of the Genetics and Clinical Presentation of Spinocerebellar Ataxia 17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SCA17 is characterized by ataxia, pyramidal and extrapyramidal signs,
      cognitive impairments, psychosis, and seizures as well as involuntary
      movements including chorea and dystonia.
    explanation: Explicitly identifies seizures as part of the SCA17 phenotype spectrum.
diagnosis:
- name: TBP repeat expansion testing
  presence: Positive
  description: >-
    Molecular confirmation is obtained by sizing or sequencing the glutamine-
    encoding CAG/CAA repeat tract in TBP, with repeat length interpreted in
    the context of reduced penetrance for smaller expanded alleles.
  evidence:
  - reference: PMID:23475385
    reference_title: "From normal gait to loss of ambulation in 6 months: a novel presentation of SCA17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More than 41 CAG/CAA repeats are considered diagnostic of SCA17, with
      more than 49 being associated with full penetrance.
    explanation: Supports molecular repeat sizing as the central diagnostic test.
  - reference: PMID:34031796
    reference_title: "Small-expanded allele spinocerebellar ataxia 17: imaging and phenotypic variability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A number of repeats higher than 49 are full penetrance-expanded. The
      range between 41 and 49 repeats is characterized by decreased
      penetrance, and it is usually referred to as "small."
    explanation: Clarifies the interpretation of small expanded alleles during diagnostic workup.
- name: Brain MRI and PET markers of early neurodegeneration
  presence: Positive in manifest and presymptomatic mutation carriers
  description: >-
    Structural MRI and functional PET can show cerebellar and caudate atrophy
    together with striatal metabolic or dopaminergic abnormalities even before
    overt symptoms.
  evidence:
  - reference: PMID:22653791
    reference_title: "PET and MRI reveal early evidence of neurodegeneration in spinocerebellar ataxia type 17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CONCLUSION: MRI volumetry, as well as (11)C-raclopride and (18)F-FDG
      PET, reveal neuronal dysfunction and neurodegeneration even in the
      presymptomatic stage and may serve as markers for disease activity in
      upcoming interventional trials on SCA17.
    explanation: Supports imaging biomarkers for early detection and disease monitoring.
genetic:
- name: TBP
  gene_term:
    preferred_term: TBP
    term:
      id: hgnc:11588
      label: TBP
  association: CAG/CAA polyglutamine repeat expansion
  presence: Positive
  notes: >-
    The pathogenic variant is an expanded glutamine-encoding repeat in exon 3
    of TBP. Normal alleles are typically in the mid-20s to 40 repeats. The
    pathogenic threshold is narrow: reduced penetrance is established for many
    43-48-repeat alleles, and some 49-51-repeat alleles can remain
    nonpenetrant or have very late onset. Longer repeat lengths correlate with
    earlier onset. CAA interruptions generally stabilize transmission, so
    anticipation is less frequent than in many other polyglutamine SCAs.
  evidence:
  - reference: PMID:30532692
    reference_title: "Complexity of the Genetics and Clinical Presentation of Spinocerebellar Ataxia 17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found a negative linear correlation between total CAG repeat length
      and age at disease onset and, unlike SCA1, there was no correlation
      between the longest contiguous CAG tract and age at disease onset.
    explanation: Supports genotype-phenotype correlation between total repeat length and age at onset.
  - reference: PMID:15989694
    reference_title: "Spinocerebellar ataxia type 17: report of a family with reduced penetrance of an unstable Gln49 TBP allele, haplotype analysis supporting a founder effect for unstable alleles and comparative analysis of SCA17 genotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Observed pathogenic expansions ranged from 43-63 glutamine (Gln)
      codons (Gln43-63). Reduced penetrance is known for Gln43-48 alleles.
    explanation: Defines the lower pathogenic range and reduced penetrance interval.
  - reference: PMID:15989694
    reference_title: "Spinocerebellar ataxia type 17: report of a family with reduced penetrance of an unstable Gln49 TBP allele, haplotype analysis supporting a founder effect for unstable alleles and comparative analysis of SCA17 genotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 76-year-old father of two SCA17 patients carries the Gln49 TBP
      allele but presents without obvious neurological symptoms.
    explanation: Demonstrates that even 49-repeat alleles can remain nonpenetrant late in life.
  - reference: PMID:29427105
    reference_title: "Spinocerebellar Ataxia Type 17 (SCA17)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Second, compared to the other SCA subtypes caused by expanded
      trinucleotide repeats, anticipation in SCA17 kindreds is rare because
      of the characteristic structure of the TBP gene.
    explanation: Supports the relative rarity of anticipation due to repeat-tract structure.
  - reference: PMID:36374860
    reference_title: "Genotype-Phenotype Correlations for ATX-TBP (SCA17): MDSGene Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, 97.7% of the patients had ≥41 repeats, while 99.6% of patients
      with PD and 99.9% of healthy individuals had ≤42 repeats, with a gray
      zone of reduced penetrance between 41 and 45 repeats.
    explanation: >-
      MDSGene systematic review of 346 ATX-TBP patients providing updated,
      data-driven repeat-size cutoffs that lower the practical lower bound of
      reduced penetrance from 43 to 41.
  - reference: PMID:36374860
    reference_title: "Genotype-Phenotype Correlations for ATX-TBP (SCA17): MDSGene Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pure parkinsonism was more common in ATX-TBP patients with 41 to 45
      repeats than in the group with ≥46 repeats, which conversely more often
      presented with a complex phenotype with mixed movement disorders.
    explanation: >-
      Establishes a genotype-phenotype correlation in which smaller expanded
      alleles are more likely to present as parkinsonism, while larger ones
      give the classical mixed ataxic/extrapyramidal/cognitive picture.
  - reference: PMID:39125760
    reference_title: "The New Face of Dynamic Mutation - The CAA[CAG]n CAA CAG Motif as a Mutable Unit in the TBP Gene Causative for Spinocerebellar Ataxia Type 17."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Detailed analysis of the CAG/CAA repeat structure, not just the number
      of repeats, in TBP-expanded alleles should be performed, as it may have
      a prognostic value in the prediction of stability/instability during
      transmission and the possible anticipation of the disease.
    explanation: >-
      Literature-based reanalysis of 67 patient alleles from 19 published
      reports supporting the recommendation that repeat-tract structure
      (CAA interruption pattern), not only repeat count, should be reported
      to predict transmission stability and anticipation risk.
treatments:
- name: Supportive and rehabilitative care
  description: >-
    Multidisciplinary symptomatic management with physical therapy, speech
    therapy, mobility aids, swallow support, and psychiatric/cognitive care
    remains the standard of care.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: gait ataxia
    term:
      id: HP:0002066
      label: Gait ataxia
  - preferred_term: dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:39614971
    reference_title: "Molecular Mechanisms of Spinocerebellar Ataxia Type 17."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      At present, there is no effective treatment for SCA17, and existing
      therapies provide only symptomatic relief.
    explanation: Supports supportive care as the current management paradigm in the absence of disease-modifying therapy.
- name: Granulocyte-colony stimulating factor (preclinical)
  description: >-
    Preclinical disease-modifying candidate that improved neurologic function
    and reduced Purkinje cell pathology in transgenic SCA17 mice. This remains
    experimental and has not been established as human therapy.
  treatment_term:
    preferred_term: hematopoietic growth factor therapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: filgrastim
      term:
        id: NCIT:C1474
        label: Filgrastim
  target_mechanisms:
  - target: Impaired proteostasis promotes mutant TBP aggregation
    treatment_effect: MODULATES
    description: >-
      Enhances chaperone and autophagy pathways to improve clearance of
      aggregation-prone mutant TBP in preclinical SCA17 models.
    evidence:
    - reference: PMID:26972528
      reference_title: "Targeting the prodromal stage of spinocerebellar ataxia type 17 mice: G-CSF in the prevention of motor deficits via upregulating chaperone and autophagy levels."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Upregulation of chaperone and autophagy levels further enhances
        the clearance of mutant protein aggregation, slowing the
        progression of pathology in SCA17 mice.
      explanation: Connects G-CSF to proteostasis restoration in vivo.
  evidence:
  - reference: PMID:21554323
    reference_title: "Neuroprotective effects of granulocyte-colony stimulating factor in a novel transgenic mouse model of SCA17."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our results suggest that granulocyte-colony stimulating factor has a
      neuroprotective effect in these transgenic mice, ameliorating their
      neurological and behavioral deficits.
    explanation: Demonstrates preclinical neuroprotective benefit of G-CSF in an SCA17 mouse model.
  - reference: PMID:26972528
    reference_title: "Targeting the prodromal stage of spinocerebellar ataxia type 17 mice: G-CSF in the prevention of motor deficits via upregulating chaperone and autophagy levels."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Treatment with G-CSF at the pre-symptomatic stage improved the motor
      coordination of SCA17 mice and reduced the cell loss, insoluble mutant
      TBP protein, and vacuole formation in the Purkinje neurons of these
      mice.
    explanation: Supports improved motor function and reduced Purkinje pathology with preclinical G-CSF treatment.
animal_models:
- species: Mus musculus
  genotype: L7-hTBP transgenic mouse
  description: >-
    Purkinje cell-targeted mutant human TBP expression produces an ataxic
    cerebellar disorder with Purkinje degeneration, gliosis, and
    neuroinflammation, modeling selective cerebellar vulnerability in SCA17.
  associated_phenotypes:
  - Ataxia
  - Purkinje cell degeneration
  - Reactive gliosis
  evidence:
  - reference: PMID:21554323
    reference_title: "Neuroprotective effects of granulocyte-colony stimulating factor in a novel transgenic mouse model of SCA17."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mice with the expanded hTBP allele developed ataxia within 2-5 months.
    explanation: Confirms that Purkinje-directed mutant TBP expression causes an ataxic phenotype.
  - reference: PMID:21554323
    reference_title: "Neuroprotective effects of granulocyte-colony stimulating factor in a novel transgenic mouse model of SCA17."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Purkinje cell degeneration was identified by immunostaining of
      calbindin and IP3R1. Reactive gliosis and neuroinflammation occurred
      in the transgenic cerebellum, accompanied by up-regulation of GFAP and
      Iba1.
    explanation: Captures both the selective Purkinje pathology and inflammatory cerebellar environment of the model.
- species: Drosophila melanogaster
  genotype: Human TBP polyQ transgenic Drosophila (Patel/Sujkowski 2023)
  description: >-
    Drosophila lines expressing human TBP with polyQ repeats in either
    wild-type or SCA17 patient range. Patient-range polyQ-expanded TBP
    accumulates more aggregation-prone protein with greater nuclear
    localization, providing a tractable invertebrate platform for biochemical
    dissection of SCA17 pathology and therapeutic target screening.
  associated_phenotypes:
  - Age-dependent neurodegeneration
  - Tissue-specific TBP toxicity
  - Nuclear TBP aggregation
  evidence:
  - reference: PMID:37551423
    reference_title: "Phenotypic defects from the expression of wild-type and pathogenic TATA-binding proteins in new Drosophila models of spinocerebellar ataxia type 17."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We find that TBP expression has age- and tissue-specific effects on
      neurodegeneration, with polyQ-expanded SCA17 protein expression
      generally having more severe effects.
    explanation: >-
      Demonstrates age- and tissue-dependent neurodegeneration driven by
      patient-range polyQ-expanded TBP in a tractable invertebrate model.
  - reference: PMID:37551423
    reference_title: "Phenotypic defects from the expression of wild-type and pathogenic TATA-binding proteins in new Drosophila models of spinocerebellar ataxia type 17."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      SCA17 model flies accumulate more aggregation-prone TBP, with a greater
      proportion localizing to the nucleus.
    explanation: >-
      Connects polyQ expansion to enhanced nuclear aggregation of TBP, the
      proposed proximate molecular lesion in SCA17.
- species: Rattus norvegicus
  genotype: TBPQ64 transgenic rat
  description: >-
    Rat model expressing full-length human TBP with 64 CAA/CAG repeats
    recapitulates ataxia, postural reflex impairment, cerebellar neuronal
    loss, and Purkinje/basket/stellate pathology while also supplying in vivo
    imaging biomarkers.
  associated_phenotypes:
  - Ataxia
  - Postural reflex impairment
  - Cerebellar neuronal loss
  evidence:
  - reference: PMID:23699518
    reference_title: "A novel transgenic rat model for spinocerebellar ataxia type 17 recapitulates neuropathological changes and supplies in vivo imaging biomarkers."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      TBPQ64 rats show a severe neurological phenotype including ataxia,
      impairment of postural reflexes, and hyperactivity in early stages
      followed by reduced activity, loss of body weight, and early death.
    explanation: Shows that the rat model recapitulates major neurologic features of advanced SCA17.
  - reference: PMID:23699518
    reference_title: "A novel transgenic rat model for spinocerebellar ataxia type 17 recapitulates neuropathological changes and supplies in vivo imaging biomarkers."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Neuropathologically, the severe phenotype of SCA17 rats was associated
      with neuronal loss, particularly in the cerebellum.
    explanation: Provides neuropathologic evidence that the rat model reproduces selective cerebellar degeneration.
notes: >-
  SCA17 is allelic with Huntington disease-like 4. Because the pathogenic repeat
  threshold is narrow and penetrance is incomplete for smaller expanded alleles,
  repeat length should be interpreted together with phenotype, family history,
  and imaging findings.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0011781
      label: spinocerebellar ataxia type 17
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: MONDO provides an exact disease term for spinocerebellar ataxia type 17.
  ncit_mappings:
  - term:
      id: NCIT:C179861
      label: Spinocerebellar Ataxia Type 17
    mapping_predicate: skos:exactMatch
    mapping_source: NCIT
    mapping_justification: NCIT provides an exact term for spinocerebellar ataxia type 17; cross-referenced from MONDO:0011781.

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Spinocerebellar ataxia type 17 (SCA17; ATX‑TBP; Huntington disease–like 4) — Disease Characteristics Research Report

Edison Scientific Literature 18 citations 2026-04-30T20:36:51.237259

Spinocerebellar ataxia type 17 (SCA17; ATX‑TBP; Huntington disease–like 4) — Disease Characteristics Research Report

Executive summary

Spinocerebellar ataxia type 17 (SCA17) is a rare, autosomal dominant neurodegenerative polyglutamine (polyQ) disorder caused by expansion of a mixed CAG/CAA repeat in TBP (TATA‑box binding protein), historically also termed Huntington disease–like 4 (HDL4) because chorea, psychiatric symptoms, and dementia can mimic Huntington disease. (toyoshima2018spinocerebellarataxiatype pages 1-5, nethisinghe2018complexityofthe pages 1-2, rossi2023genotype–phenotypecorrelationsfor pages 1-1)

A major recent development is a 2023 Movement Disorders Society Genetic Mutation Database (MDSGene) systematic review (346 curated patients) proposing revised repeat-size penetrance thresholds—reduced penetrance 41–45 and full penetrance 46–66—to guide diagnosis, counseling, and trial design. (rossi2023genotype–phenotypecorrelationsfor pages 1-1, rossi2023genotype–phenotypecorrelationsfor media 82dfeaa1)

A second 2024 advance is refined interpretation of the repeat tract structure (not only repeat count): a literature-based sequence analysis of reported alleles proposed a 3‑unit organization of the TBP repeat region and argued this structural annotation may help predict intergenerational stability and anticipation risk. (hoffmanzacharska2024thenewface pages 1-2)

1. Disease information

What is the disease?

SCA17 is an autosomal dominant cerebellar ataxia caused by a polyglutamine expansion in TBP, a general transcription initiation factor. A review chapter notes: “In 1999, a polyglutamine expansion was identiﬁed in the transcription factor TATA-binding protein (TBP)” in SCA17. (toyoshima2018spinocerebellarataxiatype pages 1-5)

Synonyms / alternative names

Spinocerebellar ataxia type 17 (SCA17) (toyoshima2018spinocerebellarataxiatype pages 1-5)
ATX‑TBP (rossi2023genotype–phenotypecorrelationsfor pages 1-1)
Huntington disease–like 4 (HDL4) (toyoshima2018spinocerebellarataxiatype pages 1-5, rossi2023genotype–phenotypecorrelationsfor pages 2-2)

Key identifiers (OMIM, Orphanet, ICD, MeSH, MONDO)

The provided tool-retrieved sources did not include OMIM/Orphanet/ICD/MeSH/MONDO identifiers; therefore these identifiers cannot be asserted from the current evidence set.

Evidence source type

The 2023 MDSGene systematic review is derived from aggregated literature (case reports and family studies) curated into a standardized database. (rossi2023genotype–phenotypecorrelationsfor pages 1-1, rossi2023genotype–phenotypecorrelationsfor pages 8-8)

2. Etiology

Disease causal factors

Primary cause (genetic): germline expansion of a mixed CAG/CAA repeat in exon 3 of TBP, encoding an expanded polyglutamine tract. (nethisinghe2018complexityofthe pages 1-2, rossi2023genotype–phenotypecorrelationsfor pages 1-1)

Mechanistic framing: SCA17 is one of the “triplet repeat diseases,” where repeat tracts can form non‑B DNA structures that predispose to instability during replication/repair, promoting dynamic mutation. (hoffmanzacharska2024thenewface pages 1-2)

Risk factors

Repeat size / penetrance: The 2023 MDSGene review reports that “97.7% of the patients had ≥41 repeats” and proposes a reduced‑penetrance “gray zone” between 41 and 45 repeats, with full penetrance above this range. (rossi2023genotype–phenotypecorrelationsfor pages 1-1)
Family history: SCA17 is typically autosomal dominant; however, reduced penetrance and variable expressivity can yield asymptomatic carriers in families. (nethisinghe2018complexityofthe pages 1-2)

Protective factors

No protective genetic variants or modifiable protective environmental factors were identified in the provided evidence set.

Gene–environment interactions

The UK cohort paper reports marked intrafamilial variability (including discordant monozygotic twins) and suggests environmental/epigenetic influences may contribute, but does not specify a particular exposure. (nethisinghe2018complexityofthe pages 1-2)

3. Phenotypes

Core phenotype spectrum

A 2018 review chapter reports broad clinical heterogeneity and provides approximate frequencies for selected manifestations: * Cerebellar ataxia: “most of the patients (>90%) developed ataxia.” (toyoshima2018spinocerebellarataxiatype pages 1-5) * Dementia/cognitive decline: “dementia is the second most common symptom (73%).” (toyoshima2018spinocerebellarataxiatype pages 1-5) * Seizures/epilepsy: ~20% (toyoshima2018spinocerebellarataxiatype pages 1-5) * Autonomic dysfunction: ~9% (toyoshima2018spinocerebellarataxiatype pages 1-5) * Apraxia: ~7% (toyoshima2018spinocerebellarataxiatype pages 1-5) * Peripheral nerve involvement: ~3% (toyoshima2018spinocerebellarataxiatype pages 1-5)

The 2023 MDSGene review emphasizes non‑ataxic presentations also occur, including “pure parkinsonism or chorea associated with dementia,” and notes psychiatric/cognitive manifestations such as psychosis and depression. (rossi2023genotype–phenotypecorrelationsfor pages 2-2)

Phenotype characteristics

Age of onset: very broad; review sources report onset approximately from childhood to later adulthood (e.g., 3–60 years). (toyoshima2018spinocerebellarataxiatype pages 1-5, grassini2024cognitivedysfunctionsocial pages 1-3)
Progression: progressive neurodegenerative disorder with variable severity across individuals and within families. (nethisinghe2018complexityofthe pages 1-2)

Genotype–phenotype notes (clinical)

The MDSGene systematic review proposes that pure parkinsonism is more common among carriers with 41–45 repeats, whereas carriers with ≥46 repeats more often show a complex mixed movement disorder phenotype. (rossi2023genotype–phenotypecorrelationsfor pages 1-1)
A review chapter reports that among repeat sizes 43–50, “more than 75%” had intellectual deterioration; among repeat sizes 50–60, 75% had reduced intellectual function. (toyoshima2018spinocerebellarataxiatype pages 1-5)

Quality of life impact

A 2024 case report noted preserved basic activities of daily living but impaired instrumental ADLs (IADL 4/8) in one patient, consistent with functional impact from cognitive/social-cognition deficits. (grassini2024cognitivedysfunctionsocial pages 1-3)

Suggested HPO terms (non-exhaustive; evidence-backed)

Cerebellar ataxia — HP:0001251 (toyoshima2018spinocerebellarataxiatype pages 1-5)
Gait ataxia — HP:0002066 (rossi2023genotype–phenotypecorrelationsfor pages 2-2)
Dysarthria — HP:0001260 (rossi2023genotype–phenotypecorrelationsfor pages 2-2)
Abnormality of eye movement — HP:0000496 (rossi2023genotype–phenotypecorrelationsfor pages 2-2)
Dementia — HP:0000726 (toyoshima2018spinocerebellarataxiatype pages 1-5)
Cognitive impairment — HP:0100543 (rossi2023genotype–phenotypecorrelationsfor pages 2-2)
Parkinsonism — HP:0001300 (rossi2023genotype–phenotypecorrelationsfor pages 1-1)
Chorea — HP:0002072 (toyoshima2018spinocerebellarataxiatype pages 1-5)
Seizure — HP:0001250 (toyoshima2018spinocerebellarataxiatype pages 1-5)
Depression — HP:0000716 (rossi2023genotype–phenotypecorrelationsfor pages 2-2)
Psychosis — HP:0000709 (rossi2023genotype–phenotypecorrelationsfor pages 2-2)

4. Genetic / molecular information

Causal gene

TBP (TATA‑box binding protein). (toyoshima2018spinocerebellarataxiatype pages 1-5, nethisinghe2018complexityofthe pages 1-2)

Pathogenic variant class

Repeat expansion of a mixed CAG/CAA tract (polyQ‑encoding) in TBP. (rossi2023genotype–phenotypecorrelationsfor pages 1-1, hoffmanzacharska2024thenewface pages 1-2)

Repeat length interpretation (current practice trend)

The 2023 MDSGene systematic review provides a data-driven reinterpretation of TBP repeat cutoffs: * “97.7% of the patients had ≥41 repeats” (curated cases) (rossi2023genotype–phenotypecorrelationsfor pages 1-1) * Proposed thresholds: reduced penetrance 41–45 and full penetrance 46–66 (rossi2023genotype–phenotypecorrelationsfor pages 1-1) * Comparative cohorts: “99.6% of patients with PD and 99.9% of healthy individuals had ≤42 repeats” (rossi2023genotype–phenotypecorrelationsfor pages 1-1)

A visual summary of clinical features across revised repeat groups (Figure 3) and an accompanying table of features by repeat group (Table 2) were extracted from the MDSGene review. (rossi2023genotype–phenotypecorrelationsfor media 82dfeaa1, rossi2023genotype–phenotypecorrelationsfor media 1829bb84)

Repeat structure (2024 development)

A 2024 IJMS paper argues that repeat composition and motif organization should be annotated to improve prognostic counseling, stating that “detailed analysis of the CAG/CAA repeat structure, not just the number of repeats, in TBP-expanded alleles should be performed” due to potential relevance for stability/anticipation. (hoffmanzacharska2024thenewface pages 1-2)

Modifier genes / digenic inheritance

A 2024 SCA17 case report summarizes literature suggesting intermediate TBP expansions may require co-occurring STUB1 variants to cause disease (digenic TBP/STUB1), implying modifier or digenic mechanisms in borderline repeat-size cases. (grassini2024cognitivedysfunctionsocial pages 1-3)

Suggested ontology terms

Gene: TBP (HGNC:11588; not provided in evidence set—listed here as a standard identifier and should be verified against HGNC directly)
Disease mechanism: trinucleotide repeat expansion (sequence feature)

5. Environmental information

No specific environmental toxins, lifestyle factors, or infectious triggers for SCA17 were identified in the provided evidence set; SCA17 is primarily genetic. (toyoshima2018spinocerebellarataxiatype pages 1-5, rossi2023genotype–phenotypecorrelationsfor pages 1-1)

6. Mechanism / pathophysiology

Current mechanistic concepts (disease-relevant)

Dynamic mutation biology: repeat tracts can form “unusual DNA structures” and undergo instability, motivating the concept of repeat unit organization and its relationship to transmission stability. (hoffmanzacharska2024thenewface pages 1-2)
PolyQ protein toxicity: SCA17 belongs to the polyQ disorders in which expanded glutamine tracts alter protein behavior, with downstream processes in polyQ SCAs broadly including transcriptional dysregulation, impaired protein quality control, mitochondrial dysfunction, and neuronal dysfunction (discussed across SCA reviews). (cui2024spinocerebellarataxiasfrom pages 1-2)

Causal chain (high-level)

TBP mixed CAG/CAA repeat expansion → expanded polyglutamine tract in TBP → altered TBP conformational/interaction behavior and/or nuclear localization/aggregation (supported in model systems) → neuronal dysfunction and neurodegeneration affecting cerebellar and extra-cerebellar circuits → progressive ataxia with cognitive/psychiatric and movement-disorder manifestations. (patel2023phenotypicdefectsfrom pages 1-2, cui2024spinocerebellarataxiasfrom pages 1-2)

Suggested GO biological process terms (candidates; align to evidence themes)

Transcription initiation from RNA polymerase II promoter — GO:0006367 (TBP function; mechanistic relevance implied) (toyoshima2018spinocerebellarataxiatype pages 1-5)
Protein aggregation — GO:0070848 (model evidence of aggregation-prone TBP) (patel2023phenotypicdefectsfrom pages 1-2)
Neuron death / neurodegeneration — GO:1901214 (disease-level phenotype; implied) (cui2024spinocerebellarataxiasfrom pages 1-2)

Suggested Cell Ontology (CL) terms (candidates)

Primary vulnerable cells are not explicitly enumerated in the provided excerpts; broadly, cerebellar neuronal populations are implicated. Candidate CL terms that should be verified/expanded with additional neuropathology sources include: * Purkinje cell — CL:0000121

7. Anatomical structures affected

Organ/system level

Nervous system, with cerebellar and extra-cerebellar involvement (dementia/psychiatric features and chorea/parkinsonism imply wider network degeneration). (toyoshima2018spinocerebellarataxiatype pages 1-5, rossi2023genotype–phenotypecorrelationsfor pages 2-2)

Imaging-supported structures (examples)

A 2024 case report described MRI atrophy of frontal cortex/hippocampus/cerebellum/brainstem and FDG‑PET with striatal hypometabolism and thalamic hypermetabolism (Huntington-like pattern). (grassini2024cognitivedysfunctionsocial pages 1-3)

Suggested UBERON terms (candidates)

Cerebellum — UBERON:0002037 (toyoshima2018spinocerebellarataxiatype pages 1-5)
Striatum — UBERON:0002435 (grassini2024cognitivedysfunctionsocial pages 1-3)

8. Temporal development

Onset

Broad onset range is reported (including childhood onset in rare cases with long expansions) with substantial heterogeneity. (toyoshima2018spinocerebellarataxiatype pages 1-5, grassini2024cognitivedysfunctionsocial pages 1-3)

Progression / course

Progressive neurodegenerative course with variable expressivity even within families; anticipation is described as uncommon compared with other polyQ disorders. (nethisinghe2018complexityofthe pages 1-2)

9. Inheritance and population

Inheritance

Autosomal dominant inheritance is repeatedly described, with reduced penetrance for small/intermediate repeat sizes and variable expressivity. (toyoshima2018spinocerebellarataxiatype pages 1-5, rossi2023genotype–phenotypecorrelationsfor pages 1-1)

Epidemiology statistics (limited by available evidence)

UK cohort allele frequency: fully penetrant pathogenic alleles were “5 in 1,316 chromosomes; 0.38%” in an ataxia cohort (not population prevalence). (nethisinghe2018complexityofthe pages 1-2)
A review chapter reports that in an HD-phenocopy series, 1.8% (5/285) had TBP expansions. (toyoshima2018spinocerebellarataxiatype pages 1-5)

Robust population prevalence/incidence estimates were not available in the provided evidence set.

10. Diagnostics

Genetic testing

Given the narrow normal–pathogenic repeat gap and phenotypic overlap with Huntington disease-like syndromes, genetic testing of TBP is central. A review chapter states: “If patients with HD-like disease have no mutations in huntingtin, the TBP and C9orf72 genes should be examined.” (toyoshima2018spinocerebellarataxiatype pages 1-5)

Repeat expansion interpretation (clinical counseling)

The 2023 MDSGene review emphasizes that establishing a strict cut-off has been challenging and proposes revised penetrance ranges with a reduced-penetrance “gray zone.” (rossi2023genotype–phenotypecorrelationsfor pages 1-1, rossi2023genotype–phenotypecorrelationsfor pages 2-2)

Imaging/biomarkers (emerging)

A 2024 case report highlights that FDG‑PET patterns may be atypical (Huntington-like striatal hypometabolism and thalamic hypermetabolism) even without marked cerebellar hypometabolism. (grassini2024cognitivedysfunctionsocial pages 1-3)

Differential diagnosis

SCA17 can phenocopy Huntington disease, including chorea/psychiatric/dementia features; the literature explicitly categorizes ATX‑TBP among Huntington disease-like syndromes. (toyoshima2018spinocerebellarataxiatype pages 1-5, rossi2023genotype–phenotypecorrelationsfor pages 2-2)

11. Outcome / prognosis

Detailed survival and quantitative progression rates were not available in the provided evidence set. The disease is progressive with substantial heterogeneity and potential severe early-onset forms in very large expansions. (toyoshima2018spinocerebellarataxiatype pages 1-5, nethisinghe2018complexityofthe pages 1-2)

12. Treatment

Current standard of care

No disease-modifying therapy is established; care is primarily symptomatic and supportive (as described broadly for SCAs). (cui2024spinocerebellarataxiasfrom pages 1-2)

Experimental / clinical trials (registry evidence)

CAD‑1883 (Synchrony‑1) — includes SCA17 explicitly * Trial: “Study of CAD‑1883 for Spinocerebellar Ataxia” * ClinicalTrials.gov ID: NCT04301284 * Phase: 2; randomized, double-blind, placebo-controlled * Status: Withdrawn; “As part of a pipeline reassessment, the Synchrony‑1 trial will not proceed as initially scheduled.” * Eligibility included multiple SCA genotypes and explicitly listed “Spinocerebellar Ataxia Type 17.” * URL: https://clinicaltrials.gov/study/NCT04301284 (registry URL format) * Trial record publication year in excerpt: 2021 (NCT04301284 chunk 1)

Troriluzole — broad hereditary SCA program (SCA17 not listed in excerpted inclusion genotypes) * Trial: “Troriluzole in Adult Participants With Spinocerebellar Ataxia” * ClinicalTrials.gov ID: NCT03701399 * Phase: 3; quadruple-masked randomized trial with open-label extension * Status: Active, not recruiting; Enrollment 299 * Included genotypes (as listed in excerpt): SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA10 * URL: https://clinicaltrials.gov/study/NCT03701399 * Trial record publication year in excerpt: 2019 (NCT03701399 chunk 1)

Recent research directions (2023–2024 reviews; not SCA17-specific efficacy)

Recent SCA therapeutic reviews emphasize disease-modifying approaches under development across polyQ SCAs, including gene editing, RNA interference, antisense oligonucleotides (ASOs), and stem cell approaches, while acknowledging delivery and off-target limitations. (cui2024spinocerebellarataxiasfrom pages 6-7, cui2024spinocerebellarataxiasfrom pages 9-10, cui2024spinocerebellarataxiasfrom pages 1-2)

Suggested MAXO terms (candidates)

Genetic testing — MAXO:0000127 (genetic diagnostic action)
Physical therapy — MAXO:0000011 (supportive care; common in SCA management though not detailed in provided SCA17-specific excerpts)
Occupational therapy — MAXO:0000014
Speech therapy — MAXO:0000121

13. Prevention

No primary prevention is available for germline repeat-expansion disorders. Secondary prevention centers on early detection in at-risk families and genetic counseling. (rossi2023genotype–phenotypecorrelationsfor pages 1-1)

14. Other species / natural disease

No naturally occurring SCA17-like disease in non-human species was identified in the provided evidence set.

15. Model organisms

Drosophila models (SCA17-specific)

A 2023 peer-reviewed study reports new Drosophila models expressing human TBP in wild-type versus SCA17-range polyQ lengths. The abstract states: “Here, we report two new Drosophila models that express human TBP with polyQ repeats in either wild-type or SCA17 patient range.” It further reports that “SCA17 model flies accumulate more aggregation prone TBP, with a greater proportion localizing to the nucleus.” (patel2023phenotypicdefectsfrom pages 1-2)

These models provide a platform for mechanistic dissection (aggregation, nuclear localization, tissue-specific neurodegeneration) and therapeutic target discovery. (patel2023phenotypicdefectsfrom pages 1-2)

Key compiled facts table (evidence-backed)

Item	Details	Evidence (PMID/DOI, year)
Disease / synonyms	Spinocerebellar ataxia type 17; ATX-TBP; Huntington disease-like 4 (HDL4); described as a rare autosomal dominant polyglutamine disorder with marked clinical heterogeneity.	DOI:10.1002/mds.29278, 2023 (rossi2023genotype–phenotypecorrelationsfor pages 1-1, rossi2023genotype–phenotypecorrelationsfor pages 2-2); DOI:10.1007/978-3-319-71779-1_10, 2018 (toyoshima2018spinocerebellarataxiatype pages 1-5)
Causal gene	TBP (TATA-box binding protein), chromosome 6q; expansion occurs in exon 3 and encodes an expanded polyglutamine tract.	DOI:10.3389/fncel.2018.00429, 2018 (nethisinghe2018complexityofthe pages 1-2); DOI:10.1007/978-3-319-71779-1_10, 2018 (toyoshima2018spinocerebellarataxiatype pages 1-5)
Mutation type	Germline mixed CAG/CAA repeat expansion in TBP; expansion of the polyglutamine-encoding tract causes SCA17.	DOI:10.3390/ijms25158190, 2024 (hoffmanzacharska2024thenewface pages 1-2); DOI:10.1002/mds.29278, 2023 (rossi2023genotype–phenotypecorrelationsfor pages 1-1)
Repeat-size categories: historical EMQN ranges	Earlier recommendations summarized as normal 25–42, reduced penetrance 43–48, full penetrance 49–66 CAG/CAA repeats.	DOI:10.1002/mds.29278, 2023 (rossi2023genotype–phenotypecorrelationsfor pages 2-2)
Repeat-size categories: updated 2023 MDSGene proposal	Updated cutoffs proposed from systematic review: reduced penetrance 41–45 repeats; full penetrance 46–66 repeats. Among curated cases, 97.7% had ≥41 repeats; 99.6% of PD patients and 99.9% of healthy individuals had ≤42 repeats.	DOI:10.1002/mds.29278, 2023 (rossi2023genotype–phenotypecorrelationsfor pages 1-1, rossi2023genotype–phenotypecorrelationsfor media 82dfeaa1, rossi2023genotype–phenotypecorrelationsfor media 1829bb84)
Pathogenic range / uncertainty	Highest reported expanded alleles reach about 66 repeats. Because the normal–pathogenic gap is narrow, defining a strict cutoff is challenging; some studies/cases suggest variable penetrance and uncertainty around intermediate/small-expanded alleles.	DOI:10.1007/978-3-319-71779-1_10, 2018 (toyoshima2018spinocerebellarataxiatype pages 1-5); DOI:10.3389/fncel.2018.00429, 2018 (nethisinghe2018complexityofthe pages 1-2); DOI:10.1007/s10072-024-07453-4, 2024 (grassini2024cognitivedysfunctionsocial pages 1-3)
Core clinical feature: ataxia	Ataxia is the dominant phenotype; reported in >90% of patients in a review. Supportive cerebellar signs include dysarthria and eye-movement abnormalities.	DOI:10.1007/978-3-319-71779-1_10, 2018 (toyoshima2018spinocerebellarataxiatype pages 1-5); DOI:10.1002/mds.29278, 2023 (rossi2023genotype–phenotypecorrelationsfor pages 2-2)
Cognitive / dementia features	Dementia or intellectual deterioration is a major feature; dementia reported in 73% overall in one review. For repeats 43–50, >75% had intellectual deterioration; for 50–60, 75% had reduced intellectual function.	DOI:10.1007/978-3-319-71779-1_10, 2018 (toyoshima2018spinocerebellarataxiatype pages 1-5)
Psychiatric / behavioral features	Psychiatric symptoms are characteristic and may include psychosis, depression, and behavioral/social-cognition abnormalities; these contribute to the Huntington-like presentation.	DOI:10.1002/mds.29278, 2023 (rossi2023genotype–phenotypecorrelationsfor pages 2-2); DOI:10.1007/s10072-024-07453-4, 2024 (grassini2024cognitivedysfunctionsocial pages 1-3)
Hyperkinetic / parkinsonian features	Chorea and parkinsonism are well recognized. Pure parkinsonism is more common in carriers with 41–45 repeats, whereas carriers with ≥46 repeats more often show a complex mixed movement-disorder phenotype.	DOI:10.1002/mds.29278, 2023 (rossi2023genotype–phenotypecorrelationsfor pages 1-1); DOI:10.1007/978-3-319-71779-1_10, 2018 (toyoshima2018spinocerebellarataxiatype pages 1-5)
Other less-common features	Epilepsy/seizures about 20%; autonomic dysfunction 9%; apraxia 7%; peripheral nerve involvement 3% in one review.	DOI:10.1007/978-3-319-71779-1_10, 2018 (toyoshima2018spinocerebellarataxiatype pages 1-5)
Age at onset / progression	Very broad onset range, approximately 3–60 years in reviews/case reports, with juvenile severe disease often associated with very long repeats; disease is progressive and clinically variable even within families.	DOI:10.1007/978-3-319-71779-1_10, 2018 (toyoshima2018spinocerebellarataxiatype pages 1-5); DOI:10.3389/fncel.2018.00429, 2018 (nethisinghe2018complexityofthe pages 1-2); DOI:10.1007/s10072-024-07453-4, 2024 (grassini2024cognitivedysfunctionsocial pages 1-3)
Genotype–phenotype correlation	Total repeat length shows a negative correlation with age at onset in some cohorts, but phenotype is highly variable; contiguous CAG tract length did not correlate with age at onset in the UK cohort.	DOI:10.3389/fncel.2018.00429, 2018 (nethisinghe2018complexityofthe pages 1-2)
Anticipation / transmission	Genetic anticipation is less prominent than in several other polyQ disorders; repeat interruptions (CAA) are thought to reduce instability.	DOI:10.3389/fncel.2018.00429, 2018 (nethisinghe2018complexityofthe pages 1-2); DOI:10.3390/ijms25158190, 2024 (hoffmanzacharska2024thenewface pages 1-2)
2024 repeat-structure development	A 2024 review reanalyzed 67 cases from 19 reports and proposed an alternative three-unit organization of the TBP repeat tract, arguing that repeat structure/composition, not only repeat count, may help predict transmission stability and anticipation.	DOI:10.3390/ijms25158190, 2024 (hoffmanzacharska2024thenewface pages 1-2)
2023–2024 clinically relevant development	The 2023 MDSGene systematic review curated 346 patients and recommended revised penetrance thresholds, which have direct implications for diagnosis, counseling, and clinical-trial design.	DOI:10.1002/mds.29278, 2023 (rossi2023genotype–phenotypecorrelationsfor pages 1-1, rossi2023genotype–phenotypecorrelationsfor media 82dfeaa1, rossi2023genotype–phenotypecorrelationsfor media 1829bb84)

Table: This table summarizes core disease-definition, genetics, repeat-size interpretation, phenotype, and recent 2023-2024 updates for Spinocerebellar ataxia type 17. It is useful as a compact evidence-backed reference for knowledge-base population and diagnostic interpretation.

Evidence-based figure/table note

An extracted Figure 3 and Table 2 from the 2023 MDSGene systematic review provide a visual schematic of clinical features across revised repeat-size penetrance groups and a tabular summary of clinical features by the 41–45 vs 46–66 repeat categories. (rossi2023genotype–phenotypecorrelationsfor media 82dfeaa1, rossi2023genotype–phenotypecorrelationsfor media 1829bb84)

Gaps / limitations of this report (based on available evidence set)

OMIM/Orphanet/ICD/MeSH/MONDO identifiers were not retrieved by the current tool context and are therefore not asserted here.
Robust prevalence/incidence estimates, survival statistics, and formal staging/progression rates were not available in the provided evidence set.
Detailed biomarker and neuropathology summaries (e.g., Purkinje cell pathology, protein inclusions across brain regions) would require additional full-text sources beyond those retrieved here.

References

(toyoshima2018spinocerebellarataxiatype pages 1-5): Yasuko Toyoshima and Hitoshi Takahashi. Spinocerebellar ataxia type 17 (sca17). Advances in experimental medicine and biology, 1049:219-231, Jan 2018. URL: https://doi.org/10.1007/978-3-319-71779-1_10, doi:10.1007/978-3-319-71779-1_10. This article has 50 citations and is from a peer-reviewed journal.
(nethisinghe2018complexityofthe pages 1-2): Suran Nethisinghe, Wei N. Lim, Heather Ging, Anna Zeitlberger, Rosella Abeti, Sally Pemble, Mary G. Sweeney, Robyn Labrum, Charisse Cervera, Henry Houlden, Elisabeth Rosser, Patricia Limousin, Angus Kennedy, Michael P. Lunn, Kailash P. Bhatia, Nicholas W. Wood, John Hardy, James M. Polke, Liana Veneziano, Alfredo Brusco, Mary B. Davis, and Paola Giunti. Complexity of the genetics and clinical presentation of spinocerebellar ataxia 17. Frontiers in Cellular Neuroscience, Nov 2018. URL: https://doi.org/10.3389/fncel.2018.00429, doi:10.3389/fncel.2018.00429. This article has 30 citations.
(rossi2023genotype–phenotypecorrelationsfor pages 1-1): Malco Rossi, Moath Hamed, Jon Rodríguez‐Antigüedad, Mario Cornejo‐Olivas, Marianthi Breza, Katja Lohmann, Christine Klein, Rajasumi Rajalingam, Connie Marras, and Bart P. van de Warrenburg. Genotype–phenotype correlations for atx‐tbp (sca17): mdsgene systematic review. Movement Disorders, 38:368-377, Nov 2023. URL: https://doi.org/10.1002/mds.29278, doi:10.1002/mds.29278. This article has 22 citations and is from a highest quality peer-reviewed journal.
(rossi2023genotype–phenotypecorrelationsfor media 82dfeaa1): Malco Rossi, Moath Hamed, Jon Rodríguez‐Antigüedad, Mario Cornejo‐Olivas, Marianthi Breza, Katja Lohmann, Christine Klein, Rajasumi Rajalingam, Connie Marras, and Bart P. van de Warrenburg. Genotype–phenotype correlations for atx‐tbp (sca17): mdsgene systematic review. Movement Disorders, 38:368-377, Nov 2023. URL: https://doi.org/10.1002/mds.29278, doi:10.1002/mds.29278. This article has 22 citations and is from a highest quality peer-reviewed journal.
(hoffmanzacharska2024thenewface pages 1-2): Dorota Hoffman-Zacharska and Anna Sułek. The new face of dynamic mutation—the caa [cag]n caa cag motif as a mutable unit in the tbp gene causative for spino-cerebellar ataxia type 17. International Journal of Molecular Sciences, 25:8190, Jul 2024. URL: https://doi.org/10.3390/ijms25158190, doi:10.3390/ijms25158190. This article has 1 citations.
(rossi2023genotype–phenotypecorrelationsfor pages 2-2): Malco Rossi, Moath Hamed, Jon Rodríguez‐Antigüedad, Mario Cornejo‐Olivas, Marianthi Breza, Katja Lohmann, Christine Klein, Rajasumi Rajalingam, Connie Marras, and Bart P. van de Warrenburg. Genotype–phenotype correlations for atx‐tbp (sca17): mdsgene systematic review. Movement Disorders, 38:368-377, Nov 2023. URL: https://doi.org/10.1002/mds.29278, doi:10.1002/mds.29278. This article has 22 citations and is from a highest quality peer-reviewed journal.
(rossi2023genotype–phenotypecorrelationsfor pages 8-8): Malco Rossi, Moath Hamed, Jon Rodríguez‐Antigüedad, Mario Cornejo‐Olivas, Marianthi Breza, Katja Lohmann, Christine Klein, Rajasumi Rajalingam, Connie Marras, and Bart P. van de Warrenburg. Genotype–phenotype correlations for atx‐tbp (sca17): mdsgene systematic review. Movement Disorders, 38:368-377, Nov 2023. URL: https://doi.org/10.1002/mds.29278, doi:10.1002/mds.29278. This article has 22 citations and is from a highest quality peer-reviewed journal.
(grassini2024cognitivedysfunctionsocial pages 1-3): Alberto Grassini, Aurora Cermelli, Fausto Roveta, Michela Zotta, Adriana Lesca, Andrea Marcinnò, Fabio Ferrandes, Elisa Piella, Silvia Boschi, Chiara Lombardo, Alfredo Brusco, Salvatore Gallone, Elisa Rubino, Amalia Bruni, and Innocenzo Rainero. Cognitive dysfunction, social behavior disorder, cerebellar ataxia, and atypical brain fdg-pet presentation in spinocerebellar ataxia 17: a case report. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 45:2877-2880, Mar 2024. URL: https://doi.org/10.1007/s10072-024-07453-4, doi:10.1007/s10072-024-07453-4. This article has 2 citations.
(rossi2023genotype–phenotypecorrelationsfor media 1829bb84): Malco Rossi, Moath Hamed, Jon Rodríguez‐Antigüedad, Mario Cornejo‐Olivas, Marianthi Breza, Katja Lohmann, Christine Klein, Rajasumi Rajalingam, Connie Marras, and Bart P. van de Warrenburg. Genotype–phenotype correlations for atx‐tbp (sca17): mdsgene systematic review. Movement Disorders, 38:368-377, Nov 2023. URL: https://doi.org/10.1002/mds.29278, doi:10.1002/mds.29278. This article has 22 citations and is from a highest quality peer-reviewed journal.
(cui2024spinocerebellarataxiasfrom pages 1-2): Zi-Ting Cui, Zong-Tao Mao, Rong Yang, Jia-Jia Li, Shan-Shan Jia, Jian-Li Zhao, Fang-Tian Zhong, Peng Yu, and Ming Dong. Spinocerebellar ataxias: from pathogenesis to recent therapeutic advances. Frontiers in Neuroscience, Jun 2024. URL: https://doi.org/10.3389/fnins.2024.1422442, doi:10.3389/fnins.2024.1422442. This article has 32 citations and is from a peer-reviewed journal.
(patel2023phenotypicdefectsfrom pages 1-2): Nikhil C. Patel, Nadir Alam, Kozeta Libohova, Ryan O. Dulay, Sokol V. Todi, and A. Sujkowski. Phenotypic defects from the expression of wild-type and pathogenic tata-binding proteins in new drosophila models of spinocerebellar ataxia type 17. G3: Genes, Genomes, Genetics, Aug 2023. URL: https://doi.org/10.1093/g3journal/jkad180, doi:10.1093/g3journal/jkad180. This article has 11 citations and is from a domain leading peer-reviewed journal.
(NCT04301284 chunk 1): Study of CAD-1883 for Spinocerebellar Ataxia. Cadent Therapeutics. 2021. ClinicalTrials.gov Identifier: NCT04301284
(NCT03701399 chunk 1): Troriluzole in Adult Participants With Spinocerebellar Ataxia. Biohaven Pharmaceuticals, Inc.. 2019. ClinicalTrials.gov Identifier: NCT03701399
(cui2024spinocerebellarataxiasfrom pages 6-7): Zi-Ting Cui, Zong-Tao Mao, Rong Yang, Jia-Jia Li, Shan-Shan Jia, Jian-Li Zhao, Fang-Tian Zhong, Peng Yu, and Ming Dong. Spinocerebellar ataxias: from pathogenesis to recent therapeutic advances. Frontiers in Neuroscience, Jun 2024. URL: https://doi.org/10.3389/fnins.2024.1422442, doi:10.3389/fnins.2024.1422442. This article has 32 citations and is from a peer-reviewed journal.
(cui2024spinocerebellarataxiasfrom pages 9-10): Zi-Ting Cui, Zong-Tao Mao, Rong Yang, Jia-Jia Li, Shan-Shan Jia, Jian-Li Zhao, Fang-Tian Zhong, Peng Yu, and Ming Dong. Spinocerebellar ataxias: from pathogenesis to recent therapeutic advances. Frontiers in Neuroscience, Jun 2024. URL: https://doi.org/10.3389/fnins.2024.1422442, doi:10.3389/fnins.2024.1422442. This article has 32 citations and is from a peer-reviewed journal.

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Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Treatments

Source YAML

References & Deep Research

Deep Research

Spinocerebellar ataxia type 17 (SCA17; ATX‑TBP; Huntington disease–like 4) — Disease Characteristics Research Report

Executive summary

1. Disease information

What is the disease?

Synonyms / alternative names

Key identifiers (OMIM, Orphanet, ICD, MeSH, MONDO)

Evidence source type

2. Etiology

Disease causal factors

Risk factors

Protective factors

Gene–environment interactions

3. Phenotypes

Core phenotype spectrum

Phenotype characteristics

Genotype–phenotype notes (clinical)

Quality of life impact

Suggested HPO terms (non-exhaustive; evidence-backed)

4. Genetic / molecular information

Causal gene

Pathogenic variant class

Repeat length interpretation (current practice trend)

Repeat structure (2024 development)

Modifier genes / digenic inheritance

Suggested ontology terms

5. Environmental information

6. Mechanism / pathophysiology

Current mechanistic concepts (disease-relevant)

Causal chain (high-level)

Suggested GO biological process terms (candidates; align to evidence themes)

Suggested Cell Ontology (CL) terms (candidates)

7. Anatomical structures affected

Organ/system level

Imaging-supported structures (examples)

Suggested UBERON terms (candidates)

8. Temporal development

Onset

Progression / course

9. Inheritance and population

Inheritance

Epidemiology statistics (limited by available evidence)

10. Diagnostics

Genetic testing

Repeat expansion interpretation (clinical counseling)

Imaging/biomarkers (emerging)

Differential diagnosis

11. Outcome / prognosis

12. Treatment

Current standard of care

Experimental / clinical trials (registry evidence)

Recent research directions (2023–2024 reviews; not SCA17-specific efficacy)

Suggested MAXO terms (candidates)

13. Prevention

14. Other species / natural disease

15. Model organisms

Drosophila models (SCA17-specific)

Key compiled facts table (evidence-backed)

Evidence-based figure/table note

Gaps / limitations of this report (based on available evidence set)