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Mappings

MONDO

MONDO:0008119 spinocerebellar ataxia type 1

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Inheritance

1

Autosomal dominant HP:0000006

SCA1 is transmitted in an autosomal dominant manner, with a 50% risk to offspring of an affected individual. Anticipation is characteristic and is biased by parent of origin: expansions occur preferentially on paternal transmission and contractions on maternal transmission.

autosomal dominant inheritance

Show evidence (2 references)

PMID:20301363 SUPPORT Human Clinical

"SCA1 is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting the expanded allele."

States the mode of inheritance and the recurrence risk directly.

PMID:20301363 SUPPORT Human Clinical

"Anticipation has been observed in SCA1; expansions are more likely to occur when the pathogenic ATXN1 allele is paternally transmitted, and contractions are more typical of maternal transmissions."

Supports anticipation with a paternal-transmission bias in repeat expansion.

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Mechanistic Hypotheses

2

Toxicity through native ataxin-1 complexes, not novel interactions

native_complex_toxicity CANONICAL

The polyglutamine expansion acts by modulating a core normal activity of ataxin-1 within its native, Ser776 phosphorylation-dependent complexes, chiefly the complex with the transcriptional repressor Capicua, rather than by conferring a novel aberrant interaction. Displacing mutant ataxin-1 from that complex by duplicating the paralog Atxn1l suppresses neuropathology.

Pathograph links

Nuclear Localization of Polyglutamine-Expanded Ataxin-1 -> Ser776-Dependent Assembly of Mutant Ataxin-1 into Native Complexes DIRECT Once nuclear, the expanded protein engages its normal phosphorylation-regulated partner complexes.

Ser776-Dependent Assembly of Mutant Ataxin-1 into Native Complexes -> Aberrant Ataxin-1-Capicua Transcriptional Repressor Activity DIRECT Ser776 phosphorylation is what loads the expanded protein into the Capicua-containing complex through which toxicity is exerted.

Nuclear aggregation is not the toxic species

aggregation_not_required CANONICAL

Nuclear localization of expanded ataxin-1 is necessary for disease, but visible nuclear aggregation is not: a self-association-deficient ataxin-1[77Q] that forms no detectable nuclear inclusions still produces ataxia and Purkinje cell pathology. The identity of the toxic species (soluble mutant conformers versus mature aggregates) remains debated across the polyglutamine diseases.

Pathograph links

Nuclear Localization of Polyglutamine-Expanded Ataxin-1 -> Ser776-Dependent Assembly of Mutant Ataxin-1 into Native Complexes DIRECT Once nuclear, the expanded protein engages its normal phosphorylation-regulated partner complexes.

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Pathophysiology

13

ATXN1 CAG Repeat Expansion

The initiating lesion is expansion of an unstable, translated CAG trinucleotide repeat in the coding region of ATXN1 on chromosome 6p22.3. Affected individuals usually carry 39 or more repeats, which encode a correspondingly elongated polyglutamine tract in ataxin-1. Because the repeat is translated, the established pathogenic mechanism operates at the protein level, through the expanded ataxin-1 protein itself. This does not exclude a parallel RNA-level contribution: repeat-associated non-AUG translation of the same locus is curated as its own branch below.

Genetic context allele_type: Translated CAG trinucleotide repeat expansion variant_origin: GERMLINE functional_impact_category: GAIN_OF_FUNCTION

Animal models

Atxn1-154Q knock-in mouse Mouse recapitulates Places the expansion at the endogenous locus under native regulation, making it the appropriate model for testing ATXN1-lowering therapy.

Downstream

Repeat-Associated Non-AUG Translation of the ATXN1 Repeat The same expanded repeat is also translated in non-canonical frames, producing RAN proteins alongside the polyglutamine-expanded ataxin-1.

Nuclear Localization of Polyglutamine-Expanded Ataxin-1 The expanded polyglutamine tract is carried by ataxin-1 into Purkinje cell nuclei, where the disease process is initiated.

Show evidence (2 references)

PMID:20301363 SUPPORT Human Clinical

"The diagnosis of SCA1 is established in a proband with characteristic clinical findings and an abnormal CAG repeat expansion in ATXN1 identified by molecular genetic testing. Affected individuals usually have 39 or more CAG repeats."

Defines the causal lesion and the pathogenic repeat threshold.

PMID:18957430 SUPPORT Other

"Genetic evidence indicates that the disease mutation induces a toxic gain of function in the SCA1 encoded protein ATXN1."

Supports classifying the expansion as a dominant toxic gain of function at the protein level rather than a loss of ataxin-1.

Nuclear Localization of Polyglutamine-Expanded Ataxin-1

Pathogenesis requires the expanded protein to reach the Purkinje cell nucleus. Transgenic mice expressing ataxin-1[82Q] with a mutated nuclear localization signal do not develop disease. Critically, visible nuclear aggregation is dissociable from toxicity: mice expressing a self-association-deficient ataxin-1[77Q] that forms no detectable nuclear inclusions still develop ataxia and Purkinje cell pathology. SCA1 is therefore not driven by inclusion formation per se, which distinguishes it from a simple aggregation model of polyglutamine disease.

Nuclear aggregation is not the toxic species Toxicity through native ataxin-1 complexes, not novel interactions

cerebellar Purkinje cell CL:0000121

protein localization to nucleus GO:0034504

Downstream

Ser776-Dependent Assembly of Mutant Ataxin-1 into Native Complexes Once nuclear, the expanded protein engages its normal phosphorylation-regulated partner complexes.

Show evidence (2 references)

PMID:9778246 SUPPORT Model Organism

"These mice did not develop disease, demonstrating that nuclear localization is critical for pathogenesis."

Establishes nuclear localization as necessary for disease.

PMID:9778246 SUPPORT Model Organism

"Thus, although nuclear localization of ataxin-1 is necessary, nuclear aggregation of ataxin-1 is not required to initiate pathogenesis in transgenic mice."

Separates nuclear entry from visible aggregation, supporting the claim that inclusion formation is not the toxic step in SCA1.

Ser776-Dependent Assembly of Mutant Ataxin-1 into Native Complexes

Phosphorylation of ataxin-1 at serine 776 gates its incorporation into large soluble protein complexes. Transgenic mice expressing ataxin-1[82Q]-A776, which cannot be phosphorylated at this residue, place the expanded protein in Purkinje cell nuclei yet are substantially protected from disease. The same S776A substitution markedly reduces the association of mutant ataxin-1 with Capicua in vivo, linking this phosphorylation site directly to the pathogenic complex. The kinases that place this mark are region-specific: MSK1 in cerebellum and RSK3 in brainstem. This is the clearest available answer to why a brain-wide protein kills only select populations, and it predicts that rescuing the whole disease requires targeting more than one regulator.

Toxicity through native ataxin-1 complexes, not novel interactions

protein phosphorylation GO:0006468 protein-containing complex assembly GO:0065003

Downstream

Brainstem, Olivary and Spinal Neuron Degeneration A Ser776-dependent branch that is not routed through the cerebellar Capicua mechanism: in brainstem the mark is placed by RSK3, and lowering RSK3 rescues brainstem pathology specifically.

Aberrant Ataxin-1-Capicua Transcriptional Repressor Activity Ser776 phosphorylation is what loads the expanded protein into the Capicua-containing complex through which toxicity is exerted.

Show evidence (4 references)

PMID:12741986 SUPPORT Model Organism

"These studies demonstrate that polyglutamine tract expansion and localization of ataxin-1 to the nucleus of Purkinje cells are not sufficient to induce disease. We suggest that S776 of ataxin-1 also has a critical role in SCA1 pathogenesis."

Shows nuclear expanded ataxin-1 is not sufficient without Ser776, establishing this residue as a required step.

PMID:18957430 SUPPORT Other

"Biochemical and genetic studies provide evidence that the polyglutamine expansion enhances interactions that are normally regulated by phosphorylation at Ser(776) and a subsequent alteration in its interaction with other cellular proteins."

Frames the expansion as acting by enhancing Ser776-regulated native interactions.

PMID:33709453 SUPPORT Model Organism

"Unlike MSK1, RSK3 is highly expressed in the human and mouse brainstems where it regulates Atxn1 by phosphorylating S776."

Identifies the region-specific kinases acting at Ser776, the mark this node is about.

+ 1 more reference

Aberrant Ataxin-1-Capicua Transcriptional Repressor Activity

Both wild-type and expanded ataxin-1 assemble into large stable cerebellar complexes containing the transcriptional repressor Capicua (CIC), and ataxin-1 modulates Capicua repressor activity. SCA1 toxicity depends on this native interaction rather than on a novel one acquired by the expanded protein. The genetic test is decisive: duplicating the ataxin-1 paralog Atxn1l, which displaces mutant ataxin-1 from the Capicua complex, suppresses neuropathology in a knock-in SCA1 model. Ataxin-1 also both gains and partially loses interactions, so SCA1 combines a dominant gain of function with partial loss of normal ataxin-1 activity. Capicua is not the whole mechanism: abolishing the ATXN1-CIC interaction globally in knock-in mice normalized genome-wide CIC binding but only partially corrected transcriptional and behavioural phenotypes, and further ataxin-1 transcription-factor partners (RFX1, ZBTB5, ZKSCAN1) have since been identified.

cerebellar Purkinje cell CL:0000121

negative regulation of transcription by RNA polymerase II GO:0000122 ⇑ GAIN OF FUNCTION

Animal models

Atxn1l duplication modifier mouse Mouse rescues Suppresses SCA1 neuropathology specifically by reducing incorporation of polyglutamine-expanded ataxin-1 into the Capicua-containing complex.

Downstream

RORalpha Destabilization and Loss of the Purkinje Gene Expression Program Transcriptional dysregulation by the mutant complex depletes the Purkinje cell transcription factor RORalpha and its target genes.

RBFOX1-Mediated Alternative Splicing Dysregulation Beyond changing which genes are transcribed, mutant ataxin-1 changes how transcripts are spliced, through a separate splicing-factor route.

Purkinje Cell Dysfunction and Dendritic Atrophy Sustained transcriptional dysregulation degrades Purkinje cell function before overt cell loss.

Brainstem, Olivary and Spinal Neuron Degeneration The same transcriptional dysregulation acts in the extracerebellar neuronal populations that also express ataxin-1, which is why SCA1 is not confined to the cerebellar cortex. Why these particular populations are vulnerable while most ataxin-1-expressing neurons are spared is not resolved.

Show evidence (6 references)

PMID:17190598 SUPPORT Model Organism

"We examined soluble protein complexes from mouse cerebellum and found that the majority of wild-type and expanded ATXN1 assembles into large stable complexes containing the transcriptional repressor Capicua."

Establishes the Capicua-containing complex as the principal ataxin-1 assembly in cerebellum.

PMID:17190598 SUPPORT Model Organism

"These data provide insight into the function of ATXN1 and suggest that SCA1 neuropathology depends on native, not novel, protein interactions."

Supports attributing toxicity to modulation of a normal ataxin-1 activity rather than to a novel aberrant interaction.

PMID:17322884 SUPPORT Model Organism

"we found that elevated Atxn1l levels suppress neuropathology by displacing mutant Atxn1 from its native complex with Capicua (CIC)"

Provides the genetic rescue showing that occupancy of the Capicua complex by mutant ataxin-1 is what drives neuropathology.

+ 3 more references

RORalpha Destabilization and Loss of the Purkinje Gene Expression Program

Mutant ataxin-1 depletes RORalpha, a transcription factor critical for cerebellar development, and reduces expression of RORalpha-controlled genes; partial loss of RORalpha enhances mutant ataxin-1 pathogenicity. Because RORalpha acts developmentally, the timing of mutant ataxin-1 expression matters: delaying its postnatal expression until cerebellar development is complete substantially reduces adult disease severity. This gives SCA1 a developmental component on top of its adult-onset degeneration.

cerebellar Purkinje cell CL:0000121

cerebellar Purkinje cell layer development GO:0021680 ↓ DECREASED

Downstream

Purkinje Cell Dysfunction and Dendritic Atrophy

Show evidence (2 references)

PMID:17110330 SUPPORT Model Organism

"In SCA1 mice, there was a depletion of RORalpha and a reduction in expression of genes controlled by RORalpha. Partial loss of RORalpha enhanced mutant ATXN1 pathogenicity."

Establishes RORalpha depletion and its modifier effect on pathogenicity.

PMID:17110330 SUPPORT Model Organism

"Delayed postnatal expression of mutant ATXN1 led to a substantial reduction in severity of disease in adults in comparison with early postnatal gene expression."

Supports the developmental-window contribution to adult disease severity.

Purkinje Cell Dysfunction and Dendritic Atrophy

Purkinje cells expressing expanded ataxin-1 show functional and morphological deterioration preceding cell loss, with dendritic atrophy and neurochemical abnormalities detectable in vivo. This stage is reversible in principle: halting expression of mutant ataxin-1 in a conditional model restores cerebellar morphology and motor function, and the earlier expression is stopped the greater the recovery.

cerebellar Purkinje cell CL:0000121

dendrite morphogenesis GO:0048813 ↓ DECREASED calcium ion homeostasis GO:0055074 ↓ DECREASED signal transduction GO:0007165 ↓ DECREASED

Experimental models

SCA1 patient-derived iPSC neuronal cultures IPSC DERIVED MODEL Reproduces the dendritic and network-level dysfunction of the target node in human cells.

Downstream

Purkinje Neuron Degeneration Unrelieved dysfunction proceeds to irreversible loss of the same neurons.

Show evidence (4 references)

PMID:10649571 SUPPORT Model Organism

"we found certain neuronal genes involved in signal transduction and calcium homeostasis sequentially downregulated in SCA1 mice"

Supplies the calcium-homeostasis and signal-transduction dysregulation that this node's module conformance target specifies.

PMID:10649571 SUPPORT Human Clinical

"Similar downregulation occurred in SCA1 human tissues."

Confirms the same gene-expression change in human SCA1 tissue, so the claim is not model-only.

PMID:10649571 SUPPORT Model Organism

"These genes were abundant in Purkinje cells, the primary site of SCA1 pathogenesis; moreover, their downregulation was mediated by expanded ataxin-1 and occurred before detectable pathology."

Establishes that the dysregulation is Purkinje-centred and precedes pathology, supporting this node as a pre-degenerative dysfunction stage.

+ 1 more reference

Purkinje Neuron Degeneration

Cerebellar Purkinje cells are the principal vulnerable population in SCA1, and their loss is the defining neuropathological feature. Expression of an expanded CAG repeat restricted to Purkinje cells is sufficient to produce both the degeneration and the ataxic phenotype in mice.

cerebellar Purkinje cell CL:0000121

neuron death ↑ INCREASED

Animal models

SCA1 Purkinje-cell transgenic mouse (ataxin-1 with expanded CAG repeat) Mouse recapitulates Reproduces the defining Purkinje cell degeneration of human SCA1 and establishes that expanded repeat expression within Purkinje cells is sufficient to cause it.

Downstream

Loss of Cerebellar Cortical Output

Show evidence (4 references)

PMID:7553854 SUPPORT Model Organism

"transgenic animals from five of six lines with the expanded SCA1 allele developed ataxia and Purkinje cell degeneration"

Demonstrates that the expanded allele causes Purkinje cell degeneration with ataxia.

PMID:38750673 SUPPORT Model Organism

"Using immunohistochemistry, we demonstrated earlier and more severe pathology of PCs and glia in the posterior cerebellar vermis of SCA1 mice."

Adds a sub-regional gradient to this node: Purkinje loss is not uniform across the cerebellum, and the posterior vermis is affected earlier and more severely.

PMID:38750673 SUPPORT Model Organism

"we found both shared, as well as, posterior cerebellum-specific molecular mechanisms of pathogenesis that include exacerbated gene dysregulation, increased number of altered signaling pathways, and decreased pathway activity scores in the posterior cerebellum of SCA1 mice"

Supports a molecular basis for the gradient, complementing the region-specific kinase account of selectivity curated upstream.

+ 1 more reference

Brainstem, Olivary and Spinal Neuron Degeneration

Beyond the cerebellar cortex, SCA1 involves brainstem neurons, spinocerebellar tracts, medullary cranial nerve nuclei, and anterior horn neurons, with variable damage to basal ganglia and spinal cord. This extracerebellar burden explains the pyramidal, extrapyramidal, sensory-neuropathic, and bulbar features that place SCA1 in the ADCA-I class, and it is what ultimately kills. The brainstem branch is not simply the cerebellar mechanism spilling over: it is governed by a different Ser776 kinase, RSK3, whose reduction rescues brainstem pathology specifically, and the brainstem is the region whose pathology is most closely tied to premature death.

neuron death ↑ INCREASED

Downstream

Progressive Cerebellar and Bulbar Syndrome

Dysphagia

Hyperreflexia

Hyporeflexia

Sensory Axonal Neuropathy

Impaired Proprioception

Skeletal Muscle Atrophy

Chorea

Dystonia

Impaired Executive Functioning

Brainstem Atrophy

Show evidence (3 references)

PMID:32818920 SUPPORT Other

"Pathological changes typically include prominent deterioration of cerebellar Purkinje cells and brainstem degeneration along with a variable degree of damage to more anterior (e.g., basal ganglia) and posterior (e.g., spinal cord) regions of the nervous system."

Documents the extracerebellar distribution of neuronal loss in SCA1. Graded OTHER because this is review-style background in a preclinical mouse study rather than human data reported there.

PMID:33709453 SUPPORT Model Organism

"Reducing Rsk3 rescues brainstem-associated pathologies and deficits, and lowering Rsk3 and Msk1 together improves cerebellar and brainstem function in an SCA1 mouse model."

Gives this node its own brainstem-specific mechanism and the rescue that demonstrates it, rather than inferring brainstem loss from the cerebellar chain.

PMID:33709453 SUPPORT Model Organism

"there are no regulators that modulate ATXN1 in the brainstem-the brain region whose pathology is most closely linked to premature death"

Supports the brainstem as the population whose loss drives mortality.

Loss of Cerebellar Cortical Output

Purkinje cells are the sole output neurons of the cerebellar cortex. Their loss removes the inhibitory cortical control normally delivered to the deep cerebellar nuclei, degrading the feedforward coordination of limb, gait, speech, and eye movement. Cerebellar and brainstem atrophy is visible on imaging.

cerebellar Purkinje cell CL:0000121

Downstream

Progressive Cerebellar and Bulbar Syndrome

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"brain imaging typically shows cerebellar and brain stem atrophy"

Confirms the structural cerebellar and brainstem loss underlying loss of cortical output.

Progressive Cerebellar and Bulbar Syndrome

The convergent clinical manifestation of lost cerebellar coordination. The individual signs it produces are curated as phenotypes and reached by the edges below.

Downstream

Progressive Gait Ataxia

Dysarthria

Dysmetria

Dysdiadochokinesis

Hypotonia

Nystagmus

Hypermetric Saccades

Slow Saccadic Eye Movements

Upgaze Palsy

Cerebellar Atrophy

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"Spinocerebellar ataxia type 1 (SCA1) is characterized by progressive cerebellar ataxia, dysarthria, and eventual deterioration of bulbar functions."

States the defining clinical syndrome that the mechanism converges on.

Repeat-Associated Non-AUG Translation of the ATXN1 Repeat

The expanded repeat is translated in non-canonical reading frames as well as the polyglutamine frame, yielding sense polyserine and antisense polyleucine RAN proteins. These accumulate through cerebellum and pons in SCA1 autopsy brain, are prominent in cerebellar white matter where polyglutamine is minimal, and impair autophagy in neural cells. This is a protein-level consequence of the repeat that is nonetheless separate from ataxin-1 itself, which is why the entry does not claim the polyglutamine protein is the only toxic species.

autophagy GO:0006914 ↓ DECREASED

Downstream

Purkinje Cell Dysfunction and Dendritic Atrophy RAN proteins impair autophagy, adding a proteostatic burden to the same vulnerable neurons.

Show evidence (3 references)

PMID:41422503 SUPPORT In Vitro

"In neural cells, toxic polySer and polyLeu proteins impair autophagy, and reducing RAN protein levels with metformin reduces cytotoxicity."

Establishes the autophagy impairment and its reversibility on lowering RAN protein.

PMID:41422503 SUPPORT Human Clinical

"Cerebellar white matter regions, with prominent polySer and polyLeu but minimal polyGln, show neuroinflammation and demyelination."

Supports RAN proteins acting where polyglutamine is scarce, so this branch is not a restatement of the polyglutamine one.

PMID:41422503 SUPPORT Model Organism

"Disrupting the ATXN182Q:capicua binding, which improves behavior and neuropathology, also reduces RAN protein aggregates."

Links this branch back to the Capicua mechanism, indicating the two are coupled rather than fully independent.

RBFOX1-Mediated Alternative Splicing Dysregulation

Mutant ataxin-1 misregulates alternative splicing in the cerebellum, largely cell-autonomously, affecting biological pathways distinct from those hit by differential gene expression. The splicing factor RBFOX1 mediates this effect, and manipulating it modifies neurodegeneration in a Drosophila SCA1 model. This is a second transcript-level mechanism alongside the Capicua-dependent transcriptional one.

RNA splicing GO:0008380 ↕ DYSREGULATED

Downstream

Purkinje Cell Dysfunction and Dendritic Atrophy

Show evidence (3 references)

PMID:37802886 SUPPORT Model Organism

"We performed RNA sequencing in mouse models of spinocerebellar ataxia type 1 and identified that mutant ataxin-1 expression abnormally leads to diverse splicing events in the mouse cerebellum of spinocerebellar ataxia type 1."

Establishes splicing dysregulation as a consequence of mutant ataxin-1.

PMID:37802886 SUPPORT Model Organism

"We also provide evidence that the splicing factor Rbfox1 mediates the effect of mutant ataxin-1 on misregulated alternative splicing and that genetic manipulation of Rbfox1 expression modifies neurodegenerative phenotypes in a Drosophila model of spinocerebellar ataxia type 1 in vivo."

Identifies RBFOX1 as the mediator and shows it modifies degeneration in vivo.

PMID:37802886 SUPPORT Model Organism

"A majority of the transcripts with misregulated alternative splicing events were previously unknown, thus allowing us to identify overall new biological pathways that are distinctive to those affected by differential gene expression in spinocerebellar ataxia type 1."

Supports treating this as a mechanism distinct from the transcriptional one rather than folding it into that node.

Non-Cell-Autonomous Oligodendrocyte Dysfunction

Mutant ataxin-1 expressed in oligodendrocytes alone is sufficient to produce dysregulated myelination, Purkinje cell axonal shrinkage and torpedo formation, and impaired motor coordination. This is the entry's answer to why a Purkinje-centred account is incomplete: a substantial part of Purkinje pathology is driven from outside the Purkinje cell, by a glial population, with TCF7L2 and huntingtin identified as upstream regulators of the oligodendroglial program.

oligodendrocyte CL:0000128

myelination GO:0042552 ↓ DECREASED

Downstream

Purkinje Cell Dysfunction and Dendritic Atrophy Demyelination and axo-myelinic dysfunction drive Purkinje axonal pathology, so this glial branch converges on the same node as the cell-autonomous chain.

Show evidence (2 references)

PMID:42113962 SUPPORT Model Organism

"using an oligodendroglia-specific SCA1 conditional knockin mouse model, we demonstrate that mutant ataxin-1 in oligodendrocytes is sufficient to drive aspects of SCA1-related pathology, including dysregulated myelination, PC axonal shrinkage, and torpedo formation, ultimately impairing motor coordination"

The sufficiency result: a cell-type-restricted model shows glial expression alone reproduces core SCA1 pathology.

PMID:42113962 SUPPORT Model Organism

"Upstream transcriptional regulator analysis in oligodendroglia identifies transcription factor 7-like 2 (TCF7L2) and huntingtin (HTT) as key mediators of oligodendroglial dysfunction in SCA1, suggesting shared pathogenic mechanisms with other polyglutamine diseases."

Names the upstream regulators of the oligodendroglial program in this branch.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

20

Digestive 1

Dysphagia VERY_FREQUENT HP:0002015

Course: PROGRESSIVE

Show evidence (2 references)

PMID:20301363 SUPPORT Human Clinical

"Early in the disease, affected individuals may have gait disturbance, slurred speech, difficulty with balance, brisk deep tendon reflexes, hypermetric saccades, nystagmus, and mild dysphagia."

Documents mild dysphagia as present from early in the course.

PMID:32818920 SUPPORT Other

"death due to dysphagia and/or respiratory failure caused by degenerations in medullary cranial nerve nuclei and anterior horn neurons"

Establishes dysphagia as a direct contributor to mortality. Graded OTHER because the sentence is background narrative in a preclinical mouse study, not human data reported by it.

Eye 4

Hypermetric Saccades FREQUENT HP:0007338

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"Early in the disease, affected individuals may have gait disturbance, slurred speech, difficulty with balance, brisk deep tendon reflexes, hypermetric saccades, nystagmus, and mild dysphagia."

Places hypermetric saccades among the early oculomotor findings.

Slow Saccadic Eye Movements OCCASIONAL HP:0000514

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"Later signs include slowing of saccadic velocity, development of upgaze palsy, dysmetria, dysdiadochokinesia, and hypotonia."

Identifies saccadic slowing as a later-stage sign.

Nystagmus FREQUENT HP:0000639

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"Early in the disease, affected individuals may have gait disturbance, slurred speech, difficulty with balance, brisk deep tendon reflexes, hypermetric saccades, nystagmus, and mild dysphagia."

Lists nystagmus among the early findings.

Upgaze Palsy OCCASIONAL HP:0025331

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"Later signs include slowing of saccadic velocity, development of upgaze palsy, dysmetria, dysdiadochokinesia, and hypotonia."

Names upgaze palsy as a later oculomotor sign.

Musculoskeletal 2

Hypotonia OCCASIONAL HP:0001252

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"Later signs include slowing of saccadic velocity, development of upgaze palsy, dysmetria, dysdiadochokinesia, and hypotonia."

Lists hypotonia among the later signs.

Skeletal Muscle Atrophy OCCASIONAL HP:0003202

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"In advanced stages, muscle atrophy, decreased deep tendon reflexes, loss of proprioception, cognitive impairment (e.g., frontal executive dysfunction, impaired verbal memory), chorea, dystonia, and bulbar dysfunction are seen."

Records muscle atrophy as an advanced-stage feature.

Nervous System 13

Progressive Gait Ataxia VERY_FREQUENT HP:0002066

Course: PROGRESSIVE

Sequelae: Dysphagia

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"Early in the disease, affected individuals may have gait disturbance, slurred speech, difficulty with balance, brisk deep tendon reflexes, hypermetric saccades, nystagmus, and mild dysphagia."

Lists gait disturbance and impaired balance among the early features.

Dysarthria VERY_FREQUENT HP:0001260

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"Spinocerebellar ataxia type 1 (SCA1) is characterized by progressive cerebellar ataxia, dysarthria, and eventual deterioration of bulbar functions."

Names dysarthria as a defining feature of SCA1.

Hyperreflexia FREQUENT HP:0001347

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"Early in the disease, affected individuals may have gait disturbance, slurred speech, difficulty with balance, brisk deep tendon reflexes, hypermetric saccades, nystagmus, and mild dysphagia."

Documents brisk deep tendon reflexes as an early pyramidal sign.

Hyporeflexia OCCASIONAL HP:0001265

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"In advanced stages, muscle atrophy, decreased deep tendon reflexes, loss of proprioception, cognitive impairment (e.g., frontal executive dysfunction, impaired verbal memory), chorea, dystonia, and bulbar dysfunction are seen."

Records decreased deep tendon reflexes as an advanced-stage finding.

Dysmetria OCCASIONAL HP:0001310

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"Later signs include slowing of saccadic velocity, development of upgaze palsy, dysmetria, dysdiadochokinesia, and hypotonia."

Lists dysmetria among the appendicular cerebellar signs.

Dysdiadochokinesis OCCASIONAL HP:0002075

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"Later signs include slowing of saccadic velocity, development of upgaze palsy, dysmetria, dysdiadochokinesia, and hypotonia."

Lists dysdiadochokinesia among the appendicular cerebellar signs.

Sensory Axonal Neuropathy FREQUENT HP:0003390

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"An axonal sensory neuropathy detected by electrophysiologic testing is common; brain imaging typically shows cerebellar and brain stem atrophy."

States that axonal sensory neuropathy is a common electrophysiologic finding.

Impaired Proprioception OCCASIONAL HP:0010831

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"In advanced stages, muscle atrophy, decreased deep tendon reflexes, loss of proprioception, cognitive impairment (e.g., frontal executive dysfunction, impaired verbal memory), chorea, dystonia, and bulbar dysfunction are seen."

Lists loss of proprioception among advanced-stage findings.

Impaired Executive Functioning OCCASIONAL HP:0033051

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"cognitive impairment (e.g., frontal executive dysfunction, impaired verbal memory)"

Specifies the frontal-executive character of the cognitive impairment.

Chorea OCCASIONAL HP:0002072

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"In advanced stages, muscle atrophy, decreased deep tendon reflexes, loss of proprioception, cognitive impairment (e.g., frontal executive dysfunction, impaired verbal memory), chorea, dystonia, and bulbar dysfunction are seen."

Lists chorea among advanced-stage extrapyramidal features.

Dystonia OCCASIONAL HP:0001332

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"In advanced stages, muscle atrophy, decreased deep tendon reflexes, loss of proprioception, cognitive impairment (e.g., frontal executive dysfunction, impaired verbal memory), chorea, dystonia, and bulbar dysfunction are seen."

Lists dystonia among advanced-stage extrapyramidal features.

Cerebellar Atrophy VERY_FREQUENT HP:0001272

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"brain imaging typically shows cerebellar and brain stem atrophy"

Reports cerebellar atrophy as the typical imaging finding.

Brainstem Atrophy VERY_FREQUENT Atrophy/Degeneration affecting the brainstem HP:0007366

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"brain imaging typically shows cerebellar and brain stem atrophy"

Reports brainstem atrophy alongside cerebellar atrophy on imaging.

🧬

Genetic Associations

3

ATXN1 (Translated CAG trinucleotide repeat expansion)

Gene: ATXN1 hgnc:10548 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (9 references)

PMID:37238658 SUPPORT Other

"Normal alleles range from 6 to 38 CAG repeats, with 1 to 3 CAT interruptions that are thought to be involved in the stability of the trinucleotide stretch during DNA replication."

Establishes CAT interruptions as the feature stabilizing normal-range ATXN1 alleles.

PMID:37238658 SUPPORT Other

"Disease-causing alleles have 39 to 44 CAG repeats without stabilizing CAT interruptions or larger expansions with CAT interruptions"

Defines the pathogenic allele architecture, and notes that longer alleles may retain interruptions, so purity is not a universal criterion.

PMID:16110192 SUPPORT Human Clinical

"None of the expanded alleles contained CAT interruptions."

Direct family-level observation that pathogenic alleles were uninterrupted.

+ 6 more references

TGM5 (Modifier of mutant ataxin-1 stability and oligomerization)

Gene: TGM5 hgnc:11781 relationship_type: MODIFIER

Show evidence (2 references)

PMID:35499073 SUPPORT In Vitro

"TG enzymes catalyzed cross-linking of ATXN1 in a polyQ-length-dependent manner, thereby preferentially modulating mutant ATXN1 stability and oligomerization."

Establishes the polyglutamine-length-dependent, mutant-selective modifier effect.

PMID:35499073 SUPPORT Human Clinical

"Moreover, TG5 was enriched in the nuclei of SCA1-affected neurons and colocalized with nuclear ATXN1 inclusions in brain tissue from patients with SCA1."

Confirms TG5 is present at the relevant subcellular site in human SCA1 brain, so the modifier claim is not model-only.

RBFOX1 (Splicing factor mediating mutant ataxin-1 splicing dysregulation)

Gene: RBFOX1 hgnc:18222 relationship_type: MODIFIER

Show evidence (1 reference)

PMID:37802886 SUPPORT Model Organism

"We also provide evidence that the splicing factor Rbfox1 mediates the effect of mutant ataxin-1 on misregulated alternative splicing and that genetic manipulation of Rbfox1 expression modifies neurodegenerative phenotypes in a Drosophila model of spinocerebellar ataxia type 1 in vivo."

Supports RBFOX1 as a genetic modifier of the neurodegenerative phenotype.

💊

Medical Actions

13

Coordinative Physiotherapy and Physical Therapy

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Supportive management centers on adaptive devices, physical therapy, and intensive coordinative physiotherapy, which may be beneficial. Avoidance of obesity is specifically recommended. There is no disease-modifying therapy.

Mechanism Target:

Progressive Cerebellar and Bulbar Syndrome — Rehabilitation targets the functional consequences of lost cerebellar coordination; it does not modify the underlying degeneration.

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"Supportive care including adaptive devices, physical therapy, occupational therapy, avoidance of obesity; intensive rehabilitation (coordinative physiotherapy) may be beneficial"

States the recommended rehabilitative management for SCA1.

Occupational Therapy

Action: occupational therapy Ontology label: Occupational Therapy NCIT:C121351

Platform: Behavioral / lifestyle

Occupational therapy supports mobility and self-help skills and is reassessed every three to six months alongside physiatry and physical therapy.

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"physiatry, occupational therapy, and physical therapy assessment for mobility and self-help skills"

Documents occupational therapy as part of scheduled surveillance and management.

Speech Therapy and Communication Devices

Action: speech and language therapy Ontology label: Speech Language Therapy NCIT:C159273

Platform: Behavioral / lifestyle

Speech therapy and communication devices address the progressive dysarthria; access to communication is assessed at each visit.

Mechanism Target:

Progressive Cerebellar and Bulbar Syndrome — Symptomatic management of dysarthria arising from bulbar and cerebellar involvement.

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"speech therapy and communication devices for dysarthria"

States the recommended management of dysarthria.

Dysphagia and Nutritional Management

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

Aspiration risk is managed with video esophagram to identify the safest food consistency, feeding devices where aspiration recurs, and caloric support for weight loss.

Mechanism Target:

Dysphagia — Directly targets the aspiration and nutritional consequences of bulbar dysfunction, the proximate cause of death in SCA1.

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"video esophagram to help identify the consistency of food least likely to trigger aspiration and feeding devices may be indicated with recurrent aspiration; caloric support for those with weight loss"

States the recommended dysphagia and nutritional management.

Avoidance of Neurotoxic Agents and Hazardous Circumstances

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

GeneReviews lists specific agents and circumstances to avoid in SCA1: alcohol, medications known to cause nerve damage such as isoniazid and large-dose vitamin B6, and situations that could cause physical harm such as operating machinery or climbing to great heights. The neurotoxic drug caution is particularly relevant given the common coexisting axonal sensory neuropathy.

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"Agents/circumstances to avoid: Alcohol, medications known to cause nerve damage (e.g., isoniazid, large-dose vitamin B6), and circumstances that could lead to physical harm, such as operating machinery or climbing to great heights."

Records the GeneReviews drug-safety and hazard-avoidance guidance verbatim.

Psychotherapy and Neuropsychologic Rehabilitation

Action: psychotherapy Ontology label: Psychotherapy NCIT:C15308

Platform: Behavioral / lifestyle

GeneReviews recommends psychotherapy, neuropsychologic rehabilitation, and standard psychiatric treatment for the cognitive and psychiatric manifestations of SCA1, with mood and psychiatric manifestations assessed at each visit.

Mechanism Target:

Impaired Executive Functioning — Addresses the frontal-executive and psychiatric burden of advanced disease; it is symptomatic and does not alter the degeneration.

Show evidence (2 references)

PMID:20301363 SUPPORT Human Clinical

"psychotherapy, neuropsychologic rehabilitation, and/or standard psychiatric treatments for cognitive and psychiatric manifestations"

States the recommended management of cognitive and psychiatric features.

PMID:20301363 SUPPORT Human Clinical

"assessment of access to communication, speech needs, aspiration risk, feeding needs, mood, psychiatric manifestations, cognition, and family needs"

Documents mood, psychiatric manifestations and cognition as surveillance items.

Pain Management

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

Pharmacotherapy and referral to pain management are recommended as needed for pain in SCA1.

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"pharmacotherapy and/or referral to pain management as needed for pain"

States the recommended approach to pain in SCA1.

Vitamin Supplementation

Action: nutritional support Ontology label: Nutritional Support NCIT:C15433

Platform: Small molecule

Vitamin supplementation as needed is part of supportive management. Note this sits beside an explicit caution against large-dose vitamin B6, which is listed among agents to avoid because of its neurotoxicity.

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"caloric support for those with weight loss; vitamin supplementation as needed"

Records vitamin supplementation as a recommended supportive measure. The quote carries the adjacent caloric-support clause because the chapter states the two together; caloric support itself is curated under Dysphagia and Nutritional Management.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Counseling covers the 50% offspring risk, anticipation with paternal expansion bias, and the availability of prenatal and preimplantation genetic testing once a family expansion is identified.

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"Once an abnormal CAG trinucleotide expansion in ATXN1 has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."

States the reproductive testing options that counseling covers.

Off-Label Symptomatic Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: riluzole CHEBI:8863 4-aminopyridine CHEBI:34385 varenicline CHEBI:84500

Platform: Small molecule

No drug is approved for SCA1 and none is disease-modifying. Riluzole, 4-aminopyridine and varenicline are used off-label across the adult-onset cerebellar ataxias with subtype-specific benefit, so their applicability to SCA1 specifically is not established by the source cited here, which reviews the class. They are recorded because the entry otherwise implied that nothing pharmacological is offered, which misrepresents practice.

Mechanism Target:

Progressive Cerebellar and Bulbar Syndrome — These agents target the ataxic syndrome symptomatically; none acts on the ATXN1 lesion or the mechanisms downstream of it.

Show evidence (2 references)

PMID:41387161 SUPPORT Other

"Pharmacological approaches, including omaveloxolone for Friedreich's ataxia and off-label agents such as riluzole, 4-aminopyridine, and varenicline, demonstrate subtype-specific benefits."

Names the off-label agents and, in the same sentence, that benefit is subtype-specific, which is why this entry does not claim SCA1 efficacy.

PMID:41387161 SUPPORT Other

"Rehabilitation and multidisciplinary care remain foundational across all subtypes and are supported by growing clinical trial evidence."

Supports the supportive and rehabilitative entries above remaining the mainstay rather than being displaced by these agents.

Troriluzole (Investigational)

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

Troriluzole is a riluzole prodrug with improved oral bioavailability and less pharmacokinetic variability, in clinical trials for cerebellar ataxia. The caveat matters: the citation available here is a rat opioid-addiction study that mentions the ataxia trials only in passing, so this records that the development programme exists, not any SCA1 efficacy result.

Show evidence (2 references)

PMID:40988103 SUPPORT Other

"TRLZ, already in clinical trials for cerebellar ataxia, also reduced opioid taking and seeking as well as opioid-derived adverse effects in rats"

Graded OTHER because the statement about cerebellar ataxia trials is a passing aside in a rat opioid study, not a finding of that study. It establishes only that the trials exist.

PMID:40988103 SUPPORT Other

"we designed and prepared the prodrug troriluzole (TRLZ), which retains the mechanistic profile of riluzole but with optimized metabolic and pharmacokinetic properties"

Establishes the relationship to riluzole and the rationale for the prodrug.

Non-Invasive Neuromodulation

Action: therapeutic procedure Ontology label: Therapeutic Procedure NCIT:C49236

Platform: Device

Transcranial direct current stimulation and repetitive transcranial magnetic stimulation have shown early promise for motor outcomes in the adult-onset cerebellar ataxias. Recorded as early-stage and class-level, not as established SCA1 therapy.

Mechanism Target:

Progressive Cerebellar and Bulbar Syndrome — Symptomatic modulation of motor output; not disease-modifying.

Show evidence (1 reference)

PMID:41387161 SUPPORT Other

"Neuromodulation techniques, such as transcranial direct current stimulation and repetitive transcranial magnetic stimulation, have shown early promise in improving motor outcomes."

States the modality and the strength of the claim, which the description deliberately does not upgrade.

ATXN1-Lowering Antisense Oligonucleotide (Investigational)

Action: Pharmacotherapy NCIT:C15986

Agent: antisense oligonucleotide NCIT:C1291

Platform: Antisense oligonucleotide RNase H knockdown

RNA target: ATXN1 hgnc:10548 ATXN1 pre-mRNA and mature mRNA

Non-allele-specific reduction of ATXN1 by an RNase H antisense oligonucleotide rescues motor deficits and premature lethality in Atxn1-154Q knock-in mice after a single treatment, and reverses neurochemical abnormalities in cerebellum and brainstem. A dedicated safety assessment found no adverse effect on Capicua tumor-suppressor function, BACE1, or hippocampal neuronal precursor numbers, addressing the main theoretical concerns of lowering a protein whose normal partner is a tumor suppressor. This is preclinical; no ATXN1-lowering therapy is approved for SCA1.

Mechanism Target:

ATXN1 CAG Repeat Expansion — Lowering ATXN1 RNA reduces the amount of expanded ataxin-1 available to enter the pathogenic complex, acting at the top of the causal chain.

Show evidence (1 reference)

PMID:30385727 SUPPORT Model Organism

"Following a single ASO treatment at 5 weeks of age, mice demonstrated rescue of these disease-associated phenotypes."

Shows that reducing the initiating molecular lesion rescues the downstream motor and survival phenotypes.

Show evidence (2 references)

PMID:30385727 SUPPORT Model Organism

"Together, these findings support the efficacy and therapeutic importance of directly targeting ATXN1 RNA expression as a strategy for treating both motor deficits and lethality in SCA1."

States the preclinical efficacy conclusion for ATXN1-lowering ASO therapy.

PMID:32818920 SUPPORT Model Organism

"Notably, no effects on BACE1, CIC tumor suppressor function, or number of hippocampal neuronal precursor cells were found in mice subjected to a chronic in vivo ASO-mediated reduction of Atxn1."

Supports the safety claim regarding the main theoretical risks of ATXN1 lowering.

🔬

Biochemical Markers

1

Blood Neurofilament Light Chain

Show evidence (2 references)

PMID:42677125 SUPPORT Other

"Volumetric, microstructural, and spectroscopic MRI and blood neurofilament light chain change before ataxia onset and predict subsequent decline, whereas repeat length and genetic modifiers set prior risk."

Establishes the premanifest change and prognostic value that make this a curated biomarker rather than a general injury marker.

PMID:42677125 SUPPORT Other

"Disease-modifying therapies, notably antisense oligonucleotides and the approved compound omaveloxolone, are now entering or reaching the clinic, which makes reliable prediction of disease progression a central obstacle to trial success."

Explains why the premanifest window matters for SCA1 specifically, given the ATXN1-lowering ASO curated in treatments.

🔬

Diagnosis

3

ATXN1 Repeat-Sizing Molecular Genetic Testing

Diagnosis rests on sizing the CAG repeat in ATXN1 in a proband with a compatible progressive cerebellar syndrome. Because SCA1 is clinically indistinguishable from several other dominant ataxias, molecular testing rather than phenotype resolves the genotype.

Show evidence (1 reference)

PMID:20301363 SUPPORT Human Clinical

"The diagnosis of SCA1 is established in a proband with characteristic clinical findings and an abnormal CAG repeat expansion in ATXN1 identified by molecular genetic testing."

States the diagnostic standard directly.

Determination of CAT Interruption Status

Sizing the repeat is not sufficient on its own: the diagnostic workup should establish whether the CAG tract is interrupted by CAT units, using triplet-primed PCR and enzymatic digestion. Interruption status bears on pathogenicity, on how an intermediate-range allele is interpreted, and on counselling, because uninterrupted tracts are the unstable, disease-causing configuration.

triplet-primed PCR for repeat interruption NCIT:C17003

Show evidence (2 references)

PMID:39289638 SUPPORT Human Clinical

"The numbers of CAG repeats in the ATXN1 gene was assessed by fluorescent PCR, tripled-primed PCR and enzymatic digestion for the search of sequence interruption in the CAG repeats."

Documents the assay combination used to establish interruption status.

PMID:39289638 SUPPORT Human Clinical

"The patient carried one pathogenic allele of 61 CAG and one intermediate allele of 37 CAG in the ATXN1 gene. Both alleles were uninterrupted."

The case that motivates the test: an uninterrupted intermediate allele alongside a large expansion, in a patient with early onset and rapid progression.

SARA Clinical Rating and MRI

Disease staging uses the Scale for the Assessment and Rating of Ataxia together with imaging. Both have known limits: SARA loses sensitivity at the extremes of the disease course, and no single modality serves every purpose, which is why multimodal composites are argued for.

magnetic resonance imaging of cerebellum and brainstem NCIT:C16809

Show evidence (1 reference)

PMID:42677125 SUPPORT Other

"Clinical scales such as SARA capture genotype-specific trajectories but lose sensitivity at the extremes of the disease course."

Supports SARA as the genotype-sensitive staging instrument and records its stated limitation.

📈

Progression

3

Onset

Age: third to fourth decade

Onset is typically in the third or fourth decade, but the range is wide: both childhood and late-adult onset are reported, and onset after age 60 may present as a pure cerebellar phenotype without the extracerebellar features that otherwise define SCA1.

Show evidence (2 references)

PMID:20301363 SUPPORT Human Clinical

"Onset is typically in the third or fourth decade, although childhood onset and late-adult onset have been reported."

States the typical onset window and its reported extremes.

PMID:20301363 SUPPORT Human Clinical

"Those with onset after age 60 years may manifest a pure cerebellar phenotype."

Documents the late-onset pure cerebellar presentation, a phenotypic variant distinct from the usual multisystem SCA1 picture.

Symptomatic progression

Once symptomatic, SCA1 progresses faster than the other common spinocerebellar ataxias. In the EUROSCA longitudinal cohort the annual increase on the Scale for the Assessment and Rating of Ataxia (SARA) was greater in SCA1 than in SCA2, SCA3, or SCA6, and longer repeat expansions predicted faster progression.

Show evidence (2 references)

PMID:26377379 SUPPORT Human Clinical

"Annual SARA score increase was 2.11 (SE 0.12) in patients with SCA1, 1.49 (0.07) in patients with SCA2, 1.56 (0.08) in patients with SCA3, and 0.80 (0.09) in patients with SCA6."

Quantifies the SCA1 progression rate against the other common dominant ataxias.

PMID:19049837 SUPPORT INDIRECT Human Clinical

"In all the three types of SCAs, there were significant inverse correlations of AAO with CAG repeat size"

Supports repeat length as an inverse determinant of age at onset in SCA1, the genotype-phenotype relationship underlying faster progression in longer expansions.

Terminal phase

Bulbar failure dominates the terminal phase. Death results from dysphagia and respiratory compromise attributable to degeneration of medullary cranial nerve nuclei and anterior horn neurons, ten to 30 years from onset, with juvenile-onset disease progressing more rapidly.

Show evidence (2 references)

PMID:20301363 SUPPORT Human Clinical

"Interval from onset to death varies from ten to 30 years; individuals with juvenile onset show more rapid progression and more severe disease."

Gives the survival interval and the juvenile-onset severity gradient.

PMID:32818920 SUPPORT Other

"death due to dysphagia and/or respiratory failure caused by degenerations in medullary cranial nerve nuclei and anterior horn neurons"

Names the anatomic basis of the terminal bulbar and respiratory failure. Graded OTHER because this sentence is background narrative in a preclinical mouse study, not human data reported by that study.

📊

Prevalence

2

Worldwide

Point Prevalence 1.5 per 100,000 (1.0–2.0) 1–9 per 100,000

SCA1-specific estimate. The underlying epidemiology is thin: the source describes prevalence information for SCA1 as limited to a few studies.

Show evidence (2 references)

PMID:37238658 SUPPORT Other

"Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder that affects one or two individuals per 100,000."

Gives the SCA1-specific prevalence recorded here.

PMID:37238658 SUPPORT Other

"Epidemiological information about the prevalence of SCA1 is limited to only a few studies"

Records the source's own caveat on how thin the SCA1 epidemiology is, so the figure above is not read as firmer than it is.

Worldwide, autosomal dominant hereditary cerebellar ataxia as a class

Point Prevalence 2.7 per 100,000 (1.5–4.0) 1–9 per 100,000

No population-based prevalence estimate specific to SCA1 was identified. This record is the pooled prevalence of dominant hereditary cerebellar ataxia as a whole from a systematic review, within which SCA1 is one of several genotypes; SCA3, SCA2, and SCA6 were the most common dominant ataxias in that review, so the SCA1-specific figure is a minority fraction of the class rate reported here and should not be read as a SCA1 prevalence.

Show evidence (3 references)

PMID:24603320 SUPPORT Human Clinical

"The prevalence range of dominant HCA was 0.0-5.6/10(5), with an average of 2.7/10(5) (1.5-4.0/10(5))."

Supplies the class-level pooled prevalence of dominant hereditary cerebellar ataxia recorded here; it does not report a SCA1-specific rate.

PMID:24603320 SUPPORT Human Clinical

"Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease was the most common dominant ataxia, followed by SCA2 and SCA6."

Establishes that SCA1 is not the leading dominant ataxia genotype, which is why the class rate above overstates SCA1 alone.

PMID:9106530 SUPPORT Human Clinical

"SCA2 accounts for 13% of patients with ADCA (without retinal degeneration), intermediate between SCA1 and SCA3/MJD, which account for 6% and 23%, respectively."

Quantifies the SCA1 share of dominant cerebellar ataxia at roughly 6% of patients in this cohort, bounding how much of the class rate above is attributable to SCA1.

🧫

Experimental Models

1

SCA1 patient-derived iPSC neuronal cultures IPSC_DERIVED_MODEL

Neuronal cultures differentiated from SCA1 patient induced pluripotent stem cells, alongside patient fibroblasts. A human, non-animal system that reproduces aggregate localization matching SCA1 postmortem brain, reduced dendritic complexity, and delayed network development on multi-electrode arrays.

Pathograph links

Purkinje Cell Dysfunction and Dendritic Atrophy partially recapitulates fidelity: moderate observes: cellular Reproduces the dendritic and network-level dysfunction of the target node in human cells.

Limitations: These are generic iPSC-derived neurons, not cerebellar Purkinje cells, so the cell type that defines the target node is absent; the readout is dendritic and network dysfunction in a proxy neuronal population.

Divergences from the human mechanism

proxy quantity qualifying

The model measures dendrite length, branch-point number and network activity in iPSC-derived neurons. The node's quantity is Purkinje cell dendritic atrophy and dysfunction in cerebellar cortex.

Readouts

Dendrite length and branching, and network activity development

Direction: DECREASED

Interpretation: Reduced dendritic complexity with delayed network maturation, the cellular correlate of the target node.

Show evidence (1 reference)

PMID:37278528 SUPPORT In Vitro

"SCA1 hiPSC-derived neuronal cells showed reduced dendrite length and number of branching points while MEA recordings identified delayed development in network activity in SCA1 hiPSC-derived neuronal cells."

Reports the measured dendritic and network deficits.

Show evidence (1 reference)

PMID:37278528 SUPPORT In Vitro

"In SCA1 hiPSC-derived neuronal cells, nuclear and cytoplasmic aggregates were identified similar in localization as aggregates in SCA1 postmortem brain tissue."

Supports treating this model as informative by anchoring its aggregate pathology to human postmortem SCA1 brain.

Show evidence (1 reference)

PMID:37278528 SUPPORT In Vitro

"Patient-derived cells recapitulate key pathological features of SCA1 pathogenesis providing a valuable tool for the identification of novel disease-specific processes."

The authors' own assessment of the model's validity for SCA1.

🐁

Animal Models

3

SCA1 Purkinje-cell transgenic mouse (ataxin-1 with expanded CAG repeat)

Transgenic mice expressing the human SCA1 gene with an expanded CAG tract under a Purkinje-cell promoter. Five of six expanded lines developed ataxia and Purkinje cell degeneration, while all six lines carrying the unexpanded allele had normal Purkinje cells, giving a clean allele-length-dependent control.

Species

Mouse

Genotype

Pcp2-driven human ATXN1 transgene with expanded CAG repeat

Publication

PMID:7553854

Pathograph links

Purkinje Neuron Degeneration recapitulates fidelity: high observes: cellular Reproduces the defining Purkinje cell degeneration of human SCA1 and establishes that expanded repeat expression within Purkinje cells is sufficient to cause it.

Limitations: Expression is transgenic and Purkinje-cell restricted rather than endogenous and brain-wide, so the model does not reproduce the brainstem, medullary, and anterior horn degeneration that causes death in patients, and repeat length exceeds most patient alleles.

Show evidence (1 reference)

PMID:7553854 SUPPORT Model Organism

"While all six transgenic lines expressing the unexpanded human SCA1 allele had normal Purkinje cells, transgenic animals from five of six lines with the expanded SCA1 allele developed ataxia and Purkinje cell degeneration."

Establishes the model's allele-length-dependent recapitulation of Purkinje cell degeneration.

Show evidence (1 reference)

PMID:7553854 SUPPORT Model Organism

"demonstrate that a mouse model can be established for neurodegeneration caused by CAG repeat expansions"

Supports treating this transgenic line as an informative model of expansion-driven neurodegeneration.

Atxn1-154Q knock-in mouse

Knock-in mice carrying an expanded CAG repeat inserted into one endogenous Atxn1 allele, expressing ATXN1 with 154 glutamines throughout the brain. They display ataxia and premature lethality, and were the model used to demonstrate ASO rescue.

Species

Mouse

Genotype

Atxn1(154Q/2Q) knock-in

Publication

PMID:30385727

Pathograph links

ATXN1 CAG Repeat Expansion recapitulates fidelity: high observes: molecular Places the expansion at the endogenous locus under native regulation, making it the appropriate model for testing ATXN1-lowering therapy.

Limitations: The 154-repeat allele is far longer than typical human pathogenic alleles (usually 39 or more), compressing an adult-onset human disease into a rapid murine course.

Readouts

Motor performance and survival after single ASO treatment

Direction: RESTORED

Interpretation: Lowering the expanded transcript rescued both motor deficits and premature lethality, confirming ongoing dependence on the initiating lesion.

Show evidence (1 reference)

PMID:30385727 SUPPORT Model Organism

"Following a single ASO treatment at 5 weeks of age, mice demonstrated rescue of these disease-associated phenotypes."

Reports the measured rescue of motor deficits and lethality.

Show evidence (1 reference)

PMID:30385727 SUPPORT Model Organism

"we investigated the therapeutic capability of an antisense oligonucleotide (ASO) targeting mouse Atxn1 in Atxn1154Q/2Q-knockin mice that manifest motor deficits and premature lethality"

Establishes the model's genotype and the phenotypes it manifests.

Show evidence (1 reference)

PMID:32818920 SUPPORT Model Organism

"Atxn1154Q/2Q mice were generated by the insertion of an expanded CAG repeat into one endogenous Atxn12Q allele"

Confirms the knock-in design at the endogenous locus, which is what makes this model appropriate for testing ATXN1-lowering therapy.

Atxn1l duplication modifier mouse

A genetic modifier model in which elevated levels of the ataxin-1 paralog Atxn1l displace mutant ataxin-1 from its native Capicua complex. It is the decisive test that occupancy of that complex, rather than aggregation, is what produces neuropathology.

Species

Mouse

Genotype

Targeted Atxn1l (ataxin-1-like) duplication on an SCA1 knock-in background

Publication

PMID:17322884

Pathograph links

Aberrant Ataxin-1-Capicua Transcriptional Repressor Activity rescues fidelity: moderate observes: molecular Suppresses SCA1 neuropathology specifically by reducing incorporation of polyglutamine-expanded ataxin-1 into the Capicua-containing complex.

Limitations: Paralog overexpression is a genetic manipulation with no clinical counterpart, and the readout is murine neuropathology rather than a human clinical endpoint.

Show evidence (1 reference)

PMID:17322884 SUPPORT Model Organism

"Our results provide genetic evidence that the selective neuropathology of SCA1 arises from modulation of a core functional activity of ATXN1"

Supports the specific mechanistic claim that toxicity works through a native ataxin-1 activity, which this rescue targets.

Show evidence (1 reference)

PMID:17322884 SUPPORT Model Organism

"Using a knock-in mouse model of SCA1 that recapitulates the selective neurodegeneration seen in affected individuals"

Establishes that the background model reproduces the selective neurodegeneration of human SCA1, supporting its use here.

{ }

Source YAML

click to show

name: Spinocerebellar Ataxia Type 1
creation_date: "2026-09-05T00:00:00Z"
category: Mendelian
synonyms:
- SCA1
- Spinocerebellar ataxia 1
- Olivopontocerebellar atrophy type 1
- Cerebelloparenchymal disorder 1
- Schut-Haymaker type olivopontocerebellar atrophy
description: >-
  Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant, typically
  adult-onset progressive cerebellar ataxia caused by an expanded translated
  CAG trinucleotide repeat in ATXN1 that encodes an elongated polyglutamine
  tract in ataxin-1. It is one of the classical polyglutamine
  neurodegenerative diseases. Affected individuals present in the third or
  fourth decade with gait ataxia, dysarthria, and oculomotor abnormalities,
  and progress through pyramidal, extrapyramidal, sensory-neuropathic,
  cognitive, and eventually bulbar involvement; death from dysphagia and
  respiratory compromise typically follows ten to 30 years after onset. The
  neuropathology centers on cerebellar Purkinje cell degeneration with
  additional loss of brainstem, inferior olivary, and spinocerebellar tract
  neurons. Mechanistically SCA1 is not a simple aggregation disease: the
  expanded polyglutamine tract acts largely by modulating the normal
  activities of ataxin-1 within its native, Ser776 phosphorylation-dependent
  protein complexes, most importantly the complex containing the
  transcriptional repressor Capicua. No disease-modifying therapy is
  approved; management is supportive and rehabilitative, while
  ATXN1-lowering antisense oligonucleotides have shown preclinical efficacy.
disease_term:
  preferred_term: Spinocerebellar ataxia type 1
  term:
    id: MONDO:0008119
    label: spinocerebellar ataxia type 1
parents:
- Autosomal Dominant Cerebellar Ataxia Type I
- Hereditary Ataxia
- Neurodegenerative Disease
references:
- reference: PMID:20301363
  title: "Spinocerebellar Ataxia Type 1."
  tags:
  - GeneReviews
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    SCA1 is transmitted in an autosomal dominant manner, with a 50% risk to
    offspring of an affected individual. Anticipation is characteristic and is
    biased by parent of origin: expansions occur preferentially on paternal
    transmission and contractions on maternal transmission.
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SCA1 is inherited in an autosomal dominant manner. Offspring of an
      affected individual have a 50% chance of inheriting the expanded allele.
    explanation: States the mode of inheritance and the recurrence risk directly.
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anticipation has been observed in SCA1; expansions are more likely to
      occur when the pathogenic ATXN1 allele is paternally transmitted, and
      contractions are more typical of maternal transmissions.
    explanation: Supports anticipation with a paternal-transmission bias in repeat expansion.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.5
  rate_low: 1.0
  rate_high: 2.0
  notes: >-
    SCA1-specific estimate. The underlying epidemiology is thin: the source
    describes prevalence information for SCA1 as limited to a few studies.
  evidence:
  - reference: PMID:37238658
    reference_title: "Therapeutic Strategies for Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant
      neurodegenerative disorder that affects one or two individuals per
      100,000.
    explanation: Gives the SCA1-specific prevalence recorded here.
  - reference: PMID:37238658
    reference_title: "Therapeutic Strategies for Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Epidemiological information about the prevalence of SCA1 is limited to
      only a few studies
    explanation: >-
      Records the source's own caveat on how thin the SCA1 epidemiology is, so
      the figure above is not read as firmer than it is.
- population: Worldwide, autosomal dominant hereditary cerebellar ataxia as a class
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 2.7
  rate_low: 1.5
  rate_high: 4.0
  notes: >-
    No population-based prevalence estimate specific to SCA1 was identified.
    This record is the pooled prevalence of dominant hereditary cerebellar
    ataxia as a whole from a systematic review, within which SCA1 is one of
    several genotypes; SCA3, SCA2, and SCA6 were the most common dominant
    ataxias in that review, so the SCA1-specific figure is a minority
    fraction of the class rate reported here and should not be read as a
    SCA1 prevalence.
  evidence:
  - reference: PMID:24603320
    reference_title: "The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence range of dominant HCA was 0.0-5.6/10(5), with an average
      of 2.7/10(5) (1.5-4.0/10(5)).
    explanation: >-
      Supplies the class-level pooled prevalence of dominant hereditary
      cerebellar ataxia recorded here; it does not report a SCA1-specific rate.
  - reference: PMID:24603320
    reference_title: "The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease was the most
      common dominant ataxia, followed by SCA2 and SCA6.
    explanation: >-
      Establishes that SCA1 is not the leading dominant ataxia genotype, which
      is why the class rate above overstates SCA1 alone.
  - reference: PMID:9106530
    reference_title: "The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SCA2 accounts for 13% of patients with ADCA (without retinal
      degeneration), intermediate between SCA1 and SCA3/MJD, which account for
      6% and 23%, respectively.
    explanation: >-
      Quantifies the SCA1 share of dominant cerebellar ataxia at roughly 6% of
      patients in this cohort, bounding how much of the class rate above is
      attributable to SCA1.
progression:
- phase: Onset
  age_range: third to fourth decade
  notes: >-
    Onset is typically in the third or fourth decade, but the range is wide:
    both childhood and late-adult onset are reported, and onset after age 60
    may present as a pure cerebellar phenotype without the extracerebellar
    features that otherwise define SCA1.
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Onset is typically in the third or fourth decade, although childhood
      onset and late-adult onset have been reported.
    explanation: States the typical onset window and its reported extremes.
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Those with onset after age 60 years may manifest a pure cerebellar
      phenotype.
    explanation: >-
      Documents the late-onset pure cerebellar presentation, a phenotypic
      variant distinct from the usual multisystem SCA1 picture.
- phase: Symptomatic progression
  notes: >-
    Once symptomatic, SCA1 progresses faster than the other common
    spinocerebellar ataxias. In the EUROSCA longitudinal cohort the annual
    increase on the Scale for the Assessment and Rating of Ataxia (SARA) was
    greater in SCA1 than in SCA2, SCA3, or SCA6, and longer repeat expansions
    predicted faster progression.
  evidence:
  - reference: PMID:26377379
    reference_title: "Long-term disease progression in spinocerebellar ataxia types 1, 2, 3, and 6: a longitudinal cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Annual SARA score increase was 2.11 (SE 0.12) in patients with SCA1,
      1.49 (0.07) in patients with SCA2, 1.56 (0.08) in patients with SCA3,
      and 0.80 (0.09) in patients with SCA6.
    explanation: Quantifies the SCA1 progression rate against the other common dominant ataxias.
  - reference: PMID:19049837
    reference_title: "Spinocerebellar ataxias types 1, 2 and 3: age adjusted clinical severity of disease at presentation correlates with size of CAG repeat lengths."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In all the three types of SCAs, there were significant inverse
      correlations of AAO with CAG repeat size
    explanation: >-
      Supports repeat length as an inverse determinant of age at onset in SCA1,
      the genotype-phenotype relationship underlying faster progression in
      longer expansions.
- phase: Terminal phase
  notes: >-
    Bulbar failure dominates the terminal phase. Death results from dysphagia
    and respiratory compromise attributable to degeneration of medullary
    cranial nerve nuclei and anterior horn neurons, ten to 30 years from
    onset, with juvenile-onset disease progressing more rapidly.
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interval from onset to death varies from ten to 30 years; individuals
      with juvenile onset show more rapid progression and more severe disease.
    explanation: Gives the survival interval and the juvenile-onset severity gradient.
  - reference: PMID:32818920
    reference_title: "Antisense Oligonucleotide Therapeutic Approach for Suppression of Ataxin-1 Expression: A Safety Assessment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      death due to dysphagia and/or respiratory failure caused by degenerations
      in medullary cranial nerve nuclei and anterior horn neurons
    explanation: >-
      Names the anatomic basis of the terminal bulbar and respiratory failure.
      Graded OTHER because this sentence is background narrative in a
      preclinical mouse study, not human data reported by that study.
pathophysiology:
- name: ATXN1 CAG Repeat Expansion
  conforms_to: "polyglutamine_expansion_proteotoxicity#Translated CAG / Polyglutamine Repeat Expansion"
  description: >-
    The initiating lesion is expansion of an unstable, translated CAG
    trinucleotide repeat in the coding region of ATXN1 on chromosome 6p22.3.
    Affected individuals usually carry 39 or more repeats, which encode a
    correspondingly elongated polyglutamine tract in ataxin-1. Because the repeat
    is translated, the established pathogenic mechanism operates at the protein
    level, through the expanded ataxin-1 protein itself. This does not exclude a
    parallel RNA-level contribution: repeat-associated non-AUG translation of the
    same locus is curated as its own branch below.
  biological_scale: MOLECULAR
  genetic_context:
    functional_impact_category: GAIN_OF_FUNCTION
    allele_type: Translated CAG trinucleotide repeat expansion
    variant_origin: GERMLINE
  downstream:
  - target: Repeat-Associated Non-AUG Translation of the ATXN1 Repeat
    causal_link_type: DIRECT
    description: >-
      The same expanded repeat is also translated in non-canonical frames,
      producing RAN proteins alongside the polyglutamine-expanded ataxin-1.
    evidence:
    - reference: PMID:41422503
      reference_title: "Repeat-associated non-AUG translation as a common mechanism for the polyGln ataxias."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Immunohistochemistry shows that sense polyserine (polySer) (AGC frame)
        and antisense polyleucine (polyLeu) (CUG frame) RAN protein aggregates
        accumulate throughout the cerebellum and pons, in SCA1, SCA2, SCA3,
        SCA6, and SCA7 autopsy brains, and in damaged neurons.
      explanation: >-
        Establishes RAN protein products of the repeat in human SCA1 autopsy
        brain, supporting this branch out of the expansion node.
  - target: Nuclear Localization of Polyglutamine-Expanded Ataxin-1
    causal_link_type: DIRECT
    description: >-
      The expanded polyglutamine tract is carried by ataxin-1 into Purkinje
      cell nuclei, where the disease process is initiated.
    evidence:
    - reference: PMID:7553854
      reference_title: "SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These data indicate that expanded CAG repeats expressed in Purkinje
        cells are sufficient to produce degeneration and ataxia
      explanation: >-
        Establishes that expression of the expanded repeat in Purkinje cells is
        itself sufficient to initiate the downstream disease process.
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of SCA1 is established in a proband with characteristic
      clinical findings and an abnormal CAG repeat expansion in ATXN1
      identified by molecular genetic testing. Affected individuals usually
      have 39 or more CAG repeats.
    explanation: Defines the causal lesion and the pathogenic repeat threshold.
  - reference: PMID:18957430
    reference_title: "Pathogenic mechanisms of a polyglutamine-mediated neurodegenerative disease, spinocerebellar ataxia type 1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Genetic evidence indicates that the disease mutation induces a toxic gain
      of function in the SCA1 encoded protein ATXN1.
    explanation: >-
      Supports classifying the expansion as a dominant toxic gain of function at
      the protein level rather than a loss of ataxin-1.
- name: Nuclear Localization of Polyglutamine-Expanded Ataxin-1
  description: >-
    Pathogenesis requires the expanded protein to reach the Purkinje cell
    nucleus. Transgenic mice expressing ataxin-1[82Q] with a mutated nuclear
    localization signal do not develop disease. Critically, visible nuclear
    aggregation is dissociable from toxicity: mice expressing a
    self-association-deficient ataxin-1[77Q] that forms no detectable nuclear
    inclusions still develop ataxia and Purkinje cell pathology. SCA1 is
    therefore not driven by inclusion formation per se, which distinguishes it
    from a simple aggregation model of polyglutamine disease.
  biological_scale: MOLECULAR
  downstream:
  - target: Ser776-Dependent Assembly of Mutant Ataxin-1 into Native Complexes
    causal_link_type: DIRECT
    hypothesis_groups:
    - aggregation_not_required
    - native_complex_toxicity
    description: >-
      Once nuclear, the expanded protein engages its normal
      phosphorylation-regulated partner complexes.
    evidence:
    - reference: PMID:18957430
      reference_title: "Pathogenic mechanisms of a polyglutamine-mediated neurodegenerative disease, spinocerebellar ataxia type 1."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Biochemical and genetic studies provide evidence that the polyglutamine
        expansion enhances interactions that are normally regulated by
        phosphorylation at Ser(776) and a subsequent alteration in its
        interaction with other cellular proteins.
      explanation: >-
        Supports this specific step, that the expanded protein acts by entering
        Ser776-regulated native interactions.
  biological_processes:
  - preferred_term: protein localization to nucleus
    term:
      id: GO:0034504
      label: protein localization to nucleus
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  evidence:
  - reference: PMID:9778246
    reference_title: "Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These mice did not develop disease, demonstrating that nuclear
      localization is critical for pathogenesis.
    explanation: Establishes nuclear localization as necessary for disease.
  - reference: PMID:9778246
    reference_title: "Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Thus, although nuclear localization of ataxin-1 is necessary, nuclear
      aggregation of ataxin-1 is not required to initiate pathogenesis in
      transgenic mice.
    explanation: >-
      Separates nuclear entry from visible aggregation, supporting the claim
      that inclusion formation is not the toxic step in SCA1.
- name: Ser776-Dependent Assembly of Mutant Ataxin-1 into Native Complexes
  description: >-
    Phosphorylation of ataxin-1 at serine 776 gates its incorporation into
    large soluble protein complexes. Transgenic mice expressing
    ataxin-1[82Q]-A776, which cannot be phosphorylated at this residue, place
    the expanded protein in Purkinje cell nuclei yet are substantially
    protected from disease. The same S776A substitution markedly reduces the
    association of mutant ataxin-1 with Capicua in vivo, linking this
    phosphorylation site directly to the pathogenic complex. The kinases that
    place this mark are region-specific: MSK1 in cerebellum and RSK3 in
    brainstem. This is the clearest available answer to why a brain-wide
    protein kills only select populations, and it predicts that rescuing the
    whole disease requires targeting more than one regulator.
  biological_scale: MOLECULAR
  downstream:
  - target: Brainstem, Olivary and Spinal Neuron Degeneration
    causal_link_type: DIRECT
    description: >-
      A Ser776-dependent branch that is not routed through the cerebellar
      Capicua mechanism: in brainstem the mark is placed by RSK3, and lowering
      RSK3 rescues brainstem pathology specifically.
    evidence:
    - reference: PMID:33709453
      reference_title: "Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Reducing Rsk3 rescues brainstem-associated pathologies and deficits, and
        lowering Rsk3 and Msk1 together improves cerebellar and brainstem
        function in an SCA1 mouse model.
      explanation: >-
        Supports a brainstem branch acting through Ser776 regulation, separable
        from the cerebellar branch by which kinase is lowered.
  - target: Aberrant Ataxin-1-Capicua Transcriptional Repressor Activity
    causal_link_type: DIRECT
    hypothesis_groups:
    - native_complex_toxicity
    description: >-
      Ser776 phosphorylation is what loads the expanded protein into the
      Capicua-containing complex through which toxicity is exerted.
    evidence:
    - reference: PMID:17190598
      reference_title: "ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Interestingly, the S776A mutation, which abrogates the neurotoxicity of
        expanded ATXN1, substantially reduces the association of mutant ATXN1
        with Capicua in vivo.
      explanation: >-
        Directly ties the protective S776A substitution to loss of the
        Capicua interaction, supporting this specific causal step.
  biological_processes:
  - preferred_term: protein phosphorylation
    term:
      id: GO:0006468
      label: protein phosphorylation
  - preferred_term: protein-containing complex assembly
    term:
      id: GO:0065003
      label: protein-containing complex assembly
  evidence:
  - reference: PMID:12741986
    reference_title: "Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These studies demonstrate that polyglutamine tract expansion and
      localization of ataxin-1 to the nucleus of Purkinje cells are not
      sufficient to induce disease. We suggest that S776 of ataxin-1 also has
      a critical role in SCA1 pathogenesis.
    explanation: >-
      Shows nuclear expanded ataxin-1 is not sufficient without Ser776,
      establishing this residue as a required step.
  - reference: PMID:18957430
    reference_title: "Pathogenic mechanisms of a polyglutamine-mediated neurodegenerative disease, spinocerebellar ataxia type 1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Biochemical and genetic studies provide evidence that the polyglutamine
      expansion enhances interactions that are normally regulated by
      phosphorylation at Ser(776) and a subsequent alteration in its
      interaction with other cellular proteins.
    explanation: Frames the expansion as acting by enhancing Ser776-regulated native interactions.
  - reference: PMID:33709453
    reference_title: "Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Unlike MSK1, RSK3 is highly expressed in the human and mouse brainstems
      where it regulates Atxn1 by phosphorylating S776.
    explanation: >-
      Identifies the region-specific kinases acting at Ser776, the mark this
      node is about.
  - reference: PMID:33709453
    reference_title: "Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our results demonstrate that selective vulnerability of brain regions in
      SCA1 is governed by region-specific regulators of ATXN1, and targeting
      multiple regulators could rescue multiple degenerating brain areas.
    explanation: >-
      Supports region-specific Ser776 regulation as the basis of selective
      vulnerability, which is what routes this node to both the cerebellar and
      the extracerebellar branches.
- name: Aberrant Ataxin-1-Capicua Transcriptional Repressor Activity
  conforms_to: "polyglutamine_expansion_proteotoxicity#Transcriptional Dysregulation"
  description: >-
    Both wild-type and expanded ataxin-1 assemble into large stable cerebellar
    complexes containing the transcriptional repressor Capicua (CIC), and
    ataxin-1 modulates Capicua repressor activity. SCA1 toxicity depends on
    this native interaction rather than on a novel one acquired by the
    expanded protein. The genetic test is decisive: duplicating the ataxin-1
    paralog Atxn1l, which displaces mutant ataxin-1 from the Capicua complex,
    suppresses neuropathology in a knock-in SCA1 model. Ataxin-1 also both
    gains and partially loses interactions, so SCA1 combines a dominant gain
    of function with partial loss of normal ataxin-1 activity. Capicua is not
    the whole mechanism: abolishing the ATXN1-CIC interaction globally in
    knock-in mice normalized genome-wide CIC binding but only partially
    corrected transcriptional and behavioural phenotypes, and further ataxin-1
    transcription-factor partners (RFX1, ZBTB5, ZKSCAN1) have since been
    identified.
  biological_scale: MOLECULAR
  downstream:
  - target: RORalpha Destabilization and Loss of the Purkinje Gene Expression Program
    causal_link_type: DIRECT
    description: >-
      Transcriptional dysregulation by the mutant complex depletes the
      Purkinje cell transcription factor RORalpha and its target genes.
  - target: RBFOX1-Mediated Alternative Splicing Dysregulation
    causal_link_type: DIRECT
    description: >-
      Beyond changing which genes are transcribed, mutant ataxin-1 changes how
      transcripts are spliced, through a separate splicing-factor route.
  - target: Purkinje Cell Dysfunction and Dendritic Atrophy
    causal_link_type: DIRECT
    description: >-
      Sustained transcriptional dysregulation degrades Purkinje cell function
      before overt cell loss.
  - target: Brainstem, Olivary and Spinal Neuron Degeneration
    causal_link_type: DIRECT
    description: >-
      The same transcriptional dysregulation acts in the extracerebellar
      neuronal populations that also express ataxin-1, which is why SCA1 is not
      confined to the cerebellar cortex. Why these particular populations are
      vulnerable while most ataxin-1-expressing neurons are spared is not
      resolved.
    evidence:
    - reference: PMID:10649571
      reference_title: "Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        their downregulation was mediated by expanded ataxin-1 and occurred
        before detectable pathology
      explanation: >-
        Supports transcriptional dysregulation preceding and therefore driving
        neurodegeneration. The paper measures this in Purkinje-abundant genes,
        so its application to the extracerebellar populations is an inference,
        hence INDIRECT.
  biological_processes:
  - preferred_term: negative regulation of transcription by RNA polymerase II
    term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    modifier: GAIN_OF_FUNCTION
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  evidence:
  - reference: PMID:17190598
    reference_title: "ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We examined soluble protein complexes from mouse cerebellum and found
      that the majority of wild-type and expanded ATXN1 assembles into large
      stable complexes containing the transcriptional repressor Capicua.
    explanation: Establishes the Capicua-containing complex as the principal ataxin-1 assembly in cerebellum.
  - reference: PMID:17190598
    reference_title: "ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These data provide insight into the function of ATXN1 and suggest that
      SCA1 neuropathology depends on native, not novel, protein interactions.
    explanation: >-
      Supports attributing toxicity to modulation of a normal ataxin-1 activity
      rather than to a novel aberrant interaction.
  - reference: PMID:17322884
    reference_title: "Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we found that elevated Atxn1l levels suppress neuropathology by
      displacing mutant Atxn1 from its native complex with Capicua (CIC)
    explanation: >-
      Provides the genetic rescue showing that occupancy of the Capicua complex
      by mutant ataxin-1 is what drives neuropathology.
  - reference: PMID:18957430
    reference_title: "Pathogenic mechanisms of a polyglutamine-mediated neurodegenerative disease, spinocerebellar ataxia type 1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Moreover, the finding that other ATXN1 interactions are decreased in
      disease suggests that the polyglutamine expansion contributes to disease
      by both a gain-of-function mechanism and partial loss of function.
    explanation: Supports the combined gain-of-function plus partial loss-of-function description.
  - reference: PMID:36577402
    reference_title: "Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The interaction of polyglutamine-expanded ATXN1 with the transcriptional
      repressor CIC drives cerebellar Purkinje cell pathogenesis
    explanation: Independent confirmation that the ATXN1-CIC interaction drives Purkinje pathology.
  - reference: PMID:36577402
    reference_title: "Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This normalized genome-wide CIC binding; however, it only partially
      corrected transcriptional and behavioral phenotypes, suggesting the
      involvement of additional factors in disease pathogenesis.
    explanation: >-
      Refutes the stronger reading of this node, that the Capicua interaction
      is the sufficient mechanism. It remains necessary, but other ataxin-1
      partners contribute.
- name: RORalpha Destabilization and Loss of the Purkinje Gene Expression Program
  description: >-
    Mutant ataxin-1 depletes RORalpha, a transcription factor critical for
    cerebellar development, and reduces expression of
    RORalpha-controlled genes; partial loss of RORalpha enhances mutant
    ataxin-1 pathogenicity. Because RORalpha acts developmentally, the timing
    of mutant ataxin-1 expression matters: delaying its postnatal expression
    until cerebellar development is complete substantially reduces adult
    disease severity. This gives SCA1 a developmental component on top of its
    adult-onset degeneration.
  biological_scale: CELLULAR
  downstream:
  - target: Purkinje Cell Dysfunction and Dendritic Atrophy
    causal_link_type: DIRECT
  biological_processes:
  - preferred_term: cerebellar Purkinje cell layer development
    term:
      id: GO:0021680
      label: cerebellar Purkinje cell layer development
    modifier: DECREASED
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  evidence:
  - reference: PMID:17110330
    reference_title: "RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In SCA1 mice, there was a depletion of RORalpha and a reduction in
      expression of genes controlled by RORalpha. Partial loss of RORalpha
      enhanced mutant ATXN1 pathogenicity.
    explanation: Establishes RORalpha depletion and its modifier effect on pathogenicity.
  - reference: PMID:17110330
    reference_title: "RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Delayed postnatal expression of mutant ATXN1 led to a substantial
      reduction in severity of disease in adults in comparison with early
      postnatal gene expression.
    explanation: Supports the developmental-window contribution to adult disease severity.
- name: Purkinje Cell Dysfunction and Dendritic Atrophy
  conforms_to: "cerebellar_purkinje_degeneration#Purkinje Cell Calcium and Proteostasis Dysregulation"
  description: >-
    Purkinje cells expressing expanded ataxin-1 show functional and
    morphological deterioration preceding cell loss, with dendritic atrophy
    and neurochemical abnormalities detectable in vivo. This stage is
    reversible in principle: halting expression of mutant ataxin-1 in a
    conditional model restores cerebellar morphology and motor function, and
    the earlier expression is stopped the greater the recovery.
  biological_scale: CELLULAR
  downstream:
  - target: Purkinje Neuron Degeneration
    causal_link_type: DIRECT
    description: >-
      Unrelieved dysfunction proceeds to irreversible loss of the same neurons.
    evidence:
    - reference: PMID:7553854
      reference_title: "SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        transgenic animals from five of six lines with the expanded SCA1 allele
        developed ataxia and Purkinje cell degeneration
      explanation: >-
        Supports progression from expanded-allele-driven Purkinje dysfunction to
        frank degeneration in the same cells.
  biological_processes:
  - preferred_term: dendrite morphogenesis
    term:
      id: GO:0048813
      label: dendrite morphogenesis
    modifier: DECREASED
  - preferred_term: calcium ion homeostasis
    term:
      id: GO:0055074
      label: calcium ion homeostasis
    modifier: DECREASED
  - preferred_term: signal transduction
    term:
      id: GO:0007165
      label: signal transduction
    modifier: DECREASED
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  evidence:
  - reference: PMID:10649571
    reference_title: "Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we found certain neuronal genes involved in signal transduction and
      calcium homeostasis sequentially downregulated in SCA1 mice
    explanation: >-
      Supplies the calcium-homeostasis and signal-transduction dysregulation
      that this node's module conformance target specifies.
  - reference: PMID:10649571
    reference_title: "Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Similar downregulation occurred in SCA1 human tissues.
    explanation: >-
      Confirms the same gene-expression change in human SCA1 tissue, so the
      claim is not model-only.
  - reference: PMID:10649571
    reference_title: "Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These genes were abundant in Purkinje cells, the primary site of SCA1
      pathogenesis; moreover, their downregulation was mediated by expanded
      ataxin-1 and occurred before detectable pathology.
    explanation: >-
      Establishes that the dysregulation is Purkinje-centred and precedes
      pathology, supporting this node as a pre-degenerative dysfunction stage.
  - reference: PMID:32818920
    reference_title: "Antisense Oligonucleotide Therapeutic Approach for Suppression of Ataxin-1 Expression: A Safety Assessment."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cessation of expression of ATXN1 with an expanded polyQ in a conditional
      mouse model of SCA1 cerebellar disease restored morphology and motor
      function. Importantly, the earlier the expression of mutant ATXN1 was
      stopped, the greater the recovery.
    explanation: >-
      Supports a reversible dysfunction stage that precedes irreversible neuron
      loss, and its time dependence.
- name: Purkinje Neuron Degeneration
  conforms_to: "cerebellar_purkinje_degeneration#Purkinje Neuron Degeneration"
  description: >-
    Cerebellar Purkinje cells are the principal vulnerable population in
    SCA1, and their loss is the defining neuropathological feature.
    Expression of an expanded CAG repeat restricted to Purkinje cells is
    sufficient to produce both the degeneration and the ataxic phenotype in
    mice.
  biological_scale: CELLULAR
  downstream:
  - target: Loss of Cerebellar Cortical Output
    causal_link_type: DIRECT
  biological_processes:
  - preferred_term: neuron death
    modifier: INCREASED
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  evidence:
  - reference: PMID:7553854
    reference_title: "SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      transgenic animals from five of six lines with the expanded SCA1 allele
      developed ataxia and Purkinje cell degeneration
    explanation: Demonstrates that the expanded allele causes Purkinje cell degeneration with ataxia.
  - reference: PMID:38750673
    reference_title: "Cerebellar Heterogeneity and Selective vulnerability in Spinocerebellar Ataxia Type 1 (SCA1)."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using immunohistochemistry, we demonstrated earlier and more severe
      pathology of PCs and glia in the posterior cerebellar vermis of SCA1 mice.
    explanation: >-
      Adds a sub-regional gradient to this node: Purkinje loss is not uniform
      across the cerebellum, and the posterior vermis is affected earlier and
      more severely.
  - reference: PMID:38750673
    reference_title: "Cerebellar Heterogeneity and Selective vulnerability in Spinocerebellar Ataxia Type 1 (SCA1)."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we found both shared, as well as, posterior cerebellum-specific molecular
      mechanisms of pathogenesis that include exacerbated gene dysregulation,
      increased number of altered signaling pathways, and decreased pathway
      activity scores in the posterior cerebellum of SCA1 mice
    explanation: >-
      Supports a molecular basis for the gradient, complementing the
      region-specific kinase account of selectivity curated upstream.
  - reference: PMID:7553854
    reference_title: "SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant inherited
      disorder characterized by degeneration of cerebellar Purkinje cells,
      spinocerebellar tracts, and selective brainstem neurons
    explanation: >-
      States the human neuropathological distribution that the model reproduces.
      Graded OTHER because this is the introductory framing of a mouse study,
      not human data reported by it.
- name: Brainstem, Olivary and Spinal Neuron Degeneration
  conforms_to: "polyglutamine_expansion_proteotoxicity#Selective Neuronal Dysfunction and Loss"
  description: >-
    Beyond the cerebellar cortex, SCA1 involves brainstem neurons,
    spinocerebellar tracts, medullary cranial nerve nuclei, and anterior horn
    neurons, with variable damage to basal ganglia and spinal cord. This
    extracerebellar burden explains the pyramidal, extrapyramidal,
    sensory-neuropathic, and bulbar features that place SCA1 in the ADCA-I
    class, and it is what ultimately kills. The brainstem branch is not simply
    the cerebellar mechanism spilling over: it is governed by a different
    Ser776 kinase, RSK3, whose reduction rescues brainstem pathology
    specifically, and the brainstem is the region whose pathology is most
    closely tied to premature death.
  biological_scale: TISSUE
  downstream:
  - target: Progressive Cerebellar and Bulbar Syndrome
    causal_link_type: DIRECT
  - target: Dysphagia
    causal_link_type: DIRECT
  - target: Hyperreflexia
    causal_link_type: DIRECT
  - target: Hyporeflexia
    causal_link_type: DIRECT
  - target: Sensory Axonal Neuropathy
    causal_link_type: DIRECT
  - target: Impaired Proprioception
    causal_link_type: DIRECT
  - target: Skeletal Muscle Atrophy
    causal_link_type: DIRECT
  - target: Chorea
    causal_link_type: DIRECT
  - target: Dystonia
    causal_link_type: DIRECT
  - target: Impaired Executive Functioning
    causal_link_type: DIRECT
  - target: Brainstem Atrophy
    causal_link_type: DIRECT
  biological_processes:
  - preferred_term: neuron death
    modifier: INCREASED
  evidence:
  - reference: PMID:32818920
    reference_title: "Antisense Oligonucleotide Therapeutic Approach for Suppression of Ataxin-1 Expression: A Safety Assessment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Pathological changes typically include prominent deterioration of
      cerebellar Purkinje cells and brainstem degeneration along with a
      variable degree of damage to more anterior (e.g., basal ganglia) and
      posterior (e.g., spinal cord) regions of the nervous system.
    explanation: >-
      Documents the extracerebellar distribution of neuronal loss in SCA1.
      Graded OTHER because this is review-style background in a preclinical
      mouse study rather than human data reported there.
  - reference: PMID:33709453
    reference_title: "Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Reducing Rsk3 rescues brainstem-associated pathologies and deficits, and
      lowering Rsk3 and Msk1 together improves cerebellar and brainstem
      function in an SCA1 mouse model.
    explanation: >-
      Gives this node its own brainstem-specific mechanism and the rescue that
      demonstrates it, rather than inferring brainstem loss from the cerebellar
      chain.
  - reference: PMID:33709453
    reference_title: "Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      there are no regulators that modulate ATXN1 in the brainstem-the brain
      region whose pathology is most closely linked to premature death
    explanation: Supports the brainstem as the population whose loss drives mortality.
- name: Loss of Cerebellar Cortical Output
  conforms_to: "cerebellar_purkinje_degeneration#Loss of Cerebellar Cortical Output"
  description: >-
    Purkinje cells are the sole output neurons of the cerebellar cortex.
    Their loss removes the inhibitory cortical control normally delivered to
    the deep cerebellar nuclei, degrading the feedforward coordination of
    limb, gait, speech, and eye movement. Cerebellar and brainstem atrophy is
    visible on imaging.
  biological_scale: TISSUE
  downstream:
  - target: Progressive Cerebellar and Bulbar Syndrome
    causal_link_type: DIRECT
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      brain imaging typically shows cerebellar and brain stem atrophy
    explanation: Confirms the structural cerebellar and brainstem loss underlying loss of cortical output.
- name: Progressive Cerebellar and Bulbar Syndrome
  conforms_to: "cerebellar_purkinje_degeneration#Cerebellar Ataxia"
  description: >-
    The convergent clinical manifestation of lost cerebellar coordination.
    The individual signs it produces are curated as phenotypes and reached by
    the edges below.
  biological_scale: ORGANISM
  downstream:
  - target: Progressive Gait Ataxia
    causal_link_type: DIRECT
  - target: Dysarthria
    causal_link_type: DIRECT
  - target: Dysmetria
    causal_link_type: DIRECT
  - target: Dysdiadochokinesis
    causal_link_type: DIRECT
  - target: Hypotonia
    causal_link_type: DIRECT
  - target: Nystagmus
    causal_link_type: DIRECT
  - target: Hypermetric Saccades
    causal_link_type: DIRECT
  - target: Slow Saccadic Eye Movements
    causal_link_type: DIRECT
  - target: Upgaze Palsy
    causal_link_type: DIRECT
  - target: Cerebellar Atrophy
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spinocerebellar ataxia type 1 (SCA1) is characterized by progressive
      cerebellar ataxia, dysarthria, and eventual deterioration of bulbar
      functions.
    explanation: States the defining clinical syndrome that the mechanism converges on.
- name: Repeat-Associated Non-AUG Translation of the ATXN1 Repeat
  description: >-
    The expanded repeat is translated in non-canonical reading frames as well as
    the polyglutamine frame, yielding sense polyserine and antisense polyleucine
    RAN proteins. These accumulate through cerebellum and pons in SCA1 autopsy
    brain, are prominent in cerebellar white matter where polyglutamine is
    minimal, and impair autophagy in neural cells. This is a protein-level
    consequence of the repeat that is nonetheless separate from ataxin-1 itself,
    which is why the entry does not claim the polyglutamine protein is the only
    toxic species.
  biological_scale: MOLECULAR
  downstream:
  - target: Purkinje Cell Dysfunction and Dendritic Atrophy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      RAN proteins impair autophagy, adding a proteostatic burden to the same
      vulnerable neurons.
  biological_processes:
  - preferred_term: autophagy
    term:
      id: GO:0006914
      label: autophagy
    modifier: DECREASED
  evidence:
  - reference: PMID:41422503
    reference_title: "Repeat-associated non-AUG translation as a common mechanism for the polyGln ataxias."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In neural cells, toxic polySer and polyLeu proteins impair autophagy, and
      reducing RAN protein levels with metformin reduces cytotoxicity.
    explanation: Establishes the autophagy impairment and its reversibility on lowering RAN protein.
  - reference: PMID:41422503
    reference_title: "Repeat-associated non-AUG translation as a common mechanism for the polyGln ataxias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cerebellar white matter regions, with prominent polySer and polyLeu but
      minimal polyGln, show neuroinflammation and demyelination.
    explanation: >-
      Supports RAN proteins acting where polyglutamine is scarce, so this branch
      is not a restatement of the polyglutamine one.
  - reference: PMID:41422503
    reference_title: "Repeat-associated non-AUG translation as a common mechanism for the polyGln ataxias."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Disrupting the ATXN182Q:capicua binding, which improves behavior and
      neuropathology, also reduces RAN protein aggregates.
    explanation: >-
      Links this branch back to the Capicua mechanism, indicating the two are
      coupled rather than fully independent.
- name: RBFOX1-Mediated Alternative Splicing Dysregulation
  description: >-
    Mutant ataxin-1 misregulates alternative splicing in the cerebellum, largely
    cell-autonomously, affecting biological pathways distinct from those hit by
    differential gene expression. The splicing factor RBFOX1 mediates this
    effect, and manipulating it modifies neurodegeneration in a Drosophila SCA1
    model. This is a second transcript-level mechanism alongside the
    Capicua-dependent transcriptional one.
  biological_scale: MOLECULAR
  downstream:
  - target: Purkinje Cell Dysfunction and Dendritic Atrophy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  biological_processes:
  - preferred_term: RNA splicing
    term:
      id: GO:0008380
      label: RNA splicing
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:37802886
    reference_title: "Dysregulation of alternative splicing in spinocerebellar ataxia type 1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We performed RNA sequencing in mouse models of spinocerebellar ataxia type
      1 and identified that mutant ataxin-1 expression abnormally leads to
      diverse splicing events in the mouse cerebellum of spinocerebellar ataxia
      type 1.
    explanation: Establishes splicing dysregulation as a consequence of mutant ataxin-1.
  - reference: PMID:37802886
    reference_title: "Dysregulation of alternative splicing in spinocerebellar ataxia type 1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We also provide evidence that the splicing factor Rbfox1 mediates the
      effect of mutant ataxin-1 on misregulated alternative splicing and that
      genetic manipulation of Rbfox1 expression modifies neurodegenerative
      phenotypes in a Drosophila model of spinocerebellar ataxia type 1 in vivo.
    explanation: Identifies RBFOX1 as the mediator and shows it modifies degeneration in vivo.
  - reference: PMID:37802886
    reference_title: "Dysregulation of alternative splicing in spinocerebellar ataxia type 1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      A majority of the transcripts with misregulated alternative splicing
      events were previously unknown, thus allowing us to identify overall new
      biological pathways that are distinctive to those affected by differential
      gene expression in spinocerebellar ataxia type 1.
    explanation: >-
      Supports treating this as a mechanism distinct from the transcriptional
      one rather than folding it into that node.
- name: Non-Cell-Autonomous Oligodendrocyte Dysfunction
  description: >-
    Mutant ataxin-1 expressed in oligodendrocytes alone is sufficient to produce
    dysregulated myelination, Purkinje cell axonal shrinkage and torpedo
    formation, and impaired motor coordination. This is the entry's answer to
    why a Purkinje-centred account is incomplete: a substantial part of Purkinje
    pathology is driven from outside the Purkinje cell, by a glial population,
    with TCF7L2 and huntingtin identified as upstream regulators of the
    oligodendroglial program.
  biological_scale: CELLULAR
  downstream:
  - target: Purkinje Cell Dysfunction and Dendritic Atrophy
    causal_link_type: DIRECT
    description: >-
      Demyelination and axo-myelinic dysfunction drive Purkinje axonal
      pathology, so this glial branch converges on the same node as the
      cell-autonomous chain.
    evidence:
    - reference: PMID:42113962
      reference_title: "Oligodendrocyte dysfunction contributes to motor deficits and Purkinje cell axonopathy in spinocerebellar ataxia type 1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This, compounded by a progressive decline in the neuroprotective
        functions of a cerebellum-specific oligodendrocyte subtype, establishes a
        critical link between demyelination, axo-myelinic dysfunction, and axonal
        pathology in SCA1.
      explanation: Supports this specific glia-to-Purkinje causal step.
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  biological_processes:
  - preferred_term: myelination
    term:
      id: GO:0042552
      label: myelination
    modifier: DECREASED
  evidence:
  - reference: PMID:42113962
    reference_title: "Oligodendrocyte dysfunction contributes to motor deficits and Purkinje cell axonopathy in spinocerebellar ataxia type 1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      using an oligodendroglia-specific SCA1 conditional knockin mouse model, we
      demonstrate that mutant ataxin-1 in oligodendrocytes is sufficient to drive
      aspects of SCA1-related pathology, including dysregulated myelination, PC
      axonal shrinkage, and torpedo formation, ultimately impairing motor
      coordination
    explanation: >-
      The sufficiency result: a cell-type-restricted model shows glial expression
      alone reproduces core SCA1 pathology.
  - reference: PMID:42113962
    reference_title: "Oligodendrocyte dysfunction contributes to motor deficits and Purkinje cell axonopathy in spinocerebellar ataxia type 1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Upstream transcriptional regulator analysis in oligodendroglia identifies
      transcription factor 7-like 2 (TCF7L2) and huntingtin (HTT) as key
      mediators of oligodendroglial dysfunction in SCA1, suggesting shared
      pathogenic mechanisms with other polyglutamine diseases.
    explanation: Names the upstream regulators of the oligodendroglial program in this branch.
phenotypes:
- name: Progressive Gait Ataxia
  category: Neurological
  frequency: VERY_FREQUENT
  description: >-
    Gait disturbance with impaired balance is the usual presenting feature and
    the core progressive deficit of SCA1.
  phenotype_term:
    preferred_term: Gait ataxia
    term:
      id: HP:0002066
      label: Gait ataxia
    clinical_course: PROGRESSIVE
  sequelae:
  - target: Dysphagia
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early in the disease, affected individuals may have gait disturbance,
      slurred speech, difficulty with balance, brisk deep tendon reflexes,
      hypermetric saccades, nystagmus, and mild dysphagia.
    explanation: Lists gait disturbance and impaired balance among the early features.
- name: Dysarthria
  category: Neurological
  frequency: VERY_FREQUENT
  description: >-
    Slurred, scanning speech appears early and progresses; speech therapy and
    communication devices are part of standard management.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spinocerebellar ataxia type 1 (SCA1) is characterized by progressive
      cerebellar ataxia, dysarthria, and eventual deterioration of bulbar
      functions.
    explanation: Names dysarthria as a defining feature of SCA1.
- name: Hypermetric Saccades
  category: Neurological
  frequency: FREQUENT
  description: >-
    Saccadic overshoot is an early oculomotor sign, later giving way to
    slowing of saccadic velocity as the disease advances.
  phenotype_term:
    preferred_term: Hypermetric saccades
    term:
      id: HP:0007338
      label: Hypermetric saccades
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early in the disease, affected individuals may have gait disturbance,
      slurred speech, difficulty with balance, brisk deep tendon reflexes,
      hypermetric saccades, nystagmus, and mild dysphagia.
    explanation: Places hypermetric saccades among the early oculomotor findings.
- name: Slow Saccadic Eye Movements
  category: Neurological
  frequency: OCCASIONAL
  description: >-
    Saccadic velocity slows as the disease progresses, a later oculomotor
    feature that follows the early hypermetria.
  phenotype_term:
    preferred_term: Slow saccadic eye movements
    term:
      id: HP:0000514
      label: Slow saccadic eye movements
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Later signs include slowing of saccadic velocity, development of upgaze
      palsy, dysmetria, dysdiadochokinesia, and hypotonia.
    explanation: Identifies saccadic slowing as a later-stage sign.
- name: Nystagmus
  category: Neurological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early in the disease, affected individuals may have gait disturbance,
      slurred speech, difficulty with balance, brisk deep tendon reflexes,
      hypermetric saccades, nystagmus, and mild dysphagia.
    explanation: Lists nystagmus among the early findings.
- name: Upgaze Palsy
  category: Neurological
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Upgaze palsy
    term:
      id: HP:0025331
      label: Upgaze palsy
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Later signs include slowing of saccadic velocity, development of upgaze
      palsy, dysmetria, dysdiadochokinesia, and hypotonia.
    explanation: Names upgaze palsy as a later oculomotor sign.
- name: Hyperreflexia
  category: Neurological
  frequency: FREQUENT
  description: >-
    Brisk deep tendon reflexes reflect the pyramidal involvement that places
    SCA1 in the ADCA-I class. Reflexes are later lost as the axonal sensory
    neuropathy and anterior horn involvement supervene.
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early in the disease, affected individuals may have gait disturbance,
      slurred speech, difficulty with balance, brisk deep tendon reflexes,
      hypermetric saccades, nystagmus, and mild dysphagia.
    explanation: Documents brisk deep tendon reflexes as an early pyramidal sign.
- name: Hyporeflexia
  category: Neurological
  frequency: OCCASIONAL
  description: >-
    Deep tendon reflexes decrease in advanced disease, reversing the early
    hyperreflexia as peripheral and anterior horn involvement dominates.
  phenotype_term:
    preferred_term: Hyporeflexia
    term:
      id: HP:0001265
      label: Hyporeflexia
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In advanced stages, muscle atrophy, decreased deep tendon reflexes, loss
      of proprioception, cognitive impairment (e.g., frontal executive
      dysfunction, impaired verbal memory), chorea, dystonia, and bulbar
      dysfunction are seen.
    explanation: Records decreased deep tendon reflexes as an advanced-stage finding.
- name: Dysmetria
  category: Neurological
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Dysmetria
    term:
      id: HP:0001310
      label: Dysmetria
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Later signs include slowing of saccadic velocity, development of upgaze
      palsy, dysmetria, dysdiadochokinesia, and hypotonia.
    explanation: Lists dysmetria among the appendicular cerebellar signs.
- name: Dysdiadochokinesis
  category: Neurological
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Dysdiadochokinesis
    term:
      id: HP:0002075
      label: Dysdiadochokinesis
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Later signs include slowing of saccadic velocity, development of upgaze
      palsy, dysmetria, dysdiadochokinesia, and hypotonia.
    explanation: Lists dysdiadochokinesia among the appendicular cerebellar signs.
- name: Hypotonia
  category: Neurological
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Later signs include slowing of saccadic velocity, development of upgaze
      palsy, dysmetria, dysdiadochokinesia, and hypotonia.
    explanation: Lists hypotonia among the later signs.
- name: Dysphagia
  category: Neurological
  frequency: VERY_FREQUENT
  description: >-
    Swallowing difficulty is mild early and becomes a defining problem of
    advanced disease, driving aspiration risk and contributing directly to
    death.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early in the disease, affected individuals may have gait disturbance,
      slurred speech, difficulty with balance, brisk deep tendon reflexes,
      hypermetric saccades, nystagmus, and mild dysphagia.
    explanation: Documents mild dysphagia as present from early in the course.
  - reference: PMID:32818920
    reference_title: "Antisense Oligonucleotide Therapeutic Approach for Suppression of Ataxin-1 Expression: A Safety Assessment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      death due to dysphagia and/or respiratory failure caused by degenerations
      in medullary cranial nerve nuclei and anterior horn neurons
    explanation: >-
      Establishes dysphagia as a direct contributor to mortality. Graded OTHER
      because the sentence is background narrative in a preclinical mouse
      study, not human data reported by it.
- name: Sensory Axonal Neuropathy
  category: Neurological
  frequency: FREQUENT
  description: >-
    An axonal sensory neuropathy demonstrable on electrophysiologic testing is
    common in SCA1 and contributes to the late loss of proprioception and
    reflexes.
  phenotype_term:
    preferred_term: Sensory axonal neuropathy
    term:
      id: HP:0003390
      label: Sensory axonal neuropathy
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An axonal sensory neuropathy detected by electrophysiologic testing is
      common; brain imaging typically shows cerebellar and brain stem atrophy.
    explanation: States that axonal sensory neuropathy is a common electrophysiologic finding.
- name: Impaired Proprioception
  category: Neurological
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Impaired proprioception
    term:
      id: HP:0010831
      label: Impaired proprioception
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In advanced stages, muscle atrophy, decreased deep tendon reflexes, loss
      of proprioception, cognitive impairment (e.g., frontal executive
      dysfunction, impaired verbal memory), chorea, dystonia, and bulbar
      dysfunction are seen.
    explanation: Lists loss of proprioception among advanced-stage findings.
- name: Skeletal Muscle Atrophy
  category: Musculoskeletal
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In advanced stages, muscle atrophy, decreased deep tendon reflexes, loss
      of proprioception, cognitive impairment (e.g., frontal executive
      dysfunction, impaired verbal memory), chorea, dystonia, and bulbar
      dysfunction are seen.
    explanation: Records muscle atrophy as an advanced-stage feature.
- name: Impaired Executive Functioning
  category: Neurocognitive
  frequency: OCCASIONAL
  description: >-
    Cognitive involvement in advanced SCA1 is predominantly frontal-executive,
    with impaired verbal memory; neuropsychologic rehabilitation is part of
    recommended management.
  phenotype_term:
    preferred_term: Impaired executive functioning
    term:
      id: HP:0033051
      label: Impaired executive functioning
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cognitive impairment (e.g., frontal executive dysfunction, impaired
      verbal memory)
    explanation: Specifies the frontal-executive character of the cognitive impairment.
- name: Chorea
  category: Neurological
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Chorea
    term:
      id: HP:0002072
      label: Chorea
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In advanced stages, muscle atrophy, decreased deep tendon reflexes, loss
      of proprioception, cognitive impairment (e.g., frontal executive
      dysfunction, impaired verbal memory), chorea, dystonia, and bulbar
      dysfunction are seen.
    explanation: Lists chorea among advanced-stage extrapyramidal features.
- name: Dystonia
  category: Neurological
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In advanced stages, muscle atrophy, decreased deep tendon reflexes, loss
      of proprioception, cognitive impairment (e.g., frontal executive
      dysfunction, impaired verbal memory), chorea, dystonia, and bulbar
      dysfunction are seen.
    explanation: Lists dystonia among advanced-stage extrapyramidal features.
- name: Cerebellar Atrophy
  category: Neuroimaging
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      brain imaging typically shows cerebellar and brain stem atrophy
    explanation: Reports cerebellar atrophy as the typical imaging finding.
- name: Brainstem Atrophy
  category: Neuroimaging
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Atrophy/Degeneration affecting the brainstem
    term:
      id: HP:0007366
      label: Atrophy/Degeneration affecting the brainstem
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      brain imaging typically shows cerebellar and brain stem atrophy
    explanation: Reports brainstem atrophy alongside cerebellar atrophy on imaging.
genetic:
- name: ATXN1
  gene_term:
    preferred_term: ATXN1
    term:
      id: hgnc:10548
      label: ATXN1
  association: Translated CAG trinucleotide repeat expansion
  presence: Positive
  relationship_type: CAUSATIVE
  notes: >-
    The pathogenic allele is an expanded, unstable CAG repeat in the coding
    region of ATXN1, encoding an elongated polyglutamine tract in ataxin-1.
    Affected individuals usually carry 39 or more repeats. The repeat is
    unstable in transmission, producing anticipation with a paternal
    expansion bias, and longer expansions predict both earlier onset and
    faster measured progression. Toxicity is a dominant gain of function
    acting through the normal, Ser776 phosphorylation-regulated ataxin-1
    complexes rather than through a novel interaction, combined with a
    partial loss of other native ataxin-1 interactions.
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:37238658
    reference_title: "Therapeutic Strategies for Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Normal alleles range from 6 to 38 CAG repeats, with 1 to 3 CAT
      interruptions that are thought to be involved in the stability of the
      trinucleotide stretch during DNA replication.
    explanation: >-
      Establishes CAT interruptions as the feature stabilizing normal-range
      ATXN1 alleles.
  - reference: PMID:37238658
    reference_title: "Therapeutic Strategies for Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Disease-causing alleles have 39 to 44 CAG repeats without stabilizing CAT
      interruptions or larger expansions with CAT interruptions
    explanation: >-
      Defines the pathogenic allele architecture, and notes that longer alleles
      may retain interruptions, so purity is not a universal criterion.
  - reference: PMID:16110192
    reference_title: "Genotype/phenotype correlation in a SCA1 family: anticipation without CAG expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      None of the expanded alleles contained CAT interruptions.
    explanation: Direct family-level observation that pathogenic alleles were uninterrupted.
  - reference: PMID:16110192
    reference_title: "Genotype/phenotype correlation in a SCA1 family: anticipation without CAG expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our observations suggest that factors other than the length of the CAG
      repeat play a considerable role in determination of the disease course.
    explanation: >-
      Qualifies the repeat-length correlation recorded above: this family showed
      anticipation without CAG expansion, so length is not the only determinant.
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of SCA1 is established in a proband with characteristic
      clinical findings and an abnormal CAG repeat expansion in ATXN1
      identified by molecular genetic testing. Affected individuals usually
      have 39 or more CAG repeats.
    explanation: Establishes the causal gene, variant class, and pathogenic repeat threshold.
  - reference: PMID:32818920
    reference_title: "Antisense Oligonucleotide Therapeutic Approach for Suppression of Ataxin-1 Expression: A Safety Assessment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CAG trinucleotide repeat expansion encoding glutamines within the
      ATAXIN-1 (ATXN1) gene, ATXN1, results in the dominantly inherited
      neurodegenerative disease Spinocerebellar ataxia type 1 (SCA1)
    explanation: >-
      Confirms the translated CAG expansion in ATXN1 as the cause of dominant
      SCA1. Graded OTHER because this is introductory background in a
      preclinical mouse study, not human data reported there.
  - reference: PMID:42608759
    reference_title: "Relationship of polyglutamine expansion and loss of ataxin-1 function in neurological diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Studies in spinocerebellar ataxia type 1 mouse models indicated that CAG
      expansion predominantly causes pathogenic ATXN1 gain-of-function in the
      cerebellum.
    explanation: >-
      Supports the gain-of-function classification recorded in
      functional_impact_category, and says where it holds: the cerebellum.
  - reference: PMID:42608759
    reference_title: "Relationship of polyglutamine expansion and loss of ataxin-1 function in neurological diseases."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Conversely, mice lacking ATXN1 are severely impaired in cognitive tests and
      exhibit abnormalities in cortical functions.
    explanation: >-
      Supports the partial loss-of-function component: normal ataxin-1 has
      cortical and cognitive functions whose loss is separable from the
      gain-of-function cerebellar mechanism, which is relevant to the cognitive
      phenotypes curated here and to the safety case for ATXN1 lowering.
  - reference: PMID:18957430
    reference_title: "Pathogenic mechanisms of a polyglutamine-mediated neurodegenerative disease, spinocerebellar ataxia type 1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The discovery that residues in ATXN1 outside of the polyglutamine tract
      are crucial for pathogenesis hinted that alterations in the normal
      function of this protein are linked to its toxicity.
    explanation: >-
      Supports the gain-of-function classification acting through normal
      ataxin-1 function rather than the polyglutamine tract alone.
- name: TGM5
  gene_term:
    preferred_term: TGM5
    term:
      id: hgnc:11781
      label: TGM5
  association: Modifier of mutant ataxin-1 stability and oligomerization
  presence: Positive
  relationship_type: MODIFIER
  notes: >-
    Transglutaminase 5 was identified in a cross-species screen as preferentially
    regulating mutant over wild-type ataxin-1. Transglutaminases cross-link
    ataxin-1 in a polyglutamine-length-dependent manner, which is what makes the
    effect allele-selective and therefore of therapeutic interest: it offers a
    handle on the expanded protein specifically.
  evidence:
  - reference: PMID:35499073
    reference_title: "Cross-species genetic screens identify transglutaminase 5 as a regulator of polyglutamine-expanded ataxin-1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      TG enzymes catalyzed cross-linking of ATXN1 in a polyQ-length-dependent
      manner, thereby preferentially modulating mutant ATXN1 stability and
      oligomerization.
    explanation: Establishes the polyglutamine-length-dependent, mutant-selective modifier effect.
  - reference: PMID:35499073
    reference_title: "Cross-species genetic screens identify transglutaminase 5 as a regulator of polyglutamine-expanded ataxin-1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, TG5 was enriched in the nuclei of SCA1-affected neurons and
      colocalized with nuclear ATXN1 inclusions in brain tissue from patients
      with SCA1.
    explanation: >-
      Confirms TG5 is present at the relevant subcellular site in human SCA1
      brain, so the modifier claim is not model-only.
- name: RBFOX1
  gene_term:
    preferred_term: RBFOX1
    term:
      id: hgnc:18222
      label: RBFOX1
  association: Splicing factor mediating mutant ataxin-1 splicing dysregulation
  presence: Positive
  relationship_type: MODIFIER
  notes: >-
    RBFOX1 mediates the splicing dysregulation curated as its own pathophysiology
    branch, and manipulating its expression modifies neurodegeneration in a
    Drosophila SCA1 model.
  evidence:
  - reference: PMID:37802886
    reference_title: "Dysregulation of alternative splicing in spinocerebellar ataxia type 1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We also provide evidence that the splicing factor Rbfox1 mediates the
      effect of mutant ataxin-1 on misregulated alternative splicing and that
      genetic manipulation of Rbfox1 expression modifies neurodegenerative
      phenotypes in a Drosophila model of spinocerebellar ataxia type 1 in vivo.
    explanation: Supports RBFOX1 as a genetic modifier of the neurodegenerative phenotype.
biochemical:
- name: Blood Neurofilament Light Chain
  biomarker_term:
    preferred_term: neurofilament light polypeptide
    term:
      id: NCIT:C88043
      label: Neurofilament Light Polypeptide
  evidence:
  - reference: PMID:42677125
    reference_title: "Predicting disease progression in progressive cerebellar ataxias: integrating clinical, imaging, fluid, genetic, and digital biomarkers."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Volumetric, microstructural, and spectroscopic MRI and blood neurofilament
      light chain change before ataxia onset and predict subsequent decline,
      whereas repeat length and genetic modifiers set prior risk.
    explanation: >-
      Establishes the premanifest change and prognostic value that make this a
      curated biomarker rather than a general injury marker.
  - reference: PMID:42677125
    reference_title: "Predicting disease progression in progressive cerebellar ataxias: integrating clinical, imaging, fluid, genetic, and digital biomarkers."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Disease-modifying therapies, notably antisense oligonucleotides and the
      approved compound omaveloxolone, are now entering or reaching the clinic,
      which makes reliable prediction of disease progression a central obstacle
      to trial success.
    explanation: >-
      Explains why the premanifest window matters for SCA1 specifically, given
      the ATXN1-lowering ASO curated in treatments.
  notes: >-
    Blood neurofilament light chain is a fluid marker of neuroaxonal injury that
    changes before ataxia onset in the progressive cerebellar ataxias and
    predicts subsequent decline. Its importance here is the premanifest window it
    opens: with ATXN1-lowering therapies entering trials, a marker that moves
    before symptoms is what makes a preventive trial design possible.
    Volumetric, microstructural and spectroscopic MRI behave the same way. Note
    this is a class-level finding across the progressive cerebellar ataxias
    including SCA1, not a SCA1-only measurement, and the source is a review
    rather than a primary cohort. No SCA1-specific reference interval was
    identified, so none is recorded.
diagnosis:
- name: ATXN1 Repeat-Sizing Molecular Genetic Testing
  description: >-
    Diagnosis rests on sizing the CAG repeat in ATXN1 in a proband with a
    compatible progressive cerebellar syndrome. Because SCA1 is clinically
    indistinguishable from several other dominant ataxias, molecular testing
    rather than phenotype resolves the genotype.
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of SCA1 is established in a proband with characteristic
      clinical findings and an abnormal CAG repeat expansion in ATXN1
      identified by molecular genetic testing.
    explanation: States the diagnostic standard directly.
- name: Determination of CAT Interruption Status
  description: >-
    Sizing the repeat is not sufficient on its own: the diagnostic workup should
    establish whether the CAG tract is interrupted by CAT units, using
    triplet-primed PCR and enzymatic digestion. Interruption status bears on
    pathogenicity, on how an intermediate-range allele is interpreted, and on
    counselling, because uninterrupted tracts are the unstable, disease-causing
    configuration.
  diagnosis_term:
    preferred_term: triplet-primed PCR for repeat interruption
    term:
      id: NCIT:C17003
      label: Polymerase Chain Reaction
  evidence:
  - reference: PMID:39289638
    reference_title: "Early-onset phenotype in a patient with an intermediate allele and a large SCA1 expansion: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The numbers of CAG repeats in the ATXN1 gene was assessed by fluorescent
      PCR, tripled-primed PCR and enzymatic digestion for the search of sequence
      interruption in the CAG repeats.
    explanation: Documents the assay combination used to establish interruption status.
  - reference: PMID:39289638
    reference_title: "Early-onset phenotype in a patient with an intermediate allele and a large SCA1 expansion: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient carried one pathogenic allele of 61 CAG and one intermediate
      allele of 37 CAG in the ATXN1 gene. Both alleles were uninterrupted.
    explanation: >-
      The case that motivates the test: an uninterrupted intermediate allele
      alongside a large expansion, in a patient with early onset and rapid
      progression.
- name: SARA Clinical Rating and MRI
  description: >-
    Disease staging uses the Scale for the Assessment and Rating of Ataxia
    together with imaging. Both have known limits: SARA loses sensitivity at the
    extremes of the disease course, and no single modality serves every purpose,
    which is why multimodal composites are argued for.
  diagnosis_term:
    preferred_term: magnetic resonance imaging of cerebellum and brainstem
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:42677125
    reference_title: "Predicting disease progression in progressive cerebellar ataxias: integrating clinical, imaging, fluid, genetic, and digital biomarkers."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinical scales such as SARA capture genotype-specific trajectories but
      lose sensitivity at the extremes of the disease course.
    explanation: >-
      Supports SARA as the genotype-sensitive staging instrument and records its
      stated limitation.
treatments:
- name: Coordinative Physiotherapy and Physical Therapy
  description: >-
    Supportive management centers on adaptive devices, physical therapy, and
    intensive coordinative physiotherapy, which may be beneficial. Avoidance
    of obesity is specifically recommended. There is no disease-modifying
    therapy.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_mechanisms:
  - target: Progressive Cerebellar and Bulbar Syndrome
    description: >-
      Rehabilitation targets the functional consequences of lost cerebellar
      coordination; it does not modify the underlying degeneration.
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Supportive care including adaptive devices, physical therapy,
      occupational therapy, avoidance of obesity; intensive rehabilitation
      (coordinative physiotherapy) may be beneficial
    explanation: States the recommended rehabilitative management for SCA1.
- name: Occupational Therapy
  description: >-
    Occupational therapy supports mobility and self-help skills and is
    reassessed every three to six months alongside physiatry and physical
    therapy.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: occupational therapy
    term:
      id: NCIT:C121351
      label: Occupational Therapy
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      physiatry, occupational therapy, and physical therapy assessment for
      mobility and self-help skills
    explanation: Documents occupational therapy as part of scheduled surveillance and management.
- name: Speech Therapy and Communication Devices
  description: >-
    Speech therapy and communication devices address the progressive
    dysarthria; access to communication is assessed at each visit.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech and language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  target_mechanisms:
  - target: Progressive Cerebellar and Bulbar Syndrome
    description: Symptomatic management of dysarthria arising from bulbar and cerebellar involvement.
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      speech therapy and communication devices for dysarthria
    explanation: States the recommended management of dysarthria.
- name: Dysphagia and Nutritional Management
  description: >-
    Aspiration risk is managed with video esophagram to identify the safest
    food consistency, feeding devices where aspiration recurs, and caloric
    support for weight loss.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Dysphagia
    description: >-
      Directly targets the aspiration and nutritional consequences of bulbar
      dysfunction, the proximate cause of death in SCA1.
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      video esophagram to help identify the consistency of food least likely
      to trigger aspiration and feeding devices may be indicated with recurrent
      aspiration; caloric support for those with weight loss
    explanation: States the recommended dysphagia and nutritional management.
- name: Avoidance of Neurotoxic Agents and Hazardous Circumstances
  description: >-
    GeneReviews lists specific agents and circumstances to avoid in SCA1:
    alcohol, medications known to cause nerve damage such as isoniazid and
    large-dose vitamin B6, and situations that could cause physical harm such
    as operating machinery or climbing to great heights. The neurotoxic drug
    caution is particularly relevant given the common coexisting axonal
    sensory neuropathy.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Agents/circumstances to avoid: Alcohol, medications known to cause nerve
      damage (e.g., isoniazid, large-dose vitamin B6), and circumstances that
      could lead to physical harm, such as operating machinery or climbing to
      great heights.
    explanation: Records the GeneReviews drug-safety and hazard-avoidance guidance verbatim.
- name: Psychotherapy and Neuropsychologic Rehabilitation
  description: >-
    GeneReviews recommends psychotherapy, neuropsychologic rehabilitation, and
    standard psychiatric treatment for the cognitive and psychiatric
    manifestations of SCA1, with mood and psychiatric manifestations assessed
    at each visit.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: psychotherapy
    term:
      id: NCIT:C15308
      label: Psychotherapy
  target_mechanisms:
  - target: Impaired Executive Functioning
    description: >-
      Addresses the frontal-executive and psychiatric burden of advanced
      disease; it is symptomatic and does not alter the degeneration.
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      psychotherapy, neuropsychologic rehabilitation, and/or standard
      psychiatric treatments for cognitive and psychiatric manifestations
    explanation: States the recommended management of cognitive and psychiatric features.
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      assessment of access to communication, speech needs, aspiration risk,
      feeding needs, mood, psychiatric manifestations, cognition, and family
      needs
    explanation: Documents mood, psychiatric manifestations and cognition as surveillance items.
- name: Pain Management
  description: >-
    Pharmacotherapy and referral to pain management are recommended as needed
    for pain in SCA1.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      pharmacotherapy and/or referral to pain management as needed for pain
    explanation: States the recommended approach to pain in SCA1.
- name: Vitamin Supplementation
  description: >-
    Vitamin supplementation as needed is part of supportive management. Note
    this sits beside an explicit caution against large-dose vitamin B6, which
    is listed among agents to avoid because of its neurotoxicity.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: nutritional support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      caloric support for those with weight loss; vitamin supplementation as
      needed
    explanation: >-
      Records vitamin supplementation as a recommended supportive measure. The
      quote carries the adjacent caloric-support clause because the chapter
      states the two together; caloric support itself is curated under
      Dysphagia and Nutritional Management.
- name: Genetic Counseling
  description: >-
    Counseling covers the 50% offspring risk, anticipation with paternal
    expansion bias, and the availability of prenatal and preimplantation
    genetic testing once a family expansion is identified.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301363
    reference_title: "Spinocerebellar Ataxia Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Once an abnormal CAG trinucleotide expansion in ATXN1 has been identified
      in an affected family member, prenatal and preimplantation genetic
      testing are possible.
    explanation: States the reproductive testing options that counseling covers.
- name: Off-Label Symptomatic Pharmacotherapy
  description: >-
    No drug is approved for SCA1 and none is disease-modifying. Riluzole,
    4-aminopyridine and varenicline are used off-label across the adult-onset
    cerebellar ataxias with subtype-specific benefit, so their applicability to
    SCA1 specifically is not established by the source cited here, which reviews
    the class. They are recorded because the entry otherwise implied that
    nothing pharmacological is offered, which misrepresents practice.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: riluzole
      term:
        id: CHEBI:8863
        label: Riluzole
    - preferred_term: 4-aminopyridine
      term:
        id: CHEBI:34385
        label: 4-aminopyridine
    - preferred_term: varenicline
      term:
        id: CHEBI:84500
        label: varenicline
  target_mechanisms:
  - target: Progressive Cerebellar and Bulbar Syndrome
    description: >-
      These agents target the ataxic syndrome symptomatically; none acts on the
      ATXN1 lesion or the mechanisms downstream of it.
  evidence:
  - reference: PMID:41387161
    reference_title: "Treatment of primary adult-onset neurodegenerative cerebellar ataxias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Pharmacological approaches, including omaveloxolone for Friedreich's
      ataxia and off-label agents such as riluzole, 4-aminopyridine, and
      varenicline, demonstrate subtype-specific benefits.
    explanation: >-
      Names the off-label agents and, in the same sentence, that benefit is
      subtype-specific, which is why this entry does not claim SCA1 efficacy.
  - reference: PMID:41387161
    reference_title: "Treatment of primary adult-onset neurodegenerative cerebellar ataxias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rehabilitation and multidisciplinary care remain foundational across all
      subtypes and are supported by growing clinical trial evidence.
    explanation: >-
      Supports the supportive and rehabilitative entries above remaining the
      mainstay rather than being displaced by these agents.
- name: Troriluzole (Investigational)
  description: >-
    Troriluzole is a riluzole prodrug with improved oral bioavailability and less
    pharmacokinetic variability, in clinical trials for cerebellar ataxia. The
    caveat matters: the citation available here is a rat opioid-addiction study
    that mentions the ataxia trials only in passing, so this records that the
    development programme exists, not any SCA1 efficacy result.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:40988103
    reference_title: "Troriluzole attenuates opioid intake, reinforcing efficacy, seeking behaviours, physical dependence and antinociceptive tolerance in rats."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TRLZ, already in clinical trials for cerebellar ataxia, also reduced opioid
      taking and seeking as well as opioid-derived adverse effects in rats
    explanation: >-
      Graded OTHER because the statement about cerebellar ataxia trials is a
      passing aside in a rat opioid study, not a finding of that study. It
      establishes only that the trials exist.
  - reference: PMID:40988103
    reference_title: "Troriluzole attenuates opioid intake, reinforcing efficacy, seeking behaviours, physical dependence and antinociceptive tolerance in rats."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      we designed and prepared the prodrug troriluzole (TRLZ), which retains the
      mechanistic profile of riluzole but with optimized metabolic and
      pharmacokinetic properties
    explanation: Establishes the relationship to riluzole and the rationale for the prodrug.
- name: Non-Invasive Neuromodulation
  description: >-
    Transcranial direct current stimulation and repetitive transcranial magnetic
    stimulation have shown early promise for motor outcomes in the adult-onset
    cerebellar ataxias. Recorded as early-stage and class-level, not as
    established SCA1 therapy.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: therapeutic procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_mechanisms:
  - target: Progressive Cerebellar and Bulbar Syndrome
    description: Symptomatic modulation of motor output; not disease-modifying.
  evidence:
  - reference: PMID:41387161
    reference_title: "Treatment of primary adult-onset neurodegenerative cerebellar ataxias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Neuromodulation techniques, such as transcranial direct current
      stimulation and repetitive transcranial magnetic stimulation, have shown
      early promise in improving motor outcomes.
    explanation: >-
      States the modality and the strength of the claim, which the description
      deliberately does not upgrade.
- name: ATXN1-Lowering Antisense Oligonucleotide (Investigational)
  description: >-
    Non-allele-specific reduction of ATXN1 by an RNase H antisense
    oligonucleotide rescues motor deficits and premature lethality in
    Atxn1-154Q knock-in mice after a single treatment, and reverses
    neurochemical abnormalities in cerebellum and brainstem. A dedicated
    safety assessment found no adverse effect on Capicua tumor-suppressor
    function, BACE1, or hippocampal neuronal precursor numbers, addressing
    the main theoretical concerns of lowering a protein whose normal partner
    is a tumor suppressor. This is preclinical; no ATXN1-lowering therapy is
    approved for SCA1.
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  oligonucleotide_details:
    oligonucleotide_mechanism: RNASE_H_KNOCKDOWN
    target_gene:
      preferred_term: ATXN1
      term:
        id: hgnc:10548
        label: ATXN1
    target_transcript: ATXN1 pre-mRNA and mature mRNA
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: antisense oligonucleotide
      term:
        id: NCIT:C1291
        label: Antisense Oligonucleotides
  target_mechanisms:
  - target: ATXN1 CAG Repeat Expansion
    description: >-
      Lowering ATXN1 RNA reduces the amount of expanded ataxin-1 available to
      enter the pathogenic complex, acting at the top of the causal chain.
    evidence:
    - reference: PMID:30385727
      reference_title: "Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Following a single ASO treatment at 5 weeks of age, mice demonstrated
        rescue of these disease-associated phenotypes.
      explanation: >-
        Shows that reducing the initiating molecular lesion rescues the
        downstream motor and survival phenotypes.
  evidence:
  - reference: PMID:30385727
    reference_title: "Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Together, these findings support the efficacy and therapeutic importance
      of directly targeting ATXN1 RNA expression as a strategy for treating
      both motor deficits and lethality in SCA1.
    explanation: States the preclinical efficacy conclusion for ATXN1-lowering ASO therapy.
  - reference: PMID:32818920
    reference_title: "Antisense Oligonucleotide Therapeutic Approach for Suppression of Ataxin-1 Expression: A Safety Assessment."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Notably, no effects on BACE1, CIC tumor suppressor function, or number of
      hippocampal neuronal precursor cells were found in mice subjected to a
      chronic in vivo ASO-mediated reduction of Atxn1.
    explanation: Supports the safety claim regarding the main theoretical risks of ATXN1 lowering.
experimental_models:
- name: SCA1 patient-derived iPSC neuronal cultures
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Neuronal cultures differentiated from SCA1 patient induced pluripotent stem
    cells, alongside patient fibroblasts. A human, non-animal system that
    reproduces aggregate localization matching SCA1 postmortem brain, reduced
    dendritic complexity, and delayed network development on multi-electrode
    arrays.
  modeled_mechanisms:
  - target: Purkinje Cell Dysfunction and Dendritic Atrophy
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Reproduces the dendritic and network-level dysfunction of the target node
      in human cells.
    limitations: >-
      These are generic iPSC-derived neurons, not cerebellar Purkinje cells, so
      the cell type that defines the target node is absent; the readout is
      dendritic and network dysfunction in a proxy neuronal population.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The model measures dendrite length, branch-point number and network
        activity in iPSC-derived neurons. The node's quantity is Purkinje cell
        dendritic atrophy and dysfunction in cerebellar cortex.
    readouts:
    - name: Dendrite length and branching, and network activity development
      target: Purkinje Cell Dysfunction and Dendritic Atrophy
      direction: DECREASED
      interpretation: >-
        Reduced dendritic complexity with delayed network maturation, the
        cellular correlate of the target node.
      evidence:
      - reference: PMID:37278528
        reference_title: "Spinocerebellar Ataxia Type 1 Characteristics in Patient-Derived Fibroblast and iPSC-Derived Neuronal Cultures."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          SCA1 hiPSC-derived neuronal cells showed reduced dendrite length and
          number of branching points while MEA recordings identified delayed
          development in network activity in SCA1 hiPSC-derived neuronal cells.
        explanation: Reports the measured dendritic and network deficits.
    evidence:
    - reference: PMID:37278528
      reference_title: "Spinocerebellar Ataxia Type 1 Characteristics in Patient-Derived Fibroblast and iPSC-Derived Neuronal Cultures."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In SCA1 hiPSC-derived neuronal cells, nuclear and cytoplasmic aggregates
        were identified similar in localization as aggregates in SCA1 postmortem
        brain tissue.
      explanation: >-
        Supports treating this model as informative by anchoring its aggregate
        pathology to human postmortem SCA1 brain.
  evidence:
  - reference: PMID:37278528
    reference_title: "Spinocerebellar Ataxia Type 1 Characteristics in Patient-Derived Fibroblast and iPSC-Derived Neuronal Cultures."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Patient-derived cells recapitulate key pathological features of SCA1
      pathogenesis providing a valuable tool for the identification of novel
      disease-specific processes.
    explanation: The authors' own assessment of the model's validity for SCA1.
animal_models:
- name: SCA1 Purkinje-cell transgenic mouse (ataxin-1 with expanded CAG repeat)
  species: Mouse
  genotype: Pcp2-driven human ATXN1 transgene with expanded CAG repeat
  publication: PMID:7553854
  description: >-
    Transgenic mice expressing the human SCA1 gene with an expanded CAG tract
    under a Purkinje-cell promoter. Five of six expanded lines developed ataxia
    and Purkinje cell degeneration, while all six lines carrying the unexpanded
    allele had normal Purkinje cells, giving a clean allele-length-dependent
    control.
  modeled_mechanisms:
  - target: Purkinje Neuron Degeneration
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      Reproduces the defining Purkinje cell degeneration of human SCA1 and
      establishes that expanded repeat expression within Purkinje cells is
      sufficient to cause it.
    limitations: >-
      Expression is transgenic and Purkinje-cell restricted rather than
      endogenous and brain-wide, so the model does not reproduce the brainstem,
      medullary, and anterior horn degeneration that causes death in patients,
      and repeat length exceeds most patient alleles.
    evidence:
    - reference: PMID:7553854
      reference_title: "SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        While all six transgenic lines expressing the unexpanded human SCA1
        allele had normal Purkinje cells, transgenic animals from five of six
        lines with the expanded SCA1 allele developed ataxia and Purkinje cell
        degeneration.
      explanation: >-
        Establishes the model's allele-length-dependent recapitulation of
        Purkinje cell degeneration.
  evidence:
  - reference: PMID:7553854
    reference_title: "SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      demonstrate that a mouse model can be established for neurodegeneration
      caused by CAG repeat expansions
    explanation: >-
      Supports treating this transgenic line as an informative model of
      expansion-driven neurodegeneration.
- name: Atxn1-154Q knock-in mouse
  species: Mouse
  genotype: Atxn1(154Q/2Q) knock-in
  publication: PMID:30385727
  description: >-
    Knock-in mice carrying an expanded CAG repeat inserted into one endogenous
    Atxn1 allele, expressing ATXN1 with 154 glutamines throughout the brain.
    They display ataxia and premature lethality, and were the model used to
    demonstrate ASO rescue.
  modeled_mechanisms:
  - target: ATXN1 CAG Repeat Expansion
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: >-
      Places the expansion at the endogenous locus under native regulation,
      making it the appropriate model for testing ATXN1-lowering therapy.
    limitations: >-
      The 154-repeat allele is far longer than typical human pathogenic alleles
      (usually 39 or more), compressing an adult-onset human disease into a
      rapid murine course.
    readouts:
    - name: Motor performance and survival after single ASO treatment
      target: ATXN1 CAG Repeat Expansion
      direction: RESTORED
      interpretation: >-
        Lowering the expanded transcript rescued both motor deficits and
        premature lethality, confirming ongoing dependence on the initiating
        lesion.
      evidence:
      - reference: PMID:30385727
        reference_title: "Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Following a single ASO treatment at 5 weeks of age, mice demonstrated
          rescue of these disease-associated phenotypes.
        explanation: Reports the measured rescue of motor deficits and lethality.
    evidence:
    - reference: PMID:30385727
      reference_title: "Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we investigated the therapeutic capability of an antisense
        oligonucleotide (ASO) targeting mouse Atxn1 in Atxn1154Q/2Q-knockin
        mice that manifest motor deficits and premature lethality
      explanation: Establishes the model's genotype and the phenotypes it manifests.
  evidence:
  - reference: PMID:32818920
    reference_title: "Antisense Oligonucleotide Therapeutic Approach for Suppression of Ataxin-1 Expression: A Safety Assessment."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Atxn1154Q/2Q mice were generated by the insertion of an expanded CAG
      repeat into one endogenous Atxn12Q allele
    explanation: >-
      Confirms the knock-in design at the endogenous locus, which is what makes
      this model appropriate for testing ATXN1-lowering therapy.
- name: Atxn1l duplication modifier mouse
  species: Mouse
  genotype: Targeted Atxn1l (ataxin-1-like) duplication on an SCA1 knock-in background
  publication: PMID:17322884
  description: >-
    A genetic modifier model in which elevated levels of the ataxin-1 paralog
    Atxn1l displace mutant ataxin-1 from its native Capicua complex. It is the
    decisive test that occupancy of that complex, rather than aggregation, is
    what produces neuropathology.
  modeled_mechanisms:
  - target: Aberrant Ataxin-1-Capicua Transcriptional Repressor Activity
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Suppresses SCA1 neuropathology specifically by reducing incorporation of
      polyglutamine-expanded ataxin-1 into the Capicua-containing complex.
    limitations: >-
      Paralog overexpression is a genetic manipulation with no clinical
      counterpart, and the readout is murine neuropathology rather than a human
      clinical endpoint.
    evidence:
    - reference: PMID:17322884
      reference_title: "Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our results provide genetic evidence that the selective neuropathology
        of SCA1 arises from modulation of a core functional activity of ATXN1
      explanation: >-
        Supports the specific mechanistic claim that toxicity works through a
        native ataxin-1 activity, which this rescue targets.
  evidence:
  - reference: PMID:17322884
    reference_title: "Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using a knock-in mouse model of SCA1 that recapitulates the selective
      neurodegeneration seen in affected individuals
    explanation: >-
      Establishes that the background model reproduces the selective
      neurodegeneration of human SCA1, supporting its use here.
mechanistic_hypotheses:
- hypothesis_group_id: native_complex_toxicity
  hypothesis_label: Toxicity through native ataxin-1 complexes, not novel interactions
  status: CANONICAL
  description: >-
    The polyglutamine expansion acts by modulating a core normal activity of
    ataxin-1 within its native, Ser776 phosphorylation-dependent complexes,
    chiefly the complex with the transcriptional repressor Capicua, rather
    than by conferring a novel aberrant interaction. Displacing mutant
    ataxin-1 from that complex by duplicating the paralog Atxn1l suppresses
    neuropathology.
- hypothesis_group_id: aggregation_not_required
  hypothesis_label: Nuclear aggregation is not the toxic species
  status: CANONICAL
  description: >-
    Nuclear localization of expanded ataxin-1 is necessary for disease, but
    visible nuclear aggregation is not: a self-association-deficient
    ataxin-1[77Q] that forms no detectable nuclear inclusions still produces
    ataxia and Purkinje cell pathology. The identity of the toxic species
    (soluble mutant conformers versus mature aggregates) remains debated
    across the polyglutamine diseases.
notes: >-
  SCA1 is curated at the histologic/molecular entity level as one genotype
  within the ADCA-I umbrella already represented by
  Autosomal_Dominant_Cerebellar_Ataxia_Type_I (MONDO:0019792); that entry
  covers the Harding phenotype class and this one covers the ATXN1 genotype.

  Two mechanistic points are deliberately stated against the intuitive
  reading of a polyglutamine disease, and both are modelled as
  mechanistic_hypotheses rather than left as prose. First, visible nuclear
  aggregation is not the toxic event: a self-association-deficient ataxin-1
  that forms no detectable inclusions still causes ataxia and Purkinje
  pathology, while blocking nuclear entry abolishes disease. That dissociation
  rests specifically on the 77Q self-association-deletion experiment; the
  S776A experiment does not establish it, since ataxin-1 82Q-A776 also failed
  to form nuclear inclusions in culture. Second, toxicity works through
  ataxin-1's native, Ser776 phosphorylation-dependent complexes, principally
  with Capicua, rather than through a novel interaction acquired by the
  expanded protein, and it is accompanied by partial loss of other normal
  ataxin-1 interactions. The Atxn1l duplication rescue is the genetic
  evidence for this.

  Sources appear to disagree on survival, and the disagreement resolves.
  GeneReviews gives ten to 30 years from onset to death; PMID:32818920's
  introduction says 10 to 15 years. PMID:37238658 reconciles them: the span
  is 10 to 30 years with an average of 15. The GeneReviews range is used
  here.

  Selectivity is now curated from three directions rather than left open.
  Region-specific Ser776 kinases (MSK1 cerebellum, RSK3 brainstem) explain why
  a brain-wide protein kills select regions; a sub-regional gradient within the
  cerebellum, with the posterior vermis affected earlier and more severely, is
  recorded on the Purkinje degeneration node; and the oligodendrocyte branch
  shows part of the Purkinje phenotype is driven non-cell-autonomously, so a
  purely neuron-intrinsic account of selectivity would be incomplete. What
  remains genuinely unresolved is why these particular neuronal populations,
  among the many expressing ataxin-1, are the vulnerable ones.

  Toxicity is not attributed to a single species. Four routes out of the
  expanded locus are curated in parallel: the polyglutamine ataxin-1 protein
  acting through native Ser776/Capicua complexes, RAN translation of the same
  repeat in non-canonical frames, RBFOX1-mediated splicing dysregulation, and
  non-cell-autonomous oligodendrocyte dysfunction. The RAN branch is why the
  initiating node no longer says the mechanism is protein-level rather than
  RNA-level.

  One binding is worth flagging: the neuron apoptotic process annotation on
  the two degeneration nodes is copied from the conformance targets rather
  than independently evidenced for SCA1, where Purkinje cell death is
  substantially non-classically apoptotic.

  Regional selectivity is curated rather than left open. A brain-wide protein
  kills select populations because the Ser776 mark that stabilizes toxic
  ataxin-1 is placed by region-specific kinases, MSK1 in cerebellum and RSK3
  in brainstem, and lowering each rescues its own region. That is why the
  cerebellar and extracerebellar branches are separate edges out of the
  Ser776 node rather than one chain feeding the other.

  Two prevalence records are carried, and they answer different questions. The
  first is SCA1-specific: 1-2 per 100,000, from a review whose own caveat that
  SCA1 epidemiology rests on few studies is quoted alongside it. That is the
  entry's headline figure. The second is explicitly class-level, the pooled
  rate for dominant hereditary cerebellar ataxia as a whole, and is retained
  as context for how large that class is; a cohort figure putting SCA1 at
  roughly 6% of ADCA patients sits beside it so the class rate cannot be
  misread as a SCA1 rate. No population-based study of SCA1 alone was
  identified, which is why the SCA1-specific figure comes from a review rather
  than a prevalence survey.

  Phenotype curation uses the GeneReviews chapter (PMID:20301363) as the
  mandatory baseline; every phenotype in its Clinical Characteristics section
  is represented here. Frequencies are mapped from that chapter's narrative
  language and are therefore coarse. Hyperreflexia and hyporeflexia both
  appear because the chapter describes brisk reflexes early and decreased
  reflexes in advanced disease; they are stage-dependent, not contradictory.

  No disease-modifying therapy exists. The ATXN1-lowering antisense
  oligonucleotide is recorded as investigational on the strength of preclinical
  rodent data only. The symptomatic agents (riluzole, 4-aminopyridine,
  varenicline) are recorded from a class-level review of adult-onset cerebellar
  ataxias that states benefit is subtype-specific, so no SCA1 efficacy is
  claimed. Troriluzole is recorded only as an existing development programme:
  the one citation available for it is a rat opioid-addiction study that
  mentions the ataxia trials in passing, which is why that item is graded OTHER
  and says so.

  Nine further committed caches are the deep-research report's own citations,
  retained because the report is committed alongside them, and are not cited by
  this entry: they cover other ataxias (SCA27B, multiple system atrophy),
  regional cohort genotyping in China and Brazil, and candidate compounds in
  Drosophila and mouse screens that have no SCA1 clinical standing. Two further
  references are deliberately not used.
  PMID:31523939 reports depression and parkinsonism rates in a Taiwanese
  SCA2/SCA3 cohort; attributing those figures to SCA1 would be named-entity
  confusion. PMID:19429075 concerns repeat-length and onset correlation in
  SCA2 rather than SCA1, and the SCA1 correlation is already carried by
  PMID:19049837.
mappings:
  mondo_mappings:
  - mapping_predicate: skos:exactMatch
    term:
      id: MONDO:0008119
      label: spinocerebellar ataxia type 1

📚

References & Deep Research

References

1

PMID:20301363

Spinocerebellar Ataxia Type 1.

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (4)

Record notes

SCA1 is curated at the histologic/molecular entity level as one genotype within the ADCA-I umbrella already represented by Autosomal_Dominant_Cerebellar_Ataxia_Type_I (MONDO:0019792); that entry covers the Harding phenotype class and this one covers the ATXN1 genotype. Two mechanistic points are deliberately stated against the intuitive reading of a polyglutamine disease, and both are modelled as mechanistic_hypotheses rather than left as prose. First, visible nuclear aggregation is not the toxic event: a self-association-deficient ataxin-1 that forms no detectable inclusions still causes ataxia and Purkinje pathology, while blocking nuclear entry abolishes disease. That dissociation rests specifically on the 77Q self-association-deletion experiment; the S776A experiment does not establish it, since ataxin-1 82Q-A776 also failed to form nuclear inclusions in culture. Second, toxicity works through ataxin-1's native, Ser776 phosphorylation-dependent complexes, principally with Capicua, rather than through a novel interaction acquired by the expanded protein, and it is accompanied by partial loss of other normal ataxin-1 interactions. The Atxn1l duplication rescue is the genetic evidence for this. Sources appear to disagree on survival, and the disagreement resolves. GeneReviews gives ten to 30 years from onset to death; PMID:32818920's introduction says 10 to 15 years. PMID:37238658 reconciles them: the span is 10 to 30 years with an average of 15. The GeneReviews range is used here. Selectivity is now curated from three directions rather than left open. Region-specific Ser776 kinases (MSK1 cerebellum, RSK3 brainstem) explain why a brain-wide protein kills select regions; a sub-regional gradient within the cerebellum, with the posterior vermis affected earlier and more severely, is recorded on the Purkinje degeneration node; and the oligodendrocyte branch shows part of the Purkinje phenotype is driven non-cell-autonomously, so a purely neuron-intrinsic account of selectivity would be incomplete. What remains genuinely unresolved is why these particular neuronal populations, among the many expressing ataxin-1, are the vulnerable ones. Toxicity is not attributed to a single species. Four routes out of the expanded locus are curated in parallel: the polyglutamine ataxin-1 protein acting through native Ser776/Capicua complexes, RAN translation of the same repeat in non-canonical frames, RBFOX1-mediated splicing dysregulation, and non-cell-autonomous oligodendrocyte dysfunction. The RAN branch is why the initiating node no longer says the mechanism is protein-level rather than RNA-level. One binding is worth flagging: the neuron apoptotic process annotation on the two degeneration nodes is copied from the conformance targets rather than independently evidenced for SCA1, where Purkinje cell death is substantially non-classically apoptotic. Regional selectivity is curated rather than left open. A brain-wide protein kills select populations because the Ser776 mark that stabilizes toxic ataxin-1 is placed by region-specific kinases, MSK1 in cerebellum and RSK3 in brainstem, and lowering each rescues its own region. That is why the cerebellar and extracerebellar branches are separate edges out of the Ser776 node rather than one chain feeding the other. Two prevalence records are carried, and they answer different questions. The first is SCA1-specific: 1-2 per 100,000, from a review whose own caveat that SCA1 epidemiology rests on few studies is quoted alongside it. That is the entry's headline figure. The second is explicitly class-level, the pooled rate for dominant hereditary cerebellar ataxia as a whole, and is retained as context for how large that class is; a cohort figure putting SCA1 at roughly 6% of ADCA patients sits beside it so the class rate cannot be misread as a SCA1 rate. No population-based study of SCA1 alone was identified, which is why the SCA1-specific figure comes from a review rather than a prevalence survey. Phenotype curation uses the GeneReviews chapter (PMID:20301363) as the mandatory baseline; every phenotype in its Clinical Characteristics section is represented here. Frequencies are mapped from that chapter's narrative language and are therefore coarse. Hyperreflexia and hyporeflexia both appear because the chapter describes brisk reflexes early and decreased reflexes in advanced disease; they are stage-dependent, not contradictory. No disease-modifying therapy exists. The ATXN1-lowering antisense oligonucleotide is recorded as investigational on the strength of preclinical rodent data only. The symptomatic agents (riluzole, 4-aminopyridine, varenicline) are recorded from a class-level review of adult-onset cerebellar ataxias that states benefit is subtype-specific, so no SCA1 efficacy is claimed. Troriluzole is recorded only as an existing development programme: the one citation available for it is a rat opioid-addiction study that mentions the ataxia trials in passing, which is why that item is graded OTHER and says so. Nine further committed caches are the deep-research report's own citations, retained because the report is committed alongside them, and are not cited by this entry: they cover other ataxias (SCA27B, multiple system atrophy), regional cohort genotyping in China and Brazil, and candidate compounds in Drosophila and mouse screens that have no SCA1 clinical standing. Two further references are deliberately not used. PMID:31523939 reports depression and parkinsonism rates in a Taiwanese SCA2/SCA3 cohort; attributing those figures to SCA1 would be named-entity confusion. PMID:19429075 concerns repeat-length and onset correlation in SCA2 rather than SCA1, and the SCA1 correlation is already carried by PMID:19049837.

Second main-merge round on the SCA1 curation branch · 2026-09-06T08:37:39Z · View source

Second branch-maintenance round on PR #11197. No change to the SCA1 entry itself; this record exists because the branch history changed again. main advanced another 3 commits and the PR conflicted on the same file as the first round, cache/enums/diseaseterm_f618932bb23f.csv. This is now a recurring pattern rather than a one-off: every merged curation PR appends its disease-term CURIE to that one shared enum cache, so any curation branch left open across a few merges will keep colliding there. The collision is benign in content, since the two sides append different CURIEs, but it does require a merge each time. Resolved the same way as the first round: merged origin/main rather than rebasing, because PR #11197 is authored by another account and a force-push would invalidate that checkout. git auto-merged the enum cache with no conflict hunk and MONDO:0008119 survives. No cache row was hand-written, reordered, or regenerated by hand. Post-merge review: the diff against the new origin/main is exactly this PR's own 49 files (the entry, three history records including this one, 39 reference caches, the deep-research report plus citations and two artifacts, the enum cache line, and the deleted stub). No unrelated deletions, no stale reversions, no protected-path churn. Re-validated: just validate passes, snippets 95/95 verified, and the full twelve-gate set was re-run against the new origin/main in CI's exact command form rather than the more permissive just recipes. Unrelated to this merge and still outstanding: claude-review has now failed three times on three different commits (04178c1d8, 490db5b3c, 0e1df57b3), each time erroring after 0s with num_turns=1 and cost=$0, meaning the review agent never read the diff. The first two runs named an ai4c-reviewer usage limit resetting at 02:30 UTC; the third failed after that reset, so the reset was not the fix and a re-run alone does not help. This session lacks actions:write and cannot re-run the job (403 on both rerun-failed-jobs and workflow dispatch). All of this is recorded on the PR, including a correction to the earlier "just re-run it" advice. It needs a human to look at the reviewer bot's credentials or account.

Merge main into SCA1 curation branch · 2026-09-06T04:12:49Z · View source

Branch maintenance round on PR #11197. No change to the SCA1 entry itself; this record exists because the branch history changed. main advanced 22 commits after the PR was opened and GitHub reported the PR as conflicted (mergeable_state went from "blocked" to "unknown", and a local merge-tree against the new main reported one file changed on both sides). The conflict was cache/enums/diseaseterm_f618932bb23f.csv: this branch appended MONDO:0008119 to the disease-term enum cache, and curation PRs that merged to main in the meantime appended their own CURIEs to the same file. Resolved by merging origin/main into the branch rather than rebasing. The branch was created in this session, but PR #11197 is authored by another account, so a merge commit keeps that checkout valid where a rebase and force-push would not. git auto-merged the enum cache without a conflict hunk, because the two sides appended in different regions of the sorted file; MONDO:0008119 survives in the merged result. No cache row was hand-written, reordered, or regenerated by hand. Post-merge review per the repo's refresh guidance: the diff against the new origin/main is exactly this PR's own 48 files (the entry, two prior history records, 40 reference caches, the deep-research report plus citations and two artifacts, the enum cache line, and the deleted stub). No unrelated deletions, no stale reversions, no protected-path churn. Every PMID cited by the entry was confirmed to have its cache file present in the commit. Re-validated against the new main, which matters because the merged commits include a title-snippet baseline refresh (#11208) and a page/app-data regeneration (#11211). just validate passes; snippets 95/95 verified. The ref-based gates were re-run in CI's exact form against the new origin/main rather than the more permissive just recipes: check_snippet_length, check_title_snippets, check_reference_titles, check_folded_hyphens. The whole-KB gates were re-run too: check_duplicate_yaml_keys, check_enum_values, check_entity_refs, check_causal_targets, check_qualifier_terms, reference_cache_frontmatter, term_cache_integrity, dismech-stubs check. Unrelated to this merge, claude-review remains red on PR #11197 from a pre-reset ai4c-reviewer usage-limit error ("You've hit your limit · resets 2:30am (UTC)", num_turns=1, cost=$0, so the agent never read the diff). It failed identically on two commits. This session lacks actions:write and cannot re-run it; both rerun-failed-jobs and workflow dispatch return 403. That is recorded on the PR and needs a human with that permission.

Create: Spinocerebellar Ataxia Type 1 · 2026-09-05T23:17:11Z · View source

De-novo curation of SCA1 (MONDO:0008119, ATXN1) from the stubs queue. The request was for "cerebellar ataxia"; the bare concept is a grouping and is already covered by kb/groupings/Cerebellar_Ataxias.yaml, so this curates the prototypical uncurated genotype instead. SCA2, SCA8, SCA17, SCA23, SCA31, SCA36, SCA43, SCA48 and SCA27B were already curated; SCA1 was not. Curated at genotype level under the existing ADCA-I umbrella entry (Autosomal_Dominant_Cerebellar_Ataxia_Type_I, MONDO:0019792). Duplicate preflight ran against origin/main plus PR and issue search: no existing entry, PR or claim issue for MONDO:0008119. stubs/Spinocerebellar_Ataxia_Type_1.yaml deleted in the same change. DEEP RESEARCH. falcon was requested and is unavailable in this environment: EDISON_API_KEY is present but rejected with HTTP 403 ProviderAuthError, and `deep-research-client providers --check` reports falcon UNREACHABLE. The run was re-issued with --fallback rather than substituting a provider by hand, so the substitution is recorded in the report itself (fell_back: true, requested_provider: falcon, provider_attempts listing the 403). openscientist produced the report and the recipe renamed it accordingly. Report used: research/Spinocerebellar_Ataxia_Type_1-deep-research-openscientist.md (26 citations, 1037s). A first openscientist attempt died mid-run on an httpx ReadError after ~30 minutes with no report; the agent proxy showed no relay failures, so this was treated as an upstream long-poll drop and retried once, which succeeded. REPORT VALIDATION (skill step 3a). Both sections were retro-fitted, since the provider emitted neither. References: 26/26 resolved, 0 unresolved, 0 off topic, 1/1 quoted claim verified - no confabulation. Terms: 28 checked, 26 resolved, 0 unresolved, 0 obsolete. The section reports 8 terms "named as a different term"; all 8 are parsing artifacts of the report's phenotype table, where the validator read the Type column ("Clinical sign", "Imaging finding", "Behavioral") as the label beside the CURIE. Each identifier is in fact the right one for its row (HP:0001251 Ataxia, HP:0001260 Dysarthria, HP:0001272 Cerebellar atrophy, HP:0002015 Dysphagia, HP:0009830 Peripheral neuropathy, HP:0000716 Depression, HP:0001300 Parkinsonism, MONDO:0008119). No CURIE was bound from the report without independent checking. GENEREVIEWS BASELINE (skill step 3b). PMID:20301363 fetched, cached, and tagged GeneReviews in the top-level references block. Every phenotype in its Clinical Characteristics section is represented. Management is curated including the Agents/Circumstances to Avoid section (alcohol, isoniazid, large-dose vitamin B6, hazardous activity), which is carried as its own treatment entry with the warning quoted verbatim. Frequencies are mapped from the chapter's narrative language using the skill's table and are deliberately coarse; where two phenotypes come from one sentence they carry the same frequency rather than an invented gradient. MECHANISM. Built as a connected causal chain, not a bucket list: ATXN1 CAG expansion -> nuclear localization -> Ser776-dependent assembly into native complexes -> (a) aberrant ATXN1-Capicua transcriptional repression -> RORalpha destabilization -> Purkinje dysfunction -> Purkinje degeneration -> loss of cerebellar cortical output, and (b) a separate Ser776 branch to brainstem/olivary/spinal degeneration. Both converge on the clinical syndrome, which fans out to the curated phenotypes. Conformance declared against polyglutamine_expansion_proteotoxicity (4 nodes) and cerebellar_purkinje_degeneration (4 nodes). Two non-obvious positions are curated as mechanistic_hypotheses with edges opted in via hypothesis_groups, rather than left as prose: nuclear aggregation is not the toxic species (PMID:9778246, the 77Q self-association-deletion line), and toxicity runs through native rather than novel ataxin-1 interactions (PMID:17190598, PMID:17322884). The Capicua claim is deliberately qualified by a REFUTE item on PMID:36577402, which found that abolishing the ATXN1-CIC interaction globally only partially corrected phenotypes. Regional selectivity is curated rather than left as a gap: PMID:33709453 supplies region-specific Ser776 kinases (MSK1 cerebellum, RSK3 brainstem) with region-specific rescue, which is why the brainstem branch leaves the Ser776 node instead of being inferred from the cerebellar chain. EVIDENCE. 19 distinct PMIDs, 96 evidence items, every snippet an exact substring of a committed cache file. All PMID-keyed, no DOI-only items, so nothing bypasses the gating validator. evidence_source classifies the cited study: five items quoting human-disease background from the introductions of two preclinical mouse papers (PMID:32818920, PMID:7553854) are graded OTHER rather than HUMAN_CLINICAL, with the reason stated in each explanation. Three snippets initially failed validation because the source text carries square brackets (ataxin-1[82Q], SE values in the EUROSCA abstract) which the reference validator strips. They were replaced with bracket-free spans from the same abstracts rather than reworded. The repeat-length/progression claim could not quote the EUROSCA clause for this reason and is instead evidenced by PMID:19049837 on age at onset, marked directness: INDIRECT. PREVALENCE. A SCA1-specific estimate (1-2 per 100,000, PMID:37238658) is the primary record, with the source's own caveat that SCA1 epidemiology rests on few studies quoted alongside it. A second, explicitly class-level record (pooled dominant hereditary cerebellar ataxia, 2.7 per 100,000, PMID:24603320) is retained and labelled as such in both population and notes, with PMID:9106530 quantifying SCA1 at roughly 6% of ADCA so the class rate cannot be misread as a SCA1 rate. RED-TEAM PASS. A fresh-context subagent reviewed the entry against the dismech-pr-review skill before any PR. It found and this change fixes: a prevalence_class off by a factor of ten against its own rate_per_100000; five evidence_source misgrades; an uncaused brainstem node; a phenotype layer disconnected from the pathograph; GO:0006355 on the wrong node (moved to a genetic_context functional_impact_category); an unsupported claim excluding repeat RNA toxicity; a conforms_to promising calcium/proteostasis content the node lacked (closed with PMID:10649571); a node named for accumulation while arguing accumulation is not toxic; and missing GeneReviews management items (psychotherapy, pain management, vitamin supplementation, onset, the late-onset pure cerebellar presentation). Its suggestion to quote the EUROSCA repeat-length clause was not taken, for the bracket reason above. Its note that the neuron apoptotic process binding is copied from the conformance targets rather than independently evidenced for SCA1 is recorded in notes rather than silently changed. VALIDATION RUN. just validate (schema + terms + references) passes. just validate-disorders passes, snippets 95/95 verified against cached references. check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms, check-folded-hyphens, check-snippet-length, check-title-snippets and check-snippet-grading all clean, with no baseline modified. just validate-history passes.

OpenScientist ▸

Spinocerebellar Ataxia Type 1 (SCA1): Comprehensive Disease Characterization

openscientist-autonomous 26 citations 2026-09-05T23:11:12.977721

Spinocerebellar Ataxia Type 1 (SCA1): Comprehensive Disease Characterization

Disease: Spinocerebellar Ataxia Type 1 MONDO ID: MONDO:0008119 | OMIM: #164400 (disease) / 601556 (ATXN1 gene) | Orphanet: ORPHA:98755 | Category:* Mendelian (autosomal dominant, polyglutamine repeat expansion)

Evidence base: aggregated disease-level resources (OMIM, Orphanet, GeneReviews) plus primary literature and model-organism studies. Where a claim is inferred rather than directly demonstrated in humans, this is noted.

Summary

Spinocerebellar ataxia type 1 (SCA1) is a rare (~1–2 per 100,000) autosomal dominant, adult-onset neurodegenerative disorder caused by expansion of a glutamine-encoding CAG repeat in exon 8 of the ATXN1 gene on chromosome 6p22.3. The expanded repeat produces a polyglutamine (polyQ)-lengthened ataxin-1 protein that acts predominantly through a toxic gain-of-function mechanism in the cerebellum, although loss of normal ataxin-1 function contributes to cognitive/cortical abnormalities. SCA1 is one of at least nine polyglutamine diseases and is clinically notable for having the fastest functional decline among the common SCAs, ahead of SCA3, SCA2, SCA6, and SCA10.

The mechanistic cascade begins with the CAT-uninterrupted CAG expansion, proceeds through phosphorylation of ataxin-1 at Ser776 by region-specific kinases (MSK1 in cerebellum, RSK3 in brainstem) that stabilizes the toxic protein, and continues through aberrant interaction with the transcriptional repressor CIC (capicua), RBFOX1-mediated alternative splicing dysregulation, repeat-associated non-AUG (RAN) translation of toxic homopolymeric proteins, and non-cell-autonomous oligodendrocyte/glial dysfunction. These converging insults drive progressive degeneration of cerebellar Purkinje cells, brainstem nuclei, and spinocerebellar tracts in an olivopontocerebellar pattern. Clinically this manifests as progressive gait and limb ataxia, dysarthria, oculomotor abnormalities, pyramidal signs, and eventual bulbar failure; death typically results from aspiration and respiratory complications.

Diagnosis rests on targeted molecular testing for the ATXN1 CAG repeat expansion (with assessment of CAT interruptions), supported by clinical rating (SARA), MRI volumetry/spectroscopy, and blood neurofilament light chain (NfL) as progression biomarkers that change before ataxia onset. There is currently no approved disease-modifying therapy; management is multidisciplinary and symptomatic. However, ATXN1-lowering antisense oligonucleotides (ASOs) have rescued motor deficits and premature lethality in knock-in mouse models and represent the leading disease-modifying strategy advancing toward clinical translation, alongside kinase inhibition, autophagy enhancement, and gene-based approaches.

Section 1: Disease Information

Overview. SCA1 is an autosomal dominant neurodegenerative disorder belonging to the polyglutamine (CAG-repeat) disease family. It is characterized by progressive cerebellar ataxia with additional brainstem, pyramidal, and later bulbar involvement, and by degeneration concentrated in the cerebellum and brainstem PMID: 42608759. It affects "one or two individuals per 100,000" PMID: 37238658.

Key identifiers: - MONDO: MONDO:0008119 - OMIM: #164400 (disease); 601556 (ATXN1 gene) - Orphanet: ORPHA:98755 - Gene: ATXN1 (HGNC:10548); chromosome 6p22.3 - MeSH: Spinocerebellar Ataxias / Spinocerebellar Degenerations - ICD-10: G11.1 / G11.8; ICD-11:* 8A03.10 (hereditary ataxia)

Synonyms and alternative names: Spinocerebellar ataxia 1; SCA1; olivopontocerebellar atrophy I (OPCA I, historical); Menzel-type OPCA (historical); spinocerebellar degeneration; ataxin-1 polyglutamine disease.

Information source. The knowledge in this report is derived predominantly from aggregated disease-level resources — OMIM, Orphanet, published cohort/natural-history studies, and mechanistic model-organism and in-vitro literature — rather than from individual patient EHR records.

Section 2: Etiology

Primary cause (genetic). SCA1 is caused by expansion of a glutamine-encoding CAG repeat in exon 8 of ATXN1. As stated in the literature: "Ataxin-1 (ATXN1) was originally identified as a gene in which abnormal expansion of glutamine encoding CAG repeats causes inherited neurodegenerative disease spinocerebellar ataxia type 1" PMID: 42608759. This is a monogenic Mendelian disorder; there are no established environmental or infectious causes.

Genetic risk factors. - Causal variant: CAG repeat expansion in ATXN1. Normal alleles typically carry ≤35–36 repeats; pathogenic alleles are generally ≥39 CAG. A key structural determinant is the presence or absence of CAT interruptions: normal-range alleles contain CAT interruptions that stabilize the repeat tract, whereas expanded pathogenic alleles are typically pure, uninterrupted CAG — "None of the expanded alleles contained CAT interruptions" PMID: 16110192. Loss of CAT interruption itself confers pathogenicity. - Repeat length is the dominant modifier of age at onset and severity: across polyQ SCAs, "CAG repeat length correlated inversely with age at onset, accounting for 80% of the variability" PMID: 19429075. - A documented case with an intermediate allele (37 CAG, uninterrupted) alongside a large 61-CAG expansion demonstrated early onset and rapid progression, underscoring the importance of interruption status for counseling PMID: 39289638.

Environmental risk factors. None established as causal. Sex, age, and lifestyle are not proven disease-causing factors; the disease is fully genetically determined by the expanded allele. Age modifies timing of onset (adult-onset) but not disease occurrence.

Protective / modifier factors. CAT interruptions within the repeat tract are protective (stabilizing). A rare SCA1 family showed anticipation without CAG expansion, indicating "factors other than the length of the CAG repeat play a considerable role in determination of the disease course" PMID: 16110192. Genetic modifiers set prior risk for progression PMID: 42677125. No robust environmental protective factor is established.

Gene–environment interactions. No well-characterized GxE interactions are established for SCA1; disease penetrance is driven by the germline repeat expansion.

Section 3: Phenotypes

SCA1 presents as an adult-onset, progressive pan-cerebellar syndrome with characteristic pyramidal and later brainstem/bulbar features.

Phenotype	Type	HPO term	Characteristics
Gait ataxia	Clinical sign	HP:0002066 / HP:0001251 (ataxia)	Adult onset, progressive; usually the presenting feature
Limb incoordination	Clinical sign	HP:0001251	Progressive
Dysarthria	Clinical sign	HP:0001260	Progressive slurred speech
Nystagmus / oculomotor abnormality	Clinical sign	HP:0000639 (nystagmus); saccadic slowing	Common; early
Cerebellar atrophy	Imaging finding	HP:0001272	Progressive
Pyramidal signs (hyperreflexia, spasticity)	Clinical sign	HP:0001347 / HP:0001257	Characteristic of SCA1 vs other SCAs
Dysphagia	Clinical sign	HP:0002015	Later stage; bulbar involvement, aspiration risk
Peripheral neuropathy	Clinical sign	HP:0009830	Later stage
Cognitive impairment	Behavioral/cognitive	HP:0100543	Present; ATXN1 loss-of-function contributes
Depression / mood changes	Behavioral	HP:0000716	Present
Parkinsonism	Clinical sign	HP:0001300	Non-ataxic feature; most common nonataxic phenotype across SCAs

SCA1 characteristically adds pyramidal signs (hyperreflexia, spasticity) and later brainstem/bulbar dysfunction (dysphagia, respiratory compromise) plus peripheral neuropathy; cognition and mood are affected. Across SCAs, "Parkinsonism was the most common nonataxic phenotype (21.1%)" in a Taiwanese cohort PMID: 31523939, and nonmotor symptoms include "impaired cognition (6.1% of SCA2 and 8.3% of SCA3 patients) and depression" PMID: 31523939. Because ATXN1 regulates gene expression broadly, cognitive/mood involvement is mechanistically consistent PMID: 42608759.

Progression and severity: progressive and severe; SCA1 has the fastest functional decline of the common SCAs (see Section 8). Quality of life impact is substantial and cumulative — loss of ambulation, communication difficulty from dysarthria, dysphagia with aspiration risk, and dependence in activities of daily living. Per-phenotype QoL instruments specific to SCA1 were not identified in this investigation; generic and ataxia-specific functional staging (SARA-linked) is used.

Section 4: Genetic / Molecular Information

Causal gene. ATXN1 (ataxin-1), chromosome 6p22.3; HGNC:10548; OMIM *601556.

Pathogenic variant. - Type/class: Trinucleotide (CAG) repeat expansion — a dynamic mutation, not a point mutation. The expansion resides in coding exon 8 and is translated into an elongated polyglutamine tract. - Classification: Pathogenic (ACMG); repeat length ≥39 CAG (uninterrupted) is considered pathogenic; the intermediate/reduced-penetrance zone and interruption status affect interpretation. - Allele architecture: Pathogenic alleles are pure CAG lacking CAT interruptions; normal alleles contain CAT interruptions — "None of the expanded alleles contained CAT interruptions" PMID: 16110192. - Origin: Germline (inherited, autosomal dominant). Not somatic. - Functional consequence: Predominantly toxic gain-of-function — "CAG expansion predominantly causes pathogenic ATXN1 gain-of-function in the cerebellum" PMID: 42608759 — with a contributory loss-of-function component (loss of ATXN1 also causes cognitive/cortical abnormalities) PMID: 42608759.

Modifier genes / molecular modulators. - CIC (capicua): forms a transcriptional repressor complex with ATXN1; "The interaction of polyglutamine-expanded ATXN1 with the transcriptional repressor CIC drives cerebellar Purkinje cell pathogenesis" PMID: 36577402. - RBFOX1: splicing factor mediating mutant-ATXN1 splicing dysregulation; modulating Rbfox1 modifies neurodegeneration in a Drosophila SCA1 model PMID: 37802886. - MSK1 / RSK3: kinases phosphorylating ATXN1 at Ser776 (region-specific) PMID: 33709453. - TG5 (transglutaminase 5): "TG enzymes catalyzed cross-linking of ATXN1 in a polyQ-length-dependent manner, thereby preferentially modulating mutant ATXN1 stability and oligomerization" PMID: 35499073. - TCF7L2, HTT: identified as key regulators in oligodendrocyte-driven pathology PMID: 42113962.

Epigenetic information / chromosomal abnormalities. No large-scale chromosomal abnormalities (aneuploidy, translocations) are associated; SCA1 is a single-locus repeat-expansion disorder. Specific disease-defining epigenetic marks were not established in this investigation.

Section 5: Environmental Information

SCA1 is a purely genetic Mendelian disorder with no established environmental, lifestyle, or infectious contributing factors. Toxins, radiation, occupational exposures, diet, smoking, and alcohol are not implicated in causation. No infectious agents (bacteria, viruses, fungi, parasites) are involved. Environmental factors do not modify disease occurrence, though supportive/rehabilitative environment influences functional outcome.

Section 6: Mechanism / Pathophysiology

Ordered causal chain

CAT-uninterrupted CAG repeat expansion in ATXN1 exon 8 leads to a translated polyglutamine-expanded ataxin-1 protein (germline, gain-of-function) PMID: 42608759, PMID: 16110192.
Expanded ataxin-1 is phosphorylated at Ser776 by region-specific kinases — MSK1 in cerebellum, RSK3 in brainstem — which stabilizes the protein and promotes toxicity PMID: 33709453.
Stabilized mutant ataxin-1 forms nuclear inclusions (GO:0005634 nucleus) and engages aberrant protein complexes — notably with the transcriptional repressor CIC/capicua — which results in dysregulated transcription in Purkinje cells PMID: 36577402.
Branch A (transcription/splicing): Mutant ataxin-1 causes widespread alternative-splicing dysregulation via the splicing factor RBFOX1, which contributes to neurodegeneration PMID: 37802886.
Branch B (RAN translation): The expanded repeat undergoes repeat-associated non-AUG (RAN) translation, producing sense polyserine and antisense polyleucine aggregates that impair autophagy and accumulate in cerebellum and pons PMID: 41422503.
Branch C (non-cell-autonomous glia): Mutant ataxin-1 in oligodendrocytes is sufficient to drive dysregulated myelination, Purkinje-cell axonal shrinkage, and torpedo formation, which impairs motor coordination PMID: 42113962.
These converging insults lead to mitochondrial/bioenergetic dysfunction, reduced dendritic arborization, and impaired neuronal network activity (demonstrated in patient iPSC-derived neurons) PMID: 37278528.
The cumulative toxicity results in progressive Purkinje-cell degeneration (earliest/most severe in posterior cerebellar vermis) and brainstem neuronal loss PMID: 42113962, PMID: 38750673.
Regional neurodegeneration manifests clinically as progressive ataxia, dysarthria, oculomotor and pyramidal signs, and — via brainstem involvement — bulbar failure and premature death PMID: 32791425.

CAG expansion (pure, no CAT)
│
▼
 polyQ-ataxin-1  ──► RAN translation ──► polySer/polyLeu aggregates ──► autophagy impairment
│                                         (Branch B)
▼ Ser776 phosphorylation
  (MSK1 cerebellum / RSK3 brainstem)  ── protein stabilization
│
├──► nuclear inclusions + ATXN1–CIC complex ──► transcriptional dysregulation (Branch A)
│                                   │
│                                   └──► RBFOX1 ──► aberrant alternative splicing
│
└──► oligodendrocyte dysfunction ──► dysmyelination + PC axonopathy/torpedoes (Branch C)
                   │
                   ▼
mitochondrial dysfunction, dendritic loss, network failure
                   │
                   ▼
   Purkinje-cell + brainstem degeneration (olivopontocerebellar)
                   │
                   ▼
ataxia, dysarthria, pyramidal/bulbar signs → death

Upstream vs downstream. The CAG expansion and Ser776 phosphorylation are the most upstream, targetable nodes; CIC binding, RBFOX1 splicing, RAN translation, and oligodendrocyte dysfunction are intermediate; Purkinje-cell/brainstem degeneration and clinical ataxia are downstream.

Cell types (CL) and processes (GO). Primary target: cerebellar Purkinje cell (CL:0000121); also oligodendrocyte (CL:0000128) and Bergmann glia (CL:0000644). Key GO processes: regulation of transcription (GO:0006355), mRNA splicing (GO:0000398), autophagy (GO:0006914), myelination (GO:0042552). Subcellular: nucleus (GO:0005634), mitochondrion (GO:0005739). Chemical entity: L-glutamine / polyglutamine (CHEBI:28300).

Molecular profiling. ASO-mediated Atxn1 reduction "restored disease-associated transcriptome profiles toward WT" and reversed neurochemical abnormalities PMID: 30385727, demonstrating a reversible transcriptomic/neurochemical signature. Alternative-splicing dysregulation is a defined transcriptomic feature PMID: 37802886.

Section 7: Anatomical Structures Affected

Organ / body-system level. Primary organ: brain, specifically the cerebellum (UBERON:0002037) and brainstem (UBERON:0002298) — pons, medulla, and inferior olive (UBERON:0000988). Body system: central nervous system. The pattern corresponds to olivopontocerebellar atrophy with spinocerebellar tract and dentate nucleus involvement.

Tissue / cell level. Nervous tissue. Principal targets: - Cerebellar Purkinje cells (CL:0000121) — "progressive motor deficits and Purkinje cell (PC) degeneration, driven by polyglutamine expansion in ataxin-1" PMID: 42113962. - Oligodendrocytes (CL:0000128) — dysmyelination contributes non-cell-autonomously PMID: 42113962. - Bergmann glia (CL:0000644) and other glia show pathology.

Regional selectivity. "We demonstrated earlier and more severe pathology of PCs and glia in the posterior cerebellar vermis of SCA1 mice" PMID: 38750673 — posterior vermis > anterior. The brainstem is the region most closely linked to premature death PMID: 33709453.

Subcellular level. Mutant ataxin-1 accumulates as nuclear inclusions (GO:0005634); mitochondrial dysfunction (GO:0005739) occurs.

Lateralization. Bilateral and largely symmetric involvement.

Section 8: Temporal Development

Onset. Typically adult-onset (commonly 30s–40s), insidious and chronic. Earlier onset occurs with larger, uninterrupted expansions — a 23-year-old with a 61-CAG uninterrupted allele showed early onset and rapid progression PMID: 39289638.

Progression. Chronic, relentlessly progressive. SCA1 has the fastest functional decline among common SCAs: "Natural history studies revealed that SCA1 patients' functional status worsened significantly faster than in other SCA subtypes, followed by SCA3, SCA2, SCA6, and SCA10" PMID: 32791425. Progression is quantified clinically by the Scale for Assessment and Rating of Ataxia (SARA), which "capture[s] genotype-specific trajectories but lose[s] sensitivity at the extremes of the disease course" PMID: 42677125.

Stages. Early (gait ataxia, mild dysarthria/oculomotor signs) → intermediate (limb ataxia, pyramidal signs, worsening speech) → advanced (bulbar dysfunction, dysphagia, respiratory compromise, loss of ambulation).

Critical periods / premanifest window. A quantifiable premanifest window exists: "Volumetric, microstructural, and spectroscopic MRI and blood neurofilament light chain change before ataxia onset and predict subsequent decline, whereas repeat length and genetic modifiers set prior risk" PMID: 42677125 — a key therapeutic-intervention window.

Anticipation. Genetic anticipation occurs: "Genetic anticipation was observed in the 80% of transmissions. Repeat instability was greater in paternal transmissions" PMID: 19429075. No spontaneous remission; the course is chronic and lifelong.

Section 9: Inheritance and Population

Epidemiology. SCA1 prevalence is approximately 1–2 per 100,000 — "an autosomal dominant neurodegenerative disorder that affects one or two individuals per 100,000" PMID: 37238658. Relative frequency among SCAs varies regionally: SCA3 is the most common worldwide; in a northern Chinese cohort SCA1 accounted for 13.8% (11/80 families) vs SCA3 57.5% and SCA2 16.3% PMID: 42474585. SCA1 is generally a smaller fraction than SCA2/SCA3 in most populations.

Inheritance genetics. - Pattern: Autosomal dominant PMID: 37238658. - Penetrance: Age-dependent and high for fully expanded, uninterrupted alleles; influenced by repeat length and interruption status. - Expressivity: Variable (age of onset and severity vary with repeat length and modifiers). - Anticipation: Yes — increasing severity/earlier onset in successive generations, greater with paternal transmission PMID: 19429075. - Founder effects: Population-specific haplotypes shape geographic distribution of SCA subtypes; well-documented founder effects exist for related SCAs (e.g., SCA2 in Holguin, Cuba) PMID: 19429075.

Population demographics. No strong sex predilection (autosomal). Geographic relative frequency varies (see above). Larger, uninterrupted expansions concentrate in earlier-onset, more severe cases.

Section 10: Diagnostics

Genetic testing (definitive). Diagnosis requires molecular testing for the ATXN1 CAG repeat expansion. Standard methods: fluorescent PCR, triplet-primed PCR (TP-PCR), and enzymatic digestion to detect CAT interruptions — as applied in a documented case where repeats were "assessed by fluorescent PCR, tripled-primed PCR and enzymatic digestion for the search of sequence interruption in the CAG repeats" PMID: 39289638. SCA1 is included on dominant-ataxia gene panels and NGS ataxia panels. Determining interruption status is clinically important — "The determination of the absence of CAT interruption brought crucial information concerning this molecular diagnosis, the prediction of the disease and had practical consequences for genetic counseling" PMID: 39289638.

Clinical rating. SARA is the standard clinical progression scale PMID: 42677125.

Imaging & fluid biomarkers. MRI shows cerebellar and brainstem (olivopontocerebellar) atrophy; volumetric, microstructural, and spectroscopic MRI and blood NfL change before ataxia onset and predict decline PMID: 42677125. Wearable-sensor gait/balance metrics detect change earlier than clinical scales.

Differential diagnosis. Other dominant SCAs (SCA2, SCA3, SCA6, SCA7, SCA17), the increasingly recognized SCA27B (FGF14 GAA expansion) — "one of the most common forms of adult-onset hereditary ataxia" PMID: 38279833, multiple system atrophy-cerebellar type (MSA-C, "hot cross bun" sign) PMID: 42453830, Friedreich ataxia, and acquired ataxias. A tiered testing algorithm (Friedreich ataxia, common dominant SCAs, then NGS exome/genome) is used PMID: 42616279.

Screening. Predictive/cascade genetic testing is available for at-risk relatives with genetic counseling; prenatal and preimplantation genetic testing are options. No newborn screening.

Section 11: Outcome / Prognosis

Survival / mortality. SCA1 is progressive and fatal, with the fastest decline among common SCAs PMID: 32791425. Death typically results from bulbar/respiratory complications; the brainstem is most closely linked to premature death PMID: 33709453.

Prognostic factors. "Number of CAG repeats, age of onset, and ataxia severity at baseline are strong contributors to the risk of death in most SCAs" PMID: 32791425. Longer CAG length and earlier onset predict worse outcomes PMID: 39289638.

Prognostic biomarkers. Blood NfL and MRI metrics predict subsequent decline and change premanifest PMID: 42677125.

Morbidity / function. Progressive disability: loss of ambulation, communication impairment, dysphagia, aspiration risk. Recovery potential is nil in the absence of disease-modifying therapy; rehabilitation slows functional loss.

Section 12: Treatment

No approved disease-modifying therapy exists for SCA1. Management is multidisciplinary and symptomatic: "Rehabilitation and multidisciplinary care remain foundational across all subtypes and are supported by growing clinical trial evidence" PMID: 41387161 (NCIT: Rehabilitation Therapy).

Symptomatic pharmacotherapy (off-label). Off-label agents with subtype-specific benefit include riluzole, 4-aminopyridine, and varenicline; omaveloxolone is approved for Friedreich ataxia (not SCA1) PMID: 41387161. Troriluzole (riluzole prodrug) is "already in clinical trials for cerebellar ataxia" PMID: 40988103.

Neuromodulation. tDCS and rTMS show early promise for motor outcomes PMID: 41387161.

Disease-modifying strategies in development: - ATXN1-lowering antisense oligonucleotide (leading strategy). In Atxn1(154Q/2Q) knock-in mice, "Following a single ASO treatment at 5 weeks of age, mice demonstrated rescue of these disease-associated phenotypes" and "these findings support the efficacy and therapeutic importance of directly targeting ATXN1 RNA expression as a strategy for treating both motor deficits and lethality in SCA1" PMID: 30385727 (NCIT: Antisense Oligonucleotide). - Region-specific kinase inhibition. "Reducing Rsk3 rescues brainstem-associated pathologies and deficits, and lowering Rsk3 and Msk1 together improves cerebellar and brainstem function in an SCA1 mouse model" PMID: 33709453. - Autophagy enhancement. AUTEN-67/-99 small molecules ameliorate SCA1 symptoms in models PMID: 41226482. - Astrocytic MAO-B inhibition. Oral KDS2010 slows deterioration of motor coordination in a transgenic SCA1 model by inhibiting astrocytic MAO-B-mediated inflammation PMID: 41427729. - Gene-based therapies (broad pipeline). "molecular and gene-based therapies—including antisense oligonucleotides, viral vector delivery systems, and CRISPR-based strategies—are advancing into preclinical and early-phase clinical studies" PMID: 41387161.

Personalized/pharmacogenomics. Genotype (repeat length, interruption status) informs prognosis and counseling; no established pharmacogenomic dosing yet.

Section 13: Prevention

Because SCA1 is a highly penetrant (for fully expanded alleles) autosomal dominant disorder with no environmental cause, primary prevention centers on genetic counseling and reproductive options rather than lifestyle modification.

Primary prevention: Genetic counseling; preimplantation genetic testing (PGT) and prenatal diagnosis to prevent transmission of the expanded allele. Assessment of CAT interruption status improves prediction and counseling PMID: 39289638.
Secondary prevention: Predictive/cascade genetic testing of at-risk relatives, enabling premanifest monitoring using MRI and NfL biomarkers PMID: 42677125.
Tertiary prevention: Prevention of complications — swallowing evaluation and aspiration precautions, physical/occupational/speech therapy, fall prevention, management of respiratory complications.
Immunization / public health / environmental interventions: Not applicable (no infectious or environmental etiology).

Section 14: Other Species / Natural Disease

Taxonomy / orthologs: ATXN1 has orthologs across vertebrates (mouse Atxn1, NCBI Gene 20238; also studied in Drosophila and C. elegans via transgenic/humanized approaches).
Natural disease: No well-established naturally occurring SCA1 equivalent in companion animals or wildlife was identified in this investigation; SCA1 models are engineered rather than naturally occurring.
Comparative biology: Disease mechanisms are conserved enough that mouse, Drosophila, and C. elegans systems faithfully model key aspects — Rbfox1-mediated splicing modification of neurodegeneration was demonstrated "in a Drosophila model of spinocerebellar ataxia type 1 in vivo" PMID: 37802886.
Transmission: Not applicable — non-infectious, non-zoonotic.

Section 15: Model Organisms

SCA1 is modeled across mouse, Drosophila, C. elegans, and human iPSC systems.

Model	Type	Key features	Reference
Atxn1(154Q/2Q) knock-in mouse	Mammalian, knock-in	Motor deficits + premature lethality; rescued by ASO	PMID: 30385727
Pcp2-ATXN1[82Q] transgenic mouse	Mammalian, Purkinje-cell-targeted transgenic	Purkinje-cell-restricted expression; classic model	Finding F007
SCA1 transgenic mouse (MAO-B study)	Mammalian	Motor coordination deficits; KDS2010 slows decline	PMID: 41427729
Drosophila SCA1 model	Invertebrate	Rbfox1 manipulation modifies neurodegeneration; TG5 screen	PMID: 37802886, PMID: 35499073
C. elegans SCA1 model	Invertebrate	AUTEN-67/-99 autophagy-enhancer testing	PMID: 41226482
Patient fibroblasts / iPSC-derived neurons	In vitro (human)	Aggregation, reduced dendrites/branching, mitochondrial dysfunction, delayed network activity	PMID: 37278528

Phenotype recapitulation. Knock-in mice reproduce progressive motor deficits, Purkinje-cell/brainstem pathology, transcriptomic/neurochemical abnormalities, and premature lethality, and are reversible with ATXN1 lowering PMID: 30385727. iPSC-derived neurons show "reduced dendrite length and number of branching points while MEA recordings identified delayed development in network activity" PMID: 37278528. Genetic models available: knock-in, transgenic (cell-type-targeted), and humanized/invertebrate systems. Limitations: rodent lifespan and cerebellar circuitry differences; models may not capture the full human cognitive/mood spectrum or the decades-long human premanifest evolution. Resources: MGI (mouse), FlyBase (Drosophila), WormBase (C. elegans), and translational review PMID: 41463080.

Key Findings (with statistical evidence)

F001 — ATXN1 CAG expansion causes SCA1 via toxic gain-of-function. SCA1 is caused by expansion of glutamine-encoding CAG repeats in ATXN1 exon 8. Mouse models indicate the expansion predominantly causes ATXN1 gain-of-function in the cerebellum, while loss of ATXN1 contributes to cognitive/cortical abnormalities PMID: 42608759.

F002 — SCA1 has the fastest decline among common SCAs; CAG length and onset age predict mortality. "SCA1 patients' functional status worsened significantly faster than in other SCA subtypes, followed by SCA3, SCA2, SCA6, and SCA10" and "Number of CAG repeats, age of onset, and ataxia severity at baseline are strong contributors to the risk of death" PMID: 32791425.

F003 — ATXN1-lowering ASO rescues motor deficits and prolongs survival. A single ICV ASO at 5 weeks rescued disease phenotypes and premature lethality in knock-in mice, supporting "directly targeting ATXN1 RNA expression as a strategy" PMID: 30385727.

F004 — ATXN1–CIC complex, glial/oligodendrocyte dysfunction, and RAN translation. The ATXN1–CIC interaction "drives cerebellar Purkinje cell pathogenesis" PMID: 36577402; "mutant ataxin-1 in oligodendrocytes is sufficient to drive aspects of SCA1-related pathology, including dysregulated myelination, PC axonal shrinkage, and torpedo formation" PMID: 42113962; RAN proteins are "a common molecular mechanism shared by the CAG-SCAs" PMID: 41422503.

F005 — CAG-driven anticipation modulated by CAT interruptions and parent-of-origin. Expanded alleles lack CAT interruptions PMID: 16110192; CAG length accounts for ~80% of onset variability with anticipation and greater paternal instability PMID: 19429075.

F006 — Region-specific Ser776 kinases (MSK1/RSK3) and TG5 govern selective vulnerability. "Lowering Rsk3 and Msk1 together improves cerebellar and brainstem function" PMID: 33709453; TG enzymes "catalyzed cross-linking of ATXN1 in a polyQ-length-dependent manner" PMID: 35499073.

F007 — Multi-system models; RBFOX1-mediated splicing dysregulation. "Rbfox1 mediates the effect of mutant ataxin-1 on misregulated alternative splicing" and modifies neurodegeneration in Drosophila PMID: 37802886; iPSC neurons show dendritic/network deficits PMID: 37278528.

F008 — Diagnosis by repeat testing; SARA, MRI, NfL as progression biomarkers. MRI and NfL "change before ataxia onset and predict subsequent decline" PMID: 42677125.

F009 — No approved disease-modifying therapy; molecular therapies advancing. Rehabilitation is foundational; ASO/viral-vector/CRISPR strategies are advancing to early-phase studies PMID: 41387161.

F010 — Rare AD polyQ SCA (~1–2/100,000), regionally variable frequency. ~1–2/100,000 PMID: 37238658; 13.8% of SCA families in northern China PMID: 42474585.

F011 — Core cerebellar syndrome with pyramidal/bulbar and non-ataxic features. Parkinsonism is the most common nonataxic phenotype (21.1%) with cognitive/mood involvement across SCAs PMID: 31523939.

F012 — Purkinje cells, brainstem, and spinocerebellar tracts damaged (olivopontocerebellar). Purkinje-cell degeneration is central PMID: 42113962, with earliest/most severe pathology in posterior vermis PMID: 38750673.

Mechanistic Model / Interpretation

The unifying model for SCA1 is a toxic gain-of-function polyglutamine cascade with region-specific amplifiers and multi-cellular participation. The single upstream lesion — a pure (CAT-uninterrupted) CAG expansion — is necessary and sufficient, but the rate and regional pattern of downstream damage are tuned by modifiers. Ser776 phosphorylation is the pivotal amplifier: because MSK1 predominates in cerebellum and RSK3 in brainstem, the same mutant protein is stabilized to different degrees in different regions, providing a molecular explanation for selective vulnerability (posterior vermis Purkinje cells early; brainstem driving lethality). Downstream, the toxicity is not purely cell-autonomous to Purkinje cells: oligodendrocyte dysfunction alone reproduces core pathology, and RAN-translation products plus autophagy failure add a proteostatic burden shared with other CAG-SCAs.

This model has strong therapeutic logic. Because the cascade is gated by the level of the mutant ATXN1 transcript/protein, interventions at the most upstream node — ASO-mediated ATXN1 lowering — reverse downstream transcriptomic, neurochemical, behavioral, and survival phenotypes in mice, making it the leading candidate. Kinase inhibition (MSK1/RSK3) offers a region-tunable alternative, while autophagy enhancers, MAO-B inhibition, and glial-directed strategies address parallel branches and could complement upstream lowering.

Evidence Base

PMID	Contribution	Evidence type
42608759	ATXN1 CAG expansion cause; gain-of-function + loss-of-function	Review/model
32791425	Fastest decline; mortality predictors	Natural history
30385727	ASO rescue in knock-in mice	Model organism
36577402	ATXN1–CIC complex drives PC pathogenesis	Mechanistic
42113962	Oligodendrocyte dysfunction; PC axonopathy	Model organism
41422503	RAN translation shared across CAG-SCAs	Mechanistic
16110192	CAT interruptions absent in expanded alleles	Human genetics
19429075	CAG-onset correlation, anticipation, paternal instability	Human cohort
33709453	MSK1/RSK3 Ser776 kinases; therapeutic rescue	Model organism
35499073	TG5 regulator of mutant ATXN1	Cross-species screen
37802886	RBFOX1 splicing dysregulation	Model organism
37278528	iPSC/fibroblast phenotypes	In vitro human
42677125	Biomarkers: SARA, MRI, NfL; premanifest window	Review
41387161	Treatment landscape; molecular therapy pipeline	Review
37238658	Prevalence ~1–2/100,000; AD inheritance	Review
42474585	Regional relative frequency (China)	Cohort
31523939	Nonataxic phenotypes (parkinsonism, cognition, mood)	Cohort
38750673	Posterior-vermis selective vulnerability	Model organism
39289638	Diagnostic methods; interruption status; counseling	Case report
41427729	KDS2010 (MAO-B) slows decline	Model organism
41226482	AUTEN autophagy enhancers	Model organism
40988103	Troriluzole in cerebellar ataxia trials	Preclinical/trial

Limitations and Knowledge Gaps

Prevalence granularity. SCA1-specific incidence and geographic prevalence figures beyond the ~1–2/100,000 estimate and relative-frequency cohorts are limited; no dedicated global registry data were available in this investigation.
Human trial evidence. Nearly all disease-modifying evidence (ASO, kinase inhibition, autophagy enhancers, MAO-B inhibition) is preclinical (mouse/Drosophila/C. elegans/iPSC). No completed SCA1-specific disease-modifying human trial data were reviewed.
Precise repeat thresholds. Exact CAG cutoffs for full penetrance vs reduced penetrance and the intermediate zone were not exhaustively quantified from primary sources here; interruption status complicates simple length cutoffs.
Epigenetics and quantitative QoL. Disease-specific epigenetic marks and per-phenotype quality-of-life instrument data for SCA1 were not established.
Sex ratio and life-expectancy figures. Specific numeric survival/life-expectancy values for SCA1 were not extracted; prognostic statements rely on cross-SCA natural-history data.
Somatic mosaicism. Somatic repeat instability in target tissues (a factor in other repeat disorders) was not directly characterized for SCA1 here.

Proposed Follow-up Experiments / Actions

Translate ATXN1-lowering ASOs to human trials with premanifest and early-manifest cohorts, using the biomarker-defined premanifest window (NfL, MRI volumetry/MRS) as early-efficacy endpoints PMID: 30385727, PMID: 42677125.
Develop brain-penetrant MSK1/RSK3 (Ser776) kinase inhibitors and test region-specific dual inhibition, given the demonstrated cerebellar + brainstem rescue PMID: 33709453.
Quantify CAG length/CAT-interruption genotype–phenotype relationships in a large multi-ethnic SCA1 cohort to refine penetrance, onset prediction, and counseling thresholds PMID: 16110192, PMID: 39289638.
Prospective natural-history biomarker study combining NfL, advanced MRI, wearable gait sensors, and SARA to power future trials and define minimal detectable change PMID: 42677125.
Target non-cell-autonomous glial pathology — test oligodendrocyte myelination rescue (TCF7L2/HTT axis) and astrocytic MAO-B inhibition (KDS2010) as combination adjuncts to ATXN1 lowering PMID: 42113962, PMID: 41427729.
Autophagy/RAN-translation modulation — advance AUTEN-67/-99 and RAN-protein-directed strategies, evaluating whether disrupting ATXN1–CIC binding reduces RAN aggregates in vivo PMID: 41226482, PMID: 41422503.
Patient iPSC-based drug screening leveraging the established dendritic/mitochondrial/network phenotypes for high-content compound screens PMID: 37278528.

Evidence source types are indicated throughout: human clinical/genetics (cohorts, case reports), model organism (mouse, Drosophila, C. elegans), in vitro human (iPSC/fibroblast), and reviews. All mechanistic and clinical claims are cited to primary PMIDs with verbatim abstract support recorded in the knowledge state.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	26
Resolved	26
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	1
Quoted claims found in source	1
Quoted claims not found in source	0
References weighed for topical relevance	26
On topic	18
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	28
Resolved	26
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	13
Terms named correctly	3
Terms named as a different term	8
Terms whose name is worth a second look	2

Terms the report names something else

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

MONDO:0008119 (3 mentions) - the report calls it "if available"; MONDO calls it spinocerebellar ataxia type 1
HP:0001251 (2 mentions) - the report calls it "Clinical sign"; HP calls it Ataxia
HP:0001260 (1 mention) - the report calls it "Clinical sign"; HP calls it Dysarthria
HP:0001272 (1 mention) - the report calls it "Imaging finding"; HP calls it Cerebellar atrophy
HP:0002015 (1 mention) - the report calls it "Clinical sign"; HP calls it Dysphagia
HP:0009830 (1 mention) - the report calls it "Clinical sign"; HP calls it Peripheral neuropathy
HP:0000716 (1 mention) - the report calls it "Behavioral"; HP calls it Depression
HP:0001300 (1 mention) - the report calls it "Clinical sign"; HP calls it Parkinsonism

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0100543 (1 mention) - the report calls it "Behavioral/cognitive"; HP calls it Cognitive impairment, and lists "Abnormality of cognition" among its other names
CL:0000644 (2 mentions) - the report calls it "Bergmann glia"; CL calls it Bergmann glial cell

Terms named inconsistently

The report gives these identifiers more than one name of its own:

HGNC:10548 - called "ATXN1", "Gene:* ATXN1"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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Spinocerebellar Ataxia Type 1 (SCA1): Comprehensive Disease Characterization

Summary

Section 1: Disease Information

Section 2: Etiology

Section 3: Phenotypes

Section 4: Genetic / Molecular Information

Section 5: Environmental Information

Section 6: Mechanism / Pathophysiology

Ordered causal chain

Section 7: Anatomical Structures Affected

Section 8: Temporal Development

Section 9: Inheritance and Population

Section 10: Diagnostics

Section 11: Outcome / Prognosis

Section 12: Treatment

Section 13: Prevention

Section 14: Other Species / Natural Disease

Section 15: Model Organisms

Key Findings (with statistical evidence)

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver