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Classifications

Harrison's Part

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Inheritance

1

Autosomal dominant inheritance HP:0000006

SCA31 is autosomal dominant with adult onset, so penetrance is strongly age-dependent; a precise age-specific penetrance curve has not been published. The insertion length correlates inversely with age at onset, and the original report documented an expansion in one family showing anticipation. Later systematic sizing across parent-child pairs found the insertion changeable but not markedly unstable in either direction, so anticipation should not be assumed as a general property of the locus.

Autosomal dominant inheritance

Show evidence (3 references)

PMID:19878914 SUPPORT Human Clinical

"Spinocerebellar ataxia type 31 (SCA31) is an adult-onset autosomal-dominant neurodegenerative disorder showing progressive cerebellar ataxia mainly affecting Purkinje cells."

Establishes dominant inheritance, adult onset, and the Purkinje-predominant target of the disease.

PMID:19878914 SUPPORT Human Clinical

"The SCA31 repeat insertion's length inversely correlated with patient age of onset, and an expansion was documented in a single family showing anticipation."

The length-onset relationship and the single documented instance of anticipation, which is quoted as the n = 1 observation it is.

PMID:28638142 SUPPORT INDIRECT Human Clinical

"We consider that the length of the inserted repeats in SCA31 is changeable during transmission, but inter-generational instability is not marked, as far as the current sizing method can determine."

Quoted with the authors' methodological caveat, and marked INDIRECT because it qualifies rather than confirms the anticipation claim above; the limitation is a property of the sizing assay rather than of the biology.

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Discussions and Knowledge Gaps

2

How much of SCA31 Purkinje cell degeneration is caused by the (UGGAA)n RNA itself versus by the poly-WNGME pentapeptide protein it is translated into?

KNOWLEDGE GAP OPEN sca31_foci_versus_ppr_contribution

Attached to

pathophysiology#Nuclear (UGGAA)n RNA Foci in Purkinje Cells pathophysiology#Repeat-Associated Translation of poly-WNGME Pentapeptide Protein

Both toxic species are present in patient Purkinje cells and both are produced by the fly model, but no experiment has separated their contributions. The obvious dissection, suppressing translation while leaving the RNA or the reverse, is complicated in SCA31 specifically, because the same manipulation affects both arms: raising TDP-43 reduces foci and PPR production together. It is complicated further by the unresolved translation route, since the repeat contains its own AUG and cannot be assumed to be RAN-translated, so a strategy that blocks RAN translation may not apply here. The answer matters for therapy: an approach that clears the transcript addresses both arms, whereas a translation-directed approach addresses only one.

Proposed experiments

Translation-silent (UGGAA)n allele in a mammalian Purkinje cell system

exp_sca31_translation_blocked_repeat

Express an (UGGAA)n repeat engineered to retain its RNA structure and foci-forming capacity while being unable to produce poly-WNGME, alongside the wild-type repeat, in a mammalian Purkinje-cell system, and compare toxicity.

Decision criterion

Comparable toxicity from the translation-silent allele would attribute the damage predominantly to the RNA; markedly reduced toxicity would implicate the PPR protein.

Direct poly-WNGME expression without the repeat RNA

exp_sca31_ppr_only_expression

Express poly-WNGME from a codon-altered, non-repetitive construct that makes the protein without producing (UGGAA)n RNA, and assay Purkinje cell toxicity.

Decision criterion

Toxicity from the protein alone would establish an RNA-independent contribution; its absence would argue the PPR protein is a marker rather than a driver.

Show evidence (1 reference)

PMID:28343865 SUPPORT Model Organism

"It is important to understand the contributions of repeat RNA and PPR proteins to disease pathogenesis."

The authors state the apportionment as an open question rather than answering it, which is what this knowledge gap records.

Does the (UGGAA)n Drosophila model, in which the repeat is overexpressed from a heterologous driver in a nervous system with no cerebellum, capture the biology that makes SCA31 a Purkinje-cell disease?

HUMAN MODEL MISMATCH OPEN sca31_drosophila_translational_validity

Attached to

animal_models#Drosophila melanogaster pathophysiology#Binding and Redistribution of RNA-Binding and Splicing Factors

Almost every mechanistic claim about SCA31 beyond the human autopsy findings rests on the fly. The mismatch is specific rather than generic. The most distinctive feature of human SCA31 is that foci and degeneration are confined to Purkinje cells and spare other neurons and glia, and Drosophila has neither a cerebellum nor a Purkinje cell, so the model cannot address selectivity at all. The fly expresses the repeat from a GAL4 driver at supraphysiological levels rather than from an endogenous intron under BEAN1 transcriptional control, and the toxicity is explicitly expression-level dependent, so the dose relationship in the model is not the dose relationship in patients. The rescue result on which the whole RNA-chaperone therapeutic hypothesis rests, that raising TDP-43, FUS or hnRNPA2B1 suppresses toxicity, has not been reproduced in a mammalian system, and those proteins are pleiotropic enough that the manipulation may not be tolerable in one. No mouse model of the SCA31 insertion has been reported.

Proposed experiments

Knock-in mouse carrying the (TGGAA)n insertion at the orthologous intron

exp_sca31_knockin_mouse

Generate a mouse carrying the human-length (TGGAA)n-containing insertion at the orthologous Bean1/Tk2 shared intron, so the repeat is transcribed under endogenous brain-restricted control, and assay for Purkinje-cell foci, PPR protein, and age-dependent ataxia.

Decision criterion

Purkinje-cell-selective foci and late-onset ataxia would establish that the fly findings translate to a mammalian cerebellum; their absence at physiological expression would show the fly phenotype depends on overexpression.

Patient-derived iPSC Purkinje cells

exp_sca31_ipsc_purkinje

Differentiate Purkinje-like neurons from SCA31 patient iPSCs carrying the endogenous insertion and test whether foci form, PPR protein accumulates, and RNA-binding-protein supplementation rescues, in a human cerebellar cell type at endogenous expression.

Decision criterion

Reproduction of the fly rescue in human Purkinje-like cells would support the RNA-chaperone strategy; failure would localize the effect to the fly's overexpression regime.

Show evidence (2 references)

PMID:35563872 SUPPORT Other

"These SCA31 RNA foci were only detected in the BEAN1-direction (no anti-sense foci), ranged from 0.2 to 1.8 µm in diameter, and accumulated in the nuclei of Purkinje cells (not observed in other neurons or glial cells)"

Documents the Purkinje-cell selectivity in humans that the fly model has no way to reproduce.

PMID:36319738 SUPPORT INDIRECT Model Organism

"Subsequent investigation by over-expressing (UGGAA)n in Drosophila revealed that the RNA containing (UGGAA)n exerts toxicity in a length- and expression level-dependent manner"

Quoted for the words over-expressing and expression level-dependent, which together are the mismatch: the model's phenotype is a function of a dose the endogenous locus does not deliver.

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Pathophysiology

8

BEAN1/TK2 Intronic (TGGAA)n Pentanucleotide Repeat Insertion

The causative lesion is a 2.5-3.8 kb insertion of complex pentanucleotide repeats at 16q22.1, located in an intronic segment shared by BEAN1 and TK2. The insertion contains (TGGAA)n, (TAGAA)n, (TAAAA)n and (TAAAATAGAA)n, but only (TGGAA)n segregates with the disease: the other motifs are encountered in control Japanese chromosomes, and the rare control insertions lack the (TGGAA)n stretch. This is the disorder-specific substitution this entry makes against the generic molecular lesion of the conserved Purkinje-degeneration module. Two negatives matter for interpretation. Insertion size alone does not establish pathogenicity, because control alleles can also carry a large insertion; the (TGGAA)n content does. And the lesion is intronic and far larger than an exome read, so standard exome sequencing does not exclude it.

cerebellar Purkinje cell CL:0000121

BEAN1 hgnc:24160 TK2 hgnc:11831

Downstream

Bidirectional Transcription of the Repeat into (UGGAA)n Repeat RNA Because the insertion sits in an intron shared by two oppositely transcribed genes, it is transcribed from both strands, and the BEAN1-direction transcript is confined to brain.

Show evidence (4 references)

PMID:19878914 SUPPORT Human Clinical

"The other was an insertion, from 2.5-3.8 kb long, consisting of complex penta-nucleotide repeats including a long (TGGAA)n stretch."

The original identification of the causal insertion and its size range.

PMID:19878914 SUPPORT Human Clinical

"In controls, shorter (1.5-2.0 kb) insertions lacking (TGGAA)n were found only rarely."

Establishes that the discriminating feature is the (TGGAA)n content rather than the presence of an insertion.

PMID:31755042 SUPPORT Human Clinical

"By comparing various pentanucleotide repeats in this particular locus among control Japanese and Caucasian populations, it was found that (TGGAA)n was the only sequence segregating with SCA31, strongly suggesting the pathogenicity of (TGGAA)n."

The cross-population comparison that isolates (TGGAA)n from the other motifs in the same insertion.

+ 1 more reference

Bidirectional Transcription of the Repeat into (UGGAA)n Repeat RNA

The insertion is transcribed as two independent non-coding repeat RNAs: (UGGAA)n in the BEAN1 direction, brain-restricted, and (UUCCA)n in the TK2 direction, ubiquitous. The (UGGAA)n species is treated as the pathogenic one on three grounds: BEAN1 is brain-only while the disease is confined to the nervous system, RNA foci in patient Purkinje cells are detected only in the BEAN1 direction with no antisense foci, and the BEAN1-direction transcript is the more toxic of the two in cultured cells. This node also carries the reason the entry does not model a loss-of-function mechanism: BEAN1, TK2 and neighbouring gene expression and splicing are comparable between patient and control cerebella, so haploinsufficiency is not the primary route. That negative comes with its own caveat, quoted below, because bulk cerebellar measurement averages over a tissue in which Purkinje cells are a small minority.

transcription of the intronic pentanucleotide repeat GO:0006351

Downstream

Nuclear (UGGAA)n RNA Foci in Purkinje Cells The transcribed repeat RNA folds into abnormal structures that accumulate as nuclear foci.

Repeat-Associated Translation of poly-WNGME Pentapeptide Protein The same repeat RNA is also translated into a pentapeptide repeat protein. This is a branch, not a step in series with foci formation: the two products of the transcript are curated as parallel toxic species.

Show evidence (3 references)

PMID:23607545 SUPPORT In Vitro

"In both transiently and stably expressed cultured cell models, we also find that the mutation transcribed in the BEAN1-direction yields more toxicity than control transcripts"

Direct comparison establishing that the BEAN1-direction transcript is the toxic species in a cell model.

PMID:35563872 SUPPORT Other

"Haploinsufficiency may not be a major contributor to SCA31 pathology, since the mRNA expression and splicing levels of BEAN1, TK2, or other nearby genes are similar in control and patient cerebella"

The negative result that argues against a loss-of-function mechanism. Evidence source is OTHER because this is a review restating the primary expression data.

PMID:35563872 SUPPORT INDIRECT Other

"It should be noted that the above observations are largely based on cell-type averaging, given that Purkinje cells are the only affected neurons in SCA31 and that they represent a small fraction of total cerebellar mass."

Curated deliberately as the reviewers' own caveat on the haploinsufficiency negative above: it means that negative is weaker than a bulk-tissue result appears. Marked INDIRECT because it bears on the claim by limiting the preceding evidence rather than by testing the claim.

Nuclear (UGGAA)n RNA Foci in Purkinje Cells

The (UGGAA)n transcript accumulates as discrete nuclear RNA foci in cerebellar Purkinje cells of SCA31 patients and not in controls. The foci are confined to Purkinje cell nuclei, are not seen in other neurons or in glia, are detected in roughly 30% of patient Purkinje cells examined, and measure about 0.2 to 1.8 micrometres. In the SCA31 fly model the number of foci tracks with disease severity, which is the closest available link between foci burden and outcome. A precise reading of what the human data show: the foci are associated with Purkinje cell degeneration. That is the word the neuropathology paper uses, and this entry keeps it. Whether foci formation is the proximal cause of the degeneration, or an accompanying marker of the toxic transcript, is not settled by an association in fixed tissue.

cerebellar Purkinje cell CL:0000121

nuclear (UGGAA)n RNA focus GO:0035770

Animal models

Transgenic expression of expanded (UGGAA)n pentanucleotide repeat RNA Drosophila melanogaster Drosophila melanogaster partially recapitulates The model reproduces (UGGAA)n foci formation and its dependence on repeat length and expression level.

Downstream

Binding and Redistribution of RNA-Binding and Splicing Factors Foci built on the repeat RNA engage RNA-binding proteins, including splicing factors, and alter their availability.

Purkinje Cell Degeneration Foci are associated with Purkinje cell degeneration in patient cerebella. The edge is typed as indirect with unknown intermediates because the association is the whole of the human evidence.

Show evidence (4 references)

PMID:23607545 SUPPORT Human Clinical

"We find that the RNA foci containing (UGGAA)n are indeed observed in PC nuclei of both SCA31 patients, whereas similar foci were not observed in control individuals."

The human demonstration of foci with the control comparison that makes it disease-specific.

PMID:35563872 SUPPORT Other

"These SCA31 RNA foci were only detected in the BEAN1-direction (no anti-sense foci), ranged from 0.2 to 1.8 µm in diameter, and accumulated in the nuclei of Purkinje cells"

Gives the strand specificity, the size range, and the cell-type restriction of the foci.

PMID:35563872 SUPPORT Other

"fluorescent in situ hybridization (FISH) assays detected RNA foci in approximately 30% of patient Purkinje cells"

Quantifies the proportion of Purkinje cells bearing foci, which is what makes the burden a partial rather than universal cellular phenotype.

+ 1 more reference

Binding and Redistribution of RNA-Binding and Splicing Factors

(UGGAA)n binds a defined set of RNA-binding proteins. The original report showed by electrophoretic mobility-shift assay that the serine/arginine-rich splicing factors SRSF1 and SRSF9 (published under the older SFRS1/SFRS9 names) bind the repeat in vitro. Later pulldown from nuclear extract confirmed sequence-specific co-precipitation of TDP-43, HNRNPM, SRSF9 and FUS with r(UGGAA)20 but not with the antisense sequence, and TDP-43 was shown to co-localize with foci in human SCA31 Purkinje cells. The direction of the effect is not the simple sequestration story it first resembles, and this is the most consequential nuance in SCA31 mechanism. TDP-43, FUS and hnRNPA2B1 do not merely get trapped: they act as RNA chaperones, and raising their level suppresses rather than worsens (UGGAA)n toxicity in Drosophila. So this node is curated as an alteration of the RNA-protein equilibrium rather than as loss of splicing-factor function, and no splicing target has been shown mis-spliced in human SCA31 cerebellum.

spliceosomal mRNA splicing GO:0000398 ↕ DYSREGULATED

(UGGAA)n repeat RNA binding by splicing factors and RNA chaperones GO:0003723 ⚠ ABNORMAL

Downstream

Purkinje Cell Degeneration Disturbance of the repeat-RNA and RNA-binding-protein equilibrium is proposed as a route to Purkinje cell toxicity. The rescue experiments are in Drosophila and the human transcript targets are undefined, so the intervening steps are not established.

Show evidence (4 references)

PMID:19878914 SUPPORT In Vitro

"An electrophoretic mobility-shift assay showed that essential splicing factors, serine/arginine-rich splicing factors SFRS1 and SFRS9, bind to (UGGAA)n in vitro."

The original splicing-factor binding result. Note the gene symbols are the pre-2010 SFRS1/SFRS9 names for SRSF1 and SRSF9.

PMID:33431896 SUPPORT In Vitro

"Among RBPs we have tested, TDP-43, heterogeneous nuclear ribonucleoprotein M (HNRNPM), serine and arginine rich splicing factor 9 (SRSF9), and FUS were co-precipitated with the r(UGGAA)20, but not with the antisense sequence r(UUCCA)20"

Independent confirmation of SRSF9 binding, with the antisense control that makes the interaction sequence-specific.

PMID:28343865 SUPPORT Model Organism

"We revealed that motor-neuron disease (MND)-linked RNA-binding proteins (RBPs), TDP-43, FUS, and hnRNPA2B1, bind to and induce structural alteration of UGGAAexp."

Establishes binding plus a structural effect on the repeat RNA, which is what distinguishes chaperoning from passive sequestration.

+ 1 more reference

Repeat-Associated Translation of poly-WNGME Pentapeptide Protein

The repeat RNA is translated into a pentapeptide repeat protein, poly-WNGME (Trp-Asn-Gly-Met-Glu), which accumulates as granular material in the cell bodies and dendrites of patient Purkinje cells and in the fly model. Whether this proceeds by repeat-associated non-AUG translation or by conventional AUG-initiated translation is explicitly unresolved: unlike most repeat-expansion disorders, the TGGAA repeat itself contains an AUG codon, and the flanking TAAAA and TAGAA sequences supply stop codons, so all three reading frames of the repeat yield the same product. In the fly, raising TDP-43 suppresses PPR protein production as well as foci formation, so the two toxic arms are not independently regulated.

cerebellar Purkinje cell CL:0000121

repeat-associated translation of the pentanucleotide repeat GO:0006412 ⚠ ABNORMAL

Animal models

Transgenic expression of expanded (UGGAA)n pentanucleotide repeat RNA Drosophila melanogaster Drosophila melanogaster recapitulates The fly produces the same poly-WNGME PPR protein detected in patient Purkinje cells, and PPR level tracks the severity of eye degeneration.

Downstream

Purkinje Cell Degeneration PPR protein is present in patient Purkinje cells and its level tracks degeneration severity in the fly eye, but no experiment has isolated its contribution from that of the repeat RNA in a mammalian system.

Show evidence (3 references)

PMID:28343865 SUPPORT Model Organism

"expression of expanded UGGAA (UGGAAexp) repeats, responsible for spinocerebellar ataxia type 31 (SCA31) in Drosophila, causes neurodegeneration accompanied by accumulation of UGGAAexp RNA foci and translation of repeat-associated pentapeptide repeat (PPR) proteins, consistent with observations..."

Couples the fly result to the human observation and names both toxic products of the transcript.

PMID:28343865 SUPPORT INDIRECT Model Organism

"Whether the PPR protein was generated through RAN translation or conventional AUG translation is currently unclear."

Curated on purpose: the authors decline to attribute the product to RAN translation, and SCA31 is often described as a RAN-translation disorder without that caveat. Marked INDIRECT because it bounds the node's claim rather than supporting it positively.

PMID:28343865 SUPPORT Model Organism

"Translation of the UGGAA repeat in all frames would thus result in the production of an identical PPR protein, poly-WNGME"

The sequence-level reason SCA31 produces a single PPR species rather than the frame-dependent set seen in other repeat disorders.

Purkinje Cell Degeneration

The tissue lesion is a Purkinje-cell-restricted degeneration of the cerebellar cortex, with the cerebrum, brainstem and spinal cord appearing normal. Purkinje cells fall in number and shrink, and the surviving cells are characteristically surrounded by halo-like amorphous material made of calbindin-positive somatic sprouts and synaptophysin-positive presynaptic terminals: that is, an aberrant reinnervation of the shrinking soma rather than a deposit of aggregated protein. Ubiquitin-positive degradation granules and fragmentation of the Golgi apparatus are enriched in the same cells. Detailed morphological work separates two degenerative processes: shrinkage with the halo, which carries the bent, elongated, folded nuclei and the Golgi fragmentation and is considered specific to SCA31, and shrinkage without it. This entry does not declare conformance to the module's Purkinje calcium and proteostasis node. Golgi fragmentation and ubiquitin-positive granules are proteostasis-adjacent findings, but nothing bearing on Purkinje calcium handling has been measured in SCA31, in patients or in a mammalian model, and the module node asserts both.

cerebellar Purkinje cell CL:0000121

fragmented Golgi apparatus GO:0005794

Downstream

Cerebellar Cortical Atrophy Loss and shrinkage of Purkinje cells with cortical degeneration produces the atrophy seen on imaging.

Show evidence (4 references)

PMID:24344778 SUPPORT Human Clinical

"Neuropathologically, cerebellar Purkinje cells are preferentially affected and reduced in number in SCA31, and they are often surrounded by halo-like amorphous materials."

The core neuropathological finding and its signature structure.

PMID:24344778 SUPPORT Human Clinical

"Correspondingly, fragmentation of the Golgi apparatus was observed more frequently in Purkinje cells with the halo-like structure than in those without this structure."

Ties the Golgi finding specifically to the halo-bearing subpopulation, which is why the two degenerative processes are described separately.

PMID:35563872 SUPPORT Other

"Histologically, the cerebrum, brainstem, and spinal cord all appear normal in SCA31 patients, while the cerebellar cortex shows signs of degeneration"

The anatomical restriction of the lesion, which is what makes SCA31 a pure cerebellar degeneration pathologically as well as clinically.

+ 1 more reference

Cerebellar Cortical Atrophy

Cerebellar atrophy, most marked in the upper vermis, with the brainstem relatively spared. In the pooled literature review it was present in 78.7% of imaged patients; brainstem and cortical atrophy were each reported in 9.1%, which is the imaging counterpart of the extracerebellar signs curated among the phenotypes.

Downstream

Progressive Cerebellar Ataxia Loss of cerebellar cortical output produces the clinical syndrome.

Show evidence (1 reference)

PMID:36563608 SUPPORT Human Clinical

"Upon radiological examination, clinicians can expect a high prevalence of cerebellar atrophy (78.7%), occasionally accompanied by brainstem (9.1%) and cortical (9.1%) atrophy."

The pooled imaging frequencies across 374 patients, including the minority with extracerebellar atrophy.

Progressive Cerebellar Ataxia

The clinical endpoint: late-onset, slowly progressive truncal and limb ataxia with cerebellar dysarthria, classically without pyramidal signs, neuropathy or gaze limitation.

Show evidence (1 reference)

PMID:36319738 SUPPORT Human Clinical

"Clinical features of SCA31 were summarized as, late-onset (average around 60 years old), slowly progressive ataxia. Extra-cerebellar features such as pyramidal tract signs, neuropathy or gaze limitations were not detected."

The classical description of the syndrome. Note that the pooled review curated elsewhere in this entry found extracerebellar signs in about half of patients, so this characterization is the founding cohorts' rather than the whole literature's.

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Histopathology

1

Purkinje cell loss with halo-like amorphous perisomatic material

The signature SCA31 finding. Surviving Purkinje cells are surrounded by halo-like amorphous material composed of calbindin-positive somatic sprouts and synaptophysin-positive presynaptic terminals innervated from basket cells, inferior olivary neurons and other Purkinje cell afferents. The halo is therefore aberrant perisomatic reinnervation, not a protein aggregate, which distinguishes SCA31 from the inclusion-body pathology of the polyglutamine ataxias. Ubiquitin-positive degradation granules and Golgi fragmentation are enriched in the same cells, and the halo-bearing cells carry bent, elongated, folded nuclei while cells without the halo shrink with slender condensed nuclei. No finding_term is bound. HistopathologyFindingTerm is reachable only from the NCIT Histopathology Result branch plus a handful of HP rosette terms; neither NCIT nor HP names perisomatic sprouting around a degenerating Purkinje cell, and binding a generic neuronal-loss term would drop what is specific about this finding.

Show evidence (4 references)

PMID:24344778 SUPPORT Human Clinical

"We found that bent, elongated, often folded nuclei were observed frequently in degenerating Purkinje cells with the halo-like structure."

The nuclear morphology that accompanies the halo, from direct examination of two SCA31 brains.

PMID:35563872 SUPPORT Other

"These amorphous materials are composed of calbindin-positive somatic sprouts (cactus-like formation) and synaptophysin-positive presynaptic terminals innervated from basket cells, neurons of the inferior olivary nucleus, or other neurons that connect to Purkinje cells"

Identifies what the halo is made of, which is what makes it reinnervation rather than aggregate.

PMID:35563872 SUPPORT Other

"Ubiquitin-positive degradation granules and Golgi fragmentation are also enriched in the amorphous materials"

The proteostasis-adjacent findings that accompany the halo.

+ 1 more reference

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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

12

Digestive 1

Dysphagia OCCASIONAL HP:0002015

Show evidence (1 reference)

PMID:36563608 SUPPORT Human Clinical

"Other common clinical features were oculomotor dysfunction (38.8%), dysphagia (22.1%), hypoacousia (23.3%), vibratory hypoesthesia (24.3%), and dysreflexia (41.6%)."

The pooled frequency for dysphagia.

Ear 1

Hearing impairment OCCASIONAL HP:0000365

Show evidence (1 reference)

PMID:36563608 SUPPORT Human Clinical

"Other common clinical features were oculomotor dysfunction (38.8%), dysphagia (22.1%), hypoacousia (23.3%), vibratory hypoesthesia (24.3%), and dysreflexia (41.6%)."

The pooled frequency for hypoacousia.

Eye 1

Abnormal eye movement FREQUENT Abnormality of eye movement HP:0000496

Show evidence (1 reference)

PMID:36563608 SUPPORT Human Clinical

"Other common clinical features were oculomotor dysfunction (38.8%), dysphagia (22.1%), hypoacousia (23.3%), vibratory hypoesthesia (24.3%), and dysreflexia (41.6%)."

The pooled frequency for oculomotor dysfunction, quoted with the surrounding extracerebellar features it was reported with.

Musculoskeletal 1

Hypotonia HP:0001252

Show evidence (1 reference)

PMID:35563872 SUPPORT Other

"Clinical features of SCA31 include truncal and limb ataxia, cerebellar speech, and reduced muscle tonus"

Names reduced muscle tone among the clinical features.

Nervous System 5

Gait ataxia VERY_FREQUENT HP:0002066

Course: PROGRESSIVE

Show evidence (2 references)

PMID:36563608 SUPPORT Human Clinical

"This review revealed that the average age of onset was 59.1 ± 3.3 years, with symptoms of slowly progressing ataxia and dysarthria."

Pooled across 374 patients, this establishes ataxia as the core manifestation and gives its onset age; the frequency band follows from its being the defining feature rather than from a reported percentage.

PMID:35563872 SUPPORT Other

"Clinical features of SCA31 include truncal and limb ataxia, cerebellar speech, and reduced muscle tonus"

Names truncal ataxia among the core clinical features.

Dysarthria VERY_FREQUENT HP:0001260

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:36563608 SUPPORT Human Clinical

"This review revealed that the average age of onset was 59.1 ± 3.3 years, with symptoms of slowly progressing ataxia and dysarthria."

Names dysarthria alongside ataxia as the defining symptom pair.

Cerebellar atrophy FREQUENT HP:0001272

Show evidence (1 reference)

PMID:36563608 SUPPORT Human Clinical

"Upon radiological examination, clinicians can expect a high prevalence of cerebellar atrophy (78.7%), occasionally accompanied by brainstem (9.1%) and cortical (9.1%) atrophy."

Gives the pooled frequency that fixes the FREQUENT band, and the minority with brainstem or cortical involvement.

Cognitive impairment OCCASIONAL HP:0100543

Show evidence (1 reference)

PMID:36563608 SUPPORT Human Clinical

"Unfrequently, abnormal movements (7.4%), extrapyramidal symptoms (4.5%) and cognitive impairment (6.9%) may be observed."

The pooled frequency, quoted with the reviewers' own framing of these as infrequent.

Parkinsonism HP:0001300

Show evidence (2 references)

PMID:35563872 SUPPORT Other

"Some patients additionally develop nigrostriatal dopaminergic dysfunction, L-DOPA responsive parkinsonism, and blepharospasm followed by ataxic dysarthria"

Documents the atypical parkinsonian presentation, including its levodopa responsiveness, as an occasional feature.

PMID:36563608 SUPPORT Human Clinical

"Unfrequently, abnormal movements (7.4%), extrapyramidal symptoms (4.5%) and cognitive impairment (6.9%) may be observed."

The pooled frequency for extrapyramidal symptoms.

Other 3

Limb ataxia VERY_FREQUENT HP:0002070

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:35563872 SUPPORT Other

"Clinical features of SCA31 include truncal and limb ataxia, cerebellar speech, and reduced muscle tonus"

Names limb ataxia as a core clinical feature.

Abnormal reflex FREQUENT HP:0031826

Show evidence (1 reference)

PMID:36563608 SUPPORT Human Clinical

"Other common clinical features were oculomotor dysfunction (38.8%), dysphagia (22.1%), hypoacousia (23.3%), vibratory hypoesthesia (24.3%), and dysreflexia (41.6%)."

The pooled frequency for dysreflexia.

Impaired vibratory sensation OCCASIONAL HP:0002495

Show evidence (2 references)

PMID:36563608 SUPPORT Human Clinical

"Other common clinical features were oculomotor dysfunction (38.8%), dysphagia (22.1%), hypoacousia (23.3%), vibratory hypoesthesia (24.3%), and dysreflexia (41.6%)."

The pooled frequency for vibratory hypoesthesia.

PMID:36563608 SUPPORT INDIRECT Human Clinical

"we must consider the old age and longstanding disease course of patients as a confounding factor for extracerebellar sign development, as some may not be directly attributable to SCA31"

Curated on this phenotype because it is exactly the kind of finding the caveat is about: vibration sense declines with age independently of SCA31. Marked INDIRECT because it qualifies the attribution rather than supporting it.

🧬

Genetic Associations

2

BEAN1 (Intronic complex pentanucleotide repeat insertion containing (TGGAA)n)

Gene: BEAN1 hgnc:24160 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (5 references)

PMID:19878914 SUPPORT Human Clinical

"The other was an insertion, from 2.5-3.8 kb long, consisting of complex penta-nucleotide repeats including a long (TGGAA)n stretch."

The gene-discovery statement describing the causal allele.

PMID:20424877 SUPPORT Human Clinical

"All patients had a 2.6- to 3.7-kb insertion. The size of the insertion was inversely correlated with the age at onset but not associated with the progression rate after onset."

A 94-patient cohort confirming the allele and separating what size does predict (onset) from what it does not (progression rate).

PMID:20424877 SUPPORT Human Clinical

"We also found that 3 of 405 control individuals (0.7%) had the insertions from 1.0 to 3.5 kb in length."

The control observation that makes insertion size on its own an insufficient diagnostic criterion.

+ 2 more references

TK2 (Shares the affected intron; transcribed in the opposite direction)

Gene: TK2 hgnc:11831 relationship_type: MODIFIER

Show evidence (2 references)

PMID:19878914 SUPPORT Human Clinical

"One was a single-nucleotide change in an intron of the thymidine kinase 2 gene (TK2). However, this did not appear to affect splicing or expression patterns."

Records the co-segregating TK2 intronic variant and the reason the original authors set it aside.

PMID:36319738 SUPPORT Human Clinical

"While TK2 is ubiquitously expressed, BEAN1 is transcribed only in the brain."

The expression difference that makes the BEAN1-direction transcript, not the TK2-direction one, the plausible pathogenic species.

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Medical Actions

2

Multidisciplinary Rehabilitation

Action: rehabilitation Ontology label: Rehabilitation NCIT:C15315

There is no disease-modifying therapy for SCA31, and management is supportive: physical therapy for balance, gait and falls prevention, occupational therapy and home-safety assessment, and speech and swallowing therapy. A seven-year follow-up of annual four-week intensive rehabilitation in patients with pure cerebellar SCA6 or SCA31 found SARA scores stable through year six, better than the expected natural history, with deterioration appearing at year seven; balance measured by the BESTest declined earlier, from year three. The study is small (seven patients) and mixes SCA6 with SCA31, so it supports rehabilitation as worthwhile maintenance rather than as an SCA31-specific intervention with a measured effect size.

Show evidence (2 references)

PMID:40906249 SUPPORT Human Clinical

"Annual intensive rehabilitation effectively slowed the progression of ataxic symptoms (SARA) for up to six years, while balance function (BESTest) showed a significant decline from the third year."

The primary result, including the divergence between coordination and balance outcomes that qualifies it.

PMID:40906249 SUPPORT INDIRECT Human Clinical

"Seven patients with genetically confirmed SCA6 or SCA31 participated in annual 4-week intensive rehabilitation programmes."

The cohort is seven patients pooling two diseases, so it cannot deliver an SCA31-specific effect estimate; recorded to bound the claim above.

Naphthyridine Carbamate Dimer (Preclinical)

An experimental small molecule, not a treatment. Naphthyridine carbamate dimer (NCD) binds the r(UGGAA)n repeat, recognizing four guanines in the UGGAA/UGGAA pentad, and disrupts RNA foci and the repeat's interactions with TDP-43, HNRNPM and SRSF9. Fed to larvae of the SCA31 Drosophila model it alleviates the repeat-induced phenotype. It is curated because it is the only compound with a demonstrated effect on the SCA31 lesion and because it targets a pathophysiology node directly, not because it is near clinical use: there is no mammalian efficacy, pharmacokinetic or safety data, and its disruption of nuclear stress bodies suppresses a physiological splicing process, which is a mechanism-level liability rather than a hypothetical one.

Mechanism Target:

Nuclear (UGGAA)n RNA Foci in Purkinje Cells — NCD binds the repeat RNA and disperses the foci built on it.

Show evidence (1 reference)

PMID:33431896 SUPPORT In Vitro

"Biological studies show that NCD disrupts naturally occurring RNA foci built on r(UGGAA)n repeat RNA known as nuclear stress bodies (nSBs) by interfering with RNA-protein interactions resulting in the suppression of nSB-mediated splicing events."

The mechanism of action on foci, quoted with the splicing consequence that is also the compound's chief liability.

Show evidence (1 reference)

PMID:33431896 SUPPORT Model Organism

"Feeding NCD to larvae of the Drosophila model of SCA31 alleviates the disease phenotype induced by toxic r(UGGAA)n repeat RNA."

The in vivo result, in the only organism in which the compound has been tested against the SCA31 lesion.

🔬

Diagnosis

3

Targeted repeat-expansion testing for the 16q22.1 insertion

Diagnosis is molecular, and the assay has to be chosen for the lesion. The insertion is large, compositionally complex and intronic, so it is not resolved by standard exome sequencing and a negative exome does not exclude SCA31. Historically the allele was characterized by Southern blot with motif-specific probes, and this remains the method that distinguishes a pathogenic (TGGAA)n-containing insertion from a non-pathogenic control insertion of comparable size. Fragment-length methods that report only insertion size cannot make that distinction.

Show evidence (2 references)

PMID:20424877 SUPPORT Human Clinical

"These data indicate that control alleles very rarely have a nonpathogenic large insertion in the SCA31 critical region and that not only the presence of the insertion but also its size is not sufficient evidence for a disease-causing allele."

The explicit statement that presence and size of the insertion are insufficient, which is the argument for motif-resolving assays.

PMID:20424877 SUPPORT Human Clinical

"The insertions in normal controls were clearly detected by Southern hybridization using (TAAAA)(5) probe, while they were not labeled with (TGGAA)(5) or (TAGAA)(5) probe."

The motif-specific hybridization result that operationalizes the distinction between a pathogenic and a control insertion.

Cerebellar-predominant MRI with brainstem sparing

MRI supports localization rather than making the diagnosis. The expected pattern is cerebellar atrophy, most marked in the upper vermis, with the brainstem spared, which separates SCA31 from multiple system atrophy of cerebellar type and from the multisystem SCAs, but not from the other pure cerebellar ataxias such as SCA6. A minority of patients do show brainstem or cortical atrophy, so a normal brainstem is not required for the diagnosis.

Show evidence (2 references)

PMID:36319738 SUPPORT Human Clinical

"magnetic resonance imaging showed cerebellar atrophy without brainstem involvement"

The expected imaging pattern in the founding cohorts.

PMID:36563608 SUPPORT INDIRECT Human Clinical

"Upon radiological examination, clinicians can expect a high prevalence of cerebellar atrophy (78.7%), occasionally accompanied by brainstem (9.1%) and cortical (9.1%) atrophy."

Qualifies the preceding claim: brainstem involvement is uncommon but not absent, so its presence does not exclude SCA31.

Recognizing the extracerebellar half of the phenotype

SCA31 is taught as a pure cerebellar ataxia, and the founding Japanese descriptions recorded no pyramidal signs, neuropathy or gaze limitation. The largest pooled review found extracerebellar signs in 52.5% of 374 patients, predominantly dysreflexia, vibratory hypoesthesia and hypoacousia. The practical consequence is that the presence of such signs should not by itself steer a workup away from SCA31, while their attribution to SCA31 in an individual patient in their seventies remains uncertain.

Show evidence (2 references)

PMID:36563608 SUPPORT Human Clinical

"Extracerebellar signs were observed in 52.5% of patients, primarily consisting of dysreflexia, vibratory hypoesthesia and hypoacousia."

The pooled frequency of extracerebellar involvement, which is the finding that complicates the pure-cerebellar characterization.

PMID:36563608 SUPPORT Human Clinical

"The clinical and radiological features of 374 patients issued from 25 studies were collected."

The denominator behind the pooled frequencies used throughout this entry.

📈

Progression

1

Late-onset slowly progressive cerebellar ataxia

Age: Mean onset 58.5 years (SD 10.3); wheelchair dependence near 79 years

SCA31 is among the latest-onset of all the spinocerebellar ataxias. A four-year prospective study of 44 genetically confirmed patients across ten Nagano referral centres measured a SARA progression of 0.8 points per year and a Barthel Index decline of 2.3 points per year, and summarized the averaged course as ataxia onset at 58.5 years, wheelchair dependence at 79.4, and death at 88.5. Shorter disease duration at baseline predicted faster SARA progression. These are cohort means from one region, not individual prognoses, and the cohort's mean age at enrolment was already 73.6 years.

Show evidence (4 references)

PMID:27830516 SUPPORT Human Clinical

"Our study indicated the averaged clinical course of SCA31 as follows: the patients develop ataxic symptoms at 58.5 ± 10.3 years, become wheelchair bound at 79.4 ± 1.7 years, and died at 88.5 ± 0.7 years."

The averaged clinical trajectory from the only prospective natural-history study.

PMID:27830516 SUPPORT Human Clinical

"The annual progression of the SARA score was 0.8 ± 0.1 points/year and that of the BI was -2.3 ± 0.4 points/year"

The quantitative progression rates that would anchor a trial's power calculation.

PMID:27830516 SUPPORT Human Clinical

"we enrolled 44 patients (mean ± standard deviation 73.6 ± 8.5 years) with genetically confirmed SCA31 from 10 ataxia referral centers in the Nagano area, Japan"

The cohort behind those figures, including the enrolment age that constrains how the onset figure should be read.

+ 1 more reference

📊

Prevalence

3

Tottori Prefecture, western Japan

Point Prevalence 1.12 per 100,000 1–9 per 100,000

From a 1998 community-based prevalence study, reported under the disease's earlier name 16q22.1-linked ADCA. This is the only population-based rate available for SCA31, and it is from a single Japanese prefecture; it should not be generalized outside Japan, where the disease is essentially absent.

Show evidence (1 reference)

PMID:17661799 SUPPORT Human Clinical

"In the community-based study, the prevalence of spinocerebellar ataxia 6 (SCA6) and 16q22.1-linked ADCA was 2.4 and 1.12 per 100,000 individuals, respectively."

The community-based point prevalence figure and its comparator.

Autosomal dominant cerebellar ataxia families in Nagano, Japan

Cases In Literature Rare

Not a population prevalence: this is SCA31's share of dominant ataxia families in the endemic Nagano region, where the founder effect is concentrated. Recorded because it is the number most often quoted for SCA31 and is routinely misread as a prevalence.

Show evidence (1 reference)

PMID:20424877 SUPPORT Human Clinical

"SCA31 was highly prevalent in Nagano, Japan, where SCA31 accounts for approximately 42% of ADCA families."

The Nagano share of ADCA families, explicitly a share of a disease population rather than a population rate.

Japan, nationwide

Cases In Literature Rare

SCA31 is ranked the third most frequent SCA in Japan and is one of the most common dominant cerebellar ataxias there, while being essentially absent from other ancestries. Cases reported outside Japan have been in people of Japanese descent, which is the epidemiological signature of the founder effect rather than of a worldwide distribution.

Show evidence (3 references)

PMID:35563872 SUPPORT Other

"It is ranked the third most frequent SCA in Japan (after SCA3 and SCA6), very rarely found in neighboring Asian countries"

The national ranking and the sharp fall-off in neighbouring populations.

PMID:35563872 SUPPORT Other

"SCA31 has also been diagnosed in Brazilian SCA patients with Japanese ancestry, suggesting a strong founder effect"

The diaspora observation that distinguishes a founder effect from a geographically restricted environmental cause.

PMID:36319738 SUPPORT Human Clinical

"SCA31 has a strong founder effect, which is consistent with the fact that this disease is basically absent in other ethnicities."

The founder effect stated directly by the discovering group.

🐁

Animal Models

1

Transgenic expression of expanded (UGGAA)n pentanucleotide repeat RNA Drosophila melanogaster

Transgenic flies expressing expanded (UGGAA)n reproduce the two molecular hallmarks of SCA31, nuclear RNA foci and poly-WNGME PPR protein, and develop compound-eye degeneration, shortened lifespan and progressive locomotor decline, with toxicity scaling with repeat length and expression level. It is the workhorse system for SCA31: the RNA-chaperone rescue by TDP-43, FUS and hnRNPA2B1, the TDP-43 suppression of PPR translation, and the NCD small-molecule result were all obtained in it.

Species

Drosophila melanogaster

Genotype

Transgenic expression of expanded (UGGAA)n pentanucleotide repeat RNA

Publication

PMID:28343865

Pathograph links

Nuclear (UGGAA)n RNA Foci in Purkinje Cells partially recapitulates fidelity: moderate The model reproduces (UGGAA)n foci formation and its dependence on repeat length and expression level.

Limitations: Foci form in fly eye imaginal discs and nervous tissue under a heterologous driver at supraphysiological expression, not in Purkinje cells from an endogenous intronic locus. Drosophila has no cerebellum and no Purkinje cell, so the model cannot address the cell-type selectivity that is the most striking feature of the human disease.

Readouts

Nuclear and cytoplasmic (UGGAA)n RNA foci burden

Direction: INCREASED

Interpretation: Foci accumulation in the fly is the direct counterpart of the foci observed in patient Purkinje cell nuclei.

Show evidence (1 reference)

PMID:28343865 SUPPORT Model Organism

"the expression of UGGAAexp induced toxicity in vivo in a manner dependent on repeat length and gene dosage, accompanied by the accumulation of RNA foci"

Reports the foci accumulation and the length and dosage dependence behind this readout.

Show evidence (1 reference)

PMID:35563872 SUPPORT Other

"flies exhibited a shorter lifespan and progressive locomotive defects with age"

Establishes that the model produces a progressive organismal phenotype, which is what makes it informative for the repeat-RNA node rather than a purely cell-biological readout.

Repeat-Associated Translation of poly-WNGME Pentapeptide Protein recapitulates fidelity: moderate The fly produces the same poly-WNGME PPR protein detected in patient Purkinje cells, and PPR level tracks the severity of eye degeneration.

Limitations: PPR protein in the fly is predominantly cytoplasmic in eye imaginal disc cells, whereas in patients it is granular material in Purkinje cell bodies and dendrites; and the translation route remains unresolved in both systems, so the model cannot yet be used to test an intervention specific to repeat-associated non-AUG translation.

Readouts

poly-WNGME PPR protein level

Direction: INCREASED

Interpretation: PPR protein accumulation in the model matched by its detection in SCA31 patient brain.

Show evidence (1 reference)

PMID:28343865 SUPPORT Model Organism

"we observed an accumulation of UGGAAexp-encoded pentapeptide (Trp-Asn-Gly-Met-Glu) repeat (PPR) proteins in Drosophila and SCA31 human brains"

The measurement in both the model and human brain, which is what makes this readout translationally anchored.

Show evidence (1 reference)

PMID:28343865 SUPPORT Model Organism

"These findings expand the growing list of microsatellite expansion disorders in which repeat-associated translation occurs, and support a dual-toxicity mechanism of repeat RNAs and PPR proteins in neurodegeneration."

The authors' summary of what the model establishes about the translation arm.

{ }

Source YAML

click to show

name: Spinocerebellar Ataxia Type 31
creation_date: "2026-09-02T13:40:00Z"
description: >-
  SCA31 is an adult-onset, slowly progressive, autosomal dominant cerebellar
  ataxia caused by a 2.5-3.8 kb insertion of complex pentanucleotide repeats at
  chromosome 16q22.1, in an intronic segment shared by BEAN1 and TK2, which are
  transcribed in opposite directions. Of the several motifs in the insertion,
  only (TGGAA)n segregates with disease; the others occur in controls. The
  proposed mechanism is a toxic RNA gain of function rather than
  haploinsufficiency: the brain-restricted BEAN1-direction transcript (UGGAA)n
  forms nuclear RNA foci in Purkinje cells, binds RNA-binding and splicing
  proteins, and is additionally translated into a repeat-encoded poly-WNGME
  pentapeptide protein detected in patient Purkinje cells. The disease has a
  strong Japanese founder effect and is essentially absent from other
  ancestries. Clinically it is a relatively pure cerebellar syndrome with onset
  near 60 years, though a large literature review found extracerebellar signs in
  about half of patients.
category: Mendelian
parents:
- Hereditary cerebellar ataxia
- Neurodegenerative Disease
synonyms:
- SCA31
- spinocerebellar ataxia 31
- spinocerebellar ataxia, 16q22-linked
- 16q22.1-linked autosomal dominant cerebellar ataxia
- 16q-ADCA
disease_term:
  preferred_term: spinocerebellar ataxia type 31
  term:
    id: MONDO:0007296
    label: spinocerebellar ataxia type 31
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      Placed with the neurological disorders as a hereditary cerebellar ataxia.
      Harrison's does not list SCA31 individually; this is a mechanism- and
      system-based placement.
references:
- reference: PMID:19878914
  title: "Spinocerebellar ataxia type 31 is associated with \"inserted\" penta-nucleotide repeats containing (TGGAA)n."
- reference: PMID:36319738
  title: "Spinocerebellar ataxia type 31 (SCA31)."
- reference: PMID:35563872
  title: "Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions."
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    SCA31 is autosomal dominant with adult onset, so penetrance is strongly
    age-dependent; a precise age-specific penetrance curve has not been
    published. The insertion length correlates inversely with age at onset, and
    the original report documented an expansion in one family showing
    anticipation. Later systematic sizing across parent-child pairs found the
    insertion changeable but not markedly unstable in either direction, so
    anticipation should not be assumed as a general property of the locus.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:19878914
    reference_title: "Spinocerebellar ataxia type 31 is associated with \"inserted\" penta-nucleotide repeats containing (TGGAA)n."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spinocerebellar ataxia type 31 (SCA31) is an adult-onset
      autosomal-dominant neurodegenerative disorder showing progressive
      cerebellar ataxia mainly affecting Purkinje cells.
    explanation: >-
      Establishes dominant inheritance, adult onset, and the Purkinje-predominant
      target of the disease.
  - reference: PMID:19878914
    reference_title: "Spinocerebellar ataxia type 31 is associated with \"inserted\" penta-nucleotide repeats containing (TGGAA)n."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The SCA31 repeat insertion's length inversely correlated with patient age
      of onset, and an expansion was documented in a single family showing
      anticipation.
    explanation: >-
      The length-onset relationship and the single documented instance of
      anticipation, which is quoted as the n = 1 observation it is.
  - reference: PMID:28638142
    reference_title: "Inter-generational instability of inserted repeats during transmission in spinocerebellar ataxia type 31."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We consider that the length of the inserted repeats in SCA31 is changeable
      during transmission, but inter-generational instability is not marked, as
      far as the current sizing method can determine.
    explanation: >-
      Quoted with the authors' methodological caveat, and marked INDIRECT
      because it qualifies rather than confirms the anticipation claim above;
      the limitation is a property of the sizing assay rather than of the
      biology.
pathophysiology:
- name: BEAN1/TK2 Intronic (TGGAA)n Pentanucleotide Repeat Insertion
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cerebellar_purkinje_degeneration#Cerebellar Neuron Insult"
  description: >-
    The causative lesion is a 2.5-3.8 kb insertion of complex pentanucleotide
    repeats at 16q22.1, located in an intronic segment shared by BEAN1 and TK2.
    The insertion contains (TGGAA)n, (TAGAA)n, (TAAAA)n and (TAAAATAGAA)n, but
    only (TGGAA)n segregates with the disease: the other motifs are encountered
    in control Japanese chromosomes, and the rare control insertions lack the
    (TGGAA)n stretch. This is the disorder-specific substitution this entry
    makes against the generic molecular lesion of the conserved
    Purkinje-degeneration module.

    Two negatives matter for interpretation. Insertion size alone does not
    establish pathogenicity, because control alleles can also carry a large
    insertion; the (TGGAA)n content does. And the lesion is intronic and far
    larger than an exome read, so standard exome sequencing does not exclude it.
  genes:
  - preferred_term: BEAN1
    term:
      id: hgnc:24160
      label: BEAN1
  - preferred_term: TK2
    term:
      id: hgnc:11831
      label: TK2
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  evidence:
  - reference: PMID:19878914
    reference_title: "Spinocerebellar ataxia type 31 is associated with \"inserted\" penta-nucleotide repeats containing (TGGAA)n."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The other was an insertion, from 2.5-3.8 kb long, consisting of complex
      penta-nucleotide repeats including a long (TGGAA)n stretch.
    explanation: The original identification of the causal insertion and its size range.
  - reference: PMID:19878914
    reference_title: "Spinocerebellar ataxia type 31 is associated with \"inserted\" penta-nucleotide repeats containing (TGGAA)n."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In controls, shorter (1.5-2.0 kb) insertions lacking (TGGAA)n were found
      only rarely.
    explanation: >-
      Establishes that the discriminating feature is the (TGGAA)n content rather
      than the presence of an insertion.
  - reference: PMID:31755042
    reference_title: "Molecular Mechanisms and Future Therapeutics for Spinocerebellar Ataxia Type 31 (SCA31)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By comparing various pentanucleotide repeats in this particular locus
      among control Japanese and Caucasian populations, it was found that
      (TGGAA)n was the only sequence segregating with SCA31, strongly suggesting
      the pathogenicity of (TGGAA)n.
    explanation: >-
      The cross-population comparison that isolates (TGGAA)n from the other
      motifs in the same insertion.
  - reference: PMID:36319738
    reference_title: "Spinocerebellar ataxia type 31 (SCA31)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the complex penta-nucleotide repeat lies in an intronic segment shared by
      two genes, BEAN1 (brain expressed, associated with Nedd4) and TK2
      (thymidine kinase 2) transcribed in mutually opposite directions
    explanation: >-
      The genomic architecture that makes the repeat bidirectionally
      transcribed, which is what the next node depends on.
  downstream:
  - target: Bidirectional Transcription of the Repeat into (UGGAA)n Repeat RNA
    causal_link_type: DIRECT
    description: >-
      Because the insertion sits in an intron shared by two oppositely
      transcribed genes, it is transcribed from both strands, and the
      BEAN1-direction transcript is confined to brain.
    evidence:
    - reference: PMID:36319738
      reference_title: "Spinocerebellar ataxia type 31 (SCA31)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        While TK2 is ubiquitously expressed, BEAN1 is transcribed only in the
        brain. Thus, the complex repeat is bi-directionally transcribed
        exclusively in the brain, as two independent non-coding repeats.
      explanation: >-
        States the bidirectional transcription and the brain restriction of the
        BEAN1-direction transcript, which is the step this edge asserts.
- name: Bidirectional Transcription of the Repeat into (UGGAA)n Repeat RNA
  biological_scale: MOLECULAR
  description: >-
    The insertion is transcribed as two independent non-coding repeat RNAs:
    (UGGAA)n in the BEAN1 direction, brain-restricted, and (UUCCA)n in the TK2
    direction, ubiquitous. The (UGGAA)n species is treated as the pathogenic one
    on three grounds: BEAN1 is brain-only while the disease is confined to the
    nervous system, RNA foci in patient Purkinje cells are detected only in the
    BEAN1 direction with no antisense foci, and the BEAN1-direction transcript
    is the more toxic of the two in cultured cells.

    This node also carries the reason the entry does not model a
    loss-of-function mechanism: BEAN1, TK2 and neighbouring gene expression and
    splicing are comparable between patient and control cerebella, so
    haploinsufficiency is not the primary route. That negative comes with its
    own caveat, quoted below, because bulk cerebellar measurement averages over
    a tissue in which Purkinje cells are a small minority.
  biological_processes:
  - preferred_term: transcription of the intronic pentanucleotide repeat
    term:
      id: GO:0006351
      label: DNA-templated transcription
  evidence:
  - reference: PMID:23607545
    reference_title: "Abnormal RNA structures (RNA foci) containing a penta-nucleotide repeat (UGGAA)n in the Purkinje cell nucleus is associated with spinocerebellar ataxia type 31 pathogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In both transiently and stably expressed cultured cell models, we also
      find that the mutation transcribed in the BEAN1-direction yields more
      toxicity than control transcripts
    explanation: >-
      Direct comparison establishing that the BEAN1-direction transcript is the
      toxic species in a cell model.
  - reference: PMID:35563872
    reference_title: "Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Haploinsufficiency may not be a major contributor to SCA31 pathology,
      since the mRNA expression and splicing levels of BEAN1, TK2, or other
      nearby genes are similar in control and patient cerebella
    explanation: >-
      The negative result that argues against a loss-of-function mechanism.
      Evidence source is OTHER because this is a review restating the primary
      expression data.
  - reference: PMID:35563872
    reference_title: "Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      It should be noted that the above observations are largely based on
      cell-type averaging, given that Purkinje cells are the only affected
      neurons in SCA31 and that they represent a small fraction of total
      cerebellar mass.
    explanation: >-
      Curated deliberately as the reviewers' own caveat on the
      haploinsufficiency negative above: it means that negative is weaker than a
      bulk-tissue result appears. Marked INDIRECT because it bears on the claim
      by limiting the preceding evidence rather than by testing the claim.
  downstream:
  - target: Nuclear (UGGAA)n RNA Foci in Purkinje Cells
    causal_link_type: DIRECT
    description: >-
      The transcribed repeat RNA folds into abnormal structures that accumulate
      as nuclear foci.
    evidence:
    - reference: PMID:19878914
      reference_title: "Spinocerebellar ataxia type 31 is associated with \"inserted\" penta-nucleotide repeats containing (TGGAA)n."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The repeat insertion was located in introns of TK2 and BEAN (brain
        expressed, associated with Nedd4) expressed in the brain and formed RNA
        foci in the nuclei of patients' Purkinje cells.
      explanation: >-
        The original observation linking the transcribed insertion to nuclear
        foci in the target cell.
  - target: Repeat-Associated Translation of poly-WNGME Pentapeptide Protein
    causal_link_type: DIRECT
    description: >-
      The same repeat RNA is also translated into a pentapeptide repeat protein.
      This is a branch, not a step in series with foci formation: the two
      products of the transcript are curated as parallel toxic species.
    evidence:
    - reference: PMID:28343865
      reference_title: "Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we observed an accumulation of UGGAAexp-encoded pentapeptide
        (Trp-Asn-Gly-Met-Glu) repeat (PPR) proteins in Drosophila and SCA31
        human brains
      explanation: >-
        Establishes that the transcript is translated into PPR protein in both
        the fly model and human SCA31 brain.
- name: Nuclear (UGGAA)n RNA Foci in Purkinje Cells
  biological_scale: CELLULAR
  description: >-
    The (UGGAA)n transcript accumulates as discrete nuclear RNA foci in
    cerebellar Purkinje cells of SCA31 patients and not in controls. The foci
    are confined to Purkinje cell nuclei, are not seen in other neurons or in
    glia, are detected in roughly 30% of patient Purkinje cells examined, and
    measure about 0.2 to 1.8 micrometres. In the SCA31 fly model the number of
    foci tracks with disease severity, which is the closest available link
    between foci burden and outcome.

    A precise reading of what the human data show: the foci are associated with
    Purkinje cell degeneration. That is the word the neuropathology paper uses,
    and this entry keeps it. Whether foci formation is the proximal cause of the
    degeneration, or an accompanying marker of the toxic transcript, is not
    settled by an association in fixed tissue.
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  cellular_components:
  - preferred_term: nuclear (UGGAA)n RNA focus
    term:
      id: GO:0035770
      label: ribonucleoprotein granule
  evidence:
  - reference: PMID:23607545
    reference_title: "Abnormal RNA structures (RNA foci) containing a penta-nucleotide repeat (UGGAA)n in the Purkinje cell nucleus is associated with spinocerebellar ataxia type 31 pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We find that the RNA foci containing (UGGAA)n are indeed observed in PC
      nuclei of both SCA31 patients, whereas similar foci were not observed in
      control individuals.
    explanation: >-
      The human demonstration of foci with the control comparison that makes it
      disease-specific.
  - reference: PMID:35563872
    reference_title: "Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These SCA31 RNA foci were only detected in the BEAN1-direction (no
      anti-sense foci), ranged from 0.2 to 1.8 µm in diameter, and accumulated
      in the nuclei of Purkinje cells
    explanation: >-
      Gives the strand specificity, the size range, and the cell-type
      restriction of the foci.
  - reference: PMID:35563872
    reference_title: "Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      fluorescent in situ hybridization (FISH) assays detected RNA foci in
      approximately 30% of patient Purkinje cells
    explanation: >-
      Quantifies the proportion of Purkinje cells bearing foci, which is what
      makes the burden a partial rather than universal cellular phenotype.
  - reference: PMID:28343865
    reference_title: "Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the number of RNA foci clearly correlated with disease severity in the
      SCA31 Drosophila model
    explanation: >-
      A correlation in the fly model, and the only quantitative link between
      foci burden and severity anywhere. Marked INDIRECT because it is not a
      human result and reaches the human claim only by analogy.
  downstream:
  - target: Binding and Redistribution of RNA-Binding and Splicing Factors
    causal_link_type: DIRECT
    description: >-
      Foci built on the repeat RNA engage RNA-binding proteins, including
      splicing factors, and alter their availability.
    evidence:
    - reference: PMID:31755042
      reference_title: "Molecular Mechanisms and Future Therapeutics for Spinocerebellar Ataxia Type 31 (SCA31)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In fact, TDP-43 was found to co-localize with RNA foci in human SCA31
        Purkinje cells.
      explanation: >-
        The human co-localization result, which is the direct evidence that the
        foci and the RNA-binding proteins are in the same place.
  - target: Purkinje Cell Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Foci are associated with Purkinje cell degeneration in patient cerebella.
      The edge is typed as indirect with unknown intermediates because the
      association is the whole of the human evidence.
    evidence:
    - reference: PMID:23607545
      reference_title: "Abnormal RNA structures (RNA foci) containing a penta-nucleotide repeat (UGGAA)n in the Purkinje cell nucleus is associated with spinocerebellar ataxia type 31 pathogenesis."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we conclude that the RNA foci containing BEAN1-direction transcript
        (UGGAA)n are associated with PC degeneration in SCA31
      explanation: >-
        Quoted with the authors' own word: they conclude association, not
        causation, so the quote reaches this causal edge only by inference and
        is marked INDIRECT.
- name: Binding and Redistribution of RNA-Binding and Splicing Factors
  biological_scale: MOLECULAR
  role: amplifier
  description: >-
    (UGGAA)n binds a defined set of RNA-binding proteins. The original report
    showed by electrophoretic mobility-shift assay that the serine/arginine-rich
    splicing factors SRSF1 and SRSF9 (published under the older SFRS1/SFRS9
    names) bind the repeat in vitro. Later pulldown from nuclear extract
    confirmed sequence-specific co-precipitation of TDP-43, HNRNPM, SRSF9 and
    FUS with r(UGGAA)20 but not with the antisense sequence, and TDP-43 was
    shown to co-localize with foci in human SCA31 Purkinje cells.

    The direction of the effect is not the simple sequestration story it first
    resembles, and this is the most consequential nuance in SCA31 mechanism.
    TDP-43, FUS and hnRNPA2B1 do not merely get trapped: they act as RNA
    chaperones, and raising their level suppresses rather than worsens (UGGAA)n
    toxicity in Drosophila. So this node is curated as an alteration of the
    RNA-protein equilibrium rather than as loss of splicing-factor function, and
    no splicing target has been shown mis-spliced in human SCA31 cerebellum.
  molecular_functions:
  - preferred_term: (UGGAA)n repeat RNA binding by splicing factors and RNA chaperones
    term:
      id: GO:0003723
      label: RNA binding
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: spliceosomal mRNA splicing
    term:
      id: GO:0000398
      label: mRNA splicing, via spliceosome
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:19878914
    reference_title: "Spinocerebellar ataxia type 31 is associated with \"inserted\" penta-nucleotide repeats containing (TGGAA)n."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      An electrophoretic mobility-shift assay showed that essential splicing
      factors, serine/arginine-rich splicing factors SFRS1 and SFRS9, bind to
      (UGGAA)n in vitro.
    explanation: >-
      The original splicing-factor binding result. Note the gene symbols are the
      pre-2010 SFRS1/SFRS9 names for SRSF1 and SRSF9.
  - reference: PMID:33431896
    reference_title: "Small molecule targeting r(UGGAA)(n) disrupts RNA foci and alleviates disease phenotype in Drosophila model."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Among RBPs we have tested, TDP-43, heterogeneous nuclear ribonucleoprotein
      M (HNRNPM), serine and arginine rich splicing factor 9 (SRSF9), and FUS
      were co-precipitated with the r(UGGAA)20, but not with the antisense
      sequence r(UUCCA)20
    explanation: >-
      Independent confirmation of SRSF9 binding, with the antisense control that
      makes the interaction sequence-specific.
  - reference: PMID:28343865
    reference_title: "Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We revealed that motor-neuron disease (MND)-linked RNA-binding proteins
      (RBPs), TDP-43, FUS, and hnRNPA2B1, bind to and induce structural
      alteration of UGGAAexp.
    explanation: >-
      Establishes binding plus a structural effect on the repeat RNA, which is
      what distinguishes chaperoning from passive sequestration.
  - reference: PMID:31755042
    reference_title: "Molecular Mechanisms and Future Therapeutics for Spinocerebellar Ataxia Type 31 (SCA31)."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found that the toxicity of (UGGAA)n is length- and expression
      level-dependent, and it was dampened by co-expressing TDP-43, FUS, and
      hnRNP A2/B1.
    explanation: >-
      The rescue direction: more RNA-binding protein means less toxicity, which
      is why this node is not curated as simple loss of splicing-factor
      function.
  downstream:
  - target: Purkinje Cell Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disturbance of the repeat-RNA and RNA-binding-protein equilibrium is
      proposed as a route to Purkinje cell toxicity. The rescue experiments are
      in Drosophila and the human transcript targets are undefined, so the
      intervening steps are not established.
    evidence:
    - reference: PMID:36319738
      reference_title: "Spinocerebellar ataxia type 31 (SCA31)."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Subsequent investigation by over-expressing (UGGAA)n in Drosophila
        revealed that the RNA containing (UGGAA)n exerts toxicity in a length-
        and expression level-dependent manner, whereas its toxicity could be
        dampened by (UGGAA)n-binding proteins, TDP-43, FUS and hnRNP A2/B1.
      explanation: >-
        Establishes that the RNA-protein balance governs toxicity in a fly, not
        that this is the route to Purkinje cell loss in patients, so it reaches
        this edge only by species inference.
- name: Repeat-Associated Translation of poly-WNGME Pentapeptide Protein
  biological_scale: MOLECULAR
  description: >-
    The repeat RNA is translated into a pentapeptide repeat protein, poly-WNGME
    (Trp-Asn-Gly-Met-Glu), which accumulates as granular material in the cell
    bodies and dendrites of patient Purkinje cells and in the fly model. Whether
    this proceeds by repeat-associated non-AUG translation or by conventional
    AUG-initiated translation is explicitly unresolved: unlike most
    repeat-expansion disorders, the TGGAA repeat itself contains an AUG codon,
    and the flanking TAAAA and TAGAA sequences supply stop codons, so all three
    reading frames of the repeat yield the same product.

    In the fly, raising TDP-43 suppresses PPR protein production as well as foci
    formation, so the two toxic arms are not independently regulated.
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  biological_processes:
  - preferred_term: repeat-associated translation of the pentanucleotide repeat
    term:
      id: GO:0006412
      label: translation
    modifier: ABNORMAL
  evidence:
  - reference: PMID:28343865
    reference_title: "Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      expression of expanded UGGAA (UGGAAexp) repeats, responsible for
      spinocerebellar ataxia type 31 (SCA31) in Drosophila, causes
      neurodegeneration accompanied by accumulation of UGGAAexp RNA foci and
      translation of repeat-associated pentapeptide repeat (PPR) proteins,
      consistent with observations in SCA31 patient brains
    explanation: >-
      Couples the fly result to the human observation and names both toxic
      products of the transcript.
  - reference: PMID:28343865
    reference_title: "Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Whether the PPR protein was generated through RAN translation or
      conventional AUG translation is currently unclear.
    explanation: >-
      Curated on purpose: the authors decline to attribute the product to RAN
      translation, and SCA31 is often described as a RAN-translation disorder
      without that caveat. Marked INDIRECT because it bounds the node's claim
      rather than supporting it positively.
  - reference: PMID:28343865
    reference_title: "Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Translation of the UGGAA repeat in all frames would thus result in the
      production of an identical PPR protein, poly-WNGME
    explanation: >-
      The sequence-level reason SCA31 produces a single PPR species rather than
      the frame-dependent set seen in other repeat disorders.
  downstream:
  - target: Purkinje Cell Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      PPR protein is present in patient Purkinje cells and its level tracks
      degeneration severity in the fly eye, but no experiment has isolated its
      contribution from that of the repeat RNA in a mammalian system.
    evidence:
    - reference: PMID:28343865
      reference_title: "Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        support a dual-toxicity mechanism of repeat RNAs and PPR proteins in
        neurodegeneration
      explanation: >-
        The authors frame dual toxicity as what the data support, without
        apportioning the contribution, so this backs the edge's existence rather
        than its weight.
- name: Purkinje Cell Degeneration
  biological_scale: TISSUE
  role: central_effector
  conforms_to: "cerebellar_purkinje_degeneration#Purkinje Neuron Degeneration"
  description: >-
    The tissue lesion is a Purkinje-cell-restricted degeneration of the
    cerebellar cortex, with the cerebrum, brainstem and spinal cord appearing
    normal. Purkinje cells fall in number and shrink, and the surviving cells
    are characteristically surrounded by halo-like amorphous material made of
    calbindin-positive somatic sprouts and synaptophysin-positive presynaptic
    terminals: that is, an aberrant reinnervation of the shrinking soma rather
    than a deposit of aggregated protein. Ubiquitin-positive degradation
    granules and fragmentation of the Golgi apparatus are enriched in the same
    cells. Detailed morphological work separates two degenerative processes:
    shrinkage with the halo, which carries the bent, elongated, folded nuclei
    and the Golgi fragmentation and is considered specific to SCA31, and
    shrinkage without it.

    This entry does not declare conformance to the module's Purkinje calcium and
    proteostasis node. Golgi fragmentation and ubiquitin-positive granules are
    proteostasis-adjacent findings, but nothing bearing on Purkinje calcium
    handling has been measured in SCA31, in patients or in a mammalian model,
    and the module node asserts both.
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  cellular_components:
  - preferred_term: fragmented Golgi apparatus
    term:
      id: GO:0005794
      label: Golgi apparatus
  evidence:
  - reference: PMID:24344778
    reference_title: "Distinctive features of degenerating Purkinje cells in spinocerebellar ataxia type 31."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neuropathologically, cerebellar Purkinje cells are preferentially affected
      and reduced in number in SCA31, and they are often surrounded by halo-like
      amorphous materials.
    explanation: The core neuropathological finding and its signature structure.
  - reference: PMID:24344778
    reference_title: "Distinctive features of degenerating Purkinje cells in spinocerebellar ataxia type 31."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Correspondingly, fragmentation of the Golgi apparatus was observed more
      frequently in Purkinje cells with the halo-like structure than in those
      without this structure.
    explanation: >-
      Ties the Golgi finding specifically to the halo-bearing subpopulation,
      which is why the two degenerative processes are described separately.
  - reference: PMID:35563872
    reference_title: "Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Histologically, the cerebrum, brainstem, and spinal cord all appear normal
      in SCA31 patients, while the cerebellar cortex shows signs of degeneration
    explanation: >-
      The anatomical restriction of the lesion, which is what makes SCA31 a pure
      cerebellar degeneration pathologically as well as clinically.
  - reference: PMID:23607545
    reference_title: "Abnormal RNA structures (RNA foci) containing a penta-nucleotide repeat (UGGAA)n in the Purkinje cell nucleus is associated with spinocerebellar ataxia type 31 pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathologically, we confirm that the PC is the main target of SCA31
      pathogenesis.
    explanation: Independent confirmation of the Purkinje-predominant target.
  downstream:
  - target: Cerebellar Cortical Atrophy
    causal_link_type: DIRECT
    description: >-
      Loss and shrinkage of Purkinje cells with cortical degeneration produces
      the atrophy seen on imaging.
    evidence:
    - reference: PMID:36319738
      reference_title: "Spinocerebellar ataxia type 31 (SCA31)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        magnetic resonance imaging showed cerebellar atrophy without brainstem
        involvement
      explanation: >-
        The imaging counterpart of the cerebellar-restricted pathology.
- name: Cerebellar Cortical Atrophy
  biological_scale: TISSUE
  description: >-
    Cerebellar atrophy, most marked in the upper vermis, with the brainstem
    relatively spared. In the pooled literature review it was present in 78.7%
    of imaged patients; brainstem and cortical atrophy were each reported in
    9.1%, which is the imaging counterpart of the extracerebellar signs curated
    among the phenotypes.
  evidence:
  - reference: PMID:36563608
    reference_title: "Spinocerebellar ataxia type 31: A clinical and radiological literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Upon radiological examination, clinicians can expect a high prevalence of
      cerebellar atrophy (78.7%), occasionally accompanied by brainstem (9.1%)
      and cortical (9.1%) atrophy.
    explanation: >-
      The pooled imaging frequencies across 374 patients, including the minority
      with extracerebellar atrophy.
  downstream:
  - target: Progressive Cerebellar Ataxia
    causal_link_type: DIRECT
    description: >-
      Loss of cerebellar cortical output produces the clinical syndrome.
    evidence:
    - reference: PMID:35563872
      reference_title: "Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Clinical features of SCA31 include truncal and limb ataxia, cerebellar
        speech, and reduced muscle tonus
      explanation: The clinical consequence of the cerebellar lesion.
- name: Progressive Cerebellar Ataxia
  biological_scale: ORGANISM
  role: consequence
  conforms_to: "cerebellar_purkinje_degeneration#Cerebellar Ataxia"
  description: >-
    The clinical endpoint: late-onset, slowly progressive truncal and limb
    ataxia with cerebellar dysarthria, classically without pyramidal signs,
    neuropathy or gaze limitation.
  evidence:
  - reference: PMID:36319738
    reference_title: "Spinocerebellar ataxia type 31 (SCA31)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features of SCA31 were summarized as, late-onset (average around
      60 years old), slowly progressive ataxia. Extra-cerebellar features such
      as pyramidal tract signs, neuropathy or gaze limitations were not
      detected.
    explanation: >-
      The classical description of the syndrome. Note that the pooled review
      curated elsewhere in this entry found extracerebellar signs in about half
      of patients, so this characterization is the founding cohorts' rather than
      the whole literature's.
phenotypes:
- name: Gait ataxia
  category: Neurologic
  frequency: VERY_FREQUENT
  description: >-
    Progressive gait and truncal ataxia is the presenting and defining feature,
    with onset near 60 years.
  phenotype_term:
    preferred_term: Gait ataxia
    term:
      id: HP:0002066
      label: Gait ataxia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:36563608
    reference_title: "Spinocerebellar ataxia type 31: A clinical and radiological literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This review revealed that the average age of onset was 59.1 ± 3.3 years,
      with symptoms of slowly progressing ataxia and dysarthria.
    explanation: >-
      Pooled across 374 patients, this establishes ataxia as the core
      manifestation and gives its onset age; the frequency band follows from its
      being the defining feature rather than from a reported percentage.
  - reference: PMID:35563872
    reference_title: "Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinical features of SCA31 include truncal and limb ataxia, cerebellar
      speech, and reduced muscle tonus
    explanation: Names truncal ataxia among the core clinical features.
- name: Limb ataxia
  category: Neurologic
  frequency: VERY_FREQUENT
  description: >-
    Limb ataxia and dysmetria accompany the gait disorder.
  phenotype_term:
    preferred_term: Limb ataxia
    term:
      id: HP:0002070
      label: Limb ataxia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:35563872
    reference_title: "Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinical features of SCA31 include truncal and limb ataxia, cerebellar
      speech, and reduced muscle tonus
    explanation: Names limb ataxia as a core clinical feature.
- name: Dysarthria
  category: Neurologic
  frequency: VERY_FREQUENT
  description: >-
    Cerebellar dysarthria is one of the two symptoms named as core in the pooled
    literature review, alongside ataxia.
  phenotype_term:
    preferred_term: Cerebellar dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:36563608
    reference_title: "Spinocerebellar ataxia type 31: A clinical and radiological literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This review revealed that the average age of onset was 59.1 ± 3.3 years,
      with symptoms of slowly progressing ataxia and dysarthria.
    explanation: Names dysarthria alongside ataxia as the defining symptom pair.
- name: Cerebellar atrophy
  category: Neurologic
  frequency: FREQUENT
  description: >-
    Cerebellar atrophy on MRI, particularly of the upper vermis, with the
    brainstem relatively spared. Present in 78.7% of imaged patients in the
    pooled review, which sits just below the VERY_FREQUENT band.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:36563608
    reference_title: "Spinocerebellar ataxia type 31: A clinical and radiological literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Upon radiological examination, clinicians can expect a high prevalence of
      cerebellar atrophy (78.7%), occasionally accompanied by brainstem (9.1%)
      and cortical (9.1%) atrophy.
    explanation: >-
      Gives the pooled frequency that fixes the FREQUENT band, and the minority
      with brainstem or cortical involvement.
- name: Abnormal eye movement
  category: Neurologic
  frequency: FREQUENT
  description: >-
    Oculomotor dysfunction in 38.8% of the pooled cohort. Bound to the parent
    HPO term rather than to a specific child: the review reports oculomotor
    dysfunction as a category without resolving which abnormality, and the
    founding Japanese descriptions explicitly recorded no gaze limitation.
  phenotype_term:
    preferred_term: Oculomotor dysfunction
    term:
      id: HP:0000496
      label: Abnormality of eye movement
  evidence:
  - reference: PMID:36563608
    reference_title: "Spinocerebellar ataxia type 31: A clinical and radiological literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other common clinical features were oculomotor dysfunction (38.8%),
      dysphagia (22.1%), hypoacousia (23.3%), vibratory hypoesthesia (24.3%),
      and dysreflexia (41.6%).
    explanation: >-
      The pooled frequency for oculomotor dysfunction, quoted with the
      surrounding extracerebellar features it was reported with.
- name: Abnormal reflex
  category: Neurologic
  frequency: FREQUENT
  description: >-
    Dysreflexia was the single most common extracerebellar finding in the pooled
    review, at 41.6%. The HPO binding is deliberately the parent term: the
    review's "dysreflexia" does not say whether reflexes were increased or
    decreased, and SCA31 series report both.
  phenotype_term:
    preferred_term: Dysreflexia
    term:
      id: HP:0031826
      label: Abnormal reflex
  evidence:
  - reference: PMID:36563608
    reference_title: "Spinocerebellar ataxia type 31: A clinical and radiological literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other common clinical features were oculomotor dysfunction (38.8%),
      dysphagia (22.1%), hypoacousia (23.3%), vibratory hypoesthesia (24.3%),
      and dysreflexia (41.6%).
    explanation: The pooled frequency for dysreflexia.
- name: Impaired vibratory sensation
  category: Neurologic
  frequency: OCCASIONAL
  description: >-
    Vibratory hypoesthesia in 24.3% of the pooled cohort. This is an
    extracerebellar sign in a disease described as purely cerebellar, and the
    reviewers themselves caution that the advanced age of SCA31 patients is a
    confounder for signs of this kind.
  phenotype_term:
    preferred_term: Vibratory hypoesthesia
    term:
      id: HP:0002495
      label: Impaired vibratory sensation
  evidence:
  - reference: PMID:36563608
    reference_title: "Spinocerebellar ataxia type 31: A clinical and radiological literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other common clinical features were oculomotor dysfunction (38.8%),
      dysphagia (22.1%), hypoacousia (23.3%), vibratory hypoesthesia (24.3%),
      and dysreflexia (41.6%).
    explanation: The pooled frequency for vibratory hypoesthesia.
  - reference: PMID:36563608
    reference_title: "Spinocerebellar ataxia type 31: A clinical and radiological literature review."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we must consider the old age and longstanding disease course of patients
      as a confounding factor for extracerebellar sign development, as some may
      not be directly attributable to SCA31
    explanation: >-
      Curated on this phenotype because it is exactly the kind of finding the
      caveat is about: vibration sense declines with age independently of SCA31.
      Marked INDIRECT because it qualifies the attribution rather than
      supporting it.
- name: Hearing impairment
  category: Neurologic
  frequency: OCCASIONAL
  description: >-
    Hypoacousia in 23.3% of the pooled cohort. As with vibratory hypoesthesia,
    the reviewers' age-confounding caveat applies directly.
  phenotype_term:
    preferred_term: Hypoacousia
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:36563608
    reference_title: "Spinocerebellar ataxia type 31: A clinical and radiological literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other common clinical features were oculomotor dysfunction (38.8%),
      dysphagia (22.1%), hypoacousia (23.3%), vibratory hypoesthesia (24.3%),
      and dysreflexia (41.6%).
    explanation: The pooled frequency for hypoacousia.
- name: Dysphagia
  category: Neurologic
  frequency: OCCASIONAL
  description: >-
    Dysphagia in 22.1% of the pooled cohort, and a target of the speech and
    swallowing arm of supportive management.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:36563608
    reference_title: "Spinocerebellar ataxia type 31: A clinical and radiological literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other common clinical features were oculomotor dysfunction (38.8%),
      dysphagia (22.1%), hypoacousia (23.3%), vibratory hypoesthesia (24.3%),
      and dysreflexia (41.6%).
    explanation: The pooled frequency for dysphagia.
- name: Cognitive impairment
  category: Neurologic
  frequency: OCCASIONAL
  description: >-
    Cognitive impairment was reported in 6.9% of the pooled cohort, at the low
    edge of the OCCASIONAL band. It is not a defining feature and its
    attribution is complicated by the patients' age.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:36563608
    reference_title: "Spinocerebellar ataxia type 31: A clinical and radiological literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Unfrequently, abnormal movements (7.4%), extrapyramidal symptoms (4.5%)
      and cognitive impairment (6.9%) may be observed.
    explanation: >-
      The pooled frequency, quoted with the reviewers' own framing of these as
      infrequent.
- name: Parkinsonism
  category: Neurologic
  description: >-
    Extrapyramidal symptoms were recorded in 4.5% of the pooled cohort, and
    individual reports describe nigrostriatal dopaminergic dysfunction with
    levodopa-responsive parkinsonism. Frequency is deliberately omitted: 4.5%
    straddles the VERY_RARE and OCCASIONAL band boundary, and the underlying
    reports are case-level rather than a systematic prevalence.
  phenotype_term:
    preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: PMID:35563872
    reference_title: "Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Some patients additionally develop nigrostriatal dopaminergic dysfunction,
      L-DOPA responsive parkinsonism, and blepharospasm followed by ataxic
      dysarthria
    explanation: >-
      Documents the atypical parkinsonian presentation, including its levodopa
      responsiveness, as an occasional feature.
  - reference: PMID:36563608
    reference_title: "Spinocerebellar ataxia type 31: A clinical and radiological literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Unfrequently, abnormal movements (7.4%), extrapyramidal symptoms (4.5%)
      and cognitive impairment (6.9%) may be observed.
    explanation: The pooled frequency for extrapyramidal symptoms.
- name: Hypotonia
  category: Neurologic
  description: >-
    Reduced muscle tone is named among the clinical features in review
    descriptions. No frequency is reported, so none is recorded.
  phenotype_term:
    preferred_term: Reduced muscle tone
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:35563872
    reference_title: "Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinical features of SCA31 include truncal and limb ataxia, cerebellar
      speech, and reduced muscle tonus
    explanation: Names reduced muscle tone among the clinical features.
genetic:
- name: BEAN1
  gene_term:
    preferred_term: BEAN1
    term:
      id: hgnc:24160
      label: BEAN1
  association: Intronic complex pentanucleotide repeat insertion containing (TGGAA)n
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    The disease allele is a heterozygous 2.5-3.8 kb insertion of complex
    pentanucleotide repeats in an intron of BEAN1 at 16q22.1. The insertion
    contains (TGGAA)n, (TAGAA)n, (TAAAA)n and (TAAAATAGAA)n, but only (TGGAA)n
    is disease-specific; the others occur on control chromosomes. Insertion size
    correlates inversely with age at onset but not with the rate of progression
    after onset.

    Interpretation caveats that matter at the bench. Size alone does not make an
    allele pathogenic: about 0.7% of controls in one Nagano series carried
    insertions of 1.0 to 3.5 kb, and those insertions lacked (TGGAA)n at their
    5' end by sequencing and by Southern hybridization. The mechanism is a toxic
    RNA gain of function rather than a coding change in BEAN1, so no
    variant-level protein consequence is recorded here; there is no protein
    product of the repeat to describe.

    A single homozygote has been reported, carrying insertions of about 3.0 and
    4.3 kb, of which only the 3.0 kb allele contained the (TGGAA)n stretch. The
    authors are explicit that whether a large insertion lacking (TGGAA)n is
    non-pathogenic remains undetermined.
  evidence:
  - reference: PMID:19878914
    reference_title: "Spinocerebellar ataxia type 31 is associated with \"inserted\" penta-nucleotide repeats containing (TGGAA)n."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The other was an insertion, from 2.5-3.8 kb long, consisting of complex
      penta-nucleotide repeats including a long (TGGAA)n stretch.
    explanation: The gene-discovery statement describing the causal allele.
  - reference: PMID:20424877
    reference_title: "Analysis of an insertion mutation in a cohort of 94 patients with spinocerebellar ataxia type 31 from Nagano, Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had a 2.6- to 3.7-kb insertion. The size of the insertion was
      inversely correlated with the age at onset but not associated with the
      progression rate after onset.
    explanation: >-
      A 94-patient cohort confirming the allele and separating what size does
      predict (onset) from what it does not (progression rate).
  - reference: PMID:20424877
    reference_title: "Analysis of an insertion mutation in a cohort of 94 patients with spinocerebellar ataxia type 31 from Nagano, Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also found that 3 of 405 control individuals (0.7%) had the insertions
      from 1.0 to 3.5 kb in length.
    explanation: >-
      The control observation that makes insertion size on its own an
      insufficient diagnostic criterion.
  - reference: PMID:20424877
    reference_title: "Analysis of an insertion mutation in a cohort of 94 patients with spinocerebellar ataxia type 31 from Nagano, Japan."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      it remains undetermined whether a large insertion lacking (TGGAA)n is
      nonpathogenic
    explanation: >-
      The authors' own limit on the interpretive rule the rest of their paper
      supports; it bounds the claim rather than establishing it, hence INDIRECT.
  - reference: PMID:35563872
    reference_title: "Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The majority of healthy controls (99.77%) do not have any insertions or,
      on very rare occasions (0.23%), have an insertion without the TGGAA
      repeats.
    explanation: >-
      Quantifies the control allele distribution at the locus across the pooled
      literature.
- name: TK2
  gene_term:
    preferred_term: TK2
    term:
      id: hgnc:11831
      label: TK2
  association: Shares the affected intron; transcribed in the opposite direction
  relationship_type: MODIFIER
  notes: >-
    TK2 is listed here because the repeat insertion lies in an intron it shares
    with BEAN1, and TK2 is therefore the source of the antisense (UUCCA)n
    transcript. This is a locus relationship, not a coding gene-disease
    relationship, and it is emphatically not TK2 deficiency: the recessive
    coding-variant mitochondrial DNA depletion syndrome caused by TK2 is a
    different disease with a different mechanism, and its clinical trials are
    not SCA31 trials. The original report also found a single-nucleotide change
    in a TK2 intron segregating with SCA31, but showed it did not affect
    splicing or expression, so it is not curated as causal. The relationship
    type is MODIFIER rather than CAUSATIVE for that reason: the gene contributes
    the antisense transcript and the shared intron, not the causal lesion.
  evidence:
  - reference: PMID:19878914
    reference_title: "Spinocerebellar ataxia type 31 is associated with \"inserted\" penta-nucleotide repeats containing (TGGAA)n."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One was a single-nucleotide change in an intron of the thymidine kinase 2
      gene (TK2). However, this did not appear to affect splicing or expression
      patterns.
    explanation: >-
      Records the co-segregating TK2 intronic variant and the reason the
      original authors set it aside.
  - reference: PMID:36319738
    reference_title: "Spinocerebellar ataxia type 31 (SCA31)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While TK2 is ubiquitously expressed, BEAN1 is transcribed only in the
      brain.
    explanation: >-
      The expression difference that makes the BEAN1-direction transcript, not
      the TK2-direction one, the plausible pathogenic species.
prevalence:
- population: Tottori Prefecture, western Japan
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.12
  notes: >-
    From a 1998 community-based prevalence study, reported under the disease's
    earlier name 16q22.1-linked ADCA. This is the only population-based rate
    available for SCA31, and it is from a single Japanese prefecture; it should
    not be generalized outside Japan, where the disease is essentially absent.
  evidence:
  - reference: PMID:17661799
    reference_title: "Clinical and genetic epidemiological study of 16q22.1-linked autosomal dominant cerebellar ataxia in western Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the community-based study, the prevalence of spinocerebellar ataxia 6
      (SCA6) and 16q22.1-linked ADCA was 2.4 and 1.12 per 100,000 individuals,
      respectively.
    explanation: The community-based point prevalence figure and its comparator.
- population: Autosomal dominant cerebellar ataxia families in Nagano, Japan
  measure_type: CASES_IN_LITERATURE
  prevalence_class: RARE
  notes: >-
    Not a population prevalence: this is SCA31's share of dominant ataxia
    families in the endemic Nagano region, where the founder effect is
    concentrated. Recorded because it is the number most often quoted for SCA31
    and is routinely misread as a prevalence.
  evidence:
  - reference: PMID:20424877
    reference_title: "Analysis of an insertion mutation in a cohort of 94 patients with spinocerebellar ataxia type 31 from Nagano, Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SCA31 was highly prevalent in Nagano, Japan, where SCA31 accounts for
      approximately 42% of ADCA families.
    explanation: >-
      The Nagano share of ADCA families, explicitly a share of a disease
      population rather than a population rate.
- population: Japan, nationwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: RARE
  notes: >-
    SCA31 is ranked the third most frequent SCA in Japan and is one of the most
    common dominant cerebellar ataxias there, while being essentially absent
    from other ancestries. Cases reported outside Japan have been in people of
    Japanese descent, which is the epidemiological signature of the founder
    effect rather than of a worldwide distribution.
  evidence:
  - reference: PMID:35563872
    reference_title: "Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It is ranked the third most frequent SCA in Japan (after SCA3 and SCA6),
      very rarely found in neighboring Asian countries
    explanation: >-
      The national ranking and the sharp fall-off in neighbouring populations.
  - reference: PMID:35563872
    reference_title: "Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      SCA31 has also been diagnosed in Brazilian SCA patients with Japanese
      ancestry, suggesting a strong founder effect
    explanation: >-
      The diaspora observation that distinguishes a founder effect from a
      geographically restricted environmental cause.
  - reference: PMID:36319738
    reference_title: "Spinocerebellar ataxia type 31 (SCA31)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SCA31 has a strong founder effect, which is consistent with the fact that
      this disease is basically absent in other ethnicities.
    explanation: The founder effect stated directly by the discovering group.
progression:
- phase: Late-onset slowly progressive cerebellar ataxia
  age_range: Mean onset 58.5 years (SD 10.3); wheelchair dependence near 79 years
  notes: >-
    SCA31 is among the latest-onset of all the spinocerebellar ataxias. A
    four-year prospective study of 44 genetically confirmed patients across ten
    Nagano referral centres measured a SARA progression of 0.8 points per year
    and a Barthel Index decline of 2.3 points per year, and summarized the
    averaged course as ataxia onset at 58.5 years, wheelchair dependence at
    79.4, and death at 88.5. Shorter disease duration at baseline predicted
    faster SARA progression. These are cohort means from one region, not
    individual prognoses, and the cohort's mean age at enrolment was already
    73.6 years.
  evidence:
  - reference: PMID:27830516
    reference_title: "Natural History of Spinocerebellar Ataxia Type 31: a 4-Year Prospective Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study indicated the averaged clinical course of SCA31 as follows: the
      patients develop ataxic symptoms at 58.5 ± 10.3 years, become wheelchair
      bound at 79.4 ± 1.7 years, and died at 88.5 ± 0.7 years.
    explanation: The averaged clinical trajectory from the only prospective natural-history study.
  - reference: PMID:27830516
    reference_title: "Natural History of Spinocerebellar Ataxia Type 31: a 4-Year Prospective Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The annual progression of the SARA score was 0.8 ± 0.1 points/year and
      that of the BI was -2.3 ± 0.4 points/year
    explanation: >-
      The quantitative progression rates that would anchor a trial's power
      calculation.
  - reference: PMID:27830516
    reference_title: "Natural History of Spinocerebellar Ataxia Type 31: a 4-Year Prospective Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we enrolled 44 patients (mean ± standard deviation 73.6 ± 8.5 years) with
      genetically confirmed SCA31 from 10 ataxia referral centers in the Nagano
      area, Japan
    explanation: >-
      The cohort behind those figures, including the enrolment age that
      constrains how the onset figure should be read.
  - reference: PMID:35563872
    reference_title: "Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The age of onset for SCA31 is 58.5 ± 10.3 years, making it the latest to
      manifest of all SCAs
    explanation: Places SCA31's onset age relative to the other spinocerebellar ataxias.
histopathology:
- name: Purkinje cell loss with halo-like amorphous perisomatic material
  diagnostic: false
  description: >-
    The signature SCA31 finding. Surviving Purkinje cells are surrounded by
    halo-like amorphous material composed of calbindin-positive somatic sprouts
    and synaptophysin-positive presynaptic terminals innervated from basket
    cells, inferior olivary neurons and other Purkinje cell afferents. The halo
    is therefore aberrant perisomatic reinnervation, not a protein aggregate,
    which distinguishes SCA31 from the inclusion-body pathology of the
    polyglutamine ataxias. Ubiquitin-positive degradation granules and Golgi
    fragmentation are enriched in the same cells, and the halo-bearing cells
    carry bent, elongated, folded nuclei while cells without the halo shrink
    with slender condensed nuclei.

    No finding_term is bound. HistopathologyFindingTerm is reachable only from
    the NCIT Histopathology Result branch plus a handful of HP rosette terms;
    neither NCIT nor HP names perisomatic sprouting around a degenerating
    Purkinje cell, and binding a generic neuronal-loss term would drop what is
    specific about this finding.
  evidence:
  - reference: PMID:24344778
    reference_title: "Distinctive features of degenerating Purkinje cells in spinocerebellar ataxia type 31."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found that bent, elongated, often folded nuclei were observed
      frequently in degenerating Purkinje cells with the halo-like structure.
    explanation: >-
      The nuclear morphology that accompanies the halo, from direct examination
      of two SCA31 brains.
  - reference: PMID:35563872
    reference_title: "Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These amorphous materials are composed of calbindin-positive somatic
      sprouts (cactus-like formation) and synaptophysin-positive presynaptic
      terminals innervated from basket cells, neurons of the inferior olivary
      nucleus, or other neurons that connect to Purkinje cells
    explanation: >-
      Identifies what the halo is made of, which is what makes it reinnervation
      rather than aggregate.
  - reference: PMID:35563872
    reference_title: "Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Ubiquitin-positive degradation granules and Golgi fragmentation are also
      enriched in the amorphous materials
    explanation: The proteostasis-adjacent findings that accompany the halo.
  - reference: PMID:35563872
    reference_title: "Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In the affected regions, Purkinje cells not only drop in number, but also
      show shrinkage and halo-like amorphous materials surrounding the cells.
    explanation: >-
      States the cell loss and the shrinkage alongside the halo, which are the
      three components of the finding.
diagnosis:
- name: Targeted repeat-expansion testing for the 16q22.1 insertion
  description: >-
    Diagnosis is molecular, and the assay has to be chosen for the lesion. The
    insertion is large, compositionally complex and intronic, so it is not
    resolved by standard exome sequencing and a negative exome does not exclude
    SCA31. Historically the allele was characterized by Southern blot with
    motif-specific probes, and this remains the method that distinguishes a
    pathogenic (TGGAA)n-containing insertion from a non-pathogenic control
    insertion of comparable size. Fragment-length methods that report only
    insertion size cannot make that distinction.
  evidence:
  - reference: PMID:20424877
    reference_title: "Analysis of an insertion mutation in a cohort of 94 patients with spinocerebellar ataxia type 31 from Nagano, Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data indicate that control alleles very rarely have a nonpathogenic
      large insertion in the SCA31 critical region and that not only the
      presence of the insertion but also its size is not sufficient evidence for
      a disease-causing allele.
    explanation: >-
      The explicit statement that presence and size of the insertion are
      insufficient, which is the argument for motif-resolving assays.
  - reference: PMID:20424877
    reference_title: "Analysis of an insertion mutation in a cohort of 94 patients with spinocerebellar ataxia type 31 from Nagano, Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The insertions in normal controls were clearly detected by Southern
      hybridization using (TAAAA)(5) probe, while they were not labeled with
      (TGGAA)(5) or (TAGAA)(5) probe.
    explanation: >-
      The motif-specific hybridization result that operationalizes the
      distinction between a pathogenic and a control insertion.
- name: Cerebellar-predominant MRI with brainstem sparing
  description: >-
    MRI supports localization rather than making the diagnosis. The expected
    pattern is cerebellar atrophy, most marked in the upper vermis, with the
    brainstem spared, which separates SCA31 from multiple system atrophy of
    cerebellar type and from the multisystem SCAs, but not from the other pure
    cerebellar ataxias such as SCA6. A minority of patients do show brainstem or
    cortical atrophy, so a normal brainstem is not required for the diagnosis.
  evidence:
  - reference: PMID:36319738
    reference_title: "Spinocerebellar ataxia type 31 (SCA31)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      magnetic resonance imaging showed cerebellar atrophy without brainstem
      involvement
    explanation: The expected imaging pattern in the founding cohorts.
  - reference: PMID:36563608
    reference_title: "Spinocerebellar ataxia type 31: A clinical and radiological literature review."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Upon radiological examination, clinicians can expect a high prevalence of
      cerebellar atrophy (78.7%), occasionally accompanied by brainstem (9.1%)
      and cortical (9.1%) atrophy.
    explanation: >-
      Qualifies the preceding claim: brainstem involvement is uncommon but not
      absent, so its presence does not exclude SCA31.
- name: Recognizing the extracerebellar half of the phenotype
  description: >-
    SCA31 is taught as a pure cerebellar ataxia, and the founding Japanese
    descriptions recorded no pyramidal signs, neuropathy or gaze limitation. The
    largest pooled review found extracerebellar signs in 52.5% of 374 patients,
    predominantly dysreflexia, vibratory hypoesthesia and hypoacousia. The
    practical consequence is that the presence of such signs should not by
    itself steer a workup away from SCA31, while their attribution to SCA31 in
    an individual patient in their seventies remains uncertain.
  evidence:
  - reference: PMID:36563608
    reference_title: "Spinocerebellar ataxia type 31: A clinical and radiological literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Extracerebellar signs were observed in 52.5% of patients, primarily
      consisting of dysreflexia, vibratory hypoesthesia and hypoacousia.
    explanation: >-
      The pooled frequency of extracerebellar involvement, which is the finding
      that complicates the pure-cerebellar characterization.
  - reference: PMID:36563608
    reference_title: "Spinocerebellar ataxia type 31: A clinical and radiological literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical and radiological features of 374 patients issued from 25
      studies were collected.
    explanation: The denominator behind the pooled frequencies used throughout this entry.
treatments:
- name: Multidisciplinary Rehabilitation
  therapeutic_modality: BEHAVIORAL
  description: >-
    There is no disease-modifying therapy for SCA31, and management is
    supportive: physical therapy for balance, gait and falls prevention,
    occupational therapy and home-safety assessment, and speech and swallowing
    therapy. A seven-year follow-up of annual four-week intensive rehabilitation
    in patients with pure cerebellar SCA6 or SCA31 found SARA scores stable
    through year six, better than the expected natural history, with
    deterioration appearing at year seven; balance measured by the BESTest
    declined earlier, from year three. The study is small (seven patients) and
    mixes SCA6 with SCA31, so it supports rehabilitation as worthwhile
    maintenance rather than as an SCA31-specific intervention with a measured
    effect size.
  treatment_term:
    preferred_term: rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  evidence:
  - reference: PMID:40906249
    reference_title: "Long-Term Effects of Annual Intensive Rehabilitation in Patients with Hereditary Pure Cerebellar Ataxia: A 7-year Follow-up Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Annual intensive rehabilitation effectively slowed the progression of
      ataxic symptoms (SARA) for up to six years, while balance function
      (BESTest) showed a significant decline from the third year.
    explanation: >-
      The primary result, including the divergence between coordination and
      balance outcomes that qualifies it.
  - reference: PMID:40906249
    reference_title: "Long-Term Effects of Annual Intensive Rehabilitation in Patients with Hereditary Pure Cerebellar Ataxia: A 7-year Follow-up Study."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven patients with genetically confirmed SCA6 or SCA31 participated in
      annual 4-week intensive rehabilitation programmes.
    explanation: >-
      The cohort is seven patients pooling two diseases, so it cannot deliver an
      SCA31-specific effect estimate; recorded to bound the claim above.
- name: Naphthyridine Carbamate Dimer (Preclinical)
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    An experimental small molecule, not a treatment. Naphthyridine carbamate
    dimer (NCD) binds the r(UGGAA)n repeat, recognizing four guanines in the
    UGGAA/UGGAA pentad, and disrupts RNA foci and the repeat's interactions with
    TDP-43, HNRNPM and SRSF9. Fed to larvae of the SCA31 Drosophila model it
    alleviates the repeat-induced phenotype. It is curated because it is the
    only compound with a demonstrated effect on the SCA31 lesion and because it
    targets a pathophysiology node directly, not because it is near clinical
    use: there is no mammalian efficacy, pharmacokinetic or safety data, and its
    disruption of nuclear stress bodies suppresses a physiological splicing
    process, which is a mechanism-level liability rather than a hypothetical
    one.
  target_mechanisms:
  - target: Nuclear (UGGAA)n RNA Foci in Purkinje Cells
    description: >-
      NCD binds the repeat RNA and disperses the foci built on it.
    evidence:
    - reference: PMID:33431896
      reference_title: "Small molecule targeting r(UGGAA)(n) disrupts RNA foci and alleviates disease phenotype in Drosophila model."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Biological studies show that NCD disrupts naturally occurring RNA foci
        built on r(UGGAA)n repeat RNA known as nuclear stress bodies (nSBs) by
        interfering with RNA-protein interactions resulting in the suppression
        of nSB-mediated splicing events.
      explanation: >-
        The mechanism of action on foci, quoted with the splicing consequence
        that is also the compound's chief liability.
  evidence:
  - reference: PMID:33431896
    reference_title: "Small molecule targeting r(UGGAA)(n) disrupts RNA foci and alleviates disease phenotype in Drosophila model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Feeding NCD to larvae of the Drosophila model of SCA31 alleviates the
      disease phenotype induced by toxic r(UGGAA)n repeat RNA.
    explanation: >-
      The in vivo result, in the only organism in which the compound has been
      tested against the SCA31 lesion.
animal_models:
- species: Drosophila melanogaster
  genotype: Transgenic expression of expanded (UGGAA)n pentanucleotide repeat RNA
  publication: PMID:28343865
  description: >-
    Transgenic flies expressing expanded (UGGAA)n reproduce the two molecular
    hallmarks of SCA31, nuclear RNA foci and poly-WNGME PPR protein, and develop
    compound-eye degeneration, shortened lifespan and progressive locomotor
    decline, with toxicity scaling with repeat length and expression level. It
    is the workhorse system for SCA31: the RNA-chaperone rescue by TDP-43, FUS
    and hnRNPA2B1, the TDP-43 suppression of PPR translation, and the NCD
    small-molecule result were all obtained in it.
  associated_phenotypes:
  - Compound eye degeneration
  - Shortened lifespan
  - Progressive locomotor defect
  modeled_mechanisms:
  - target: Nuclear (UGGAA)n RNA Foci in Purkinje Cells
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      The model reproduces (UGGAA)n foci formation and its dependence on repeat
      length and expression level.
    limitations: >-
      Foci form in fly eye imaginal discs and nervous tissue under a
      heterologous driver at supraphysiological expression, not in Purkinje
      cells from an endogenous intronic locus. Drosophila has no cerebellum and
      no Purkinje cell, so the model cannot address the cell-type selectivity
      that is the most striking feature of the human disease.
    readouts:
    - name: Nuclear and cytoplasmic (UGGAA)n RNA foci burden
      target: Nuclear (UGGAA)n RNA Foci in Purkinje Cells
      direction: INCREASED
      interpretation: >-
        Foci accumulation in the fly is the direct counterpart of the foci
        observed in patient Purkinje cell nuclei.
      evidence:
      - reference: PMID:28343865
        reference_title: "Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          the expression of UGGAAexp induced toxicity in vivo in a manner
          dependent on repeat length and gene dosage, accompanied by the
          accumulation of RNA foci
        explanation: >-
          Reports the foci accumulation and the length and dosage dependence
          behind this readout.
    evidence:
    - reference: PMID:35563872
      reference_title: "Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        flies exhibited a shorter lifespan and progressive locomotive defects
        with age
      explanation: >-
        Establishes that the model produces a progressive organismal phenotype,
        which is what makes it informative for the repeat-RNA node rather than a
        purely cell-biological readout.
  - target: Repeat-Associated Translation of poly-WNGME Pentapeptide Protein
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The fly produces the same poly-WNGME PPR protein detected in patient
      Purkinje cells, and PPR level tracks the severity of eye degeneration.
    limitations: >-
      PPR protein in the fly is predominantly cytoplasmic in eye imaginal disc
      cells, whereas in patients it is granular material in Purkinje cell bodies
      and dendrites; and the translation route remains unresolved in both
      systems, so the model cannot yet be used to test an intervention specific
      to repeat-associated non-AUG translation.
    readouts:
    - name: poly-WNGME PPR protein level
      target: Repeat-Associated Translation of poly-WNGME Pentapeptide Protein
      direction: INCREASED
      interpretation: >-
        PPR protein accumulation in the model matched by its detection in SCA31
        patient brain.
      evidence:
      - reference: PMID:28343865
        reference_title: "Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          we observed an accumulation of UGGAAexp-encoded pentapeptide
          (Trp-Asn-Gly-Met-Glu) repeat (PPR) proteins in Drosophila and SCA31
          human brains
        explanation: >-
          The measurement in both the model and human brain, which is what makes
          this readout translationally anchored.
    evidence:
    - reference: PMID:28343865
      reference_title: "Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These findings expand the growing list of microsatellite expansion
        disorders in which repeat-associated translation occurs, and support a
        dual-toxicity mechanism of repeat RNAs and PPR proteins in
        neurodegeneration.
      explanation: >-
        The authors' summary of what the model establishes about the translation
        arm.
discussions:
- discussion_id: sca31_foci_versus_ppr_contribution
  prompt: >-
    How much of SCA31 Purkinje cell degeneration is caused by the (UGGAA)n RNA
    itself versus by the poly-WNGME pentapeptide protein it is translated into?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Nuclear (UGGAA)n RNA Foci in Purkinje Cells
  - pathophysiology#Repeat-Associated Translation of poly-WNGME Pentapeptide Protein
  rationale: >-
    Both toxic species are present in patient Purkinje cells and both are
    produced by the fly model, but no experiment has separated their
    contributions. The obvious dissection, suppressing translation while leaving
    the RNA or the reverse, is complicated in SCA31 specifically, because the
    same manipulation affects both arms: raising TDP-43 reduces foci and PPR
    production together. It is complicated further by the unresolved translation
    route, since the repeat contains its own AUG and cannot be assumed to be
    RAN-translated, so a strategy that blocks RAN translation may not apply
    here. The answer matters for therapy: an approach that clears the transcript
    addresses both arms, whereas a translation-directed approach addresses only
    one.
  proposed_experiments:
  - experiment_id: exp_sca31_translation_blocked_repeat
    name: Translation-silent (UGGAA)n allele in a mammalian Purkinje cell system
    description: >-
      Express an (UGGAA)n repeat engineered to retain its RNA structure and
      foci-forming capacity while being unable to produce poly-WNGME, alongside
      the wild-type repeat, in a mammalian Purkinje-cell system, and compare
      toxicity.
    decision_criterion: >-
      Comparable toxicity from the translation-silent allele would attribute the
      damage predominantly to the RNA; markedly reduced toxicity would implicate
      the PPR protein.
  - experiment_id: exp_sca31_ppr_only_expression
    name: Direct poly-WNGME expression without the repeat RNA
    description: >-
      Express poly-WNGME from a codon-altered, non-repetitive construct that
      makes the protein without producing (UGGAA)n RNA, and assay Purkinje cell
      toxicity.
    decision_criterion: >-
      Toxicity from the protein alone would establish an RNA-independent
      contribution; its absence would argue the PPR protein is a marker rather
      than a driver.
  evidence:
  - reference: PMID:28343865
    reference_title: "Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      It is important to understand the contributions of repeat RNA and PPR
      proteins to disease pathogenesis.
    explanation: >-
      The authors state the apportionment as an open question rather than
      answering it, which is what this knowledge gap records.
- discussion_id: sca31_drosophila_translational_validity
  prompt: >-
    Does the (UGGAA)n Drosophila model, in which the repeat is overexpressed
    from a heterologous driver in a nervous system with no cerebellum, capture
    the biology that makes SCA31 a Purkinje-cell disease?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - animal_models#Drosophila melanogaster
  - pathophysiology#Binding and Redistribution of RNA-Binding and Splicing Factors
  rationale: >-
    Almost every mechanistic claim about SCA31 beyond the human autopsy findings
    rests on the fly. The mismatch is specific rather than generic. The most
    distinctive feature of human SCA31 is that foci and degeneration are
    confined to Purkinje cells and spare other neurons and glia, and Drosophila
    has neither a cerebellum nor a Purkinje cell, so the model cannot address
    selectivity at all. The fly expresses the repeat from a GAL4 driver at
    supraphysiological levels rather than from an endogenous intron under BEAN1
    transcriptional control, and the toxicity is explicitly expression-level
    dependent, so the dose relationship in the model is not the dose
    relationship in patients. The rescue result on which the whole
    RNA-chaperone therapeutic hypothesis rests, that raising TDP-43, FUS or
    hnRNPA2B1 suppresses toxicity, has not been reproduced in a mammalian
    system, and those proteins are pleiotropic enough that the manipulation may
    not be tolerable in one. No mouse model of the SCA31 insertion has been
    reported.
  proposed_experiments:
  - experiment_id: exp_sca31_knockin_mouse
    name: Knock-in mouse carrying the (TGGAA)n insertion at the orthologous intron
    description: >-
      Generate a mouse carrying the human-length (TGGAA)n-containing insertion
      at the orthologous Bean1/Tk2 shared intron, so the repeat is transcribed
      under endogenous brain-restricted control, and assay for Purkinje-cell
      foci, PPR protein, and age-dependent ataxia.
    decision_criterion: >-
      Purkinje-cell-selective foci and late-onset ataxia would establish that
      the fly findings translate to a mammalian cerebellum; their absence at
      physiological expression would show the fly phenotype depends on
      overexpression.
  - experiment_id: exp_sca31_ipsc_purkinje
    name: Patient-derived iPSC Purkinje cells
    description: >-
      Differentiate Purkinje-like neurons from SCA31 patient iPSCs carrying the
      endogenous insertion and test whether foci form, PPR protein accumulates,
      and RNA-binding-protein supplementation rescues, in a human cerebellar
      cell type at endogenous expression.
    decision_criterion: >-
      Reproduction of the fly rescue in human Purkinje-like cells would support
      the RNA-chaperone strategy; failure would localize the effect to the fly's
      overexpression regime.
  evidence:
  - reference: PMID:35563872
    reference_title: "Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These SCA31 RNA foci were only detected in the BEAN1-direction (no
      anti-sense foci), ranged from 0.2 to 1.8 µm in diameter, and accumulated
      in the nuclei of Purkinje cells (not observed in other neurons or glial
      cells)
    explanation: >-
      Documents the Purkinje-cell selectivity in humans that the fly model has
      no way to reproduce.
  - reference: PMID:36319738
    reference_title: "Spinocerebellar ataxia type 31 (SCA31)."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Subsequent investigation by over-expressing (UGGAA)n in Drosophila
      revealed that the RNA containing (UGGAA)n exerts toxicity in a length- and
      expression level-dependent manner
    explanation: >-
      Quoted for the words over-expressing and expression level-dependent, which
      together are the mismatch: the model's phenotype is a function of a dose
      the endogenous locus does not deliver.
notes: >-
  Curation caveat on the disease's reputation as a pure cerebellar ataxia. The
  founding Japanese descriptions, still the basis of most textbook summaries,
  explicitly recorded no pyramidal signs, neuropathy or gaze limitation, and the
  neuropathology finds cerebrum, brainstem and spinal cord normal. The largest
  pooled review nonetheless found extracerebellar signs in 52.5% of 374
  patients. This entry curates both, and does not resolve the tension, because
  the reviewers themselves note that SCA31 patients are old and long-diseased,
  which confounds the attribution of hearing loss, reduced vibration sense and
  reflex changes to the disease rather than to age.

📚

References & Deep Research

References

3

PMID:19878914

Spinocerebellar ataxia type 31 is associated with "inserted" penta-nucleotide repeats containing (TGGAA)n.

No top-level findings curated for this source.

PMID:36319738

Spinocerebellar ataxia type 31 (SCA31).

No top-level findings curated for this source.

PMID:35563872

Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Spinocerebellar Ataxia Type 31 (SCA31): Disease Characteristics Report

Edison Scientific Literature 12 citations 2026-09-02T13:24:20.370011

Spinocerebellar Ataxia Type 31 (SCA31): Disease Characteristics Report

Executive summary

Spinocerebellar ataxia type 31 (SCA31) is a rare, late-onset, slowly progressive, autosomal-dominant cerebellar neurodegenerative disorder caused by a complex pentanucleotide-repeat insertion at chromosome 16q22.1 in an intronic region shared by BEAN1 and TK2. The disease-associated element is approximately 2.5–3.8 kb and contains (TGGAA)n, (TAGAA)n, (TAAAA)n, and (TAAAATAGAA)n; among these, (TGGAA)n is the motif consistently associated with pathogenicity. SCA31 has a pronounced Japanese founder effect and is essentially absent from most non-Japanese populations. Clinically, it is usually a relatively “pure” cerebellar syndrome beginning near 60 years of age, with gait/truncal and limb ataxia and dysarthria. Human pathology and experimental data support toxic gain-of-function by brain-expressed (UGGAA)n RNA, nuclear RNA foci, altered RNA-binding-protein homeostasis, repeat-associated translation of poly-WNGME pentapeptide protein, and selective Purkinje-cell injury. No disease-modifying treatment has been established; current care is supportive, while toxic-RNA-binding compounds and manipulation of RNA chaperones remain preclinical concepts. (ishikawa2023spinocerebellarataxiatype pages 2-3, ishikawa2019molecularmechanismsand pages 1-3, ishikawa2023spinocerebellarataxiatype pages 1-2, zhang2022mechanisticandtherapeutic pages 7-9)

The following table provides a compact knowledge-base representation.

Domain	Key findings	Quantitative / implementation details	Suggested ontology terms	Evidence
Identity / identifiers	Spinocerebellar ataxia type 31 (SCA31), a disease-level aggregated Mendelian disorder; one of the most common autosomal-dominant cerebellar ataxias in Japan; also described as a pure cerebellar ataxia	MONDO:0007296; common synonyms: SCA31, spinocerebellar ataxia 31; other identifiers not firmly established from available context	MONDO:0007296	(OpenTargets Search: spinocerebellar ataxia type 31-BEAN1,TK2, ishikawa2023spinocerebellarataxiatype pages 2-3, ishikawa2023spinocerebellarataxiatype pages 1-2)
Inheritance	Autosomal dominant; strong founder effect in Japan; age-dependent expression is likely, but formal penetrance estimates are not established in the available context	Founder disease; essentially absent in most non-Japanese populations except reported Japanese diaspora cases; anticipation not established from available context	HP:0000006 (Autosomal dominant inheritance)	(ishikawa2019molecularmechanismsand pages 1-3, ishikawa2023spinocerebellarataxiatype pages 1-2, zhang2022mechanisticandtherapeutic pages 5-7)
Causal lesion	Pathogenic lesion is a 2.5-3.8 kb complex pentanucleotide repeat insertion in the shared intronic region of BEAN1 and TK2 at 16q22.1; (TGGAA)n is the disease-segregating pathogenic motif	Repeat composition includes (TGGAA)n, (TAGAA)n, (TAAAA)n, and (TAAAATAGAA)n; controls may carry nonpathogenic short (TAAAA)8-20 tracts; healthy controls rarely have insertions lacking TGGAA (~0.23%)	Gene: BEAN1, TK2; SO conceptually: intronic repeat expansion / short tandem repeat expansion	(ishikawa2023spinocerebellarataxiatype pages 2-3, ishikawa2019molecularmechanismsand pages 1-3, zhang2022mechanisticandtherapeutic pages 7-9)
Phenotype / onset	Late-onset, slowly progressive cerebellar ataxia with truncal and limb ataxia, dysarthria/cerebellar speech, reduced muscle tone; usually without brainstem involvement; occasional reported parkinsonism or blepharospasm	Mean onset about 58.5-63.8 years; considered among the latest-onset SCAs	HP:0001251 (Ataxia); HP:0002060 (Dysarthria); HP:0001252 (Hypotonia); HP:0002313 (Cerebellar atrophy)	(ishikawa2019molecularmechanismsand pages 1-3, ishikawa2023spinocerebellarataxiatype pages 1-2, zhang2022mechanisticandtherapeutic pages 5-7)
Progression / prognosis	Chronic lifelong course with slow progression; quantitative natural history available; disability accumulates gradually	SARA progression ~0.8 points/year; wheelchair dependence around 79.4 ± 1.7 years; death around 88.5 ± 0.7 years in reported cohort summaries	HP:0001251; NCIT:C99568 (Wheelchair dependence, approximate mapping not guaranteed)	(ishikawa2019molecularmechanismsand pages 1-3, zhang2022mechanisticandtherapeutic pages 5-7)
Anatomy / pathology	Primary pathology is cerebellar, especially Purkinje-cell-predominant degeneration and cerebellar cortical atrophy; upper vermis atrophy is typical on MRI	Purkinje-cell nuclear RNA foci seen in ~30% of patient Purkinje cells; foci ~0.2-1.8 µm; pathology includes Purkinje cell loss, shrinkage, halo-like amorphous material, calbindin-positive somatic sprouts, synaptophysin-positive terminals, ubiquitin-positive degradation granules, Golgi fragmentation	UBERON:0002037 (cerebellum); UBERON:0002245 (cerebellar vermis); CL:0000121 (Purkinje cell); GO:0005730 (nucleolus not established), GO:0005634 (nucleus)	(ishikawa2019molecularmechanismsand pages 1-3, zhang2022mechanisticandtherapeutic pages 7-9, zhang2022mechanisticandtherapeutic pages 5-7)
Mechanism	Repeat is bidirectionally transcribed; brain-specific BEAN1-derived (UGGAA)n RNA forms toxic secondary structures and RNA foci in Purkinje-cell nuclei; UGGAA RNA binds TDP-43, FUS, hnRNPA2/B1; toxicity is likely mediated by RNA toxicity plus repeat-associated translation to pentapeptide repeat protein	TDP-43 acts as an RNA chaperone in fly/in vitro systems and suppresses toxicity; UGGAA translation yields poly-WNGME pentapeptide repeat protein detected in patient Purkinje cells; some mechanistic steps remain inferred rather than fully proven in humans	GO:0008380 (RNA splicing, broad RBP relevance); GO:0003723 (RNA binding); GO:0016070 (RNA metabolic process); GO:0034644 (cellular response to UV? not applicable); GO:0031047 (gene silencing by RNA not established)	(ishikawa2023spinocerebellarataxiatype pages 2-3, ishikawa2019molecularmechanismsand pages 1-3, zhang2022mechanisticandtherapeutic pages 7-9, zhang2022mechanisticandtherapeutic pages 9-11)
Diagnostics	Real-world diagnosis relies on targeted repeat-expansion testing in suspected hereditary ataxia; Southern blot and PCR-based methods are described; long-read sequencing and WGS-based repeat detection are emerging adjuncts for complex repeat loci	Historical SCA31 mapping used Southern blot, BAC tiling/shotgun sequencing, PCR/Sanger; 2014 hybrid short+long read sequencing resolved 2.3-3.1 kb SCA31 repeats in 11 samples; current general ataxia RE practice uses repeat-primed PCR or Southern blot, with WGS pipelines increasingly feasible	NCIT:C120299 (Genetic Testing); NCIT:C71484 (Magnetic Resonance Imaging); HP:0001272 (Cerebellar atrophy on neuroimaging, approximate phenotype mapping)	(ishikawa2023spinocerebellarataxiatype pages 1-2, ishikawa2023spinocerebellarataxiatype pages 2-3)
Treatment / trials	No disease-modifying therapy is established in available SCA31-specific context; management is supportive and rehabilitative; experimental preclinical strategies target toxic RNA structure/RBP balance	Preclinical naphthyridine carbamate dimer (NCD) binds UGGAA repeats and reduced foci/degeneration in fly systems; trial search found no clearly relevant SCA31-specific interventional trial	NCIT:C15413 (Physical Therapy); NCIT:C15697 (Occupational Therapy); NCIT:C94533 (Speech Therapy); experimental small-molecule therapy not established	(zhang2022mechanisticandtherapeutic pages 9-11)
Epidemiology	Strongly enriched in Japan; reported as the third most frequent SCA in Japan; rare in neighboring Asian populations and absent from large European cohorts; Brazilian cases linked to Japanese ancestry support founder effect	One review notes 99.7% of controls carry short 8-20 TAAAA repeats at the locus; disease largely population-restricted	MONDO:0007296; HP:0012823 (Founder effect, no HPO term standardly used for disease, use narrative)	(ishikawa2023spinocerebellarataxiatype pages 2-3, ishikawa2023spinocerebellarataxiatype pages 1-2, zhang2022mechanisticandtherapeutic pages 5-7)
Environmental / protective factors	No established environmental, infectious, lifestyle, or protective factors were identified in the available SCA31-specific evidence; gene-environment interaction not established	Not established / unknown	None reliably assignable	(ishikawa2019molecularmechanismsand pages 1-3, ishikawa2023spinocerebellarataxiatype pages 1-2)
Models	Drosophila transgenic models expressing expanded UGGAA/TGGAA repeats recapitulate RNA foci, degeneration, locomotor defects, and shortened lifespan; used for modifier and small-molecule testing	Toxicity is length- and expression-level-dependent; TDP-43/FUS/hnRNPA2B1 co-expression ameliorates phenotypes; poly-WNGME burden correlates with severity in flies	NCBITaxon:7227 (Drosophila melanogaster); CL terms not directly applicable to fly eye models; GO:0003723 (RNA binding)	(ishikawa2019molecularmechanismsand pages 1-3, zhang2022mechanisticandtherapeutic pages 7-9, zhang2022mechanisticandtherapeutic pages 9-11)

Table: This table condenses the highest-confidence, knowledge-base-ready facts on Spinocerebellar Ataxia Type 31, including its causal repeat expansion, core phenotype, mechanistic evidence, diagnostics, and model systems. It also flags domains where the current evidence is limited or not established.

1. Disease information

Definition and classification

SCA31 is a Mendelian autosomal-dominant repeat-expansion disorder and neurodegenerative cerebellar ataxia. Its cardinal manifestation is progressive cerebellar ataxia, generally without the prominent brainstem, pyramidal, peripheral-neuropathic, cognitive, or systemic manifestations found in many multisystem SCAs. The source material summarized here is principally aggregated disease-level evidence from pedigrees, clinical cohorts, human postmortem tissue, and experimental models—not individual EHR records. (ishikawa2019molecularmechanismsand pages 1-3, ishikawa2023spinocerebellarataxiatype pages 1-2, zhang2022mechanisticandtherapeutic pages 5-7)

Identifiers and synonyms

MONDO: MONDO:0007296.
Principal names: spinocerebellar ataxia type 31; spinocerebellar ataxia 31; SCA31.
Historical/locus terminology: chromosome 16q22.1-linked autosomal-dominant cerebellar ataxia; the phenotype was historically associated with “16q-ADCA.”
Disease-associated targets: Open Targets links SCA31 to BEAN1 (Ensembl ENSG00000166546) and, with substantially weaker association evidence, TK2 (ENSG00000166548). The underlying literature records include PMIDs 17611710, 19878914, 22992774, 20301317, and 35084690. (OpenTargets Search: spinocerebellar ataxia type 31-BEAN1,TK2)
OMIM/Orphanet/MeSH and dedicated ICD codes: not reliably established in the retrieved evidence. General coding systems may classify the condition under hereditary ataxia or spinocerebellar ataxia rather than a unique SCA31 code; these mappings should be verified directly against current releases before database ingestion.

A concise statement from the November 2023 disease review is: “Spinocerebellar ataxia type 31 (SCA31) is one of the most common forms of autosomal-dominant cerebellar ataxia in Japan.” DOI: 10.1038/s10038-022-01091-4. (ishikawa2023spinocerebellarataxiatype pages 2-3, ishikawa2023spinocerebellarataxiatype pages 1-2)

2. Etiology, risk, protective factors, and gene–environment interaction

Causal factor

The causal lesion is a germline, heterozygous, complex intronic pentanucleotide-repeat expansion at 16q22.1. It lies in an intron shared by oppositely transcribed BEAN1 and TK2. Disease alleles are approximately 2.5–3.8 kb and contain several repeat motifs, but (TGGAA)n is the sequence that segregates with SCA31 and was not observed on control chromosomes in the foundational comparisons. Short (TAAAA)8–20 alleles are common in unaffected Japanese controls. (ishikawa2023spinocerebellarataxiatype pages 2-3, ishikawa2019molecularmechanismsand pages 1-3, ishikawa2023spinocerebellarataxiatype pages 1-2)

Risk factors

Genetic: inheritance of the disease-associated (TGGAA)n-containing expansion is the primary risk factor. Longer insertion length correlates inversely with age at onset, although repeat composition and technical measurement complexity limit simple repeat-count prediction. (ishikawa2019molecularmechanismsand pages 1-3, zhang2022mechanisticandtherapeutic pages 7-9)
Family history: an affected first-degree relative is a major clinical risk indicator under autosomal-dominant inheritance.
Population ancestry: Japanese ancestry substantially raises prior probability because of a strong founder effect. Cases outside Japan have notably included people of Japanese descent, including Brazilian families. (ishikawa2023spinocerebellarataxiatype pages 2-3, ishikawa2023spinocerebellarataxiatype pages 1-2, zhang2022mechanisticandtherapeutic pages 5-7)
Age: age is not an etiologic exposure, but clinical penetrance is strongly age-dependent because onset is usually in late adulthood.
Sex: no reproducible sex-specific risk or sex-ratio difference was established in the retrieved studies.
Modifier genes: TDP-43/TARDBP, FUS, and HNRNPA2B1 modify toxicity experimentally, but they are not established human genetic modifier loci. (ishikawa2019molecularmechanismsand pages 1-3, zhang2022mechanisticandtherapeutic pages 9-11)

Environmental and protective factors

No validated toxin, infection, diet, smoking pattern, alcohol exposure, occupational factor, medication, or other environmental exposure has been shown to cause or specifically modify SCA31. No protective human allele, dietary intervention, or lifestyle factor has been validated. Consequently, a specific SCA31 gene–environment interaction is not established. General avoidance of alcohol excess and cerebellotoxic medications may reduce superimposed ataxia but does not prevent the inherited disease.

3. Phenotypes

Core phenotype

Manifestation	Type and characteristics	Suggested HPO term
Gait/truncal ataxia	Core sign; late-onset and slowly progressive; progressively compromises balance and independent ambulation	HP:0002066 Gait ataxia; HP:0001251 Ataxia; HP:0002078 Truncal ataxia
Limb ataxia/dysmetria	Common cerebellar sign, usually progressive	HP:0002070 Limb ataxia; HP:0001310 Dysmetria
Dysarthria/cerebellar speech	Common progressive sign affecting communication	HP:0001260 Dysarthria / current HPO preferred cerebellar dysarthria mapping should be release-verified
Cerebellar atrophy	MRI and pathological abnormality, particularly cerebellar cortex/upper vermis; brainstem relatively spared	HP:0001272 Cerebellar atrophy
Hypotonia/reduced tone	Reported in clinical descriptions; less defining than ataxia	HP:0001252 Hypotonia
Parkinsonism	Uncommon/non-core; occasional L-DOPA-responsive cases reported	HP:0001300 Parkinsonism
Blepharospasm	Uncommon/non-core	HP:0000643 Blepharospasm

Mean reported onset ranges from 58.5 ± 10.3 years to 63.8 years, making SCA31 one of the latest-onset SCAs. The course is chronic and progressive rather than episodic, relapsing, or remitting. Available reports do not supply robust percentage frequencies for every symptom; ataxia and dysarthria are core, whereas parkinsonism and blepharospasm are occasional. (ishikawa2019molecularmechanismsand pages 1-3, ishikawa2023spinocerebellarataxiatype pages 1-2, zhang2022mechanisticandtherapeutic pages 5-7)

Functional and quality-of-life effects

Progressive gait and balance impairment affect community mobility, falls risk, driving, self-care, and ultimately independent ambulation. Dysarthria impairs communication, while limb incoordination affects feeding, writing, dressing, and other fine-motor tasks. Wheelchair dependence was reported at a mean age of 79.4 ± 1.7 years. No SCA31-specific EQ-5D, SF-36, PROMIS, or validated disease-specific quality-of-life estimates were identified. SARA is the principal quantitative neurological severity scale reported. (ishikawa2019molecularmechanismsand pages 1-3, zhang2022mechanisticandtherapeutic pages 5-7)

4. Genetic and molecular information

Genes and variant class

BEAN1—brain expressed associated with NEDD4 1; principal disease-linked gene/locus in Open Targets.
TK2—thymidine kinase 2; shares the affected intronic interval and is transcribed in the opposite direction. This SCA31 mechanism is distinct from recessive coding-variant TK2 deficiency.
Variant type: complex intronic tandem-repeat insertion/expansion; germline; heterozygous.
Functional class: toxic gain of function at the RNA level, with an additional toxic repeat-associated translation product; not a conventional BEAN1 or TK2 coding loss-of-function allele. (OpenTargets Search: spinocerebellar ataxia type 31-BEAN1,TK2, ishikawa2023spinocerebellarataxiatype pages 2-3, zhang2022mechanisticandtherapeutic pages 7-9)

The repeat is bidirectionally transcribed. BEAN1 produces brain-specific (UGGAA)n-containing RNA, whereas the opposite TK2 direction produces (UUCCA)n RNA more broadly. The clinical and pathological restriction to the nervous system, together with BEAN1’s brain-restricted expression, supports the (UGGAA)n transcript as the dominant pathogenic species. (ishikawa2023spinocerebellarataxiatype pages 2-3, ishikawa2023spinocerebellarataxiatype pages 1-2)

Classification, frequency, and structural features

The canonical expansion is pathogenic by segregation, population specificity, human pathology, and functional-model evidence. Conventional SNV-focused ACMG/AMP criteria are not sufficient by themselves for this complex repeat; laboratories should use repeat-expansion-specific validation and locus expertise. Approximately 99.7% of controls in one summary carried short (TAAAA)8–20 repeats, and control insertions lacking TGGAA were rare (approximately 0.23%). Standard gnomAD SNV allele-frequency fields are not an adequate representation of this lesion. (zhang2022mechanisticandtherapeutic pages 7-9, ishikawa2023spinocerebellarataxiatype pages 2-3)

No established large deletion, translocation, inversion, aneuploidy, somatic mosaic mechanism, DNA-methylation signature, or chromatin biomarker specific to SCA31 was found. Somatic repeat instability is biologically plausible for repeat diseases but was not established as a clinical driver in the retrieved SCA31 evidence.

5. Environmental information

SCA31 is not infectious, zoonotic, toxic, radiation-induced, or lifestyle-caused. No infectious agent or environmental trigger is implicated. Alcohol, sedatives, anticonvulsants, and other cerebellar-toxic exposures can worsen balance nonspecifically and should be reviewed clinically, but they are not SCA31 causes. CTD-style disease–chemical causal relationships and SCA31-specific lifestyle-effect estimates were not identified.

6. Mechanism and pathophysiology

Ordered causal chain

A germline (TGGAA)n-containing complex repeat expansion in the shared BEAN1/TK2 intron leads to bidirectional transcription of expanded noncoding repeat RNA at 16q22.1. (ishikawa2023spinocerebellarataxiatype pages 2-3, ishikawa2019molecularmechanismsand pages 1-3)
Brain-specific BEAN1 transcription results in expanded (UGGAA)n RNA in cerebellar neurons, especially Purkinje cells. (ishikawa2023spinocerebellarataxiatype pages 2-3, ishikawa2023spinocerebellarataxiatype pages 1-2)
(UGGAA)n RNA folds into abnormal hairpin-like structures with GGA loops leading to nuclear RNA-foci formation; this is demonstrated in human SCA31 Purkinje cells. (zhang2022mechanisticandtherapeutic pages 7-9, zhang2022mechanisticandtherapeutic pages 9-11)
The structured RNA leads to binding and altered availability/activity of TDP-43, FUS, and hnRNPA2/B1; whether classical sequestration alone is sufficient for human disease remains incompletely demonstrated. (ishikawa2019molecularmechanismsand pages 1-3, zhang2022mechanisticandtherapeutic pages 7-9)
Branch A: disturbed RNA–RNA-binding-protein equilibrium results in RNA-mediated cellular toxicity; fly rescue by RBP co-expression supports causality, but downstream human transcript targets remain insufficiently defined. (ishikawa2019molecularmechanismsand pages 1-3, zhang2022mechanisticandtherapeutic pages 9-11)
Branch B: repeat-associated non-AUG translation of (UGGAA)n results in poly-WNGME pentapeptide-repeat protein; this product is detected in patient Purkinje cells and correlates with toxicity in flies. (zhang2022mechanisticandtherapeutic pages 7-9)
RNA and translated-product toxicity lead to Golgi fragmentation, ubiquitin-positive degradation granules, abnormal somatic sprouts/synaptic remodeling, Purkinje-cell shrinkage and loss; the exact ordering of these downstream events is partly inferred. (zhang2022mechanisticandtherapeutic pages 5-7)
Progressive Purkinje-cell and cerebellar cortical degeneration results in cerebellar atrophy, impaired cerebellar output, gait/limb ataxia, and dysarthria. (ishikawa2019molecularmechanismsand pages 1-3, ishikawa2023spinocerebellarataxiatype pages 1-2, zhang2022mechanisticandtherapeutic pages 5-7)

Mechanistic detail and evidence strength

Human evidence: RNA foci occur in approximately 30% of examined patient Purkinje cells and measure about 0.2–1.8 μm. Poly-WNGME material has also been detected in affected Purkinje cells. Neuropathology shows Purkinje-cell loss and shrinkage, halo-like amorphous structures containing calbindin-positive somatic sprouts and synaptophysin-positive terminals, ubiquitin-positive granules, and Golgi fragmentation. (zhang2022mechanisticandtherapeutic pages 7-9, zhang2022mechanisticandtherapeutic pages 5-7)

Model evidence: In Drosophila, (TGGAA)80–100/expanded (UGGAA)n expression causes nuclear and cytoplasmic foci, compound-eye degeneration, shortened lifespan, and progressive locomotor defects in a length- and expression-dependent fashion. Co-expression of TDP-43, FUS, or hnRNPA2/B1 reduces toxicity. TDP-43 appears to act as an RNA chaperone, remodeling abnormal UGGAA RNA rather than simply increasing its degradation, and also reduces pentapeptide-repeat synthesis. (ishikawa2019molecularmechanismsand pages 1-3, zhang2022mechanisticandtherapeutic pages 7-9, zhang2022mechanisticandtherapeutic pages 9-11)

Pathways and profiling: No well-validated primary Wnt, MAPK, mTOR, PI3K–AKT, metabolic, immune, or inflammatory pathway has been established for SCA31. Likewise, no mature single-cell, spatial-transcriptomic, patient proteomic, metabolomic, lipidomic, or integrated multi-omic signature was identified. The best-supported biology is repeat-RNA structure, RNA-binding-protein homeostasis, noncanonical translation, protein quality control, Golgi integrity, and neuronal degeneration.

Suggested GO terms: GO:0003723 RNA binding; GO:0016070 RNA metabolic process; GO:0006412 translation; GO:0006914 autophagy only if directly documented in a future dataset; GO:0008219 cell death; GO:0051603 proteolysis involved in cellular protein catabolic process; GO:0007005 mitochondrion organization is not currently supported as a core SCA31 mechanism. Suggested cell ontology: CL:0000121 Purkinje cell, with cerebellar granule neurons and glia not yet established as primary targets.

7. Anatomical structures affected

Organ/system: central nervous system, principally cerebellum.
Regional localization: cerebellar cortex and upper vermis; MRI generally shows cerebellar atrophy without substantial brainstem atrophy.
Cell: Purkinje neurons are the best-established vulnerable population.
Subcellular compartments: nucleus/RNA foci; cytoplasm for translated pentapeptide material; Golgi apparatus and protein-degradation compartments are pathologically altered.
Lateralization: bilateral/diffuse rather than unilateral; no consistent asymmetry is established.

Suggested terms include UBERON:0002037 cerebellum, UBERON:0002245 cerebellar vermis, CL:0000121 Purkinje cell, GO:0005634 nucleus, GO:0005794 Golgi apparatus, and GO:0005737 cytoplasm. (ishikawa2019molecularmechanismsand pages 1-3, ishikawa2023spinocerebellarataxiatype pages 1-2, zhang2022mechanisticandtherapeutic pages 7-9, zhang2022mechanisticandtherapeutic pages 5-7)

8. Temporal development

Onset is insidious and typically late adult/geriatric, averaging roughly 59–64 years. The course is monophasic, chronic, lifelong, and slowly progressive, without spontaneous remission. A natural-history summary reports SARA worsening of approximately 0.8 points/year, wheelchair use near age 79, and death near age 88.5. These are cohort means rather than deterministic predictions for an individual. (ishikawa2019molecularmechanismsand pages 1-3, zhang2022mechanisticandtherapeutic pages 5-7)

Practical stages are: (1) subtle imbalance or dysarthria; (2) clinically evident gait and limb ataxia with retained ambulation; (3) assistive-device dependence; and (4) advanced mobility dependence. These are pragmatic clinical stages, not formally validated SCA31 staging criteria. The long presymptomatic period creates a theoretical intervention window for future allele- or RNA-directed therapies, but no biomarker-defined critical window is established.

9. Inheritance and population

SCA31 is autosomal dominant; each child of a heterozygous affected person has a 50% transmission risk. Penetrance is likely strongly age-dependent, but a precise age-specific penetrance curve was not identified. Expressivity is variable, although the phenotype is usually relatively pure and slowly progressive. An inverse repeat-length/onset relationship exists. Robust genetic anticipation, germline mosaicism rates, de novo frequency, and carrier frequency have not been established. Consanguinity is not a causal factor for this dominant disorder. (ishikawa2019molecularmechanismsand pages 1-3, zhang2022mechanisticandtherapeutic pages 7-9)

SCA31 is described as the third most frequent SCA in Japan in one review, but a reliable population prevalence per 100,000 and annual incidence were not available in the retrieved evidence. It is rare in neighboring Asian groups and absent from large European cohorts; Japanese-ancestry cases abroad reinforce a founder origin. No convincing male:female imbalance is known. (ishikawa2023spinocerebellarataxiatype pages 1-2, zhang2022mechanisticandtherapeutic pages 5-7)

10. Diagnostics

Clinical evaluation

Diagnosis begins with late-onset, slowly progressive, predominantly cerebellar ataxia; a three-generation pedigree and Japanese ancestry increase suspicion. Examination should document gait, stance, limb coordination, speech, ocular motor function, tone, pyramidal/extrapyramidal signs, neuropathy, cognition, swallowing, and falls. Serial SARA scoring is suitable for monitoring.

Brain MRI typically demonstrates cerebellar—often upper vermian—atrophy with relative brainstem sparing. MRI supports localization and excludes acquired mimics but is not molecularly diagnostic. No validated blood, CSF, protein, metabolite, neurofilament, electrophysiological, or liquid-biopsy biomarker is specific to SCA31. Biopsy is not indicated for routine diagnosis. (ishikawa2019molecularmechanismsand pages 1-3, ishikawa2023spinocerebellarataxiatype pages 1-2)

Genetic testing strategy

Order a targeted SCA31 repeat-expansion assay when phenotype/ancestry suggests SCA31, or include it in a comprehensive repeat-expansion ataxia panel.
Use locus-specific PCR/fragment methods where technically validated; because the allele is large and compositionally complex, confirmatory Southern blot, long-range PCR, or validated long-read analysis may be required.
Standard WES generally performs poorly because the lesion is intronic and much larger than an exome read. A negative WES does not exclude SCA31.
Short-read WGS with dedicated repeat-expansion software is more useful than WES but may not fully resolve motif composition. Long-read sequencing can directly characterize complex alleles and interruptions.
CMA, karyotyping, FISH, and mitochondrial DNA testing are not first-line assays for the canonical lesion.

Historical discovery used Southern blotting, BAC tiling/shotgun sequencing, and PCR/Sanger analysis. A hybrid sequencing study resolved 2.3–3.1-kb SCA31 alleles at nucleotide resolution in 11 samples. More broadly, 2023 work characterizes repeat-primed PCR and Southern blot as current repeat-expansion diagnostic standards and identifies WGS pipelines as an increasingly practical first step. (ishikawa2023spinocerebellarataxiatype pages 1-2, ishikawa2023spinocerebellarataxiatype pages 2-3)

Differential diagnosis

Important inherited differentials include SCA6 and other late-onset dominant “pure” cerebellar ataxias, SCA5, SCA26, SCA30, SCA36, RFC1-related CANVAS, and episodic ataxias. Acquired and sporadic mimics include multiple-system atrophy–cerebellar type, immune/paraneoplastic ataxia, alcohol or medication toxicity, nutritional deficiencies, thyroid disease, structural lesions, and degenerative idiopathic late-onset cerebellar ataxia. Molecular confirmation distinguishes SCA31 from phenotypically overlapping SCAs.

Cascade testing of adult relatives is appropriate after counseling. Predictive testing of asymptomatic adults should include informed consent and discussion of age-dependent onset, uncertain individual prognosis, psychological effects, insurance/employment issues where relevant, and reproductive choices. Testing asymptomatic minors is generally deferred for an adult-onset condition without proven preventive therapy.

11. Outcome and prognosis

SCA31 produces gradually accumulating neurological disability but appears compatible with survival into advanced age in reported cohorts. Mean wheelchair dependence near 79.4 years and death near 88.5 years suggest that many affected people retain substantial longevity, although these numbers should not be interpreted as controlled life-expectancy estimates. No validated 5- or 10-year survival rates, disease-specific mortality rates, or treatment-stratified survival data were identified. (ishikawa2019molecularmechanismsand pages 1-3, zhang2022mechanisticandtherapeutic pages 5-7)

Major morbidity consists of falls, impaired mobility and activities of daily living, communication difficulty, and advanced dependence. Dysphagia, aspiration, deconditioning, fractures, and social isolation should be monitored as general complications of progressive ataxia, although SCA31-specific rates are unavailable. Recovery of lost cerebellar neurons is not expected; rehabilitation can preserve function and compensate for deficits. Earlier onset/longer alleles and baseline severity may predict greater lifetime disability, but no validated multivariable prognostic calculator or molecular prognostic biomarker exists.

12. Treatment

Current clinical management

There is no approved SCA31-specific disease-modifying pharmacotherapy, gene therapy, cell therapy, ASO, siRNA, or surgical treatment. Care is multidisciplinary:

physical therapy for balance, gait, strength, aerobic conditioning, falls prevention, and mobility aids;
occupational therapy and home-safety/adaptive-equipment assessment;
speech-language therapy for dysarthria and swallowing assessment when indicated;
nutrition support if intake or swallowing declines;
management of mood, sleep, pain, spasticity, parkinsonism, or blepharospasm when present;
avoidance of unnecessary sedating or cerebellotoxic drugs.

Suggested NCIt intervention concepts include Physical Therapy, Occupational Therapy, Speech Therapy, Genetic Counseling, Assistive Device, and Supportive Care; exact NCIt identifiers should be release-verified before ingestion.

Experimental strategies

Enhancing or mimicking the RNA-chaperone actions of TDP-43, FUS, or hnRNPA2/B1 may reduce abnormal UGGAA structure and translation, but systemic manipulation of these pleiotropic proteins could itself be hazardous. (ishikawa2019molecularmechanismsand pages 1-3, ishikawa2023spinocerebellarataxiatype pages 1-2)
Naphthyridine carbamate dimer (NCD) preferentially binds UGGAA repeats, reduces RNA foci and TDP-43 interaction, and ameliorates fly-eye degeneration. This remains preclinical and has no established human response rate or safety profile. (zhang2022mechanisticandtherapeutic pages 9-11)
Allele-selective ASOs, RNA degradation, inhibition of repeat-associated translation, and gene editing are rational future approaches but were not demonstrated clinically in the retrieved SCA31 literature.

The clinical-trial search produced no clearly SCA31-specific interventional trial. Trials for recessive TK2 deficiency are mechanistically unrelated and must not be misclassified as SCA31 trials.

13. Prevention

There is no vaccine, medication, lifestyle intervention, environmental remediation, or population screening program that prevents the expansion carrier state.

Primary prevention: reproductive genetic counseling; where desired and legally available, preimplantation genetic testing or prenatal diagnosis after the familial expansion has been molecularly defined.
Secondary prevention: cascade/predictive testing in consenting adult relatives and neurological surveillance; this may shorten diagnostic delay but has not been shown to prevent onset.
Tertiary prevention: falls prevention, exercise and rehabilitation, swallowing surveillance, mobility aids, home modification, and management of complications.
Newborn screening: not indicated because of late onset, rarity, population restriction, and absence of proven presymptomatic treatment.

14. Other species and natural disease

No naturally occurring SCA31-equivalent disease was identified in companion animals, livestock, or wildlife. The disorder has no infectious transmission or zoonotic potential. Although BEAN1 and TK2 orthologs occur across vertebrates, the pathogenic human repeat configuration and Japanese founder haplotype are the relevant disease features. Species-level NCBI Gene IDs and VBO breed terms were not established in the retrieved material.

15. Model organisms

The best-developed model is transgenic Drosophila melanogaster (NCBI Taxonomy 7227) expressing expanded TGGAA/UGGAA repeats. It recapitulates RNA foci, repeat-length/expression-dependent degeneration, locomotor decline, reduced lifespan, and poly-WNGME production. It has enabled genetic modifier experiments with TDP-43, FUS, and hnRNPA2/B1 and testing of NCD. (ishikawa2019molecularmechanismsand pages 1-3, zhang2022mechanisticandtherapeutic pages 7-9, zhang2022mechanisticandtherapeutic pages 9-11)

Limitations are substantial: fly compound-eye degeneration is not human cerebellar ataxia; transgene overexpression may exceed endogenous levels; repeat context and aging differ from the native human locus; and fly rescue does not establish human efficacy or safety. No well-validated knock-in mouse, rat, zebrafish, patient iPSC-derived Purkinje-cell, cerebellar organoid, or naturally occurring animal model was identified in the retrieved evidence.

Recent developments and evidence gaps

The key recent disease-focused source is Ishikawa’s November 2023 review, which consolidates the Japanese founder genetics, brain-specific bidirectional transcription, Purkinje-cell RNA foci, and RNA-chaperone model (DOI 10.1038/s10038-022-01091-4). Its abstract states that the complex repeat “lies in an intronic segment shared by two genes, BEAN1 … and TK2 … transcribed in mutually opposite directions” and that (UGGAA)n forms “abnormal RNA structures, called RNA foci, in cerebellar Purkinje cell nuclei.” (ishikawa2023spinocerebellarataxiatype pages 2-3, ishikawa2023spinocerebellarataxiatype pages 1-2)

The most relevant 2023–2024 field-wide developments are improved WGS repeat-detection pipelines, increasing clinical use of long-read sequencing for large complex expansions, and continued use of CRISPR-enabled Drosophila models for repeat-disease mechanism and therapeutic screening. These advances improve SCA31 diagnosis and model design but have not yet produced a human disease-modifying therapy.

Critical gaps include precise population prevalence and penetrance, prospective modern natural-history cohorts, validated fluid/imaging biomarkers, native-locus mammalian and human iPSC models, cell-type-resolved omics, direct quantification of RNA versus poly-WNGME contributions in humans, and SCA31-specific interventional trials. Claims about immune activation, mitochondrial dysfunction, epigenetic silencing, environmental modifiers, and systemic disease should therefore be recorded as not established, rather than inferred from other repeat-expansion ataxias.

References

(ishikawa2023spinocerebellarataxiatype pages 2-3): Kinya Ishikawa. Spinocerebellar ataxia type 31 (sca31). Journal of Human Genetics, 68:153-156, Nov 2023. URL: https://doi.org/10.1038/s10038-022-01091-4, doi:10.1038/s10038-022-01091-4. This article has 15 citations and is from a peer-reviewed journal.
(ishikawa2019molecularmechanismsand pages 1-3): Kinya Ishikawa and Yoshitaka Nagai. Molecular mechanisms and future therapeutics for spinocerebellar ataxia type 31 (sca31). Neurotherapeutics, 16:1106-1114, Oct 2019. URL: https://doi.org/10.1007/s13311-019-00804-6, doi:10.1007/s13311-019-00804-6. This article has 24 citations and is from a peer-reviewed journal.
(ishikawa2023spinocerebellarataxiatype pages 1-2): Kinya Ishikawa. Spinocerebellar ataxia type 31 (sca31). Journal of Human Genetics, 68:153-156, Nov 2023. URL: https://doi.org/10.1038/s10038-022-01091-4, doi:10.1038/s10038-022-01091-4. This article has 15 citations and is from a peer-reviewed journal.
(zhang2022mechanisticandtherapeutic pages 7-9): Nan Zhang and Tetsuo Ashizawa. Mechanistic and therapeutic insights into ataxic disorders with pentanucleotide expansions. May 2022. URL: https://doi.org/10.3390/cells11091567, doi:10.3390/cells11091567. This article has 15 citations.
(OpenTargets Search: spinocerebellar ataxia type 31-BEAN1,TK2): Open Targets Query (spinocerebellar ataxia type 31-BEAN1,TK2, 4 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(zhang2022mechanisticandtherapeutic pages 5-7): Nan Zhang and Tetsuo Ashizawa. Mechanistic and therapeutic insights into ataxic disorders with pentanucleotide expansions. May 2022. URL: https://doi.org/10.3390/cells11091567, doi:10.3390/cells11091567. This article has 15 citations.
(zhang2022mechanisticandtherapeutic pages 9-11): Nan Zhang and Tetsuo Ashizawa. Mechanistic and therapeutic insights into ataxic disorders with pentanucleotide expansions. May 2022. URL: https://doi.org/10.3390/cells11091567, doi:10.3390/cells11091567. This article has 15 citations.

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Spinocerebellar Ataxia Type 31 (SCA31): Disease Characteristics Report

Executive summary

1. Disease information

Definition and classification

Identifiers and synonyms

2. Etiology, risk, protective factors, and gene–environment interaction

Causal factor

Risk factors

Environmental and protective factors

3. Phenotypes

Core phenotype

Functional and quality-of-life effects

4. Genetic and molecular information

Genes and variant class

Classification, frequency, and structural features

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Mechanistic detail and evidence strength

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical evaluation

Genetic testing strategy

Differential diagnosis

11. Outcome and prognosis

12. Treatment

Current clinical management

Experimental strategies

13. Prevention

14. Other species and natural disease

15. Model organisms

Recent developments and evidence gaps

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