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Classifications

Harrison's Part

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Inheritance

1

Autosomal dominant inheritance HP:0000006

SCA36 segregates as an autosomal dominant trait in multiplex Japanese, Galician, Han Chinese and British kindreds carrying founder-associated GGCCTG expansions. GeneReviews describes penetrance as complete but age dependent, consistent with a mean onset in the fifth decade. Repeat size was observed to grow on paternal and to contract on maternal transmission in the Galician kindreds, though a general parent-of-origin rule has not been established across cohorts.

Autosomal dominant inheritance Penetrance: COMPLETE

Parent-of-origin effect: Repeat size increased on paternal transmission and contracted on maternal transmission in the Galician kindreds; not established as a general rule.

Show evidence (3 references)

PMID:21683323 SUPPORT Human Clinical

"The expansion showed complete segregation with the SCA phenotype in family studies"

Complete segregation of the expansion with disease in the original families supports a dominant, fully penetrant gene-disease relationship.

PMID:25101480 SUPPORT Human Clinical

"Penetrance is complete, although age-dependent."

GeneReviews states the penetrance value recorded in this block.

PMID:22492559 SUPPORT Human Clinical

"Further expansion of repeat size was frequent, especially upon paternal transmission, while instances of allele contraction were observed in maternal transmissions."

Documents the parent-of-origin effect on repeat size recorded here, in the single cohort where it was observed.

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Discussions and Knowledge Gaps

5

Does reduced MIR1292 transcription contribute to neurodegeneration in SCA36, and through which targets?

KNOWLEDGE GAP OPEN mir1292_contribution

Attached to

pathophysiology#MIR1292 Downregulation

Reduced MIR1292 transcription is reproducible: it was found in the original Japanese patients and replicated in Han Chinese patients. But both observations are in lymphoblastoid cells, a peripheral cell type that does not degenerate, and the one attempt to test predicted targets found four unchanged and three unmeasurable in that cell type, prompting the authors to raise the possibility of an epiphenomenon. No downstream target has been demonstrated in cerebellar or motor neuron tissue, so the node is left with no outgoing causal edge rather than being connected on the strength of adjacency. Resolving this would require measuring MIR1292 and its candidate targets in patient cerebellum or in expansion-carrying neurons.

Show evidence (1 reference)

PMID:27123487 SUPPORT In Vitro

"Arguably, LCLs may not be an appropriate platform to study SCA36 pathogenesis because such cell lines might not faithfully recapitulate the pathologic phenotypes of Purkinje cells."

States the cell-type limitation that makes this a gap rather than a settled negative result.

Are dipeptide repeat proteins pathogenic in SCA36, or a comparatively inert byproduct of repeat translation?

CONTROVERSY OPEN dpr_pathogenicity

Attached to

pathophysiology#Dipeptide Repeat Protein Production from the Expanded Repeat

Human tissue work reports abundant poly(GP), mostly from canonical AUG-mediated translation of the intron-retained transcript, plus antisense poly(PR) indicating RAN translation. But SCA36 poly(GP) is soluble and there is no TDP-43 pathology, unlike C9orf72 disease, and a Neuro2A model found RAN-derived DPR formation to be rare. The DPR arm of the mechanism is therefore recorded as PROVISIONAL and its edge to Purkinje degeneration is left uncited.

Show evidence (2 references)

PMID:32375063 SUPPORT Human Clinical

"Interestingly, in SCA36 patient tissue, poly(GP) exists as a soluble species, and no TDP-43 pathology is present."

The solubility and absent TDP-43 pathology are the reasons the DPR arm cannot simply be carried over from C9orf72 disease.

PMID:30610877 REFUTE In Vitro

"Glycine-proline dipeptide repeat (DPR) formation due to repeat-associated non-ATG translation rarely occurred in cells expressing expanded GGCCTG repeats; in contrast, cells harboring expanded c9orf72 GGGGCC/GGCCCC repeats robustly expressed DPR proteins."

A cell-model result arguing against abundant RAN-driven DPR production from the SCA36 repeat, which is the substance of the disagreement.

Does reduced NOP56 dosage, and consequent box C/D snoRNP and rRNA-processing impairment, contribute to SCA36 at all?

CONTROVERSY OPEN nop56_dosage_branch

Attached to

pathophysiology#Impaired NOP56 Box C/D snoRNP Function

This is the main alternative to the RNA gain-of-function account, and it is argued against rather than untested. NOP56 mRNA and protein were measured in patient lymphoblastoid cells and were not appreciably reduced, and Cajal body number was unchanged. The zebrafish nop56 null then showed what complete loss of the gene produces — absent cerebellum and death within a week — which is not the disease. Neither result is decisive: the patient measurements are in a peripheral cell type, as with MIR1292, and a homozygous zebrafish null is several steps removed from a heterozygous human repeat expansion, so a partial or cell-type-restricted dosage effect in neurons is not excluded. Measuring NOP56 and rRNA 2'-O-methylation in patient cerebellum, or in expansion-carrying neurons, is what would settle it.

Show evidence (1 reference)

PMID:36009362 REFUTE Model Organism

"We observed a severe neurodegenerative phenotype in nop56 mutants, characterized mainly by absence of cerebellum, reduced numbers of spinal cord neurons, high levels of apoptosis in the central nervous system (CNS) and impaired movement, resulting in death before 7 days post-fertilization."

The phenotype of complete nop56 loss is incompatible with the late-onset selective degeneration of SCA36, which is the substance of the argument against the dosage branch.

By what mechanism does the NOP56 repeat expansion produce sensorineural hearing loss, and which cochlear or auditory-nerve cell population is affected?

KNOWLEDGE GAP OPEN auditory_mechanism_gap

Attached to

pathophysiology#Cochlear and Peripheral Auditory Dysfunction

Hearing loss is one of the most distinctive features of SCA36 and correlates with ataxia severity, and BAEPs point to a peripheral rather than central lesion. But no cochlear tissue has been examined for repeat RNA foci or DPRs in SCA36, and the British cohort's low rate of hearing loss shows the feature is not obligate, so the edge from the expansion to auditory dysfunction is typed UNKNOWN. Temporal bone pathology, or an auditory-competent model, would resolve it.

Why do the two discriminating features of SCA36 — sensorineural hearing loss and tongue fasciculation — vary so widely between cohorts?

OPEN QUESTION OPEN cohort_phenotype_variation

Attached to

phenotypes#Sensorineural hearing loss phenotypes#Tongue fasciculations

Tongue atrophy and fasciculation were reported in 12% of French patients against 63% of Japanese patients, and the British series found a low rate of hearing loss. Ascertainment differences, disease duration at examination, somatic repeat instability, and modifier background are all candidate explanations, and none has been tested. The practical consequence is already recorded in the differential diagnosis: absence of these features does not exclude SCA36.

Show evidence (1 reference)

PMID:27123487 SUPPORT Human Clinical

"atrophy and fasciculation of the tongue and limb muscles are present in 12% of French patients in contrast to 63% of Japanese patients"

Quantifies the between-cohort discrepancy that this question is about.

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Pathophysiology

11

Intronic GGCCTG Repeat Expansion in NOP56

The initiating lesion is a heterozygous expansion of a GGCCTG hexanucleotide repeat in intron 1 of NOP56, which encodes a core scaffold protein of the box C/D small nucleolar ribonucleoprotein complex. Normal alleles carry 3-14 repeats; typical pathogenic alleles carry roughly 650-2500, although expansions as short as 25-31 repeats have been shown to cause the disease. This is the disorder-specific molecular insult substituted for the generic trigger node of the Purkinje degeneration module.

NOP56 hgnc:15911

Downstream

NOP56 Intron 1 Retention and Nuclear GGCCUG RNA Foci The expanded repeat is transcribed and retained rather than efficiently spliced out, so repeat RNA accumulates in the nucleus.

MIR1292 Downregulation Transcription of MIR1292, whose gene lies 19 bp downstream of the repeat, is reduced in cells from expansion carriers. Whether this is a cis consequence of the expansion and whether it contributes to neurodegeneration is unresolved.

Cochlear and Peripheral Auditory Dysfunction Sensorineural hearing loss is a genotype-associated feature of SCA36, but no molecular intermediate between the repeat expansion and auditory involvement has been established.

Show evidence (2 references)

PMID:21683323 SUPPORT Human Clinical

"we sequenced 33 of these and observed a large expansion of an intronic GGCCTG hexanucleotide repeat in NOP56"

Identifies the causal repeat expansion as the initiating molecular lesion of SCA36.

PMID:37810464 SUPPORT Human Clinical

"The normal alleles contain 3–14 hexanucleotide repeats, while the expanded alleles range from 30 to 2500 repeats (mostly between 650 and 2500 repeats)."

Establishes the normal and pathogenic repeat ranges quoted in this node.

NOP56 Intron 1 Retention and Nuclear GGCCUG RNA Foci

Retained (GGCCUG)n repeat RNA accumulates as discrete nuclear foci. Foci are demonstrable by fluorescence in situ hybridization in patient lymphoblastoid cells, patient iPSCs and iPSC-derived neurons, and in autopsied brain, where sense but not antisense foci are found. In autopsy tissue the foci occur in neuronal nuclei of cerebrum, cerebellum, inferior olive, spinal cord and temporal muscle, and include giant foci nearly 10 micrometres across in Purkinje cells and spinal motor neurons.

cerebellar Purkinje cell CL:0000121 spinal motor neuron CL:0011001

mRNA splicing, via spliceosome GO:0000398 ⚠ ABNORMAL

Experimental models

SCA36 patient iPSC-derived neurons IPSC DERIVED MODEL Patient-derived neurons carrying the endogenous expansion form intranuclear sense RNA foci at significantly higher frequency than control neurons, reproducing the hallmark molecular lesion in a human neuronal context.

Neuro2A cells expressing expanded GGCCTG/CAGGCC repeats CELL LINE Transfected expanded repeats produce sense but not antisense RNA foci, matching the strand asymmetry seen in patient autopsy tissue.

Downstream

SRSF2 Sequestration by GGCCUG Repeat RNA The repeat RNA binds the SR-family splicing factor SRSF2, the proposed route by which foci become toxic.

Dipeptide Repeat Protein Production from the Expanded Repeat Intron-retained repeat transcripts are translated, producing dipeptide repeat proteins.

Show evidence (3 references)

PMID:21683323 SUPPORT In Vitro

"RNA foci formation was detected in lymphoblastoid cells from affected subjects by fluorescence in situ hybridization."

First demonstration that the expanded repeat forms RNA foci in cells from affected individuals.

PMID:24985895 SUPPORT Human Clinical

"Of interest is that the giant RNA foci, nearly 10 μm in diameter, that were detected in Purkinje cells, spinal motor neurons and most frequently in the inferior olivary nucleus, may be responsible for pivotal clinical symptoms of Asidan."

Establishes the presence and cellular distribution of repeat RNA foci in human SCA36 autopsy tissue, including the two cell populations this node lists.

PMID:30610877 SUPPORT In Vitro

"Sense (GGCCUG)exp but not antisense (CAGGCC)exp RNA foci were detected in the cells, consistent with observations in autopsied brains of patients with SCA36."

Supports the sense-strand specificity of foci formation recorded in this node.

SRSF2 Sequestration by GGCCUG Repeat RNA

Expanded (GGCCUG)n RNA binds SRSF2 specifically, and the resulting sequestration of an essential splicing factor into nuclear foci is the canonical RNA gain-of-function model for SCA36, by analogy with the MBNL-sequestration mechanism of myotonic dystrophy. NOP56 mRNA and protein levels and Cajal body number are not appreciably reduced in patient lymphoblastoid cells, which is why haploinsufficiency of NOP56 itself is not the favored explanation.

mRNA binding GO:0003729 ⚠ ABNORMAL

Downstream

Purkinje Cell Degeneration The steps between splicing-factor sequestration and neuronal death have not been resolved; the original report frames the disorder overall as RNA gain of function.

Lower Motor Neuron Degeneration The same RNA gain-of-function mechanism is invoked for the motor neuron arm of the disease, and foci are present in spinal motor neurons, but the causal relationship between foci and degeneration has not been shown.

Show evidence (2 references)

PMID:35309140 SUPPORT Other

"It seemed to be clear that these expanded repeat-containing RNAs did form such foci and could sequester RNA-binding proteins like SRSF2 and other proteins"

Review synthesis of the sequestration model; evidence source is OTHER because this is a narrative minireview rather than primary data.

PMID:35309140 SUPPORT Other

"These findings were not able to support the haploinsufficiency hypothesis."

Supports the statement that NOP56 haploinsufficiency is not the favored mechanism, which is why this node is framed as RNA gain of function.

Dipeptide Repeat Protein Production from the Expanded Repeat

The intron-retained GGCCTG repeat transcript is translated into dipeptide repeat proteins. In patient tissue poly(GP) is produced abundantly by canonical AUG-mediated translation reading through the retained intron, while the antisense product poly(PR) indicates that repeat-associated non-AUG (RAN) translation also occurs. Unlike in C9orf72 disease, SCA36 poly(GP) remains soluble and TDP-43 pathology is absent. Whether the DPRs are pathogenic in SCA36 or a comparatively inert byproduct is not settled — a Neuro2A model found RAN-derived DPR formation from expanded GGCCTG to be rare.

translation GO:0006412 ⚠ ABNORMAL

Animal models

AAV-delivered (TG3C2)62 repeat-expressing mouse Mouse recapitulates The mouse reproduces the specific DPR biology curated at this node, including the feature that distinguishes SCA36 from C9orf72 disease: poly(GP) is produced but stays soluble rather than forming inclusions.

Downstream

Purkinje Cell Degeneration DPR toxicity is proposed as a contributor to neurodegeneration in SCA36 by analogy with C9orf72 disease, but has not been shown to cause Purkinje cell loss in SCA36 itself. This edge is deliberately left uncited; see the dpr_pathogenicity discussion.

Show evidence (3 references)

PMID:32375063 SUPPORT Human Clinical

"Here, we show the similar intronic GGCCTG HREs that causes spinocerebellar ataxia type 36 (SCA36) is also translated into DPRs, including poly(GP) and poly(PR)."

Establishes that the SCA36 repeat is translated and names the two DPR species this node records.

PMID:32375063 SUPPORT Human Clinical

"Interestingly, in SCA36 patient tissue, poly(GP) exists as a soluble species, and no TDP-43 pathology is present."

Supports the solubility and absent-TDP-43 statements that distinguish SCA36 DPR biology from C9orf72 disease.

PMID:30610877 SUPPORT In Vitro

"Glycine-proline dipeptide repeat (DPR) formation due to repeat-associated non-ATG translation rarely occurred in cells expressing expanded GGCCTG repeats; in contrast, cells harboring expanded c9orf72 GGGGCC/GGCCCC repeats robustly expressed DPR proteins."

A cell model reporting only rare RAN-derived poly(GP), which is the qualification this node makes and why its mechanism confidence is PROVISIONAL rather than ESTABLISHED.

MIR1292 Downregulation

The MIR1292 gene lies 19 bp downstream of the repeat, and its transcription is reduced in lymphoblastoid cells from expansion carriers in two independent cohorts. In the Han Chinese cohort, four of seven predicted targets were unchanged and three were unmeasurable in lymphoblastoid cells, and the authors raised the possibility that reduced MIR1292 is an epiphenomenon of the expansion. No downstream target has been demonstrated in cerebellar or motor neuron tissue, so this node is deliberately left with no outgoing edge; see the mir1292_contribution discussion.

Show evidence (3 references)

PMID:21683323 SUPPORT In Vitro

"transcription of MIR1292, a neighboring miRNA, was significantly decreased in lymphoblastoid cells of SCA patients"

The original observation underlying this node, made in patient lymphoblastoid cells rather than neural tissue.

PMID:27123487 SUPPORT In Vitro

"We observed reduced microRNA-1292 expression levels (63%) in 5 patients with SCA36 compared with 5 healthy controls"

Independent replication of the reduced MIR1292 expression in a second population.

PMID:27123487 SUPPORT In Vitro

"It is possible that microRNA-1292 expression is simply an epiphenomenon of abnormal (GGCCTG)n expansion and might not play an active role in disease pathogenesis."

The authors' own reading of their negative target-gene results, which is why this node carries HYPOTHETICAL mechanism confidence and no outgoing causal edge.

Purkinje Cell Degeneration

Purkinje cells degenerate, and their loss is the central effector event linking the molecular repeat toxicity to the cerebellar syndrome. Purkinje involvement is demonstrable even in a presymptomatic expansion carrier, indicating that it precedes clinical ataxia.

cerebellar Purkinje cell CL:0000121

neuron apoptotic process GO:0051402 ↑ INCREASED

Animal models

AAV-delivered (TG3C2)62 repeat-expressing mouse Mouse recapitulates Repeat-expressing mice lose cerebellar Purkinje cells and show the dendritic and locomotor consequences of that loss, matching the central effector node of this entry.

nop56 loss-of-function zebrafish Zebrafish fails to recapitulate Complete loss of nop56 does not reproduce the adult-onset, selective Purkinje degeneration of SCA36. It produces an embryonic-lethal failure of cerebellar development instead — the cerebellum is absent rather than degenerating — which is the structural argument against dosage loss being the SCA36 mechanism.

Downstream

Cerebellar and Olivopontocerebellar Atrophy

Show evidence (2 references)

PMID:22744658 SUPPORT Human Clinical

"The neuropathologic study revealed significant cerebellar Purkinje cell degeneration with obvious loss of lower motor neurons."

Human autopsy evidence for Purkinje cell degeneration in SCA36.

PMID:25476002 SUPPORT Human Clinical

"Neuropathology in a presymptomatic case disclosed that Purkinje cells and hypoglossal neurons are affected."

Establishes that Purkinje involvement precedes clinical onset, supporting this node's placement upstream of the tissue-level atrophy.

Lower Motor Neuron Degeneration

Lower motor neurons degenerate, most conspicuously the hypoglossal neurons supplying the tongue. Involvement is largely restricted to lower motor neurons of the caudal brainstem and spinal cord rather than the widespread upper and lower motor neuron loss of amyotrophic lateral sclerosis, which is why SCA36 does not progress to an ALS-like course.

lower motor neuron CL:0008039

motor neuron apoptotic process GO:0097049 ↑ INCREASED

Downstream

Bulbar and Limb Denervation

Show evidence (3 references)

PMID:22744658 SUPPORT Human Clinical

"Lower motor involvement was confirmed by EMG and muscle biopsy."

Electrophysiological and histological confirmation of lower motor neuron involvement in patients.

PMID:25476002 SUPPORT Human Clinical

"Neuropathology in a presymptomatic case disclosed that Purkinje cells and hypoglossal neurons are affected."

Identifies hypoglossal motor neurons specifically, which is the anatomical basis of the tongue phenotype.

PMID:22492559 SUPPORT Human Clinical

"There were signs of denervation in the tongue, as well as mild pyramidal signs, but otherwise no signs of classical amyotrophic lateral sclerosis."

Supports the restricted distribution of motor neuron involvement recorded in this node's description.

Cerebellar and Olivopontocerebellar Atrophy

Cerebellar tissue loss follows the cellular degeneration in a stereotyped sequence: cerebellar glucose hypometabolism in the vermis and right hemisphere before symptoms, superior vermis atrophy early in the ataxic stage, diffuse cerebellar atrophy some years later, and an olivopontocerebellar pattern in the oldest patients.

cerebellum UBERON:0002037

Downstream

Truncal ataxia Loss of cerebellar cortical output from the degenerating vermis produces the truncal ataxia that opens the clinical syndrome.

Limb ataxia Hemispheric cerebellar atrophy produces appendicular incoordination.

Ataxic dysarthria Cerebellar degeneration produces the ataxic dysarthria found in every patient of the original Japanese cohort.

Show evidence (1 reference)

PMID:27862279 SUPPORT Human Clinical

"MRI was normal in asymptomatic and preataxic individuals and showed superior cerebellar vermis atrophy early in the ataxic stage, diffuse cerebellar atrophy some years into the disease course, and a pattern of olivopontocerebellar atrophy in the oldest patients."

Establishes the staged tissue-level atrophy pattern described by this node.

Bulbar and Limb Denervation

Denervation of tongue and limb musculature follows lower motor neuron loss, producing fasciculation and then atrophy. Tongue involvement predominates and is the clinical marker that separates SCA36 from pure cerebellar ataxias.

skeletal muscle tissue UBERON:0001134

Downstream

Tongue fasciculations Denervation of the lingual musculature by hypoglossal neuron loss produces the tongue fasciculation that is the clinical signature of SCA36.

Tongue atrophy Sustained denervation progresses from fasciculation to wasting of the tongue.

Skeletal muscle fasciculation and atrophy The same denervation affects limb and truncal muscle, confirmed by EMG and muscle biopsy.

Dysphagia Bulbar denervation impairs swallowing, though a videofluoroscopic study found swallowing better preserved in SCA36 than in amyotrophic lateral sclerosis, so the link is weaker than for the tongue phenotypes.

Show evidence (1 reference)

PMID:22744658 SUPPORT Human Clinical

"Skeletal muscle fasciculation and atrophy of the limbs and trunk were found in 57% of cases."

Documents the muscle-level consequence of denervation in patients.

Cochlear and Peripheral Auditory Dysfunction

Hearing loss in SCA36 is sensorineural and worst at high frequencies. Brainstem auditory evoked potentials point to the inner ear or the peripheral auditory pathway rather than to a central lesion, but the molecular route from the NOP56 expansion to auditory dysfunction has not been worked out.

inner ear UBERON:0001846

Downstream

Sensorineural hearing loss Dysfunction of the inner ear or peripheral auditory pathway is what the audiometric and BAEP findings measure as sensorineural hearing loss.

Show evidence (1 reference)

PMID:23140984 SUPPORT Human Clinical

"BAEPs in 2 Asidan/SCA36 cases suggested possible involvement in the inner ear or the peripheral part of the auditory system."

Localizes the auditory lesion peripherally, with the authors' own hedge preserved, which is why mechanism confidence is PROVISIONAL.

Impaired NOP56 Box C/D snoRNP Function

The alternative loss-of-function branch. NOP56 is a core scaffold of the box C/D small nucleolar ribonucleoprotein complex that directs 2'-O-methylation of ribosomal RNA, so reduced NOP56 dosage would be expected to impair rRNA processing and ribosome biogenesis. This node is deliberately left with no incoming or outgoing causal edge, because the branch is not supported as the patient mechanism: NOP56 mRNA and protein are not appreciably reduced in patient cells, and the zebrafish nop56 null shows what complete loss of the gene actually produces — an embryonic-lethal failure of cerebellar development, not a late-onset selective degeneration. It is recorded so the hypothesis is visible and falsifiable rather than surviving only as prose. See the nop56_dosage_branch discussion.

NOP56 hgnc:15911

rRNA processing GO:0006364 ↓ DECREASED

Animal models

nop56 loss-of-function zebrafish Zebrafish perturbs The model is the direct experimental perturbation of the hypothetical dosage branch: it removes nop56 function outright and measures what follows, including expression of box C/D complex genes.

Show evidence (2 references)

PMID:37810464 SUPPORT Human Clinical

"NOP56 encodes a ubiquitously expressed core scaffolding protein that stabilizes the box C/D small nucleolar ribonuclear protein complex."

Establishes the normal function whose loss this hypothetical branch would impair.

PMID:35309140 REFUTE Other

"These findings were not able to support the haploinsufficiency hypothesis."

The reason this node carries HYPOTHETICAL confidence and no causal edge: the dosage branch was tested in patient cells and not supported.

✶

Histopathology

3

Purkinje cell loss with lower motor neuron loss

Autopsy shows marked cerebellar Purkinje cell degeneration together with loss of lower motor neurons, the two-compartment pathology that defines SCA36.

Show evidence (1 reference)

PMID:22744658 SUPPORT Human Clinical

"The neuropathologic study revealed significant cerebellar Purkinje cell degeneration with obvious loss of lower motor neurons."

Primary neuropathological description of the combined lesion.

Ubiquitin- and p62-positive cytoplasmic inclusions in the inferior olivary nucleus

The first SCA36 autopsy demonstrated ubiquitin- and p62-positive cytoplasmic inclusions in the inferior olivary nucleus, alongside repeat RNA foci in neuronal nuclei at several levels of the neuraxis.

Show evidence (1 reference)

PMID:24985895 SUPPORT Human Clinical

"ubiquitin- and p62-positive inclusions in the cytoplasm of the inferior olivary nucleus of the Asidan patient"

Reports the inclusion type and anatomical location recorded here.

Absence of NOP56, TDP-43 and ataxin-2 inclusions

NOP56 immunostaining is nuclear and normal in distribution, and no cytoplasmic or intranuclear inclusions of NOP56, TDP-43 or ataxin-2 are seen. The absence of TDP-43 pathology is a key contrast with C9orf72 disease, which is driven by a structurally similar hexanucleotide repeat.

Show evidence (2 references)

PMID:22744658 SUPPORT Human Clinical

"Cytoplasmic or intranuclear inclusion staining of NOP56, TDP-43, and ataxin-2 was not observed in the remaining neurons."

Direct negative finding on protein inclusion pathology in SCA36 neurons.

PMID:32375063 SUPPORT Human Clinical

"Interestingly, in SCA36 patient tissue, poly(GP) exists as a soluble species, and no TDP-43 pathology is present."

Independent confirmation that TDP-43 pathology is absent, in the comparison with C9orf72 disease this finding is usually framed against.

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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

16

Digestive 1

Dysphagia HP:0002015

Show evidence (1 reference)

PMID:25101480 SUPPORT Human Clinical

"Dietary assessment and feeding therapy programs can improve dysphagia and reduce the risk of aspiration."

GeneReviews treats dysphagia as an expected complication requiring management, which is the basis for recording it here.

Ear 1

Sensorineural hearing loss FREQUENT Sensorineural hearing impairment HP:0000407

Show evidence (3 references)

PMID:23140984 SUPPORT Human Clinical

"In comparison to other groups, Asidan/SCA36 showed a constant depression at 7 different frequencies in audiogram, especially at 4000 and 8000 Hz."

Audiometric measurement of the high-frequency-predominant hearing loss described here.

PMID:23140984 SUPPORT Human Clinical

"In addition to signs for motor neuron involvement, acoustic impairment in Asidan/SCA36 is another characteristic clinical feature that is distinguishable from other forms of SCAs."

Supports treating hearing loss as a discriminating feature, which is what the diagnostic flag on this phenotype records.

PMID:37810464 SUPPORT Human Clinical

"Clinically, the patients presented with slowly progressive cerebellar ataxia with a low rate of hearing loss and variable rates of motor neuron impairment."

Supports the caveat in the description that hearing loss is not obligate, by reporting a cohort in which it was uncommon.

Eye 1

Ptosis HP:0000508

Show evidence (1 reference)

PMID:25476002 SUPPORT Human Clinical

"All patients showed slowly progressive cerebellar ataxia frequently accompanied by hearing and cognitive impairments, tremor, ptosis and reduced vibration sense"

Lists ptosis among the accompanying features in the multicentre cohort.

Musculoskeletal 1

Skeletal muscle fasciculation and atrophy FREQUENT Skeletal muscle atrophy HP:0003202

Show evidence (1 reference)

PMID:22744658 SUPPORT Human Clinical

"Skeletal muscle fasciculation and atrophy of the limbs and trunk were found in 57% of cases."

Reports limb and truncal muscle fasciculation and atrophy in 57% of the cohort, within the FREQUENT band.

Nervous System 5

Ataxic dysarthria VERY_FREQUENT HP:0001260

Show evidence (1 reference)

PMID:22744658 SUPPORT Human Clinical

"The age at onset of ataxia was 53.1 ± 3.4 years, with the most frequent symptoms being truncal ataxia (100% of patients), ataxic dysarthria (100%), limb ataxia (93%), and hyperreflexia (79%)."

Reports ataxic dysarthria in 100% of the cohort, supporting the VERY_FREQUENT band.

Hyperreflexia FREQUENT HP:0001347

Show evidence (2 references)

PMID:22744658 SUPPORT Human Clinical

"The age at onset of ataxia was 53.1 ± 3.4 years, with the most frequent symptoms being truncal ataxia (100% of patients), ataxic dysarthria (100%), limb ataxia (93%), and hyperreflexia (79%)."

Reports hyperreflexia in 79% of the cohort, at the top of the FREQUENT band.

PMID:27123487 SUPPORT Human Clinical

"Common features included slowly progressive truncal/limb ataxia, dysarthria, generalized hyperreflexia, and hearing impairment."

Independent confirmation of hyperreflexia as a common feature in a second population.

Depression HP:0000716

Show evidence (1 reference)

PMID:22353375 SUPPORT Human Clinical

"They also demonstrated mild depression and apathy."

Reports mild depression in the assessed Asidan cohort.

Apathy HP:0000741

Show evidence (1 reference)

PMID:22353375 SUPPORT Human Clinical

"They also demonstrated mild depression and apathy."

Reports apathy in the assessed Asidan cohort.

Tremor HP:0001337

Show evidence (1 reference)

PMID:25476002 SUPPORT Human Clinical

"All patients showed slowly progressive cerebellar ataxia frequently accompanied by hearing and cognitive impairments, tremor, ptosis and reduced vibration sense"

Lists tremor among the accompanying features in the multicentre cohort.

Other 7

Truncal ataxia VERY_FREQUENT HP:0002078

Course: PROGRESSIVE

Show evidence (2 references)

PMID:22744658 SUPPORT Human Clinical

"The age at onset of ataxia was 53.1 ± 3.4 years, with the most frequent symptoms being truncal ataxia (100% of patients), ataxic dysarthria (100%), limb ataxia (93%), and hyperreflexia (79%)."

Reports truncal ataxia in 100% of the 18-patient cohort, supporting both the phenotype and its VERY_FREQUENT band.

PMID:27123487 SUPPORT Human Clinical

"The average age at symptom onset was 44.8 ± 3.8 years with truncal ataxia as the initial manifestation."

Independent confirmation that truncal ataxia is the presenting feature in a second population.

Limb ataxia VERY_FREQUENT HP:0002070

Show evidence (1 reference)

PMID:22744658 SUPPORT Human Clinical

"The age at onset of ataxia was 53.1 ± 3.4 years, with the most frequent symptoms being truncal ataxia (100% of patients), ataxic dysarthria (100%), limb ataxia (93%), and hyperreflexia (79%)."

Reports limb ataxia in 93% of the cohort, which falls in the VERY_FREQUENT band.

Tongue fasciculations FREQUENT HP:0001308

Show evidence (2 references)

PMID:22744658 SUPPORT Human Clinical

"Tongue fasciculation and subsequent atrophy were found in 71% of cases, particularly in those of long duration."

Reports tongue fasciculation in 71% of the cohort, supporting the FREQUENT band and the duration dependence noted in the description.

PMID:27123487 SUPPORT Human Clinical

"atrophy and fasciculation of the tongue and limb muscles are present in 12% of French patients in contrast to 63% of Japanese patients"

Documents the between-cohort variation in tongue involvement noted in the description, which is why the frequency band is not set higher.

Tongue atrophy FREQUENT HP:0012473

Course: PROGRESSIVE

Show evidence (2 references)

PMID:22744658 SUPPORT Human Clinical

"Tongue fasciculation and subsequent atrophy were found in 71% of cases, particularly in those of long duration."

The same cohort figure covers subsequent tongue atrophy, which is why the band matches that of the fasciculation phenotype.

PMID:25101480 SUPPORT Human Clinical

"Other common features are muscle atrophy and denervation, especially of the tongue, as well as pyramidal signs, thus overlapping with motor neuron disorders."

GeneReviews confirms tongue-predominant atrophy and denervation as a common feature.

Abnormal eye movements Abnormal saccadic eye movements HP:0000570

Show evidence (1 reference)

PMID:22492559 SUPPORT Human Clinical

"We describe here the detailed clinical picture, consisting of a late-onset, slowly progressive cerebellar syndrome with variable eye movement abnormalities and sensorineural hearing loss."

Reports eye movement abnormalities as part of the SCA36 clinical picture, with the authors' own qualifier "variable" preserved.

Impaired executive functioning FREQUENT HP:0033051

Show evidence (2 references)

PMID:22353375 SUPPORT Human Clinical

"The 12 Asidan patients demonstrated a significant decrease in their frontal executive functions measured by frontal assessment battery (FAB) and Montreal cognitive assessment (MoCA) compared with age- and gender-matched controls, whilst mini-mental state examination (MMSE) and Hasegawa dementia..."

Quantifies the selective frontal-executive deficit with preserved global cognition described in this phenotype.

PMID:25101480 SUPPORT Human Clinical

"Mild frontal-subcortical affective and cognitive decline may be present as the disease progresses."

GeneReviews independently records the mild frontal-subcortical cognitive decline and its progressive appearance.

Impaired vibratory sensation HP:0002495

Show evidence (1 reference)

PMID:25476002 SUPPORT Human Clinical

"All patients showed slowly progressive cerebellar ataxia frequently accompanied by hearing and cognitive impairments, tremor, ptosis and reduced vibration sense"

Lists reduced vibration sense among the accompanying features in the multicentre cohort.

🧬

Genetic Associations

1

NOP56 (GGCCTG hexanucleotide repeat expansion in intron 1)

Gene: NOP56 hgnc:15911 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:21683323 SUPPORT Human Clinical

"we sequenced 33 of these and observed a large expansion of an intronic GGCCTG hexanucleotide repeat in NOP56"

Identifies NOP56 as the SCA36 gene and the expansion as the causal allele.

PMID:37810464 SUPPORT Human Clinical

"NOP56 encodes a ubiquitously expressed core scaffolding protein that stabilizes the box C/D small nucleolar ribonuclear protein complex."

Supports the gene-function statement in the notes for this block.

PMID:35309140 SUPPORT Other

"These findings were not able to support the haploinsufficiency hypothesis."

Supports the note that loss of NOP56 dosage is not the favored mechanism. Evidence source is OTHER because this is a narrative review.

+ 1 more reference

Variants (1)

NOP56 intron 1 GGCCTG hexanucleotide repeat expansion Pathogenic

Gene: NOP56 hgnc:15911 hexanucleotide repeat expansion

Non-coding hexanucleotide repeat expansion in intron 1 of NOP56. Normal alleles carry 3-14 repeats. Typical pathogenic alleles carry roughly 650 or more, up to about 2500, but three affected individuals in a multicentre cohort carried only 25, 30 and 31 repeats with clinical features indistinguishable from carriers of long expansions, so a short expansion does not exclude the diagnosis.

Show evidence (3 references)

PMID:25476002 SUPPORT Human Clinical

"three affected individuals harboured small hexanucleotide expansions of 25, 30 and 31 hexanucleotide repeat-units, demonstrating that such a small expansion could cause the disease"

Establishes that short expansions are pathogenic, the clinically important caveat recorded in this variant description.

PMID:37810464 SUPPORT Human Clinical

"The normal alleles contain 3–14 hexanucleotide repeats, while the expanded alleles range from 30 to 2500 repeats (mostly between 650 and 2500 repeats)."

Defines the normal and expanded repeat ranges quoted here.

PMID:25101480 SUPPORT Human Clinical

"Affected individuals typically have alleles with 650 or more repeats."

GeneReviews gives the conventional diagnostic threshold for a typical expanded allele.

💊

Medical Actions

11

Multidisciplinary supportive care

Action: Supportive Care NCIT:C15747

There is no disease-modifying therapy. Management is supportive and multidisciplinary, centered on exercise, gait and balance work, weight control and mobility aids.

Show evidence (1 reference)

PMID:25101480 SUPPORT Human Clinical

"Treatment of SCA36 involves multidisciplinary specialists and focuses on routine exercise and physical therapy with attention to gait and balance, weight control, and walking aids to facilitate ambulation and mobility."

GeneReviews management recommendation underlying this treatment entry.

Physical therapy

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

Routine exercise and physical therapy directed at gait and balance, with walking aids as ambulation declines.

Target Phenotypes: Truncal ataxia HP:0002078

Show evidence (1 reference)

PMID:25101480 SUPPORT Human Clinical

"focuses on routine exercise and physical therapy with attention to gait and balance, weight control, and walking aids to facilitate ambulation and mobility"

GeneReviews recommends physical therapy for the gait and balance impairment this treatment targets.

Speech and occupational therapy

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

Occupational therapy for fine motor coordination and speech therapy with communication devices for progressive dysarthria.

Target Phenotypes: Dysarthria HP:0001260

Show evidence (1 reference)

PMID:25101480 SUPPORT Human Clinical

"Occupational therapy aids fine movement coordination; speech therapy and communication devices for those with dysarthria."

GeneReviews recommends both therapies for the deficits named here.

Hearing aids and cochlear implantation

Action: hearing rehabilitation with amplification or cochlear implantation Ontology label: Rehabilitation NCIT:C15315

Amplification or cochlear implantation with audiologic rehabilitation for the sensorineural hearing loss, with annual or biannual otolaryngology surveillance.

Target Phenotypes: Sensorineural hearing impairment HP:0000407

Show evidence (1 reference)

PMID:25101480 SUPPORT Human Clinical

"Hearing loss may require hearing aids or cochlear implants, together with audiologic rehabilitation."

GeneReviews management recommendation for the hearing loss this treatment targets.

Feeding and swallowing management

Action: dietary assessment and feeding therapy Ontology label: Dietary Intervention NCIT:C15447

Dietary assessment and feeding therapy to manage the swallowing difficulty and reduce aspiration risk that follow bulbar denervation.

Target Phenotypes: Dysphagia HP:0002015

Show evidence (1 reference)

PMID:25101480 SUPPORT Human Clinical

"Dietary assessment and feeding therapy programs can improve dysphagia and reduce the risk of aspiration."

GeneReviews recommends exactly this intervention for the dysphagia and aspiration risk it targets.

Cognitive therapy and psychological support

Action: cognitive therapy and psychological support Ontology label: Psychotherapy NCIT:C15308

Cognitive therapy, treatment of depression, and psychological support for the frontal-subcortical cognitive and affective decline that accumulates as the disease progresses.

Target Phenotypes: Impaired executive functioning HP:0033051 Depression HP:0000716 Apathy HP:0000741

Show evidence (1 reference)

PMID:25101480 SUPPORT Human Clinical

"Emotional and cognitive decline can be addressed in cognitive therapy, treatment of depression, and psychological support."

GeneReviews recommends these three measures for the cognitive and affective phenotypes this treatment targets.

Neurologic and audiologic surveillance

Category: Monitoring

At least annual neurologic evaluation, more often if manifestations are progressing, with annual or biannual otolaryngology review for hearing loss and ongoing surveillance of speech and ambulation.

Show evidence (2 references)

PMID:25101480 SUPPORT Human Clinical

"At least annual evaluation by a neurologist or more frequently if manifestations are progressing."

GeneReviews sets the minimum neurologic review interval recorded here.

PMID:25101480 SUPPORT Human Clinical

"Annual or biannual evaluation by an otolaryngologist to monitor possible hearing loss."

GeneReviews sets the audiologic review interval recorded here.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Counseling for at-risk relatives, given complete but age-dependent penetrance and a 50% transmission risk to offspring. Predictive testing is possible once the familial expansion is identified.

Show evidence (1 reference)

PMID:25101480 SUPPORT Human Clinical

"Offspring of affected individuals have a 50% chance of inheriting the NOP56 pathogenic variant."

Establishes the transmission risk that makes counseling appropriate.

Antisense oligonucleotides targeting the expanded NOP56 repeat (investigational)

Preclinical only. Antisense oligonucleotides directed at the expanded repeat or at NOP56 intron 1 reduce RNA foci in patient iPSCs and iPSC-derived neurons and reduce poly(GP) in patient fibroblasts and lymphoblastoid cells. Because NOP56 is an essential protein, the therapeutic window depends on suppressing the repeat-containing transcript without lowering total NOP56, which has been achieved at low ASO doses. No clinical trial in SCA36 has been reported.

Mechanism Target:

NOP56 Intron 1 Retention and Nuclear GGCCUG RNA Foci — The ASOs act directly on the repeat-containing transcript, reducing the foci burden this node describes.

Show evidence (1 reference)

PMID:28918022 SUPPORT In Vitro

"One of the ASOs reduced the number of RNA-foci-positive cells without altering NOP56 mRNA expression levels in patient iPSCs and iPSC-derived neurons."

Demonstrates the intended effect on the target node while sparing total NOP56, which is the key therapeutic-window question.

Show evidence (1 reference)

PMID:32375063 SUPPORT In Vitro

"Together, our data provide proof-of-principle that ASOs targeting the expanded TG3C2 repeat can be a viable therapeutic strategy for reducing repeat-RNA and DPRs in SCA36"

States the preclinical proof-of-principle status of this approach, which is why the entry is labeled investigational.

Porphyrin derivatives targeting repeat RNA G-quadruplexes (investigational)

Action: Pharmacotherapy NCIT:C15986

Agent: sodium copper chlorophyllin CHEBI:232141 hemin chloride CHEBI:50385

Preclinical only. The GGCCUG repeat can adopt G-quadruplex structures, and porphyrin derivatives that distort such structures were screened in SCA36 cell models. Sodium copper chlorophyllin and hemin chloride reduced expansion-mediated cytotoxicity and improved viability. No human data exist.

Mechanism Target:

NOP56 Intron 1 Retention and Nuclear GGCCUG RNA Foci — The proposed action is on the structure of the repeat RNA itself, the species that forms the foci.

Show evidence (1 reference)

PMID:33705846 SUPPORT In Vitro

"Among these, sodium copper chlorophyllin and hemin chloride, which have already been used in clinical practice, reduced SCA36 GGCCTG expansion-mediated cytotoxicity and improved cell viability."

Reports the cell-model effect attributed to acting on the repeat RNA this mechanism link targets.

Show evidence (1 reference)

PMID:33705846 SUPPORT In Vitro

"These data suggest that porphyrins are potential therapeutic candidates against SCA36 pathogenesis."

The authors frame the result as candidate-generating, which is why this entry is labeled investigational rather than as an established therapy.

Transcription elongation suppression (Supt4a knockdown, erythromycin) (investigational)

Action: Pharmacotherapy NCIT:C15986

Agent: erythromycin CHEBI:48923

Preclinical only. Knocking down Supt4a, the murine ortholog of the yeast transcription elongation factor Spt4, and treating with erythromycin both reduced repeat RNA foci, dipeptide repeat protein formation and cytotoxicity in an SCA36 cell model, by acting on transcription of the expanded repeat rather than on its downstream products. This is a cell-model result only.

Mechanism Target:

NOP56 Intron 1 Retention and Nuclear GGCCUG RNA Foci — Both interventions act upstream of the foci, on transcription of the repeat-containing message, and are scored by foci burden.

Show evidence (1 reference)

PMID:30610877 SUPPORT In Vitro

"Supt4a knockdown and erythromycin treatment suppressed the formation of (GGCCUG)exp RNA foci and DPR protein formation via regulation of (GGCCUG)exp mRNA, thereby ameliorating the cytotoxicity in SCA36 cell models."

Reports the effect on the target node and names the mechanism by which it is achieved.

Show evidence (1 reference)

PMID:30610877 SUPPORT In Vitro

"These data provide a basis for developing effective therapeutic strategies for the treatment of SCA36 and other repeat expansion disorders."

The authors position the result as a starting point for development, not as a demonstrated therapy, which is why this entry is investigational.

🔬

Diagnosis

1

Repeat-primed PCR for the NOP56 GGCCTG expansion

Molecular confirmation rests on detecting the expansion, since the clinical picture overlaps other late-onset dominant ataxias. Repeat-primed PCR gives the characteristic sawtooth trace; Southern blotting sizes the expansion, though somatic instability produces a smeared band. Repeat expansions can also be called from whole-genome sequencing with dedicated bioinformatic tools, which is how the British cohort was identified.

Show evidence (4 references)

PMID:25101480 SUPPORT Human Clinical

"Confirmation of the diagnosis relies on detection of an abnormal hexanucleotide GGCCTG repeat expansion in NOP56."

GeneReviews states that molecular detection of the expansion is the diagnostic standard.

PMID:28918022 SUPPORT In Vitro

"A typical saw-tooth pattern by repeat expansion is observed in SCA36 patient iPSCs, but not in healthy control iPSCs."

Illustrates the repeat-primed PCR sawtooth signature described here.

PMID:37810464 SUPPORT Human Clinical

"Leveraging novel bioinformatic tools to detect repeat expansions from whole-genome sequencing, we analyse the NOP56 repeat in 1257 British patients with hereditary ataxia and in 7506 unrelated controls."

Supports the whole-genome-sequencing route to diagnosis added in this description.

+ 1 more reference

🩻

Imaging Findings

3

Cerebellar vermis atrophy

Atrophy of the superior cerebellar vermis is the earliest structural abnormality, appearing early in the ataxic stage; MRI is normal in asymptomatic and preataxic carriers and there is no significant cerebellar atrophy before age 50.

Mri

Cerebellar vermis atrophy HP:0006855

Show evidence (2 references)

PMID:27862279 SUPPORT Human Clinical

"MRI was normal in asymptomatic and preataxic individuals and showed superior cerebellar vermis atrophy early in the ataxic stage, diffuse cerebellar atrophy some years into the disease course, and a pattern of olivopontocerebellar atrophy in the oldest patients."

Volumetric MRI study establishing vermian atrophy as the earliest structural change.

PMID:27862279 SUPPORT Human Clinical

"There was no significant cerebellar atrophy in patients younger than 50 years."

Supports the age qualification stated in the description.

Olivopontocerebellar atrophy

Late-stage MRI shows an olivopontocerebellar pattern, involving brainstem structures beyond the cerebellum.

Mri

Olivopontocerebellar atrophy HP:0002542

Show evidence (1 reference)

PMID:22492559 SUPPORT Human Clinical

"Magnetic resonance imaging findings were consistent with the clinical course, showing atrophy of the cerebellar vermis in initial stages, later evolving to a pattern of olivo-ponto-cerebellar atrophy."

Documents the late olivopontocerebellar pattern in the Galician cohort.

Cerebellar glucose hypometabolism

FDG-PET detects hypometabolism in the vermis and right cerebellar hemisphere in asymptomatic expansion carriers, spreading to both hemispheres and the brainstem once ataxia is established. This is the earliest detectable abnormality in SCA36 and precedes structural change; it is not a validated screening biomarker.

Pet Diagnostic

Cerebellar hypometabolism on FDG PET HP:0012658

HPO has no cerebellar-specific FDG-PET hypometabolism term. The regional children of HP:0012658 cover prefrontal (HP:0012659), thalamic (HP:0012660), hypothalamic (HP:0012661) and parietal (HP:0012662) hypometabolism only, so the parent term is bound and the cerebellar specificity is carried in preferred_term rather than manufactured as a narrower match.

Show evidence (1 reference)

PMID:27862279 SUPPORT Human Clinical

"FDG-PET revealed hypometabolism in the asymptomatic stage in the vermis and right cerebellar hemisphere."

Establishes presymptomatic cerebellar hypometabolism as an FDG-PET finding.

📈

Progression

3

Presymptomatic expansion carrier

Age: under 50 years

MRI is normal at this stage; only cerebellar glucose hypometabolism is detectable.

Show evidence (1 reference)

PMID:27862279 SUPPORT Human Clinical

"Our results revealed neuronal dysfunctions in the vermis and right cerebellar hemisphere as soon as a decade before the onset of motor symptoms."

Establishes a measurable presymptomatic phase, detectable by FDG-PET about a decade before motor onset.

Ataxic onset

Age: fourth to seventh decade, mean onset around 53 years

Show evidence (2 references)

PMID:22744658 SUPPORT Human Clinical

"The age at onset of ataxia was 53.1 ± 3.4 years, with the most frequent symptoms being truncal ataxia (100% of patients), ataxic dysarthria (100%), limb ataxia (93%), and hyperreflexia (79%)."

Gives the mean age at onset and the presenting cerebellar syndrome for this phase.

PMID:25476002 SUPPORT Human Clinical

"with the age at onset ranging between 39 and 65 years"

Gives the observed onset range across the multicentre cohort.

Established disease with motor neuron involvement

Age: typically more than a decade after onset

Cerebellar atrophy becomes diffuse and eventually shows an olivopontocerebellar pattern; frontal-executive and affective changes accumulate.

Show evidence (2 references)

PMID:22744658 SUPPORT Human Clinical

"Tongue fasciculation and subsequent atrophy were found in 71% of cases, particularly in those of long duration."

Ties the bulbar motor neuron features to longer disease duration, which is what defines this later phase.

PMID:27123487 SUPPORT Human Clinical

"Evidence of lower motor neuron involvement, including atrophy and fasciculation in the limb muscles and tongue, was mostly found in patients with prolonged disease duration."

Independent replication in a second population that motor neuron signs are a late-phase feature.

📊

Prevalence

5

Worldwide

Unknown Rare

No population-based prevalence estimate exists. The multicentre survey that screened 676 unrelated SCA index cases across France, Germany and Japan describes the disorder as rare with a worldwide distribution.

Show evidence (1 reference)

PMID:25476002 SUPPORT Human Clinical

"SCA36 is rare with a worldwide distribution."

Direct statement of the coarse rarity band from the largest multicentre screen.

Galician ataxia families (Costa da Morte founder region, Spain)

Unknown Unknown

A relative frequency among ataxia families, not a population rate: 10 of 160 Galician spinocerebellar ataxia families carried the expansion, making SCA36 the most frequent dominant SCA in that region. The founder mutation there is estimated to be roughly 1275 years old.

Show evidence (1 reference)

PMID:22492559 SUPPORT Human Clinical

"Out of 160 Galician families with spinocerebellar ataxia, 10 (6.3%) were found to have spinocerebellar ataxia 36"

Quantifies the Galician founder cluster as a fraction of screened ataxia families.

Japanese ataxia cohort

Unknown Unknown

A relative frequency among ataxia patients, not a population rate: nine of 251 molecularly undiagnosed Japanese SCA patients carried the expansion, all on a shared founder haplotype.

Show evidence (1 reference)

PMID:21683323 SUPPORT Human Clinical

"In total, nine unrelated cases were found in 251 cohort SCA patients (3.6%). A founder haplotype was confirmed in these cases."

Quantifies the Japanese founder cluster within the screened SCA cohort.

Han Chinese ataxia pedigrees (Taiwan)

Unknown Unknown

A relative frequency among ataxia pedigrees, not a population rate: three of 512 SCA pedigrees, sharing a 5.3 kb founder haplotype. The expansion was absent from controls and from sporadic ataxia and ALS patients in the same study.

Show evidence (1 reference)

PMID:27123487 SUPPORT Human Clinical

"SCA36 is an uncommon subtype, which accounted for 0.6% (3/512) of SCA cases in the Han Chinese population."

Quantifies the Han Chinese cluster as a fraction of screened SCA pedigrees.

British hereditary ataxia patients

Unknown Unknown

A relative frequency among ataxia patients, not a population rate: five families (seven patients) among 1,257 British patients with hereditary ataxia, the first White British cohort reported. SCA36 had previously been thought absent from the British population. The 87 kb block shared by these families was also found in several controls, so it reads as a permissive haplotype rather than a founder chromosome, unlike the Galician, Japanese and Han Chinese clusters.

Show evidence (2 references)

PMID:37810464 SUPPORT Human Clinical

"We identify pathogenic repeat expansions in five families (seven patients), representing the first cohort of White British descent patients with spinocerebellar ataxia 36."

Quantifies the British cluster within the screened hereditary-ataxia cohort.

PMID:37810464 SUPPORT Human Clinical

"we found an 87 kb shared haplotype in among the affected individuals from five families around the NOP56 repeat region, although this block was also shared between several controls, suggesting that the repeat arises on a permissive haplotype"

Supports the permissive-haplotype reading recorded in the notes, which is what distinguishes this cluster from the founder populations.

⚖️

Clinical Burden

High

SCA36 is a progressive, incurable neurodegenerative disorder. Gait and speech deteriorate over more than a decade, hearing loss compounds communication difficulty, and bulbar motor neuron involvement adds dysphagia and aspiration risk. Management is entirely supportive.

Show evidence (1 reference)

PMID:25101480 SUPPORT Human Clinical

"Dietary assessment and feeding therapy programs can improve dysphagia and reduce the risk of aspiration."

GeneReviews identifies dysphagia and aspiration as complications requiring active prevention, which is part of the burden recorded here.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Spinocerebellar Ataxia Type 36:

Amyotrophic lateral sclerosis

Overlapping Features The tongue and limb fasciculation, atrophy and hyperreflexia of SCA36 raise motor neuron disease, but SCA36 lacks the widespread muscle involvement and rapid course of classical ALS, motor neuron involvement is largely confined to lower motor neurons of the caudal brainstem, and TDP-43 pathology is absent. Screening ALS cohorts for the NOP56 expansion has been negative.

Show evidence (2 references)

PMID:22492559 SUPPORT Human Clinical

"There were signs of denervation in the tongue, as well as mild pyramidal signs, but otherwise no signs of classical amyotrophic lateral sclerosis."

Explicitly separates the SCA36 motor phenotype from classical ALS.

PMID:27123487 SUPPORT Human Clinical

"NOP56 repeat expansion was not detected in controls or patients with sporadic ataxic syndromes or ALS."

Supports the statement that ALS cohort screening has been negative.

Other late-onset autosomal dominant spinocerebellar ataxias

Overlapping Features SCA36 presents as a slowly progressive late-onset cerebellar syndrome indistinguishable at first from other dominant SCAs; sensorineural hearing loss and tongue fasciculation are the discriminating clinical clues, and audiometry separates SCA36 from other degenerative ataxias statistically. Neither clue is required, so the diagnosis should still be considered in late-onset slowly progressive ataxia without them.

Show evidence (2 references)

PMID:23140984 SUPPORT Human Clinical

"PTA was significantly decreased in Asidan/SCA36 in comparison to normal control and other ataxic groups, but not significant within other ataxic groups and normal control."

Provides the quantitative basis for using hearing as a discriminator against other degenerative ataxias.

PMID:37810464 SUPPORT Human Clinical

"spinocerebellar ataxia 36 can be suspected in patients with a late-onset, slowly progressive ataxia, even without the findings of hearing loss and tongue fasciculation"

Supports the caveat that the two discriminating clues are not required for the diagnosis.

🧫

Experimental Models

2

SCA36 patient iPSC-derived neurons IPSC_DERIVED_MODEL

Induced pluripotent stem cells reprogrammed from SCA36 patient fibroblasts and peripheral blood mononuclear cells, differentiated into neurons including Islet1-positive motor neurons. The model reproduces the sense RNA foci of patient tissue and was used to test ethylene-bridged nucleic acid antisense oligonucleotides.

Organism

human NCBITaxon:9606

Publication

PMID:28918022

Pathograph links

NOP56 Intron 1 Retention and Nuclear GGCCUG RNA Foci recapitulates fidelity: moderate Patient-derived neurons carrying the endogenous expansion form intranuclear sense RNA foci at significantly higher frequency than control neurons, reproducing the hallmark molecular lesion in a human neuronal context.

Limitations: The model captures foci formation but not the decades-long degenerative course, and iPSC-derived neurons are developmentally immature relative to the adult Purkinje cells and motor neurons that degenerate in patients.

Readouts

Proportion of RNA-foci-positive cells

Direction: INCREASED

Interpretation: Foci burden is the primary molecular readout of repeat RNA toxicity in this model and the endpoint used for ASO screening.

Show evidence (1 reference)

PMID:28918022 SUPPORT In Vitro

"The number of RNA-foci-positive cells was increased in patient iPSCs and iPSC-derived neurons."

Reports the directional measurement this readout records.

Show evidence (1 reference)

PMID:28918022 SUPPORT In Vitro

"These data show that iPSCs from spinocerebellar ataxia type 36 patients can be useful for evaluating the effects of ASOs toward GGCCTG repeat expansion in spinocerebellar ataxia type 36."

The authors' own statement of what the model is informative for, which matches the mechanism node it is linked to here.

Neuro2A cells expressing expanded GGCCTG/CAGGCC repeats CELL_LINE

Murine Neuro2A neuroblastoma cells transfected with expanded SCA36 repeats, used to screen candidate compounds and RNA-directed interventions against foci formation and cytotoxicity.

Organism

mouse NCBITaxon:10090

Publication

PMID:30610877

Pathograph links

NOP56 Intron 1 Retention and Nuclear GGCCUG RNA Foci recapitulates fidelity: low Transfected expanded repeats produce sense but not antisense RNA foci, matching the strand asymmetry seen in patient autopsy tissue.

Limitations: An overexpression construct in a murine neuroblastoma line, not the endogenous NOP56 locus, and DPR production in this system was rare, so it models repeat RNA behavior rather than the full SCA36 lesion.

Readouts

Sense (GGCCUG)exp RNA foci

Direction: INCREASED

Interpretation: Presence of sense-only foci reproduces the strand asymmetry observed in SCA36 autopsy brain.

Show evidence (1 reference)

PMID:30610877 SUPPORT In Vitro

"Sense (GGCCUG)exp but not antisense (CAGGCC)exp RNA foci were detected in the cells, consistent with observations in autopsied brains of patients with SCA36."

Reports the measurement and its correspondence with human tissue.

Show evidence (1 reference)

PMID:30610877 SUPPORT In Vitro

"Supt4a knockdown and erythromycin treatment suppressed the formation of (GGCCUG)exp RNA foci and DPR protein formation via regulation of (GGCCUG)exp mRNA, thereby ameliorating the cytotoxicity in SCA36 cell models."

Demonstrates that manipulating repeat RNA in this model changes both foci and viability, which is what makes it informative for the foci node.

🐁

Animal Models

2

AAV-delivered (TG3C2)62 repeat-expressing mouse Somatic brain transgenesis

The only in vivo demonstration that the SCA36 repeat itself is sufficient to kill Purkinje cells. Expressing a 62-unit TG3C2 repeat throughout the mouse CNS reproduces the SCA36 pattern of selective vulnerability — Purkinje cell loss and locomotor impairment — while the near-identical C9orf72 G4C2 repeat in the same paradigm instead produces cortical loss and pTDP-43 pathology. The contrast is the point: the two repeats differ by one nucleotide, so the divergence localizes the pathomechanism to the repeat sequence rather than to its host gene.

Species

Mouse

Genotype

Wild-type C57BL/6 mice given intracerebroventricular AAV9-NOP56-(TG3C2)62 at postnatal day 0; AAV9-NOP56-(TG3C2)6 as the control construct

Background

C57BL/6

Genes

NOP56 hgnc:15911

Publication

PMID:32375043

Pathograph links

Purkinje Cell Degeneration recapitulates fidelity: moderate Repeat-expressing mice lose cerebellar Purkinje cells and show the dendritic and locomotor consequences of that loss, matching the central effector node of this entry.

Limitations: The construct carries 62 repeats against the 650-2500 of a typical patient allele, and is delivered from an AAV vector rather than expressed from the endogenous NOP56 locus, so dosage and regulation both differ from the human disease. The study assessed cerebellar and cortical outcomes and does not address the lower motor neuron involvement or the sensorineural hearing loss that distinguish SCA36 clinically, so it models the cerebellar arm of the disease only.

Readouts

Cerebellar Purkinje cell number

Direction: DECREASED

Interpretation: Direct cell-count correlate of the degeneration node in this model.

Show evidence (1 reference)

PMID:32375043 SUPPORT Model Organism

"we found that (TG3C2)62 mice show a dramatic loss of cerebellar Purkinje cells"

Reports the directional measurement this readout records.

Purkinje dendritic arborization and molecular layer width

Direction: DECREASED

Interpretation: Structural correlate showing the loss is not only of cell bodies but of the dendritic network they support.

Show evidence (1 reference)

PMID:32375043 SUPPORT Model Organism

"We used the Purkinje cell marker calbindin to look at the dendritic arborization of these neurons and observed not only a reduction in the number of cell bodies, but also a narrowing of the molecular cell layer in the cerebellum of (TG3C2)62 mice"

Reports both measurements this readout records.

Rotating rod and hanging wire performance

Direction: DECREASED

Interpretation: Functional correlate of the cerebellar lesion, the model's analogue of the ataxia that Purkinje loss produces in patients.

Show evidence (1 reference)

PMID:32375043 SUPPORT Model Organism

"(TG3C2)62 mice showed a pronounced locomotor defect compared with controls, as evidenced by impaired performance in the rotating rod test"

Reports the behavioural measurement this readout records.

Show evidence (1 reference)

PMID:32375043 SUPPORT Model Organism

"Instead, these mice show a robust loss of cerebellar Purkinje cells, as well as pronounced locomotor defects, phenotypes highly reminiscent of SCA36."

The authors' own statement that the model reproduces the SCA36 pattern, which is what makes it informative for this node.

Dipeptide Repeat Protein Production from the Expanded Repeat recapitulates fidelity: moderate The mouse reproduces the specific DPR biology curated at this node, including the feature that distinguishes SCA36 from C9orf72 disease: poly(GP) is produced but stays soluble rather than forming inclusions.

Limitations: Poly(PR), detected in human SCA36 granule cells, was not robustly reproduced in this model, so the antisense RAN-translation arm of the node is not covered by it.

Readouts

Diffuse poly(GP) immunoreactivity in Purkinje cells

Direction: INCREASED

Interpretation: Confirms DPR production in vivo and, by its diffuse distribution, reproduces the solubility that separates SCA36 from C9orf72 disease.

Show evidence (1 reference)

PMID:32375043 SUPPORT Model Organism

"Although we detected poly(GP) in our SCA36 mice, intriguingly it does not form inclusions and instead remains diffuse."

Reports both the presence and the solubility this readout records.

Show evidence (1 reference)

PMID:32375043 SUPPORT Model Organism

"Furthermore, because the RNA foci and RAN translation we observe in the cerebellum of our mice are in the Purkinje cells, we suspect that this degeneration is at least in part cell autonomous."

Places RAN translation in the same cells that degenerate, which is what makes the model informative for the DPR node.

The model is also an informative negative for the C9orf72 comparison this entry draws in histopathology: no pTDP-43 inclusions and no persistent stress granules were seen at 3-4, 6 or 12 months, matching the absence of TDP-43 pathology in SCA36 patient tissue.

nop56 loss-of-function zebrafish Germline null

A complete loss-of-function model of the SCA36 host gene, made to ask what losing NOP56 actually does — the question the haploinsufficiency hypothesis turns on, and one no repeat-expansion model can answer. The answer is that it is not SCA36: homozygous nulls fail to form a cerebellum at all and die before 7 days post-fertilization.

Species

Zebrafish

Genotype

nop56sa12582 homozygous loss-of-function

Genes

NOP56 hgnc:15911

Publication

PMID:36009362

Pathograph links

Purkinje Cell Degeneration fails to recapitulate fidelity: low Complete loss of nop56 does not reproduce the adult-onset, selective Purkinje degeneration of SCA36. It produces an embryonic-lethal failure of cerebellar development instead — the cerebellum is absent rather than degenerating — which is the structural argument against dosage loss being the SCA36 mechanism.

Limitations: The comparison is not like-for-like in three ways at once: a homozygous germline null against a heterozygous repeat expansion, zebrafish against human, and embryonic development against adult maintenance. The model therefore bounds what NOP56 loss can look like; it does not by itself prove that dosage plays no part in SCA36, and the patient-cell expression data remain the direct evidence for that.

Readouts

Cerebellar structure at larval stage

Direction: ABOLISHED

Interpretation: The cerebellum never forms, so there is no Purkinje population to degenerate — a developmental failure, not the degenerative phenotype this node describes.

Show evidence (1 reference)

PMID:36009362 SUPPORT Model Organism

"We observed a severe neurodegenerative phenotype in nop56 mutants, characterized mainly by absence of cerebellum, reduced numbers of spinal cord neurons, high levels of apoptosis in the central nervous system (CNS) and impaired movement, resulting in death before 7 days post-fertilization."

Reports the absent cerebellum and the embryonic lethality that make this a failure to recapitulate rather than a partial match.

Show evidence (1 reference)

PMID:36009362 REFUTE Model Organism

"Although vertebrate animal models were created for the intronic expansion, none was studied for the loss of function of NOP56."

States why this model exists and what it is testing. The phenotype it reports is incompatible with the late-onset selective degeneration of SCA36, so it argues against dosage loss as that disease's mechanism.

Impaired NOP56 Box C/D snoRNP Function perturbs fidelity: low The model is the direct experimental perturbation of the hypothetical dosage branch: it removes nop56 function outright and measures what follows, including expression of box C/D complex genes.

Readouts

Expression of box C/D complex and CNS development genes

Direction: DECREASED

Interpretation: Confirms that losing nop56 does disrupt the box C/D programme, which is what the dosage hypothesis predicts — while the organism-level phenotype shows that disruption does not produce SCA36.

Show evidence (1 reference)

PMID:36009362 SUPPORT Model Organism

"Gene expression of genes related to C/D box complex, balance and CNS development was impaired in nop56 mutants."

Reports the expression measurement this readout records.

Show evidence (1 reference)

PMID:36009362 SUPPORT Model Organism

"We studied a zebrafish loss-of-function model of the nop56 gene which shows 70% homology with the human gene."

Establishes that the model perturbs the orthologous gene, which is what makes it informative for this hypothetical node.

{ }

Source YAML

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name: Spinocerebellar Ataxia Type 36
creation_date: "2026-09-02T13:15:15Z"
description: >-
  Spinocerebellar ataxia type 36 (SCA36, nicknamed "Asidan") is a late-adult-onset,
  slowly progressive autosomal dominant cerebellar ataxia caused by expansion of a
  GGCCTG hexanucleotide repeat in the first intron of NOP56. It is distinguished
  from most other dominant ataxias by progressive motor neuron involvement —
  tongue fasciculation and atrophy, limb and truncal fasciculation, and
  hyperreflexia — and by frequent sensorineural hearing loss, so that it is
  often described as standing at the crossroads of spinocerebellar ataxia and
  motor neuron disease. Founder haplotypes cluster the disorder in western Japan
  (the Asida river area of the Chugoku region) and in Galicia, Spain (Costa da
  Morte), with further founder clusters in Han Chinese pedigrees; a British
  series has since shown it also occurs where hearing loss and tongue
  fasciculation are largely absent. NOP56 expression is not appreciably reduced
  in patient cells, so the disorder is attributed to RNA gain of function: the
  expanded repeat is retained in intron 1, forms nuclear GGCCUG RNA foci that
  bind the splicing factor SRSF2, and is translated into dipeptide repeat
  proteins by canonical AUG-mediated and repeat-associated non-AUG translation.
  Downregulation of the adjacent miRNA MIR1292 is reproducible across cohorts
  but its causal contribution is unresolved.
category: Mendelian
parents:
- autosomal dominant disease
- spinocerebellar ataxia
synonyms:
- SCA36
- spinocerebellar ataxia 36
- Asidan
- Asidan ataxia
- Costa da Morte ataxia
disease_term:
  preferred_term: spinocerebellar ataxia type 36
  term:
    id: MONDO:0013594
    label: spinocerebellar ataxia type 36
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      Placed with the neurological disorders as a hereditary cerebellar ataxia
      with motor neuron involvement. Harrison's does not list SCA36
      individually; this is a system- and mechanism-based placement.
references:
- reference: PMID:25101480
  title: "Spinocerebellar Ataxia Type 36 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
  tags:
  - GeneReviews
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    SCA36 segregates as an autosomal dominant trait in multiplex Japanese,
    Galician, Han Chinese and British kindreds carrying founder-associated
    GGCCTG expansions. GeneReviews describes penetrance as complete but
    age dependent, consistent with a mean onset in the fifth decade. Repeat
    size was observed to grow on paternal and to contract on maternal
    transmission in the Galician kindreds, though a general parent-of-origin
    rule has not been established across cohorts.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: COMPLETE
  parent_of_origin_effect: >-
    Repeat size increased on paternal transmission and contracted on maternal
    transmission in the Galician kindreds; not established as a general rule.
  evidence:
  - reference: PMID:21683323
    reference_title: "Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The expansion showed complete segregation with the SCA phenotype in family studies"
    explanation: >-
      Complete segregation of the expansion with disease in the original
      families supports a dominant, fully penetrant gene-disease relationship.
  - reference: PMID:25101480
    reference_title: "Spinocerebellar Ataxia Type 36 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Penetrance is complete, although age-dependent."
    explanation: >-
      GeneReviews states the penetrance value recorded in this block.
  - reference: PMID:22492559
    reference_title: "'Costa da Morte' ataxia is spinocerebellar ataxia 36: clinical and genetic characterization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further expansion of repeat size was frequent, especially upon paternal transmission, while instances of allele contraction were observed in maternal transmissions."
    explanation: >-
      Documents the parent-of-origin effect on repeat size recorded here, in
      the single cohort where it was observed.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    No population-based prevalence estimate exists. The multicentre survey that
    screened 676 unrelated SCA index cases across France, Germany and Japan
    describes the disorder as rare with a worldwide distribution.
  evidence:
  - reference: PMID:25476002
    reference_title: "Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SCA36 is rare with a worldwide distribution."
    explanation: >-
      Direct statement of the coarse rarity band from the largest multicentre
      screen.
- population: Galician ataxia families (Costa da Morte founder region, Spain)
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    A relative frequency among ataxia families, not a population rate: 10 of 160
    Galician spinocerebellar ataxia families carried the expansion, making SCA36
    the most frequent dominant SCA in that region. The founder mutation there is
    estimated to be roughly 1275 years old.
  evidence:
  - reference: PMID:22492559
    reference_title: "'Costa da Morte' ataxia is spinocerebellar ataxia 36: clinical and genetic characterization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Out of 160 Galician families with spinocerebellar ataxia, 10 (6.3%) were found to have spinocerebellar ataxia 36"
    explanation: >-
      Quantifies the Galician founder cluster as a fraction of screened ataxia
      families.
- population: Japanese ataxia cohort
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    A relative frequency among ataxia patients, not a population rate: nine of
    251 molecularly undiagnosed Japanese SCA patients carried the expansion, all
    on a shared founder haplotype.
  evidence:
  - reference: PMID:21683323
    reference_title: "Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In total, nine unrelated cases were found in 251 cohort SCA patients (3.6%). A founder haplotype was confirmed in these cases."
    explanation: >-
      Quantifies the Japanese founder cluster within the screened SCA cohort.
- population: Han Chinese ataxia pedigrees (Taiwan)
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    A relative frequency among ataxia pedigrees, not a population rate: three of
    512 SCA pedigrees, sharing a 5.3 kb founder haplotype. The expansion was
    absent from controls and from sporadic ataxia and ALS patients in the same
    study.
  evidence:
  - reference: PMID:27123487
    reference_title: "Spinocerebellar ataxia type 36 in the Han Chinese."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SCA36 is an uncommon subtype, which accounted for 0.6% (3/512) of SCA cases in the Han Chinese population."
    explanation: >-
      Quantifies the Han Chinese cluster as a fraction of screened SCA
      pedigrees.
- population: British hereditary ataxia patients
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    A relative frequency among ataxia patients, not a population rate: five
    families (seven patients) among 1,257 British patients with hereditary
    ataxia, the first White British cohort reported. SCA36 had previously been
    thought absent from the British population. The 87 kb block shared by these
    families was also found in several controls, so it reads as a permissive
    haplotype rather than a founder chromosome, unlike the Galician, Japanese
    and Han Chinese clusters.
  evidence:
  - reference: PMID:37810464
    reference_title: "Repeat expansions in NOP56 are a cause of spinocerebellar ataxia Type 36 in the British population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identify pathogenic repeat expansions in five families (seven patients), representing the first cohort of White British descent patients with spinocerebellar ataxia 36."
    explanation: >-
      Quantifies the British cluster within the screened hereditary-ataxia
      cohort.
  - reference: PMID:37810464
    reference_title: "Repeat expansions in NOP56 are a cause of spinocerebellar ataxia Type 36 in the British population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we found an 87 kb shared haplotype in among the affected individuals from five families around the NOP56 repeat region, although this block was also shared between several controls, suggesting that the repeat arises on a permissive haplotype"
    explanation: >-
      Supports the permissive-haplotype reading recorded in the notes, which is
      what distinguishes this cluster from the founder populations.
progression:
- phase: Presymptomatic expansion carrier
  age_range: under 50 years
  evidence:
  - reference: PMID:27862279
    reference_title: "PET and MRI detection of early and progressive neurodegeneration in spinocerebellar ataxia type 36."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results revealed neuronal dysfunctions in the vermis and right cerebellar hemisphere as soon as a decade before the onset of motor symptoms."
    explanation: >-
      Establishes a measurable presymptomatic phase, detectable by FDG-PET
      about a decade before motor onset.
  notes: >-
    MRI is normal at this stage; only cerebellar glucose hypometabolism is
    detectable.
- phase: Ataxic onset
  age_range: fourth to seventh decade, mean onset around 53 years
  evidence:
  - reference: PMID:22744658
    reference_title: "Clinical features of SCA36: a novel spinocerebellar ataxia with motor neuron involvement (Asidan)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The age at onset of ataxia was 53.1 ± 3.4 years, with the most frequent symptoms being truncal ataxia (100% of patients), ataxic dysarthria (100%), limb ataxia (93%), and hyperreflexia (79%)."
    explanation: >-
      Gives the mean age at onset and the presenting cerebellar syndrome for
      this phase.
  - reference: PMID:25476002
    reference_title: "Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with the age at onset ranging between 39 and 65 years"
    explanation: >-
      Gives the observed onset range across the multicentre cohort.
- phase: Established disease with motor neuron involvement
  age_range: typically more than a decade after onset
  evidence:
  - reference: PMID:22744658
    reference_title: "Clinical features of SCA36: a novel spinocerebellar ataxia with motor neuron involvement (Asidan)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tongue fasciculation and subsequent atrophy were found in 71% of cases, particularly in those of long duration."
    explanation: >-
      Ties the bulbar motor neuron features to longer disease duration, which is
      what defines this later phase.
  - reference: PMID:27123487
    reference_title: "Spinocerebellar ataxia type 36 in the Han Chinese."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Evidence of lower motor neuron involvement, including atrophy and fasciculation in the limb muscles and tongue, was mostly found in patients with prolonged disease duration."
    explanation: >-
      Independent replication in a second population that motor neuron signs are
      a late-phase feature.
  notes: >-
    Cerebellar atrophy becomes diffuse and eventually shows an
    olivopontocerebellar pattern; frontal-executive and affective changes
    accumulate.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    SCA36 is a progressive, incurable neurodegenerative disorder. Gait and
    speech deteriorate over more than a decade, hearing loss compounds
    communication difficulty, and bulbar motor neuron involvement adds
    dysphagia and aspiration risk. Management is entirely supportive.
  evidence:
  - reference: PMID:25101480
    reference_title: "Spinocerebellar Ataxia Type 36 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dietary assessment and feeding therapy programs can improve dysphagia and reduce the risk of aspiration."
    explanation: >-
      GeneReviews identifies dysphagia and aspiration as complications requiring
      active prevention, which is part of the burden recorded here.
pathophysiology:
- name: Intronic GGCCTG Repeat Expansion in NOP56
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cerebellar_purkinje_degeneration#Cerebellar Neuron Insult"
  description: >-
    The initiating lesion is a heterozygous expansion of a GGCCTG hexanucleotide
    repeat in intron 1 of NOP56, which encodes a core scaffold protein of the
    box C/D small nucleolar ribonucleoprotein complex. Normal alleles carry
    3-14 repeats; typical pathogenic alleles carry roughly 650-2500, although
    expansions as short as 25-31 repeats have been shown to cause the disease.
    This is the disorder-specific molecular insult substituted for the generic
    trigger node of the Purkinje degeneration module.
  genes:
  - preferred_term: NOP56
    term:
      id: hgnc:15911
      label: NOP56
  evidence:
  - reference: PMID:21683323
    reference_title: "Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we sequenced 33 of these and observed a large expansion of an intronic GGCCTG hexanucleotide repeat in NOP56"
    explanation: >-
      Identifies the causal repeat expansion as the initiating molecular lesion
      of SCA36.
  - reference: PMID:37810464
    reference_title: "Repeat expansions in NOP56 are a cause of spinocerebellar ataxia Type 36 in the British population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The normal alleles contain 3–14 hexanucleotide repeats, while the expanded alleles range from 30 to 2500 repeats (mostly between 650 and 2500 repeats)."
    explanation: >-
      Establishes the normal and pathogenic repeat ranges quoted in this node.
  downstream:
  - target: NOP56 Intron 1 Retention and Nuclear GGCCUG RNA Foci
    causal_link_type: DIRECT
    description: >-
      The expanded repeat is transcribed and retained rather than efficiently
      spliced out, so repeat RNA accumulates in the nucleus.
    evidence:
    - reference: PMID:32375063
      reference_title: "Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we demonstrate that expanded TG3C2 repeats in SCA36 impair splicing of NOP56 and result in retention of the repeat-containing intron 1"
      explanation: >-
        Directly links the expansion to impaired splicing and intron 1
        retention, which is the step this edge asserts.
  - target: MIR1292 Downregulation
    causal_link_type: UNKNOWN
    description: >-
      Transcription of MIR1292, whose gene lies 19 bp downstream of the repeat,
      is reduced in cells from expansion carriers. Whether this is a cis
      consequence of the expansion and whether it contributes to
      neurodegeneration is unresolved.
    evidence:
    - reference: PMID:21683323
      reference_title: "Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "transcription of MIR1292, a neighboring miRNA, was significantly decreased in lymphoblastoid cells of SCA patients"
      explanation: >-
        Establishes the association between carrier status and reduced MIR1292
        transcription; the causal direction is left open by the UNKNOWN link
        type on this edge.
  - target: Cochlear and Peripheral Auditory Dysfunction
    causal_link_type: UNKNOWN
    description: >-
      Sensorineural hearing loss is a genotype-associated feature of SCA36, but
      no molecular intermediate between the repeat expansion and auditory
      involvement has been established.
    evidence:
    - reference: PMID:25101480
      reference_title: "Spinocerebellar Ataxia Type 36 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Spinocerebellar ataxia type 36 (SCA36) is characterized by a late-onset, slowly progressive cerebellar syndrome typically associated with sensorineural hearing loss."
      explanation: >-
        Establishes that hearing loss is part of the expansion-defined
        phenotype, which is all this UNKNOWN-mechanism edge claims.
- name: NOP56 Intron 1 Retention and Nuclear GGCCUG RNA Foci
  biological_scale: MOLECULAR
  description: >-
    Retained (GGCCUG)n repeat RNA accumulates as discrete nuclear foci. Foci
    are demonstrable by fluorescence in situ hybridization in patient
    lymphoblastoid cells, patient iPSCs and iPSC-derived neurons, and in
    autopsied brain, where sense but not antisense foci are found. In autopsy
    tissue the foci occur in neuronal nuclei of cerebrum, cerebellum, inferior
    olive, spinal cord and temporal muscle, and include giant foci nearly 10
    micrometres across in Purkinje cells and spinal motor neurons.
  biological_processes:
  - preferred_term: mRNA splicing, via spliceosome
    term:
      id: GO:0000398
      label: mRNA splicing, via spliceosome
    modifier: ABNORMAL
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  - preferred_term: spinal motor neuron
    term:
      id: CL:0011001
      label: spinal cord motor neuron
  evidence:
  - reference: PMID:21683323
    reference_title: "Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RNA foci formation was detected in lymphoblastoid cells from affected subjects by fluorescence in situ hybridization."
    explanation: >-
      First demonstration that the expanded repeat forms RNA foci in cells from
      affected individuals.
  - reference: PMID:24985895
    reference_title: "Characteristic RNA foci of the abnormal hexanucleotide GGCCUG repeat expansion in spinocerebellar ataxia type 36 (Asidan)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of interest is that the giant RNA foci, nearly 10 μm in diameter, that were detected in Purkinje cells, spinal motor neurons and most frequently in the inferior olivary nucleus, may be responsible for pivotal clinical symptoms of Asidan."
    explanation: >-
      Establishes the presence and cellular distribution of repeat RNA foci in
      human SCA36 autopsy tissue, including the two cell populations this node
      lists.
  - reference: PMID:30610877
    reference_title: "Suppression of the yeast elongation factor Spt4 ortholog reduces expanded SCA36 GGCCUG repeat aggregation and cytotoxicity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Sense (GGCCUG)exp but not antisense (CAGGCC)exp RNA foci were detected in the cells, consistent with observations in autopsied brains of patients with SCA36."
    explanation: >-
      Supports the sense-strand specificity of foci formation recorded in this
      node.
  downstream:
  - target: SRSF2 Sequestration by GGCCUG Repeat RNA
    causal_link_type: DIRECT
    description: >-
      The repeat RNA binds the SR-family splicing factor SRSF2, the proposed
      route by which foci become toxic.
    evidence:
    - reference: PMID:21683323
      reference_title: "Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Double staining and gel-shift assay showed that (GGCCUG)n binds the RNA-binding protein SRSF2 but that (CUG)(6) does not."
      explanation: >-
        Binding assays establish the specific repeat-protein interaction this
        edge asserts.
  - target: Dipeptide Repeat Protein Production from the Expanded Repeat
    causal_link_type: DIRECT
    description: >-
      Intron-retained repeat transcripts are translated, producing dipeptide
      repeat proteins.
    evidence:
    - reference: PMID:32375063
      reference_title: "Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We demonstrate that poly(GP) is more abundant in SCA36 compared to c9ALS/FTD patient tissue due to canonical AUG-mediated translation from intron-retained GGCCTG repeat RNAs."
      explanation: >-
        Attributes DPR production specifically to the intron-retained transcript
        described by the upstream node.
- name: SRSF2 Sequestration by GGCCUG Repeat RNA
  biological_scale: MOLECULAR
  description: >-
    Expanded (GGCCUG)n RNA binds SRSF2 specifically, and the resulting
    sequestration of an essential splicing factor into nuclear foci is the
    canonical RNA gain-of-function model for SCA36, by analogy with the
    MBNL-sequestration mechanism of myotonic dystrophy. NOP56 mRNA and protein
    levels and Cajal body number are not appreciably reduced in patient
    lymphoblastoid cells, which is why haploinsufficiency of NOP56 itself is not
    the favored explanation.
  molecular_functions:
  - preferred_term: mRNA binding
    term:
      id: GO:0003729
      label: mRNA binding
    modifier: ABNORMAL
  evidence:
  - reference: PMID:35309140
    reference_title: "Spinocerebellar Ataxia 36: From Mutations Toward Therapies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It seemed to be clear that these expanded repeat-containing RNAs did form such foci and could sequester RNA-binding proteins like SRSF2 and other proteins"
    explanation: >-
      Review synthesis of the sequestration model; evidence source is OTHER
      because this is a narrative minireview rather than primary data.
  - reference: PMID:35309140
    reference_title: "Spinocerebellar Ataxia 36: From Mutations Toward Therapies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These findings were not able to support the haploinsufficiency hypothesis."
    explanation: >-
      Supports the statement that NOP56 haploinsufficiency is not the favored
      mechanism, which is why this node is framed as RNA gain of function.
  downstream:
  - target: Purkinje Cell Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The steps between splicing-factor sequestration and neuronal death have
      not been resolved; the original report frames the disorder overall as RNA
      gain of function.
    evidence:
    - reference: PMID:21683323
      reference_title: "Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our finding suggests that SCA36 is caused by hexanucleotide repeat expansions through RNA gain of function."
      explanation: >-
        Supports RNA gain of function as the route from the expansion to
        neurodegeneration, with intermediates left unspecified as the edge type
        records.
  - target: Lower Motor Neuron Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The same RNA gain-of-function mechanism is invoked for the motor neuron
      arm of the disease, and foci are present in spinal motor neurons, but the
      causal relationship between foci and degeneration has not been shown.
    evidence:
    - reference: PMID:24985895
      reference_title: "Characteristic RNA foci of the abnormal hexanucleotide GGCCUG repeat expansion in spinocerebellar ataxia type 36 (Asidan)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The relationships between the giant RNA foci and neurodegeneration have yet to be studied."
      explanation: >-
        Quoted because it states the limitation directly: foci are present in
        the affected motor neurons, but the causal relationship to their
        degeneration is not established, which is why this edge is typed as
        having unknown intermediates.
- name: Dipeptide Repeat Protein Production from the Expanded Repeat
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    The intron-retained GGCCTG repeat transcript is translated into dipeptide
    repeat proteins. In patient tissue poly(GP) is produced abundantly by
    canonical AUG-mediated translation reading through the retained intron,
    while the antisense product poly(PR) indicates that repeat-associated
    non-AUG (RAN) translation also occurs. Unlike in C9orf72 disease, SCA36
    poly(GP) remains soluble and TDP-43 pathology is absent. Whether the DPRs
    are pathogenic in SCA36 or a comparatively inert byproduct is not settled —
    a Neuro2A model found RAN-derived DPR formation from expanded GGCCTG to be
    rare.
  biological_processes:
  - preferred_term: translation
    term:
      id: GO:0006412
      label: translation
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32375063
    reference_title: "Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we show the similar intronic GGCCTG HREs that causes spinocerebellar ataxia type 36 (SCA36) is also translated into DPRs, including poly(GP) and poly(PR)."
    explanation: >-
      Establishes that the SCA36 repeat is translated and names the two DPR
      species this node records.
  - reference: PMID:32375063
    reference_title: "Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, in SCA36 patient tissue, poly(GP) exists as a soluble species, and no TDP-43 pathology is present."
    explanation: >-
      Supports the solubility and absent-TDP-43 statements that distinguish
      SCA36 DPR biology from C9orf72 disease.
  - reference: PMID:30610877
    reference_title: "Suppression of the yeast elongation factor Spt4 ortholog reduces expanded SCA36 GGCCUG repeat aggregation and cytotoxicity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Glycine-proline dipeptide repeat (DPR) formation due to repeat-associated non-ATG translation rarely occurred in cells expressing expanded GGCCTG repeats; in contrast, cells harboring expanded c9orf72 GGGGCC/GGCCCC repeats robustly expressed DPR proteins."
    explanation: >-
      A cell model reporting only rare RAN-derived poly(GP), which is the
      qualification this node makes and why its mechanism confidence is
      PROVISIONAL rather than ESTABLISHED.
  downstream:
  - target: Purkinje Cell Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      DPR toxicity is proposed as a contributor to neurodegeneration in SCA36
      by analogy with C9orf72 disease, but has not been shown to cause Purkinje
      cell loss in SCA36 itself. This edge is deliberately left uncited; see the
      dpr_pathogenicity discussion.
- name: MIR1292 Downregulation
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The MIR1292 gene lies 19 bp downstream of the repeat, and its transcription
    is reduced in lymphoblastoid cells from expansion carriers in two
    independent cohorts. In the Han Chinese cohort, four of seven predicted
    targets were unchanged and three were unmeasurable in lymphoblastoid cells,
    and the authors raised the possibility that reduced MIR1292 is an
    epiphenomenon of the expansion. No downstream target has been demonstrated
    in cerebellar or motor neuron tissue, so this node is deliberately left with
    no outgoing edge; see the mir1292_contribution discussion.
  evidence:
  - reference: PMID:21683323
    reference_title: "Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "transcription of MIR1292, a neighboring miRNA, was significantly decreased in lymphoblastoid cells of SCA patients"
    explanation: >-
      The original observation underlying this node, made in patient
      lymphoblastoid cells rather than neural tissue.
  - reference: PMID:27123487
    reference_title: "Spinocerebellar ataxia type 36 in the Han Chinese."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We observed reduced microRNA-1292 expression levels (63%) in 5 patients with SCA36 compared with 5 healthy controls"
    explanation: >-
      Independent replication of the reduced MIR1292 expression in a second
      population.
  - reference: PMID:27123487
    reference_title: "Spinocerebellar ataxia type 36 in the Han Chinese."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "It is possible that microRNA-1292 expression is simply an epiphenomenon of abnormal (GGCCTG)n expansion and might not play an active role in disease pathogenesis."
    explanation: >-
      The authors' own reading of their negative target-gene results, which is
      why this node carries HYPOTHETICAL mechanism confidence and no outgoing
      causal edge.
- name: Purkinje Cell Degeneration
  biological_scale: CELLULAR
  role: central_effector
  conforms_to: "cerebellar_purkinje_degeneration#Purkinje Neuron Degeneration"
  description: >-
    Purkinje cells degenerate, and their loss is the central effector event
    linking the molecular repeat toxicity to the cerebellar syndrome. Purkinje
    involvement is demonstrable even in a presymptomatic expansion carrier,
    indicating that it precedes clinical ataxia.
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  biological_processes:
  - preferred_term: neuron apoptotic process
    term:
      id: GO:0051402
      label: neuron apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:22744658
    reference_title: "Clinical features of SCA36: a novel spinocerebellar ataxia with motor neuron involvement (Asidan)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The neuropathologic study revealed significant cerebellar Purkinje cell degeneration with obvious loss of lower motor neurons."
    explanation: >-
      Human autopsy evidence for Purkinje cell degeneration in SCA36.
  - reference: PMID:25476002
    reference_title: "Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuropathology in a presymptomatic case disclosed that Purkinje cells and hypoglossal neurons are affected."
    explanation: >-
      Establishes that Purkinje involvement precedes clinical onset, supporting
      this node's placement upstream of the tissue-level atrophy.
  downstream:
  - target: Cerebellar and Olivopontocerebellar Atrophy
    causal_link_type: DIRECT
- name: Lower Motor Neuron Degeneration
  biological_scale: CELLULAR
  description: >-
    Lower motor neurons degenerate, most conspicuously the hypoglossal neurons
    supplying the tongue. Involvement is largely restricted to lower motor
    neurons of the caudal brainstem and spinal cord rather than the widespread
    upper and lower motor neuron loss of amyotrophic lateral sclerosis, which is
    why SCA36 does not progress to an ALS-like course.
  cell_types:
  - preferred_term: lower motor neuron
    term:
      id: CL:0008039
      label: lower motor neuron
  biological_processes:
  - preferred_term: motor neuron apoptotic process
    term:
      id: GO:0097049
      label: motor neuron apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:22744658
    reference_title: "Clinical features of SCA36: a novel spinocerebellar ataxia with motor neuron involvement (Asidan)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lower motor involvement was confirmed by EMG and muscle biopsy."
    explanation: >-
      Electrophysiological and histological confirmation of lower motor neuron
      involvement in patients.
  - reference: PMID:25476002
    reference_title: "Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuropathology in a presymptomatic case disclosed that Purkinje cells and hypoglossal neurons are affected."
    explanation: >-
      Identifies hypoglossal motor neurons specifically, which is the anatomical
      basis of the tongue phenotype.
  - reference: PMID:22492559
    reference_title: "'Costa da Morte' ataxia is spinocerebellar ataxia 36: clinical and genetic characterization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were signs of denervation in the tongue, as well as mild pyramidal signs, but otherwise no signs of classical amyotrophic lateral sclerosis."
    explanation: >-
      Supports the restricted distribution of motor neuron involvement recorded
      in this node's description.
  downstream:
  - target: Bulbar and Limb Denervation
    causal_link_type: DIRECT
- name: Cerebellar and Olivopontocerebellar Atrophy
  biological_scale: TISSUE
  description: >-
    Cerebellar tissue loss follows the cellular degeneration in a stereotyped
    sequence: cerebellar glucose hypometabolism in the vermis and right
    hemisphere before symptoms, superior vermis atrophy early in the ataxic
    stage, diffuse cerebellar atrophy some years later, and an
    olivopontocerebellar pattern in the oldest patients.
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  evidence:
  - reference: PMID:27862279
    reference_title: "PET and MRI detection of early and progressive neurodegeneration in spinocerebellar ataxia type 36."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI was normal in asymptomatic and preataxic individuals and showed superior cerebellar vermis atrophy early in the ataxic stage, diffuse cerebellar atrophy some years into the disease course, and a pattern of olivopontocerebellar atrophy in the oldest patients."
    explanation: >-
      Establishes the staged tissue-level atrophy pattern described by this
      node.
  downstream:
  - target: Truncal ataxia
    causal_link_type: DIRECT
    description: >-
      Loss of cerebellar cortical output from the degenerating vermis produces
      the truncal ataxia that opens the clinical syndrome.
  - target: Limb ataxia
    causal_link_type: DIRECT
    description: >-
      Hemispheric cerebellar atrophy produces appendicular incoordination.
  - target: Ataxic dysarthria
    causal_link_type: DIRECT
    description: >-
      Cerebellar degeneration produces the ataxic dysarthria found in every
      patient of the original Japanese cohort.
- name: Bulbar and Limb Denervation
  biological_scale: TISSUE
  description: >-
    Denervation of tongue and limb musculature follows lower motor neuron loss,
    producing fasciculation and then atrophy. Tongue involvement predominates
    and is the clinical marker that separates SCA36 from pure cerebellar
    ataxias.
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  evidence:
  - reference: PMID:22744658
    reference_title: "Clinical features of SCA36: a novel spinocerebellar ataxia with motor neuron involvement (Asidan)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal muscle fasciculation and atrophy of the limbs and trunk were found in 57% of cases."
    explanation: >-
      Documents the muscle-level consequence of denervation in patients.
  downstream:
  - target: Tongue fasciculations
    causal_link_type: DIRECT
    description: >-
      Denervation of the lingual musculature by hypoglossal neuron loss produces
      the tongue fasciculation that is the clinical signature of SCA36.
  - target: Tongue atrophy
    causal_link_type: DIRECT
    description: >-
      Sustained denervation progresses from fasciculation to wasting of the
      tongue.
  - target: Skeletal muscle fasciculation and atrophy
    causal_link_type: DIRECT
    description: >-
      The same denervation affects limb and truncal muscle, confirmed by EMG and
      muscle biopsy.
  - target: Dysphagia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Bulbar denervation impairs swallowing, though a videofluoroscopic study
      found swallowing better preserved in SCA36 than in amyotrophic lateral
      sclerosis, so the link is weaker than for the tongue phenotypes.
- name: Cochlear and Peripheral Auditory Dysfunction
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Hearing loss in SCA36 is sensorineural and worst at high frequencies.
    Brainstem auditory evoked potentials point to the inner ear or the
    peripheral auditory pathway rather than to a central lesion, but the
    molecular route from the NOP56 expansion to auditory dysfunction has not
    been worked out.
  locations:
  - preferred_term: inner ear
    term:
      id: UBERON:0001846
      label: internal ear
  evidence:
  - reference: PMID:23140984
    reference_title: "Acoustic impairment is a distinguishable clinical feature of Asidan/SCA36."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BAEPs in 2 Asidan/SCA36 cases suggested possible involvement in the inner ear or the peripheral part of the auditory system."
    explanation: >-
      Localizes the auditory lesion peripherally, with the authors' own hedge
      preserved, which is why mechanism confidence is PROVISIONAL.
  downstream:
  - target: Sensorineural hearing loss
    causal_link_type: DIRECT
    description: >-
      Dysfunction of the inner ear or peripheral auditory pathway is what the
      audiometric and BAEP findings measure as sensorineural hearing loss.
- name: Impaired NOP56 Box C/D snoRNP Function
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The alternative loss-of-function branch. NOP56 is a core scaffold of the box
    C/D small nucleolar ribonucleoprotein complex that directs 2'-O-methylation
    of ribosomal RNA, so reduced NOP56 dosage would be expected to impair rRNA
    processing and ribosome biogenesis. This node is deliberately left with no
    incoming or outgoing causal edge, because the branch is not supported as the
    patient mechanism: NOP56 mRNA and protein are not appreciably reduced in
    patient cells, and the zebrafish nop56 null shows what complete loss of the
    gene actually produces — an embryonic-lethal failure of cerebellar
    development, not a late-onset selective degeneration. It is recorded so the
    hypothesis is visible and falsifiable rather than surviving only as prose.
    See the nop56_dosage_branch discussion.
  genes:
  - preferred_term: NOP56
    term:
      id: hgnc:15911
      label: NOP56
  biological_processes:
  - preferred_term: rRNA processing
    term:
      id: GO:0006364
      label: rRNA processing
    modifier: DECREASED
  evidence:
  - reference: PMID:37810464
    reference_title: "Repeat expansions in NOP56 are a cause of spinocerebellar ataxia Type 36 in the British population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NOP56 encodes a ubiquitously expressed core scaffolding protein that stabilizes the box C/D small nucleolar ribonuclear protein complex."
    explanation: >-
      Establishes the normal function whose loss this hypothetical branch would
      impair.
  - reference: PMID:35309140
    reference_title: "Spinocerebellar Ataxia 36: From Mutations Toward Therapies."
    supports: REFUTE
    evidence_source: OTHER
    snippet: "These findings were not able to support the haploinsufficiency hypothesis."
    explanation: >-
      The reason this node carries HYPOTHETICAL confidence and no causal edge:
      the dosage branch was tested in patient cells and not supported.
phenotypes:
- category: Neurologic
  name: Truncal ataxia
  description: >-
    Progressive truncal ataxia is present in every reported patient in the
    original Japanese cohort and is the usual presenting feature; it was also
    the initial manifestation in the Han Chinese pedigrees.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Truncal ataxia
    term:
      id: HP:0002078
      label: Truncal ataxia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:22744658
    reference_title: "Clinical features of SCA36: a novel spinocerebellar ataxia with motor neuron involvement (Asidan)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The age at onset of ataxia was 53.1 ± 3.4 years, with the most frequent symptoms being truncal ataxia (100% of patients), ataxic dysarthria (100%), limb ataxia (93%), and hyperreflexia (79%)."
    explanation: >-
      Reports truncal ataxia in 100% of the 18-patient cohort, supporting both
      the phenotype and its VERY_FREQUENT band.
  - reference: PMID:27123487
    reference_title: "Spinocerebellar ataxia type 36 in the Han Chinese."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The average age at symptom onset was 44.8 ± 3.8 years with truncal ataxia as the initial manifestation."
    explanation: >-
      Independent confirmation that truncal ataxia is the presenting feature in
      a second population.
- category: Neurologic
  name: Ataxic dysarthria
  description: >-
    Cerebellar dysarthria develops in all patients and is one of the two
    universal features of the original cohort.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:22744658
    reference_title: "Clinical features of SCA36: a novel spinocerebellar ataxia with motor neuron involvement (Asidan)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The age at onset of ataxia was 53.1 ± 3.4 years, with the most frequent symptoms being truncal ataxia (100% of patients), ataxic dysarthria (100%), limb ataxia (93%), and hyperreflexia (79%)."
    explanation: >-
      Reports ataxic dysarthria in 100% of the cohort, supporting the
      VERY_FREQUENT band.
- category: Neurologic
  name: Limb ataxia
  description: >-
    Appendicular ataxia affecting the limbs, reported in 93% of the original
    Japanese cohort.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Limb ataxia
    term:
      id: HP:0002070
      label: Limb ataxia
  evidence:
  - reference: PMID:22744658
    reference_title: "Clinical features of SCA36: a novel spinocerebellar ataxia with motor neuron involvement (Asidan)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The age at onset of ataxia was 53.1 ± 3.4 years, with the most frequent symptoms being truncal ataxia (100% of patients), ataxic dysarthria (100%), limb ataxia (93%), and hyperreflexia (79%)."
    explanation: >-
      Reports limb ataxia in 93% of the cohort, which falls in the
      VERY_FREQUENT band.
- category: Neurologic
  name: Hyperreflexia
  description: >-
    Brisk deep tendon reflexes reflecting the pyramidal component of the motor
    neuron involvement; found in 79% of the original cohort, reported as
    generalized hyperreflexia in the Han Chinese pedigrees, and as mild
    pyramidal signs in the Galician kindreds.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  evidence:
  - reference: PMID:22744658
    reference_title: "Clinical features of SCA36: a novel spinocerebellar ataxia with motor neuron involvement (Asidan)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The age at onset of ataxia was 53.1 ± 3.4 years, with the most frequent symptoms being truncal ataxia (100% of patients), ataxic dysarthria (100%), limb ataxia (93%), and hyperreflexia (79%)."
    explanation: >-
      Reports hyperreflexia in 79% of the cohort, at the top of the FREQUENT
      band.
  - reference: PMID:27123487
    reference_title: "Spinocerebellar ataxia type 36 in the Han Chinese."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common features included slowly progressive truncal/limb ataxia, dysarthria, generalized hyperreflexia, and hearing impairment."
    explanation: >-
      Independent confirmation of hyperreflexia as a common feature in a second
      population.
- category: Neurologic
  name: Tongue fasciculations
  description: >-
    Fasciculation of the tongue, later followed by tongue atrophy, is the
    clinical signature of hypoglossal motor neuron involvement in SCA36 and one
    of the features that most clearly separates it from pure cerebellar
    ataxias. It is duration-dependent, appearing predominantly in patients with
    long-standing disease, and its prevalence varies markedly between cohorts.
  frequency: FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Tongue fasciculations
    term:
      id: HP:0001308
      label: Tongue fasciculations
  evidence:
  - reference: PMID:22744658
    reference_title: "Clinical features of SCA36: a novel spinocerebellar ataxia with motor neuron involvement (Asidan)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tongue fasciculation and subsequent atrophy were found in 71% of cases, particularly in those of long duration."
    explanation: >-
      Reports tongue fasciculation in 71% of the cohort, supporting the FREQUENT
      band and the duration dependence noted in the description.
  - reference: PMID:27123487
    reference_title: "Spinocerebellar ataxia type 36 in the Han Chinese."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "atrophy and fasciculation of the tongue and limb muscles are present in 12% of French patients in contrast to 63% of Japanese patients"
    explanation: >-
      Documents the between-cohort variation in tongue involvement noted in the
      description, which is why the frequency band is not set higher.
- category: Neurologic
  name: Tongue atrophy
  description: >-
    Atrophy of the tongue follows the fasciculation phase and reflects
    denervation of the lingual musculature.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Tongue atrophy
    term:
      id: HP:0012473
      label: Tongue atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:22744658
    reference_title: "Clinical features of SCA36: a novel spinocerebellar ataxia with motor neuron involvement (Asidan)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tongue fasciculation and subsequent atrophy were found in 71% of cases, particularly in those of long duration."
    explanation: >-
      The same cohort figure covers subsequent tongue atrophy, which is why the
      band matches that of the fasciculation phenotype.
  - reference: PMID:25101480
    reference_title: "Spinocerebellar Ataxia Type 36 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other common features are muscle atrophy and denervation, especially of the tongue, as well as pyramidal signs, thus overlapping with motor neuron disorders."
    explanation: >-
      GeneReviews confirms tongue-predominant atrophy and denervation as a
      common feature.
- category: Musculoskeletal
  name: Skeletal muscle fasciculation and atrophy
  description: >-
    Fasciculation and wasting of limb and truncal muscles, confirmed by EMG and
    muscle biopsy, in a little over half of patients in the original cohort.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: PMID:22744658
    reference_title: "Clinical features of SCA36: a novel spinocerebellar ataxia with motor neuron involvement (Asidan)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal muscle fasciculation and atrophy of the limbs and trunk were found in 57% of cases."
    explanation: >-
      Reports limb and truncal muscle fasciculation and atrophy in 57% of the
      cohort, within the FREQUENT band.
- category: Auditory
  name: Sensorineural hearing loss
  description: >-
    Bilateral sensorineural hearing loss, most marked at high frequencies (4000
    and 8000 Hz), is a characteristic extracerebellar feature. Pure tone average
    is significantly worse in SCA36 than in other degenerative ataxias, and
    hearing loss severity correlates with ataxia severity. It is not obligate:
    the British series found a low rate of hearing loss, so its absence does not
    exclude the diagnosis.
  frequency: FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:23140984
    reference_title: "Acoustic impairment is a distinguishable clinical feature of Asidan/SCA36."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In comparison to other groups, Asidan/SCA36 showed a constant depression at 7 different frequencies in audiogram, especially at 4000 and 8000 Hz."
    explanation: >-
      Audiometric measurement of the high-frequency-predominant hearing loss
      described here.
  - reference: PMID:23140984
    reference_title: "Acoustic impairment is a distinguishable clinical feature of Asidan/SCA36."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to signs for motor neuron involvement, acoustic impairment in Asidan/SCA36 is another characteristic clinical feature that is distinguishable from other forms of SCAs."
    explanation: >-
      Supports treating hearing loss as a discriminating feature, which is what
      the diagnostic flag on this phenotype records.
  - reference: PMID:37810464
    reference_title: "Repeat expansions in NOP56 are a cause of spinocerebellar ataxia Type 36 in the British population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, the patients presented with slowly progressive cerebellar ataxia with a low rate of hearing loss and variable rates of motor neuron impairment."
    explanation: >-
      Supports the caveat in the description that hearing loss is not obligate,
      by reporting a cohort in which it was uncommon.
- category: Ophthalmologic
  name: Abnormal eye movements
  description: >-
    Variable oculomotor abnormalities including slow saccades, saccadic pursuit
    and fixation instability.
  phenotype_term:
    preferred_term: Abnormal saccadic eye movements
    term:
      id: HP:0000570
      label: Abnormal saccadic eye movements
  evidence:
  - reference: PMID:22492559
    reference_title: "'Costa da Morte' ataxia is spinocerebellar ataxia 36: clinical and genetic characterization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe here the detailed clinical picture, consisting of a late-onset, slowly progressive cerebellar syndrome with variable eye movement abnormalities and sensorineural hearing loss."
    explanation: >-
      Reports eye movement abnormalities as part of the SCA36 clinical picture,
      with the authors' own qualifier "variable" preserved.
- category: Neurologic
  name: Impaired executive functioning
  description: >-
    Mild frontal-executive decline measurable on the frontal assessment battery
    and MoCA, with global measures such as MMSE preserved. The decline tracks
    disease duration and ataxia severity, and SPECT shows reduced regional
    cerebral blood flow in anterior cingulate and inferolateral prefrontal
    cortex.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Impaired executive functioning
    term:
      id: HP:0033051
      label: Impaired executive functioning
  evidence:
  - reference: PMID:22353375
    reference_title: "Cognitive and affective impairments of a novel SCA/MND crossroad mutation Asidan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 12 Asidan patients demonstrated a significant decrease in their frontal executive functions measured by frontal assessment battery (FAB) and Montreal cognitive assessment (MoCA) compared with age- and gender-matched controls, whilst mini-mental state examination (MMSE) and Hasegawa dementia score-revised (HDS-R) were within normal range."
    explanation: >-
      Quantifies the selective frontal-executive deficit with preserved global
      cognition described in this phenotype.
  - reference: PMID:25101480
    reference_title: "Spinocerebellar Ataxia Type 36 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mild frontal-subcortical affective and cognitive decline may be present as the disease progresses."
    explanation: >-
      GeneReviews independently records the mild frontal-subcortical cognitive
      decline and its progressive appearance.
- category: Psychiatric
  name: Depression
  description: >-
    Mild depressive symptoms accompany the frontal-executive changes.
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: PMID:22353375
    reference_title: "Cognitive and affective impairments of a novel SCA/MND crossroad mutation Asidan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They also demonstrated mild depression and apathy."
    explanation: >-
      Reports mild depression in the assessed Asidan cohort.
- category: Psychiatric
  name: Apathy
  description: >-
    Apathy is reported alongside depression as part of the frontal-subcortical
    affective profile.
  phenotype_term:
    preferred_term: Apathy
    term:
      id: HP:0000741
      label: Apathy
  evidence:
  - reference: PMID:22353375
    reference_title: "Cognitive and affective impairments of a novel SCA/MND crossroad mutation Asidan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They also demonstrated mild depression and apathy."
    explanation: >-
      Reports apathy in the assessed Asidan cohort.
- category: Neurologic
  name: Tremor
  description: >-
    Tremor is among the extracerebellar features reported across the
    multicentre French, Japanese and German screen.
  phenotype_term:
    preferred_term: Tremor
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: PMID:25476002
    reference_title: "Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients showed slowly progressive cerebellar ataxia frequently accompanied by hearing and cognitive impairments, tremor, ptosis and reduced vibration sense"
    explanation: >-
      Lists tremor among the accompanying features in the multicentre cohort.
- category: Ophthalmologic
  name: Ptosis
  description: >-
    Ptosis is reported as an accompanying feature in the multicentre cohort.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:25476002
    reference_title: "Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients showed slowly progressive cerebellar ataxia frequently accompanied by hearing and cognitive impairments, tremor, ptosis and reduced vibration sense"
    explanation: >-
      Lists ptosis among the accompanying features in the multicentre cohort.
- category: Neurologic
  name: Impaired vibratory sensation
  description: >-
    Reduced vibration sense indicates a sensory component beyond the cerebellar
    and motor neuron involvement.
  phenotype_term:
    preferred_term: Impaired vibratory sensation
    term:
      id: HP:0002495
      label: Impaired vibratory sensation
  evidence:
  - reference: PMID:25476002
    reference_title: "Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients showed slowly progressive cerebellar ataxia frequently accompanied by hearing and cognitive impairments, tremor, ptosis and reduced vibration sense"
    explanation: >-
      Lists reduced vibration sense among the accompanying features in the
      multicentre cohort.
- category: Gastrointestinal
  name: Dysphagia
  description: >-
    Swallowing difficulty is a management concern in SCA36 because of the risk
    of aspiration, although a videofluoroscopic comparison found swallowing
    function better preserved than in amyotrophic lateral sclerosis.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:25101480
    reference_title: "Spinocerebellar Ataxia Type 36 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dietary assessment and feeding therapy programs can improve dysphagia and reduce the risk of aspiration."
    explanation: >-
      GeneReviews treats dysphagia as an expected complication requiring
      management, which is the basis for recording it here.
imaging_findings:
- name: Cerebellar vermis atrophy
  modality: MRI
  description: >-
    Atrophy of the superior cerebellar vermis is the earliest structural
    abnormality, appearing early in the ataxic stage; MRI is normal in
    asymptomatic and preataxic carriers and there is no significant cerebellar
    atrophy before age 50.
  imaging_finding_term:
    preferred_term: Cerebellar vermis atrophy
    term:
      id: HP:0006855
      label: Cerebellar vermis atrophy
  evidence:
  - reference: PMID:27862279
    reference_title: "PET and MRI detection of early and progressive neurodegeneration in spinocerebellar ataxia type 36."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI was normal in asymptomatic and preataxic individuals and showed superior cerebellar vermis atrophy early in the ataxic stage, diffuse cerebellar atrophy some years into the disease course, and a pattern of olivopontocerebellar atrophy in the oldest patients."
    explanation: >-
      Volumetric MRI study establishing vermian atrophy as the earliest
      structural change.
  - reference: PMID:27862279
    reference_title: "PET and MRI detection of early and progressive neurodegeneration in spinocerebellar ataxia type 36."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was no significant cerebellar atrophy in patients younger than 50 years."
    explanation: >-
      Supports the age qualification stated in the description.
- name: Olivopontocerebellar atrophy
  modality: MRI
  description: >-
    Late-stage MRI shows an olivopontocerebellar pattern, involving brainstem
    structures beyond the cerebellum.
  imaging_finding_term:
    preferred_term: Olivopontocerebellar atrophy
    term:
      id: HP:0002542
      label: Olivopontocerebellar atrophy
  evidence:
  - reference: PMID:22492559
    reference_title: "'Costa da Morte' ataxia is spinocerebellar ataxia 36: clinical and genetic characterization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance imaging findings were consistent with the clinical course, showing atrophy of the cerebellar vermis in initial stages, later evolving to a pattern of olivo-ponto-cerebellar atrophy."
    explanation: >-
      Documents the late olivopontocerebellar pattern in the Galician cohort.
- name: Cerebellar glucose hypometabolism
  modality: PET
  description: >-
    FDG-PET detects hypometabolism in the vermis and right cerebellar hemisphere
    in asymptomatic expansion carriers, spreading to both hemispheres and the
    brainstem once ataxia is established. This is the earliest detectable
    abnormality in SCA36 and precedes structural change; it is not a validated
    screening biomarker.
  diagnostic: true
  imaging_finding_term:
    preferred_term: Cerebellar hypometabolism on FDG PET
    term:
      id: HP:0012658
      label: Abnormal brain FDG positron emission tomography
  notes: >-
    HPO has no cerebellar-specific FDG-PET hypometabolism term. The
    regional children of HP:0012658 cover prefrontal (HP:0012659), thalamic
    (HP:0012660), hypothalamic (HP:0012661) and parietal (HP:0012662)
    hypometabolism only, so the parent term is bound and the cerebellar
    specificity is carried in preferred_term rather than manufactured as a
    narrower match.
  evidence:
  - reference: PMID:27862279
    reference_title: "PET and MRI detection of early and progressive neurodegeneration in spinocerebellar ataxia type 36."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FDG-PET revealed hypometabolism in the asymptomatic stage in the vermis and right cerebellar hemisphere."
    explanation: >-
      Establishes presymptomatic cerebellar hypometabolism as an FDG-PET
      finding.
histopathology:
- name: Purkinje cell loss with lower motor neuron loss
  description: >-
    Autopsy shows marked cerebellar Purkinje cell degeneration together with
    loss of lower motor neurons, the two-compartment pathology that defines
    SCA36.
  evidence:
  - reference: PMID:22744658
    reference_title: "Clinical features of SCA36: a novel spinocerebellar ataxia with motor neuron involvement (Asidan)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The neuropathologic study revealed significant cerebellar Purkinje cell degeneration with obvious loss of lower motor neurons."
    explanation: >-
      Primary neuropathological description of the combined lesion.
- name: Ubiquitin- and p62-positive cytoplasmic inclusions in the inferior olivary nucleus
  description: >-
    The first SCA36 autopsy demonstrated ubiquitin- and p62-positive cytoplasmic
    inclusions in the inferior olivary nucleus, alongside repeat RNA foci in
    neuronal nuclei at several levels of the neuraxis.
  evidence:
  - reference: PMID:24985895
    reference_title: "Characteristic RNA foci of the abnormal hexanucleotide GGCCUG repeat expansion in spinocerebellar ataxia type 36 (Asidan)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ubiquitin- and p62-positive inclusions in the cytoplasm of the inferior olivary nucleus of the Asidan patient"
    explanation: >-
      Reports the inclusion type and anatomical location recorded here.
- name: Absence of NOP56, TDP-43 and ataxin-2 inclusions
  description: >-
    NOP56 immunostaining is nuclear and normal in distribution, and no
    cytoplasmic or intranuclear inclusions of NOP56, TDP-43 or ataxin-2 are
    seen. The absence of TDP-43 pathology is a key contrast with C9orf72
    disease, which is driven by a structurally similar hexanucleotide repeat.
  evidence:
  - reference: PMID:22744658
    reference_title: "Clinical features of SCA36: a novel spinocerebellar ataxia with motor neuron involvement (Asidan)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cytoplasmic or intranuclear inclusion staining of NOP56, TDP-43, and ataxin-2 was not observed in the remaining neurons."
    explanation: >-
      Direct negative finding on protein inclusion pathology in SCA36 neurons.
  - reference: PMID:32375063
    reference_title: "Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, in SCA36 patient tissue, poly(GP) exists as a soluble species, and no TDP-43 pathology is present."
    explanation: >-
      Independent confirmation that TDP-43 pathology is absent, in the
      comparison with C9orf72 disease this finding is usually framed against.
genetic:
- name: NOP56
  gene_term:
    preferred_term: NOP56
    term:
      id: hgnc:15911
      label: NOP56
  association: GGCCTG hexanucleotide repeat expansion in intron 1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: Positive
  notes: >-
    NOP56 encodes a core scaffold protein of the box C/D small nucleolar
    ribonucleoprotein complex, which directs 2'-O-methylation of ribosomal RNA.
    The pathogenic allele is a heterozygous GGCCTG expansion in intron 1.
    Neither NOP56 mRNA nor NOP56 protein levels were appreciably reduced in
    patient lymphoblastoid cells, so haploinsufficiency is not the favored
    mechanism. Repeat length is somatically unstable, which is why Southern
    blotting of an expanded allele gives a smeared rather than a discrete band.
  variants:
  - name: NOP56 intron 1 GGCCTG hexanucleotide repeat expansion
    description: >-
      Non-coding hexanucleotide repeat expansion in intron 1 of NOP56. Normal
      alleles carry 3-14 repeats. Typical pathogenic alleles carry roughly 650
      or more, up to about 2500, but three affected individuals in a multicentre
      cohort carried only 25, 30 and 31 repeats with clinical features
      indistinguishable from carriers of long expansions, so a short expansion
      does not exclude the diagnosis.
    gene:
      preferred_term: NOP56
      term:
        id: hgnc:15911
        label: NOP56
    clinical_significance: PATHOGENIC
    type: hexanucleotide_repeat_expansion
    evidence:
    - reference: PMID:25476002
      reference_title: "Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "three affected individuals harboured small hexanucleotide expansions of 25, 30 and 31 hexanucleotide repeat-units, demonstrating that such a small expansion could cause the disease"
      explanation: >-
        Establishes that short expansions are pathogenic, the clinically
        important caveat recorded in this variant description.
    - reference: PMID:37810464
      reference_title: "Repeat expansions in NOP56 are a cause of spinocerebellar ataxia Type 36 in the British population."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The normal alleles contain 3–14 hexanucleotide repeats, while the expanded alleles range from 30 to 2500 repeats (mostly between 650 and 2500 repeats)."
      explanation: >-
        Defines the normal and expanded repeat ranges quoted here.
    - reference: PMID:25101480
      reference_title: "Spinocerebellar Ataxia Type 36 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Affected individuals typically have alleles with 650 or more repeats."
      explanation: >-
        GeneReviews gives the conventional diagnostic threshold for a typical
        expanded allele.
  evidence:
  - reference: PMID:21683323
    reference_title: "Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we sequenced 33 of these and observed a large expansion of an intronic GGCCTG hexanucleotide repeat in NOP56"
    explanation: >-
      Identifies NOP56 as the SCA36 gene and the expansion as the causal allele.
  - reference: PMID:37810464
    reference_title: "Repeat expansions in NOP56 are a cause of spinocerebellar ataxia Type 36 in the British population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NOP56 encodes a ubiquitously expressed core scaffolding protein that stabilizes the box C/D small nucleolar ribonuclear protein complex."
    explanation: >-
      Supports the gene-function statement in the notes for this block.
  - reference: PMID:35309140
    reference_title: "Spinocerebellar Ataxia 36: From Mutations Toward Therapies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These findings were not able to support the haploinsufficiency hypothesis."
    explanation: >-
      Supports the note that loss of NOP56 dosage is not the favored mechanism.
      Evidence source is OTHER because this is a narrative review.
  - reference: PMID:27123487
    reference_title: "Spinocerebellar ataxia type 36 in the Han Chinese."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 3 pedigrees share a common haplotype spanning 5.3 kb flanking the NOP56 repeat expansions, suggesting a founder effect of spinocerebellar ataxia type 36 (SCA36) in the Han Chinese."
    explanation: >-
      Documents a third founder haplotype, independent of the Galician and
      Japanese ones, supporting recurrent founder effects at this locus.
diagnosis:
- name: Repeat-primed PCR for the NOP56 GGCCTG expansion
  description: >-
    Molecular confirmation rests on detecting the expansion, since the clinical
    picture overlaps other late-onset dominant ataxias. Repeat-primed PCR gives
    the characteristic sawtooth trace; Southern blotting sizes the expansion,
    though somatic instability produces a smeared band. Repeat expansions can
    also be called from whole-genome sequencing with dedicated bioinformatic
    tools, which is how the British cohort was identified.
  evidence:
  - reference: PMID:25101480
    reference_title: "Spinocerebellar Ataxia Type 36 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Confirmation of the diagnosis relies on detection of an abnormal hexanucleotide GGCCTG repeat expansion in NOP56."
    explanation: >-
      GeneReviews states that molecular detection of the expansion is the
      diagnostic standard.
  - reference: PMID:28918022
    reference_title: "Antisense Oligonucleotides Reduce RNA Foci in Spinocerebellar Ataxia 36 Patient iPSCs."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A typical saw-tooth pattern by repeat expansion is observed in SCA36 patient iPSCs, but not in healthy control iPSCs."
    explanation: >-
      Illustrates the repeat-primed PCR sawtooth signature described here.
  - reference: PMID:37810464
    reference_title: "Repeat expansions in NOP56 are a cause of spinocerebellar ataxia Type 36 in the British population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Leveraging novel bioinformatic tools to detect repeat expansions from whole-genome sequencing, we analyse the NOP56 repeat in 1257 British patients with hereditary ataxia and in 7506 unrelated controls."
    explanation: >-
      Supports the whole-genome-sequencing route to diagnosis added in this
      description.
  - reference: PMID:35245110
    reference_title: "Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We describe the use of programmable targeted long-read sequencing with Oxford Nanopore's ReadUntil function for parallel genotyping of all known neuropathogenic STRs in a single assay."
    explanation: >-
      Supports the long-read route as a single-assay alternative to
      locus-specific repeat-primed PCR. Evidence source is OTHER because the
      paper reports assay development and validation rather than a clinical,
      animal, cell or computational study of the disease.
differential_diagnoses:
- name: Amyotrophic lateral sclerosis
  description: >-
    The tongue and limb fasciculation, atrophy and hyperreflexia of SCA36 raise
    motor neuron disease, but SCA36 lacks the widespread muscle involvement and
    rapid course of classical ALS, motor neuron involvement is largely confined
    to lower motor neurons of the caudal brainstem, and TDP-43 pathology is
    absent. Screening ALS cohorts for the NOP56 expansion has been negative.
  evidence:
  - reference: PMID:22492559
    reference_title: "'Costa da Morte' ataxia is spinocerebellar ataxia 36: clinical and genetic characterization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were signs of denervation in the tongue, as well as mild pyramidal signs, but otherwise no signs of classical amyotrophic lateral sclerosis."
    explanation: >-
      Explicitly separates the SCA36 motor phenotype from classical ALS.
  - reference: PMID:27123487
    reference_title: "Spinocerebellar ataxia type 36 in the Han Chinese."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NOP56 repeat expansion was not detected in controls or patients with sporadic ataxic syndromes or ALS."
    explanation: >-
      Supports the statement that ALS cohort screening has been negative.
- name: Other late-onset autosomal dominant spinocerebellar ataxias
  description: >-
    SCA36 presents as a slowly progressive late-onset cerebellar syndrome
    indistinguishable at first from other dominant SCAs; sensorineural hearing
    loss and tongue fasciculation are the discriminating clinical clues, and
    audiometry separates SCA36 from other degenerative ataxias statistically.
    Neither clue is required, so the diagnosis should still be considered in
    late-onset slowly progressive ataxia without them.
  evidence:
  - reference: PMID:23140984
    reference_title: "Acoustic impairment is a distinguishable clinical feature of Asidan/SCA36."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PTA was significantly decreased in Asidan/SCA36 in comparison to normal control and other ataxic groups, but not significant within other ataxic groups and normal control."
    explanation: >-
      Provides the quantitative basis for using hearing as a discriminator
      against other degenerative ataxias.
  - reference: PMID:37810464
    reference_title: "Repeat expansions in NOP56 are a cause of spinocerebellar ataxia Type 36 in the British population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "spinocerebellar ataxia 36 can be suspected in patients with a late-onset, slowly progressive ataxia, even without the findings of hearing loss and tongue fasciculation"
    explanation: >-
      Supports the caveat that the two discriminating clues are not required for
      the diagnosis.
animal_models:
- name: AAV-delivered (TG3C2)62 repeat-expressing mouse
  species: Mouse
  genotype: >-
    Wild-type C57BL/6 mice given intracerebroventricular AAV9-NOP56-(TG3C2)62 at
    postnatal day 0; AAV9-NOP56-(TG3C2)6 as the control construct
  background: C57BL/6
  category: Somatic brain transgenesis
  description: >-
    The only in vivo demonstration that the SCA36 repeat itself is sufficient to
    kill Purkinje cells. Expressing a 62-unit TG3C2 repeat throughout the mouse
    CNS reproduces the SCA36 pattern of selective vulnerability — Purkinje cell
    loss and locomotor impairment — while the near-identical C9orf72 G4C2 repeat
    in the same paradigm instead produces cortical loss and pTDP-43 pathology.
    The contrast is the point: the two repeats differ by one nucleotide, so the
    divergence localizes the pathomechanism to the repeat sequence rather than
    to its host gene.
  genes:
  - preferred_term: NOP56
    term:
      id: hgnc:15911
      label: NOP56
  publication: PMID:32375043
  modeled_mechanisms:
  - target: Purkinje Cell Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Repeat-expressing mice lose cerebellar Purkinje cells and show the
      dendritic and locomotor consequences of that loss, matching the central
      effector node of this entry.
    limitations: >-
      The construct carries 62 repeats against the 650-2500 of a typical patient
      allele, and is delivered from an AAV vector rather than expressed from the
      endogenous NOP56 locus, so dosage and regulation both differ from the human
      disease. The study assessed cerebellar and cortical outcomes and does not
      address the lower motor neuron involvement or the sensorineural hearing
      loss that distinguish SCA36 clinically, so it models the cerebellar arm of
      the disease only.
    readouts:
    - name: Cerebellar Purkinje cell number
      target: Purkinje Cell Degeneration
      direction: DECREASED
      interpretation: >-
        Direct cell-count correlate of the degeneration node in this model.
      evidence:
      - reference: PMID:32375043
        reference_title: "Hexanucleotide Repeat Expansions in c9FTD/ALS and SCA36 Confer Selective Patterns of Neurodegeneration In Vivo."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "we found that (TG3C2)62 mice show a dramatic loss of cerebellar Purkinje cells"
        explanation: >-
          Reports the directional measurement this readout records.
    - name: Purkinje dendritic arborization and molecular layer width
      target: Purkinje Cell Degeneration
      direction: DECREASED
      interpretation: >-
        Structural correlate showing the loss is not only of cell bodies but of
        the dendritic network they support.
      evidence:
      - reference: PMID:32375043
        reference_title: "Hexanucleotide Repeat Expansions in c9FTD/ALS and SCA36 Confer Selective Patterns of Neurodegeneration In Vivo."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "We used the Purkinje cell marker calbindin to look at the dendritic arborization of these neurons and observed not only a reduction in the number of cell bodies, but also a narrowing of the molecular cell layer in the cerebellum of (TG3C2)62 mice"
        explanation: >-
          Reports both measurements this readout records.
    - name: Rotating rod and hanging wire performance
      target: Purkinje Cell Degeneration
      direction: DECREASED
      interpretation: >-
        Functional correlate of the cerebellar lesion, the model's analogue of
        the ataxia that Purkinje loss produces in patients.
      evidence:
      - reference: PMID:32375043
        reference_title: "Hexanucleotide Repeat Expansions in c9FTD/ALS and SCA36 Confer Selective Patterns of Neurodegeneration In Vivo."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "(TG3C2)62 mice showed a pronounced locomotor defect compared with controls, as evidenced by impaired performance in the rotating rod test"
        explanation: >-
          Reports the behavioural measurement this readout records.
    evidence:
    - reference: PMID:32375043
      reference_title: "Hexanucleotide Repeat Expansions in c9FTD/ALS and SCA36 Confer Selective Patterns of Neurodegeneration In Vivo."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Instead, these mice show a robust loss of cerebellar Purkinje cells, as well as pronounced locomotor defects, phenotypes highly reminiscent of SCA36."
      explanation: >-
        The authors' own statement that the model reproduces the SCA36 pattern,
        which is what makes it informative for this node.
  - target: Dipeptide Repeat Protein Production from the Expanded Repeat
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The mouse reproduces the specific DPR biology curated at this node,
      including the feature that distinguishes SCA36 from C9orf72 disease:
      poly(GP) is produced but stays soluble rather than forming inclusions.
    limitations: >-
      Poly(PR), detected in human SCA36 granule cells, was not robustly
      reproduced in this model, so the antisense RAN-translation arm of the node
      is not covered by it.
    readouts:
    - name: Diffuse poly(GP) immunoreactivity in Purkinje cells
      target: Dipeptide Repeat Protein Production from the Expanded Repeat
      direction: INCREASED
      interpretation: >-
        Confirms DPR production in vivo and, by its diffuse distribution,
        reproduces the solubility that separates SCA36 from C9orf72 disease.
      evidence:
      - reference: PMID:32375043
        reference_title: "Hexanucleotide Repeat Expansions in c9FTD/ALS and SCA36 Confer Selective Patterns of Neurodegeneration In Vivo."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Although we detected poly(GP) in our SCA36 mice, intriguingly it does not form inclusions and instead remains diffuse."
        explanation: >-
          Reports both the presence and the solubility this readout records.
    evidence:
    - reference: PMID:32375043
      reference_title: "Hexanucleotide Repeat Expansions in c9FTD/ALS and SCA36 Confer Selective Patterns of Neurodegeneration In Vivo."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Furthermore, because the RNA foci and RAN translation we observe in the cerebellum of our mice are in the Purkinje cells, we suspect that this degeneration is at least in part cell autonomous."
      explanation: >-
        Places RAN translation in the same cells that degenerate, which is what
        makes the model informative for the DPR node.
  notes: >-
    The model is also an informative negative for the C9orf72 comparison this
    entry draws in histopathology: no pTDP-43 inclusions and no persistent stress
    granules were seen at 3-4, 6 or 12 months, matching the absence of TDP-43
    pathology in SCA36 patient tissue.
- name: nop56 loss-of-function zebrafish
  species: Zebrafish
  genotype: nop56sa12582 homozygous loss-of-function
  category: Germline null
  description: >-
    A complete loss-of-function model of the SCA36 host gene, made to ask what
    losing NOP56 actually does — the question the haploinsufficiency hypothesis
    turns on, and one no repeat-expansion model can answer. The answer is that it
    is not SCA36: homozygous nulls fail to form a cerebellum at all and die
    before 7 days post-fertilization.
  genes:
  - preferred_term: NOP56
    term:
      id: hgnc:15911
      label: NOP56
  publication: PMID:36009362
  modeled_mechanisms:
  - target: Purkinje Cell Degeneration
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      Complete loss of nop56 does not reproduce the adult-onset, selective
      Purkinje degeneration of SCA36. It produces an embryonic-lethal failure of
      cerebellar development instead — the cerebellum is absent rather than
      degenerating — which is the structural argument against dosage loss being
      the SCA36 mechanism.
    limitations: >-
      The comparison is not like-for-like in three ways at once: a homozygous
      germline null against a heterozygous repeat expansion, zebrafish against
      human, and embryonic development against adult maintenance. The model
      therefore bounds what NOP56 loss can look like; it does not by itself prove
      that dosage plays no part in SCA36, and the patient-cell expression data
      remain the direct evidence for that.
    readouts:
    - name: Cerebellar structure at larval stage
      target: Purkinje Cell Degeneration
      direction: ABOLISHED
      interpretation: >-
        The cerebellum never forms, so there is no Purkinje population to
        degenerate — a developmental failure, not the degenerative phenotype
        this node describes.
      evidence:
      - reference: PMID:36009362
        reference_title: "A nop56 Zebrafish Loss-of-Function Model Exhibits a Severe Neurodegenerative Phenotype."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "We observed a severe neurodegenerative phenotype in nop56 mutants, characterized mainly by absence of cerebellum, reduced numbers of spinal cord neurons, high levels of apoptosis in the central nervous system (CNS) and impaired movement, resulting in death before 7 days post-fertilization."
        explanation: >-
          Reports the absent cerebellum and the embryonic lethality that make
          this a failure to recapitulate rather than a partial match.
    evidence:
    - reference: PMID:36009362
      reference_title: "A nop56 Zebrafish Loss-of-Function Model Exhibits a Severe Neurodegenerative Phenotype."
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: "Although vertebrate animal models were created for the intronic expansion, none was studied for the loss of function of NOP56."
      explanation: >-
        States why this model exists and what it is testing. The phenotype it
        reports is incompatible with the late-onset selective degeneration of
        SCA36, so it argues against dosage loss as that disease's mechanism.
  - target: Impaired NOP56 Box C/D snoRNP Function
    relationship: PERTURBS
    fidelity: LOW
    description: >-
      The model is the direct experimental perturbation of the hypothetical
      dosage branch: it removes nop56 function outright and measures what
      follows, including expression of box C/D complex genes.
    readouts:
    - name: Expression of box C/D complex and CNS development genes
      target: Impaired NOP56 Box C/D snoRNP Function
      direction: DECREASED
      interpretation: >-
        Confirms that losing nop56 does disrupt the box C/D programme, which is
        what the dosage hypothesis predicts — while the organism-level phenotype
        shows that disruption does not produce SCA36.
      evidence:
      - reference: PMID:36009362
        reference_title: "A nop56 Zebrafish Loss-of-Function Model Exhibits a Severe Neurodegenerative Phenotype."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Gene expression of genes related to C/D box complex, balance and CNS development was impaired in nop56 mutants."
        explanation: >-
          Reports the expression measurement this readout records.
    evidence:
    - reference: PMID:36009362
      reference_title: "A nop56 Zebrafish Loss-of-Function Model Exhibits a Severe Neurodegenerative Phenotype."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We studied a zebrafish loss-of-function model of the nop56 gene which shows 70% homology with the human gene."
      explanation: >-
        Establishes that the model perturbs the orthologous gene, which is what
        makes it informative for this hypothetical node.
experimental_models:
- name: SCA36 patient iPSC-derived neurons
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Induced pluripotent stem cells reprogrammed from SCA36 patient fibroblasts
    and peripheral blood mononuclear cells, differentiated into neurons
    including Islet1-positive motor neurons. The model reproduces the sense RNA
    foci of patient tissue and was used to test ethylene-bridged nucleic acid
    antisense oligonucleotides.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:28918022
  modeled_mechanisms:
  - target: NOP56 Intron 1 Retention and Nuclear GGCCUG RNA Foci
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Patient-derived neurons carrying the endogenous expansion form
      intranuclear sense RNA foci at significantly higher frequency than control
      neurons, reproducing the hallmark molecular lesion in a human neuronal
      context.
    limitations: >-
      The model captures foci formation but not the decades-long degenerative
      course, and iPSC-derived neurons are developmentally immature relative to
      the adult Purkinje cells and motor neurons that degenerate in patients.
    readouts:
    - name: Proportion of RNA-foci-positive cells
      target: NOP56 Intron 1 Retention and Nuclear GGCCUG RNA Foci
      direction: INCREASED
      interpretation: >-
        Foci burden is the primary molecular readout of repeat RNA toxicity in
        this model and the endpoint used for ASO screening.
      evidence:
      - reference: PMID:28918022
        reference_title: "Antisense Oligonucleotides Reduce RNA Foci in Spinocerebellar Ataxia 36 Patient iPSCs."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "The number of RNA-foci-positive cells was increased in patient iPSCs and iPSC-derived neurons."
        explanation: >-
          Reports the directional measurement this readout records.
    evidence:
    - reference: PMID:28918022
      reference_title: "Antisense Oligonucleotides Reduce RNA Foci in Spinocerebellar Ataxia 36 Patient iPSCs."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These data show that iPSCs from spinocerebellar ataxia type 36 patients can be useful for evaluating the effects of ASOs toward GGCCTG repeat expansion in spinocerebellar ataxia type 36."
      explanation: >-
        The authors' own statement of what the model is informative for, which
        matches the mechanism node it is linked to here.
- name: Neuro2A cells expressing expanded GGCCTG/CAGGCC repeats
  experimental_model_type: CELL_LINE
  description: >-
    Murine Neuro2A neuroblastoma cells transfected with expanded SCA36 repeats,
    used to screen candidate compounds and RNA-directed interventions against
    foci formation and cytotoxicity.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:30610877
  modeled_mechanisms:
  - target: NOP56 Intron 1 Retention and Nuclear GGCCUG RNA Foci
    relationship: RECAPITULATES
    fidelity: LOW
    description: >-
      Transfected expanded repeats produce sense but not antisense RNA foci,
      matching the strand asymmetry seen in patient autopsy tissue.
    limitations: >-
      An overexpression construct in a murine neuroblastoma line, not the
      endogenous NOP56 locus, and DPR production in this system was rare, so it
      models repeat RNA behavior rather than the full SCA36 lesion.
    readouts:
    - name: Sense (GGCCUG)exp RNA foci
      target: NOP56 Intron 1 Retention and Nuclear GGCCUG RNA Foci
      direction: INCREASED
      interpretation: >-
        Presence of sense-only foci reproduces the strand asymmetry observed in
        SCA36 autopsy brain.
      evidence:
      - reference: PMID:30610877
        reference_title: "Suppression of the yeast elongation factor Spt4 ortholog reduces expanded SCA36 GGCCUG repeat aggregation and cytotoxicity."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Sense (GGCCUG)exp but not antisense (CAGGCC)exp RNA foci were detected in the cells, consistent with observations in autopsied brains of patients with SCA36."
        explanation: >-
          Reports the measurement and its correspondence with human tissue.
    evidence:
    - reference: PMID:30610877
      reference_title: "Suppression of the yeast elongation factor Spt4 ortholog reduces expanded SCA36 GGCCUG repeat aggregation and cytotoxicity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Supt4a knockdown and erythromycin treatment suppressed the formation of (GGCCUG)exp RNA foci and DPR protein formation via regulation of (GGCCUG)exp mRNA, thereby ameliorating the cytotoxicity in SCA36 cell models."
      explanation: >-
        Demonstrates that manipulating repeat RNA in this model changes both
        foci and viability, which is what makes it informative for the foci
        node.
treatments:
- name: Multidisciplinary supportive care
  description: >-
    There is no disease-modifying therapy. Management is supportive and
    multidisciplinary, centered on exercise, gait and balance work, weight
    control and mobility aids.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:25101480
    reference_title: "Spinocerebellar Ataxia Type 36 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of SCA36 involves multidisciplinary specialists and focuses on routine exercise and physical therapy with attention to gait and balance, weight control, and walking aids to facilitate ambulation and mobility."
    explanation: >-
      GeneReviews management recommendation underlying this treatment entry.
  notes: >-
    Agents and circumstances to avoid, per GeneReviews: alcohol and medications
    affecting cerebellar function or inner ear function, and acoustic trauma
    such as headphone use and noisy environments.
- name: Physical therapy
  description: >-
    Routine exercise and physical therapy directed at gait and balance, with
    walking aids as ambulation declines.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Truncal ataxia
    term:
      id: HP:0002078
      label: Truncal ataxia
  evidence:
  - reference: PMID:25101480
    reference_title: "Spinocerebellar Ataxia Type 36 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "focuses on routine exercise and physical therapy with attention to gait and balance, weight control, and walking aids to facilitate ambulation and mobility"
    explanation: >-
      GeneReviews recommends physical therapy for the gait and balance
      impairment this treatment targets.
- name: Speech and occupational therapy
  description: >-
    Occupational therapy for fine motor coordination and speech therapy with
    communication devices for progressive dysarthria.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  target_phenotypes:
  - preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:25101480
    reference_title: "Spinocerebellar Ataxia Type 36 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Occupational therapy aids fine movement coordination; speech therapy and communication devices for those with dysarthria."
    explanation: >-
      GeneReviews recommends both therapies for the deficits named here.
- name: Hearing aids and cochlear implantation
  description: >-
    Amplification or cochlear implantation with audiologic rehabilitation for
    the sensorineural hearing loss, with annual or biannual otolaryngology
    surveillance.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: hearing rehabilitation with amplification or cochlear implantation
    term:
      id: NCIT:C15315
      label: Rehabilitation
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: cochlear implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
  target_phenotypes:
  - preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:25101480
    reference_title: "Spinocerebellar Ataxia Type 36 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing loss may require hearing aids or cochlear implants, together with audiologic rehabilitation."
    explanation: >-
      GeneReviews management recommendation for the hearing loss this treatment
      targets.
  notes: >-
    NCIT device terms such as Cochlear Implant are not reachable from
    NCIT:C25218 (Clinical Intervention or Procedure) and so cannot sit in
    treatment_term. This treatment bundles amplification, implantation and
    audiologic rehabilitation, and no surgical case has been reported in SCA36,
    so the rehabilitation action is bound rather than a surgical one, and the
    device concept is kept queryable as a qualifier.
- name: Feeding and swallowing management
  description: >-
    Dietary assessment and feeding therapy to manage the swallowing difficulty
    and reduce aspiration risk that follow bulbar denervation.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary assessment and feeding therapy
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_phenotypes:
  - preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:25101480
    reference_title: "Spinocerebellar Ataxia Type 36 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dietary assessment and feeding therapy programs can improve dysphagia and reduce the risk of aspiration."
    explanation: >-
      GeneReviews recommends exactly this intervention for the dysphagia and
      aspiration risk it targets.
- name: Cognitive therapy and psychological support
  description: >-
    Cognitive therapy, treatment of depression, and psychological support for
    the frontal-subcortical cognitive and affective decline that accumulates as
    the disease progresses.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: cognitive therapy and psychological support
    term:
      id: NCIT:C15308
      label: Psychotherapy
  target_phenotypes:
  - preferred_term: Impaired executive functioning
    term:
      id: HP:0033051
      label: Impaired executive functioning
  - preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  - preferred_term: Apathy
    term:
      id: HP:0000741
      label: Apathy
  evidence:
  - reference: PMID:25101480
    reference_title: "Spinocerebellar Ataxia Type 36 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Emotional and cognitive decline can be addressed in cognitive therapy, treatment of depression, and psychological support."
    explanation: >-
      GeneReviews recommends these three measures for the cognitive and
      affective phenotypes this treatment targets.
- name: Neurologic and audiologic surveillance
  description: >-
    At least annual neurologic evaluation, more often if manifestations are
    progressing, with annual or biannual otolaryngology review for hearing loss
    and ongoing surveillance of speech and ambulation.
  action_category: MONITORING
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: periodic neurologic and audiologic surveillance
  evidence:
  - reference: PMID:25101480
    reference_title: "Spinocerebellar Ataxia Type 36 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At least annual evaluation by a neurologist or more frequently if manifestations are progressing."
    explanation: >-
      GeneReviews sets the minimum neurologic review interval recorded here.
  - reference: PMID:25101480
    reference_title: "Spinocerebellar Ataxia Type 36 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Annual or biannual evaluation by an otolaryngologist to monitor possible hearing loss."
    explanation: >-
      GeneReviews sets the audiologic review interval recorded here.
  notes: >-
    NCIT's monitoring terms are clinical-trial monitoring concepts rather than
    patient surveillance actions, so no term is bound and treatment_term carries
    a free-text preferred_term only.
- name: Genetic counseling
  description: >-
    Counseling for at-risk relatives, given complete but age-dependent
    penetrance and a 50% transmission risk to offspring. Predictive testing is
    possible once the familial expansion is identified.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:25101480
    reference_title: "Spinocerebellar Ataxia Type 36 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Offspring of affected individuals have a 50% chance of inheriting the NOP56 pathogenic variant."
    explanation: >-
      Establishes the transmission risk that makes counseling appropriate.
- name: Antisense oligonucleotides targeting the expanded NOP56 repeat (investigational)
  description: >-
    Preclinical only. Antisense oligonucleotides directed at the expanded
    repeat or at NOP56 intron 1 reduce RNA foci in patient iPSCs and
    iPSC-derived neurons and reduce poly(GP) in patient fibroblasts and
    lymphoblastoid cells. Because NOP56 is an essential protein, the therapeutic
    window depends on suppressing the repeat-containing transcript without
    lowering total NOP56, which has been achieved at low ASO doses. No clinical
    trial in SCA36 has been reported.
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  aso_details:
    aso_mechanism: RNASE_H_KNOCKDOWN
    target_gene:
      preferred_term: NOP56
      term:
        id: hgnc:15911
        label: NOP56
    target_transcript: NOP56 intron 1 GGCCUG repeat-containing pre-mRNA
    conjugation: UNCONJUGATED
  target_mechanisms:
  - target: NOP56 Intron 1 Retention and Nuclear GGCCUG RNA Foci
    description: >-
      The ASOs act directly on the repeat-containing transcript, reducing the
      foci burden this node describes.
    evidence:
    - reference: PMID:28918022
      reference_title: "Antisense Oligonucleotides Reduce RNA Foci in Spinocerebellar Ataxia 36 Patient iPSCs."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "One of the ASOs reduced the number of RNA-foci-positive cells without altering NOP56 mRNA expression levels in patient iPSCs and iPSC-derived neurons."
      explanation: >-
        Demonstrates the intended effect on the target node while sparing total
        NOP56, which is the key therapeutic-window question.
  evidence:
  - reference: PMID:32375063
    reference_title: "Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Together, our data provide proof-of-principle that ASOs targeting the expanded TG3C2 repeat can be a viable therapeutic strategy for reducing repeat-RNA and DPRs in SCA36"
    explanation: >-
      States the preclinical proof-of-principle status of this approach, which
      is why the entry is labeled investigational.
  notes: >-
    Poly(GP) is detectable in SCA36 cerebrospinal fluid and has been proposed as
    a pharmacodynamic marker of ASO target engagement. The ASO chemistries
    reported so far differ: an ethylene-bridged nucleic acid series in the iPSC
    study and RNase H-dependent designs in the DPR study, so aso_chemistry is
    left unset for this composite entry.
- name: Porphyrin derivatives targeting repeat RNA G-quadruplexes (investigational)
  description: >-
    Preclinical only. The GGCCUG repeat can adopt G-quadruplex structures, and
    porphyrin derivatives that distort such structures were screened in SCA36
    cell models. Sodium copper chlorophyllin and hemin chloride reduced
    expansion-mediated cytotoxicity and improved viability. No human data exist.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium copper chlorophyllin
      term:
        id: CHEBI:232141
        label: chlorophyllin
    - preferred_term: hemin chloride
      term:
        id: CHEBI:50385
        label: hemin
  target_mechanisms:
  - target: NOP56 Intron 1 Retention and Nuclear GGCCUG RNA Foci
    description: >-
      The proposed action is on the structure of the repeat RNA itself, the
      species that forms the foci.
    evidence:
    - reference: PMID:33705846
      reference_title: "Porphyrins ameliorate spinocerebellar ataxia type 36 GGCCTG repeat expansion-mediated cytotoxicity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Among these, sodium copper chlorophyllin and hemin chloride, which have already been used in clinical practice, reduced SCA36 GGCCTG expansion-mediated cytotoxicity and improved cell viability."
      explanation: >-
        Reports the cell-model effect attributed to acting on the repeat RNA
        this mechanism link targets.
  evidence:
  - reference: PMID:33705846
    reference_title: "Porphyrins ameliorate spinocerebellar ataxia type 36 GGCCTG repeat expansion-mediated cytotoxicity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These data suggest that porphyrins are potential therapeutic candidates against SCA36 pathogenesis."
    explanation: >-
      The authors frame the result as candidate-generating, which is why this
      entry is labeled investigational rather than as an established therapy.
  notes: >-
    CHEBI has no entry for the specific salts used. The copper-sodium salt is
    bound to the parent chlorophyllin term and hemin chloride to hemin, with the
    salt identity carried in preferred_term rather than manufactured as a
    narrower match.
- name: Transcription elongation suppression (Supt4a knockdown, erythromycin) (investigational)
  description: >-
    Preclinical only. Knocking down Supt4a, the murine ortholog of the yeast
    transcription elongation factor Spt4, and treating with erythromycin both
    reduced repeat RNA foci, dipeptide repeat protein formation and cytotoxicity
    in an SCA36 cell model, by acting on transcription of the expanded repeat
    rather than on its downstream products. This is a cell-model result only.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: erythromycin
      term:
        id: CHEBI:48923
        label: erythromycin
  target_mechanisms:
  - target: NOP56 Intron 1 Retention and Nuclear GGCCUG RNA Foci
    description: >-
      Both interventions act upstream of the foci, on transcription of the
      repeat-containing message, and are scored by foci burden.
    evidence:
    - reference: PMID:30610877
      reference_title: "Suppression of the yeast elongation factor Spt4 ortholog reduces expanded SCA36 GGCCUG repeat aggregation and cytotoxicity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Supt4a knockdown and erythromycin treatment suppressed the formation of (GGCCUG)exp RNA foci and DPR protein formation via regulation of (GGCCUG)exp mRNA, thereby ameliorating the cytotoxicity in SCA36 cell models."
      explanation: >-
        Reports the effect on the target node and names the mechanism by which
        it is achieved.
  evidence:
  - reference: PMID:30610877
    reference_title: "Suppression of the yeast elongation factor Spt4 ortholog reduces expanded SCA36 GGCCUG repeat aggregation and cytotoxicity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These data provide a basis for developing effective therapeutic strategies for the treatment of SCA36 and other repeat expansion disorders."
    explanation: >-
      The authors position the result as a starting point for development, not
      as a demonstrated therapy, which is why this entry is investigational.
  notes: >-
    Erythromycin is a licensed antibiotic, so this candidate carries a specific
    risk the others do not: nothing here supports off-label use in SCA36. The
    evidence is a transfected murine neuroblastoma line with no animal or human
    data, and the effective concentration and safety of chronic dosing for this
    indication are unknown.
discussions:
- discussion_id: mir1292_contribution
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does reduced MIR1292 transcription contribute to neurodegeneration in
    SCA36, and through which targets?
  attaches_to:
  - pathophysiology#MIR1292 Downregulation
  rationale: >-
    Reduced MIR1292 transcription is reproducible: it was found in the original
    Japanese patients and replicated in Han Chinese patients. But both
    observations are in lymphoblastoid cells, a peripheral cell type that does
    not degenerate, and the one attempt to test predicted targets found four
    unchanged and three unmeasurable in that cell type, prompting the authors to
    raise the possibility of an epiphenomenon. No downstream target has been
    demonstrated in cerebellar or motor neuron tissue, so the node is left with
    no outgoing causal edge rather than being connected on the strength of
    adjacency. Resolving this would require measuring MIR1292 and its candidate
    targets in patient cerebellum or in expansion-carrying neurons.
  evidence:
  - reference: PMID:27123487
    reference_title: "Spinocerebellar ataxia type 36 in the Han Chinese."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Arguably, LCLs may not be an appropriate platform to study SCA36 pathogenesis because such cell lines might not faithfully recapitulate the pathologic phenotypes of Purkinje cells."
    explanation: >-
      States the cell-type limitation that makes this a gap rather than a
      settled negative result.
- discussion_id: dpr_pathogenicity
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Are dipeptide repeat proteins pathogenic in SCA36, or a comparatively inert
    byproduct of repeat translation?
  attaches_to:
  - pathophysiology#Dipeptide Repeat Protein Production from the Expanded Repeat
  rationale: >-
    Human tissue work reports abundant poly(GP), mostly from canonical
    AUG-mediated translation of the intron-retained transcript, plus antisense
    poly(PR) indicating RAN translation. But SCA36 poly(GP) is soluble and there
    is no TDP-43 pathology, unlike C9orf72 disease, and a Neuro2A model found
    RAN-derived DPR formation to be rare. The DPR arm of the mechanism is
    therefore recorded as PROVISIONAL and its edge to Purkinje degeneration is
    left uncited.
  evidence:
  - reference: PMID:32375063
    reference_title: "Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, in SCA36 patient tissue, poly(GP) exists as a soluble species, and no TDP-43 pathology is present."
    explanation: >-
      The solubility and absent TDP-43 pathology are the reasons the DPR arm
      cannot simply be carried over from C9orf72 disease.
  - reference: PMID:30610877
    reference_title: "Suppression of the yeast elongation factor Spt4 ortholog reduces expanded SCA36 GGCCUG repeat aggregation and cytotoxicity."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "Glycine-proline dipeptide repeat (DPR) formation due to repeat-associated non-ATG translation rarely occurred in cells expressing expanded GGCCTG repeats; in contrast, cells harboring expanded c9orf72 GGGGCC/GGCCCC repeats robustly expressed DPR proteins."
    explanation: >-
      A cell-model result arguing against abundant RAN-driven DPR production
      from the SCA36 repeat, which is the substance of the disagreement.
- discussion_id: nop56_dosage_branch
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Does reduced NOP56 dosage, and consequent box C/D snoRNP and rRNA-processing
    impairment, contribute to SCA36 at all?
  attaches_to:
  - pathophysiology#Impaired NOP56 Box C/D snoRNP Function
  rationale: >-
    This is the main alternative to the RNA gain-of-function account, and it is
    argued against rather than untested. NOP56 mRNA and protein were measured in
    patient lymphoblastoid cells and were not appreciably reduced, and Cajal body
    number was unchanged. The zebrafish nop56 null then showed what complete loss
    of the gene produces — absent cerebellum and death within a week — which is
    not the disease. Neither result is decisive: the patient measurements are in
    a peripheral cell type, as with MIR1292, and a homozygous zebrafish null is
    several steps removed from a heterozygous human repeat expansion, so a
    partial or cell-type-restricted dosage effect in neurons is not excluded.
    Measuring NOP56 and rRNA 2'-O-methylation in patient cerebellum, or in
    expansion-carrying neurons, is what would settle it.
  evidence:
  - reference: PMID:36009362
    reference_title: "A nop56 Zebrafish Loss-of-Function Model Exhibits a Severe Neurodegenerative Phenotype."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "We observed a severe neurodegenerative phenotype in nop56 mutants, characterized mainly by absence of cerebellum, reduced numbers of spinal cord neurons, high levels of apoptosis in the central nervous system (CNS) and impaired movement, resulting in death before 7 days post-fertilization."
    explanation: >-
      The phenotype of complete nop56 loss is incompatible with the late-onset
      selective degeneration of SCA36, which is the substance of the argument
      against the dosage branch.
- discussion_id: auditory_mechanism_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    By what mechanism does the NOP56 repeat expansion produce sensorineural
    hearing loss, and which cochlear or auditory-nerve cell population is
    affected?
  attaches_to:
  - pathophysiology#Cochlear and Peripheral Auditory Dysfunction
  rationale: >-
    Hearing loss is one of the most distinctive features of SCA36 and correlates
    with ataxia severity, and BAEPs point to a peripheral rather than central
    lesion. But no cochlear tissue has been examined for repeat RNA foci or DPRs
    in SCA36, and the British cohort's low rate of hearing loss shows the
    feature is not obligate, so the edge from the expansion to auditory
    dysfunction is typed UNKNOWN. Temporal bone pathology, or an
    auditory-competent model, would resolve it.
- discussion_id: cohort_phenotype_variation
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Why do the two discriminating features of SCA36 — sensorineural hearing loss
    and tongue fasciculation — vary so widely between cohorts?
  attaches_to:
  - phenotypes#Sensorineural hearing loss
  - phenotypes#Tongue fasciculations
  rationale: >-
    Tongue atrophy and fasciculation were reported in 12% of French patients
    against 63% of Japanese patients, and the British series found a low rate of
    hearing loss. Ascertainment differences, disease duration at examination,
    somatic repeat instability, and modifier background are all candidate
    explanations, and none has been tested. The practical consequence is already
    recorded in the differential diagnosis: absence of these features does not
    exclude SCA36.
  evidence:
  - reference: PMID:27123487
    reference_title: "Spinocerebellar ataxia type 36 in the Han Chinese."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "atrophy and fasciculation of the tongue and limb muscles are present in 12% of French patients in contrast to 63% of Japanese patients"
    explanation: >-
      Quantifies the between-cohort discrepancy that this question is about.
notes: >-
  The GeneReviews SCA36 chapter (PMID:25101480) has been retired and the cached
  record is the archival version. It remains the only expert-curated clinical
  synthesis for this disorder and is used here as the phenotype and management
  baseline, with primary cohort reports cited alongside it wherever they cover
  the same claim.

  A generic Fasciculations phenotype was considered and dropped: Tongue
  fasciculations and Skeletal muscle fasciculation and atrophy already carry the
  finding with cohort frequencies attached, and the generic term added no
  queryable information the two specific ones do not.

  NCT06467175 (ALICA) is deliberately not curated as a clinical trial. It is a
  long-read sequencing diagnostic study rather than a trial of an intervention
  in SCA36, and the diagnosis section already records the long-read and
  whole-genome-sequencing routes to detecting the expansion.

  SCA36 is also represented at the group level: the NOP56 genetic block in
  Autosomal_Dominant_Cerebellar_Ataxia_Type_I describes this disorder in its
  ADCA-I context, and the Cerebellar_Ataxias grouping collects the ataxias.
  This dedicated entry coexists with both, following the pattern already used
  for SCA2, SCA17 and SCA23.

📚

References & Deep Research

References

1

PMID:25101480

Spinocerebellar Ataxia Type 36 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Spinocerebellar Ataxia Type 36 (SCA36): Disease-Characteristics Report

Edison Scientific Literature 32 citations 2026-09-02T13:27:52.330807

Spinocerebellar Ataxia Type 36 (SCA36): Disease-Characteristics Report

Scope. This synthesis prioritizes primary human evidence, supplemented by experimental models and recent 2023–2024 diagnostic literature. SCA36 remains exceptionally rare; consequently, many estimates derive from referral cohorts or pedigrees rather than population surveillance. “Not reported” below means that no disease-specific evidence was identified in the retrieved literature, not proof of absence.

Executive summary

Spinocerebellar ataxia type 36 is a late-onset, slowly progressive, autosomal-dominant neurodegenerative disorder caused by a heterozygous GGCCTG hexanucleotide repeat expansion in intron 1 of NOP56. The defining syndrome is gait/truncal and limb ataxia with dysarthria, frequently accompanied by hyperreflexia, sensorineural hearing loss, and—usually later—lower-motor-neuron manifestations such as tongue or limb atrophy and fasciculations. Cognitive-affective abnormalities, tremor, sensory impairment, and ptosis occur in subsets. Hearing loss and tongue fasciculation are useful diagnostic clues but are not required. (lee2016spinocerebellarataxiatype pages 1-2, obayashi2015spinocerebellarataxiatype pages 3-4, lam2023repeatexpansionsin pages 1-3)

The strongest mechanistic model is toxic gain of function from expanded repeat RNA, involving nuclear RNA foci and altered RNA-protein interactions, together with intron retention and translation of dipeptide-repeat proteins. A contribution from reduced NOP56 function remains possible but is not established as the principal human mechanism. There is currently no approved disease-modifying treatment; care is supportive and multidisciplinary. Repeat-targeting antisense oligonucleotides and transcriptional suppression have reduced molecular pathology only in preclinical systems. (lopez2022spinocerebellarataxia36 pages 3-5, quelleregaldie2022anop56zebrafish pages 1-2, mceachin2020chimericpeptidespecies pages 1-3, matsuzono2017antisenseoligonucleotidesreduce pages 1-2, furuta2019suppressionofthe pages 1-2)

The following table summarizes the principal evidence.

Domain	Current evidence	Evidence type	Key quantitative detail	Caveat
Definition / identifier	Spinocerebellar ataxia type 36 (SCA36) is a late-onset autosomal dominant cerebellar ataxia caused by a NOP56 intron 1 hexanucleotide repeat expansion; MONDO: MONDO_0013594; common synonyms include Costa da Morte ataxia and Asidan ataxia. (OpenTargets Search: spinocerebellar ataxia type 36-NOP56, quelleregaldie2022anop56zebrafish pages 1-2, lam2023repeatexpansionsin pages 1-3)	Disease database + human cohort + review	Open Targets links SCA36 to NOP56; British paper screened 1257 hereditary ataxia patients and 7506 controls. (OpenTargets Search: spinocerebellar ataxia type 36-NOP56, lam2023repeatexpansionsin pages 1-3)	MONDO and disease-target association are database-level resources; clinical phenotype still derived from relatively small family-based cohorts.
Causal variant and repeat range	Causal lesion is a heterozygous GGCCTG repeat expansion in intron 1 of NOP56. Normal alleles are reported as 3–14 or 5–14 repeats; expanded alleles range from ~30 to 2500, with many clinically typical alleles 650–2500 repeats; short pathogenic alleles of 25–31 repeat tracts have also been reported. (lee2016spinocerebellarataxiatype pages 1-2, obayashi2015spinocerebellarataxiatype pages 2-3, obayashi2015spinocerebellarataxiatype pages 7-9, lam2023repeatexpansionsin pages 1-3)	Primary human genetic studies + review	Han Chinese families: 650–2500 units; Obayashi et al.: controls 5–14, affected 25–31 repeat units; Lam 2023: expanded alleles 30–2500, mostly 650–2500. (lee2016spinocerebellarataxiatype pages 1-2, obayashi2015spinocerebellarataxiatype pages 2-3, lam2023repeatexpansionsin pages 1-3)	Cross-study nomenclature differs because some studies estimate tract size by Southern blot while others infer smaller “short expansions” by RP-PCR/fragment analysis.
Hallmark phenotype / onset	Core phenotype is slowly progressive cerebellar ataxia, usually beginning with gait/truncal ataxia, with dysarthria, hyperreflexia, sensorineural hearing loss, and later upper/lower motor neuron involvement including tongue fasciculations/atrophy. (lee2016spinocerebellarataxiatype pages 1-2, obayashi2015spinocerebellarataxiatype pages 3-4, lam2023repeatexpansionsin pages 1-3, lam2023repeatexpansionsin pages 3-4)	Primary human clinical cohorts	Mean age at onset: 44.8 ± 3.8 y in Han Chinese families; 50.4 ± 7.2 y in multinational cohort; British cohort mean 48.4 y (range 28–62). Frequencies in Obayashi et al.: hearing impairment 60%, reduced vibration sense 52%, lower motor neuron signs 28%, postural tremor 28%, ptosis 24%, cognitive impairment 24%. (lee2016spinocerebellarataxiatype pages 1-2, obayashi2015spinocerebellarataxiatype pages 3-4, lam2023repeatexpansionsin pages 3-4)	Hearing loss and tongue fasciculation are not universal; British patients had a lower rate of hearing loss, so absence of these signs does not exclude SCA36. (lam2023repeatexpansionsin pages 1-3)
Epidemiology	SCA36 is rare globally but enriched in founder populations from western Japan and Galicia, Spain, and is also present in France, Taiwan/Han Chinese populations, the US, and White British families. (lee2016spinocerebellarataxiatype pages 1-2, obayashi2015spinocerebellarataxiatype pages 4-5, lopez2022spinocerebellarataxia36 pages 2-3, lam2023repeatexpansionsin pages 1-3)	Primary human cohort studies + review	Reported proportions among ataxia cohorts: 6.3% in Galicia, 1.9% in France, 1.5% in Japan, 0.6% (3/512) in Han Chinese SCA pedigrees, 0.7% (4/577) in a US undiagnosed ataxia cohort. British WGS study found 5 families / 7 patients among 1257 hereditary ataxia patients. (lee2016spinocerebellarataxiatype pages 1-2, obayashi2015spinocerebellarataxiatype pages 4-5, lopez2022spinocerebellarataxia36 pages 2-3, lam2023repeatexpansionsin pages 1-3)	Most figures are cohort proportions rather than population prevalence/incidence; true population-level prevalence remains uncertain.
Mechanism	Best-supported mechanism is toxic RNA gain-of-function with sense RNA foci, intron retention, and repeat translation into DPRs; RAN/canonical translation products include poly(GP), poly(PR), poly(GL) and poly(WA), with disease-context-specific aggregation behavior. NOP56 loss of function may contribute but is less directly established in patients. (lopez2022spinocerebellarataxia36 pages 3-5, mceachin2020chimericpeptidespecies pages 1-3, matsuzono2017antisenseoligonucleotidesreduce pages 1-2, furuta2019suppressionofthe pages 1-2)	Human tissue + iPSC + cell + mouse + review	RNA foci reported in cerebrum, cerebellum, inferior olive, spinal cord, and temporal muscle; iPSC study reduced RNA-foci-positive cells to ~50% after ASO treatment; Furuta et al. found RAN translation from GGCCTG direction was rare in Neuro2A cells, while McEachin et al. found poly(GP) and poly(PR) in patient tissue and showed poly(GP) is soluble in SCA36. (lopez2022spinocerebellarataxia36 pages 3-5, mceachin2020chimericpeptidespecies pages 1-3, matsuzono2017antisenseoligonucleotidesreduce pages 1-2, furuta2019suppressionofthe pages 1-2)	Relative contribution of RNA toxicity versus DPR toxicity versus haploinsufficiency remains unresolved; some mechanistic findings differ by model system.
Diagnostics	Standard molecular confirmation uses repeat-primed PCR (RP-PCR) and Southern blot; newer approaches include short-read WGS with repeat-expansion calling and long-read sequencing for direct sizing/haplotype resolution. (lee2016spinocerebellarataxiatype pages 1-2, obayashi2015spinocerebellarataxiatype pages 4-5, lam2023repeatexpansionsin pages 1-3, rafehi2023detectionanddiscovery pages 1-2, stevanovski2022comprehensivegeneticdiagnosis pages 1-3)	Clinical molecular diagnostics + review + sequencing-method studies	RP-PCR identifies characteristic decremental/sawtooth peaks; Southern blot can detect long unstable alleles of roughly 8–15 kb and short expansions of ~3.5 kb; British study used ExpansionHunter on WGS and RP-PCR confirmation; long-read nanopore assays can genotype all known neuropathogenic STRs in one assay. (obayashi2015spinocerebellarataxiatype pages 4-5, lam2023repeatexpansionsin pages 1-3, rafehi2023detectionanddiscovery pages 1-2, stevanovski2022comprehensivegeneticdiagnosis pages 1-3)	WES is generally poor for direct repeat-expansion detection; WGS/long-read pipelines still require confirmatory review and are not yet uniformly available clinically.
Treatments	No approved disease-modifying therapy specific to SCA36. Current care is supportive/rehabilitative, while experimental strategies target toxic RNA or repeat transcription. (lopez2022spinocerebellarataxia36 pages 2-3, matsuzono2017antisenseoligonucleotidesreduce pages 1-2, furuta2019suppressionofthe pages 1-2)	Review + iPSC preclinical + cell preclinical	In patient iPSCs/iPSC-derived neurons, ENA ASOs targeting NOP56 pre-mRNA reduced RNA-foci-positive cells to ~50%; one ASO reduced foci without lowering NOP56 mRNA. In cell models, Supt4a knockdown and erythromycin reduced RNA foci and cytotoxicity. (matsuzono2017antisenseoligonucleotidesreduce pages 1-2, furuta2019suppressionofthe pages 1-2)	Preclinical only; no SCA36-specific interventional efficacy trial was identified. Long-read diagnostic study NCT06467175 is recruiting (210 planned participants) for cerebellar ataxias broadly, not a therapeutic SCA36 trial. (NCT06467175 chunk 1)
Models	SCA36 has been studied in patient iPSCs/iPSC-derived neurons, Neuro2A and yeast/cell models of expanded repeats, transgenic mouse systems, and a zebrafish nop56 loss-of-function model. (todd2020hexanucleotiderepeatexpansions pages 8-9, quelleregaldie2022anop56zebrafish pages 1-2, matsuzono2017antisenseoligonucleotidesreduce pages 1-2, furuta2019suppressionofthe pages 1-2)	Cellular + animal models	Zebrafish nop56 mutants showed absence of cerebellum, reduced spinal cord neurons, high CNS apoptosis, impaired movement, and death before 7 days post-fertilization; mouse repeat models showed cerebellar degeneration with Purkinje cell loss; behavioral/pathology cohorts included up to 20 mice per genotype group in Todd et al. (todd2020hexanucleotiderepeatexpansions pages 16-17, quelleregaldie2022anop56zebrafish pages 1-2)	No single model captures the full human combination of late onset, slow progression, hearing loss, and motor neuron involvement; zebrafish model addresses loss-of-function more than repeat toxicity.

Table: This table condenses the main disease-level evidence for Spinocerebellar Ataxia Type 36 across genetics, phenotype, mechanism, diagnostics, treatment, and models. It is designed for direct embedding into a technical report and highlights both quantitative findings and major caveats.

1. Disease information

Definition and identifiers

Preferred name: Spinocerebellar ataxia type 36.
MONDO: MONDO:0013594.
OMIM: 614153 is commonly assigned to SCA36; NOP56 is OMIM 614154. Database releases should be checked before production ingestion.
Orphanet: commonly represented under ORPHA:276161; verify against the current Orphanet release before committing the identifier.
MeSH: no retrieved disease-specific MeSH descriptor; broader terms include Spinocerebellar Ataxias and Cerebellar Ataxia (ClinicalTrials.gov maps cerebellar ataxia to MeSH D002524).
ICD-10/ICD-11: no uniquely retrieved SCA36-specific code. It is generally coded under hereditary/degenerative ataxia categories; local coding systems vary.
Causal target: Open Targets associates MONDO:0013594 with NOP56, supported by literature including PMID 21683323 and 22492559. (OpenTargets Search: spinocerebellar ataxia type 36-NOP56)

Synonyms: SCA36; NOP56-related spinocerebellar ataxia; Costa da Morte ataxia; Asidan ataxia. The two geographic names preceded recognition that the Spanish and Japanese syndromes shared the same molecular cause. (quelleregaldie2022anop56zebrafish pages 1-2, mceachin2020chimericpeptidespecies pages 1-3)

Category and evidence granularity: This is a Mendelian disease entity summarized from aggregated disease resources and family/cohort-level research. The cited clinical studies analyze individual participants, but the present report contains no EHR-derived patient-level record.

2. Etiology

Causal and genetic factors

The primary cause is a germline, heterozygous GGCCTG expansion in NOP56 intron 1. Normal alleles have generally been reported as 3–14 or 5–14 repeats. Most classic expanded alleles contain approximately 650–2,500 repeats, although pathogenic short alleles around 25–31 repeat units have been reported. The lesion acts dominantly and exhibits somatic instability. (lee2016spinocerebellarataxiatype pages 1-2, obayashi2015spinocerebellarataxiatype pages 2-3, lam2023repeatexpansionsin pages 1-3)

The canonical discovery study is Kobayashi et al., American Journal of Human Genetics (2011), PMID 21683323. A related Spanish genetic study is represented by PMID 22492559. Open Targets integrates these publications with ClinVar records including RCV000024102. (OpenTargets Search: spinocerebellar ataxia type 36-NOP56)

Risk, modifiers, and protection

Established risk: carrying the pathogenic expansion; an affected parent; ancestry from a founder population increases prior probability but is neither necessary nor sufficient.
Family history: high-value evidence because inheritance is autosomal dominant, although apparently sporadic cases may occur through unrecognized late-onset disease or limited family information.
Repeat length: short expansions may have later onset, but one comparison—57.3 years for short versus 49.4 years for long expansions—was not statistically significant (p=0.408). Repeat size is therefore not a validated individual prognostic biomarker. (obayashi2015spinocerebellarataxiatype pages 4-5)
Modifier genes/protective variants: none validated for SCA36.
Environmental, lifestyle, occupational, toxic, or infectious risk factors: none demonstrated as causal or penetrance-modifying.
Protective diet, exercise exposure, or medication: none demonstrated to prevent molecular disease.
Gene–environment interaction: no SCA36-specific interaction has been established. Exercise may preserve function in degenerative ataxia generally, but this is tertiary management rather than primary protection.

3. Phenotypes

The best quantified multinational series included 25 symptomatic individuals, with mean onset 50.4±7.2 years (range 39–65). Progressive cerebellar ataxia was universal. Hearing impairment occurred in 60%, reduced vibration sense in 52%, lower-motor-neuron signs in 28%, postural tremor in 28%, ptosis in 24%, and cognitive impairment in 24%; peripheral nerve abnormalities were detected in 32% of tested patients. These percentages should not be treated as universal because ascertainment, ancestry, and disease duration differ among studies. (obayashi2015spinocerebellarataxiatype pages 3-4)

Phenotype	Type/course and frequency	Suggested HPO term
Gait/truncal ataxia	Usually presenting sign; progressive, typically universal	HP:0002066 Cerebellar ataxia, HP:0001288 Gait disturbance
Limb ataxia/dysmetria	Common, progressive	HP:0002070 Limb ataxia, HP:0001310 Dysmetria
Dysarthria	Common cerebellar sign	HP:0001260 Dysarthria
Abnormal ocular movements	Variable; impaired pursuit/overshoot described	HP:0000496 Abnormality of eye movement
Hyperreflexia/pyramidal signs	Common; one review reports hyperreflexia in 79%	HP:0001347 Hyperreflexia
Sensorineural hearing impairment	Often high-frequency; 60% in one multinational cohort, lower in British series	HP:0000407 Sensorineural hearing impairment
Tongue/limb atrophy and fasciculations	Usually later with prolonged disease; 28% lower-motor-neuron signs in one cohort	HP:0003473 Lower motor neuron dysfunction, HP:0001308 Tongue fasciculations, HP:0002460 Distal muscle weakness
Reduced vibration sensation/neuropathy	52% reduced vibration; abnormal sensory potentials in 32% tested	HP:0002495 Impaired vibratory sensation, HP:0009830 Peripheral neuropathy
Tremor	Postural tremor 28%	HP:0002173 Postural tremor
Cognitive-affective impairment	Cognitive impairment 24%; frontal-executive/cerebellar cognitive-affective changes reported	HP:0100543 Cognitive impairment
Ptosis	24% in one cohort	HP:0000508 Ptosis
Cerebellar atrophy	MRI abnormality; 100% of 14 examined in one series	HP:0001272 Cerebellar atrophy

Human cohort evidence supports mean onset 44.8±3.8 years in Taiwanese Han Chinese families, with truncal ataxia first; the 2023 British series found mean onset 48.4 years (range 28–62). (lee2016spinocerebellarataxiatype pages 1-2, lam2023repeatexpansionsin pages 3-4)

Quality of life. No SCA36-specific EQ-5D, SF-36, or PROMIS dataset was retrieved. Clinically, progressive gait impairment, falls risk, dysarthria, hearing loss, and weakness affect mobility, communication, employment, and independence. This impact is strongly plausible but has not been adequately quantified with disease-specific patient-reported outcomes.

4. Genetic and molecular information

Gene: NOP56 (HGNC:15911; Ensembl ENSG00000101361), encoding a 594-amino-acid nucleolar ribonucleoprotein. It is a core scaffold of the box C/D small nucleolar RNP complex, which participates in pre-rRNA processing, 2′-O-ribose methylation, and 60S ribosomal-subunit assembly. (OpenTargets Search: spinocerebellar ataxia type 36-NOP56, lopez2022spinocerebellarataxia36 pages 3-5, quelleregaldie2022anop56zebrafish pages 1-2)

Variant representation: the expansion is often described as (GGCCTG)n, alternatively strand-oriented as TGGGCC/TG3C2. Precise HGVS description is technically difficult because expanded length and somatic mosaicism vary. It is a noncoding tandem-repeat expansion rather than a missense, nonsense, or conventional structural deletion.

Classification: a sufficiently expanded allele segregating with the characteristic phenotype is pathogenic. Classic very large expansions and reported short pathogenic expansions require laboratory interpretation using assay-specific thresholds, segregation, phenotype, and orthogonal confirmation. The expansion is germline; tissue-dependent repeat-size heterogeneity is somatic instability, not a primary somatic disease.

Population frequency: expansions were absent from 727 controls in one multinational study and from 323 Taiwanese controls; no reliable gnomAD allele frequency is available because conventional short-read population databases poorly genotype very large repeats. (lee2016spinocerebellarataxiatype pages 1-2, obayashi2015spinocerebellarataxiatype pages 2-3)

Functional consequence: toxic RNA/protein gain of function is best supported. Human lymphoblastoid studies did not consistently show reduced NOP56 protein, arguing against simple haploinsufficiency, although patient iPSCs and neurons showed lower NOP56 mRNA and loss of function remains a possible contributor. (lopez2022spinocerebellarataxia36 pages 3-5, quelleregaldie2022anop56zebrafish pages 1-2, matsuzono2017antisenseoligonucleotidesreduce pages 1-2)

Modifiers, epigenetics, chromosomal abnormalities: no validated modifier gene, disease-specific methylation signature, aneuploidy, translocation, inversion, or pathogenic copy-number change is established. A 2023 British study identified a shared 72.2–87-kb haplotype and estimated a founder mutation age of 31.7 generations (95% CI 16.9–60), but the haplotype also occurred in controls, suggesting a permissive background rather than a fully penetrant modifier. (lam2023repeatexpansionsin pages 1-3, lam2023repeatexpansionsin pages 3-4)

5. Environmental information

SCA36 is not an infectious, toxic, radiation-induced, or occupational disease. No smoking, alcohol, diet, pollution, or pathogen association has been demonstrated. Acquired causes of ataxia—alcohol/toxins, vitamin deficiencies, immune-mediated ataxia, infection, neoplasm, and medication effects—remain clinically important differential diagnoses but do not explain genetically confirmed SCA36.

6. Mechanism and pathophysiology

Ordered causal chain

A germline heterozygous NOP56 intron-1 GGCCTG expansion leads to transcription of a very long, unstable GGCCUG-containing pre-mRNA. (lopez2022spinocerebellarataxia36 pages 3-5, lam2023repeatexpansionsin pages 1-3)
Expanded repeat RNA leads to abnormal secondary structure, intron retention, and nuclear RNA-foci formation in vulnerable neural cells; RNA foci are demonstrated in human tissue and patient-derived cells. (lopez2022spinocerebellarataxia36 pages 3-5, mceachin2020chimericpeptidespecies pages 1-3, matsuzono2017antisenseoligonucleotidesreduce pages 1-2)
RNA foci lead to, or are inferred to lead to, sequestration/dysregulation of RNA-binding proteins, including reported SRSF2 interaction, thereby disturbing RNA processing. The downstream transcript-wide consequences remain incompletely mapped. (lopez2022spinocerebellarataxia36 pages 3-5)
Branch A: repeat-containing RNA leads to unconventional RAN translation and, for poly(GP), canonical upstream-AUG/intron-retention-dependent translation, producing DPR species including poly(GP), poly(PR), poly(GL), and poly(WA). (mceachin2020chimericpeptidespecies pages 1-3)
DPR production results in soluble or aggregate-prone peptide species and cellular stress; poly(GP) is unusually soluble in SCA36 tissue, and the precise toxic DPR species remain unresolved. (todd2020hexanucleotiderepeatexpansions pages 8-9, mceachin2020chimericpeptidespecies pages 1-3)
Branch B: altered NOP56 expression/function may lead to impaired box C/D snoRNP activity, rRNA processing, ribosome biogenesis, and cell-cycle/homeostatic defects; this is biologically plausible and strong in knockout models but not demonstrated as the dominant patient mechanism. (quelleregaldie2022anop56zebrafish pages 1-2, matsuzono2017antisenseoligonucleotidesreduce pages 1-2)
RNA/protein toxicity, and possibly partial NOP56 dysfunction, lead to cellular dysfunction and death in Purkinje cells, inferior-olivary neurons, brainstem/hypoglossal motor neurons, and spinal motor systems. (lopez2022spinocerebellarataxia36 pages 3-5, obayashi2015spinocerebellarataxiatype pages 4-5, todd2020hexanucleotiderepeatexpansions pages 8-9)
Selective neuronal degeneration results in cerebellar atrophy and progressive gait/limb ataxia; motor-neuron injury results in fasciculation and atrophy; auditory-system involvement results in sensorineural hearing loss. (obayashi2015spinocerebellarataxiatype pages 3-4, obayashi2015spinocerebellarataxiatype pages 4-5)

Mechanistic detail and evidence grading

Human tissue: RNA foci occur in cerebrum, cerebellum, inferior olive, spinal cord, and temporal muscle, with particularly large foci in Purkinje and inferior-olivary neurons. Neuropathology shows mild Purkinje-cell loss, Bergmann gliosis, distorted dendrites, Purkinje “torpedoes,” and mild hypoglossal neuronal loss; ubiquitin, TDP-43, FUS, and p62 inclusions were absent in the examined case. (lopez2022spinocerebellarataxia36 pages 3-5, obayashi2015spinocerebellarataxiatype pages 4-5)

Human iPSC evidence: three SCA36 and three control clones were differentiated into neurons. Patient cells recapitulated RNA foci and showed lower NOP56 mRNA. The authors reported: “Treatment … targeting NOP56 pre-mRNA reduced RNA-foci-positive cells to 50% in patient iPSCs and iPSC-derived neurons.” One ASO reduced foci without lowering NOP56 mRNA, supporting RNA toxicity as a tractable mechanism. (matsuzono2017antisenseoligonucleotidesreduce pages 1-2, matsuzono2017antisenseoligonucleotidesreduce pages 6-7)

DPR evidence: McEachin et al. stated: “the similar intronic GGCCTG HREs that causes … SCA36 is also translated into DPRs, including poly(GP) and poly(PR).” Poly(GP) was more abundant but soluble in SCA36 tissue, while TDP-43 pathology was absent. This indicates that DPR presence does not automatically imply the aggregation pattern seen in C9ORF72 ALS/FTD. (mceachin2020chimericpeptidespecies pages 1-3)

Mouse evidence: transient/transgenic repeat-expression models develop selective cerebellar degeneration and Purkinje-cell loss. Poly(PR) was detected in human granule cells but not robustly in one SCA36 mouse model, showing that model-specific DPR expression limits causal inference. (todd2020hexanucleotiderepeatexpansions pages 8-9, todd2020hexanucleotiderepeatexpansions pages 16-17)

Suggested annotations: biological processes—GO:0006364 rRNA processing, GO:0006396 RNA processing, GO:0006412 translation, GO:0006915 apoptotic process, GO:0008219 cell death, and GO:0048856 anatomical structure development. Cell types—CL:0000121 Purkinje cell, CL:0000100 motor neuron, neuron, and astrocyte/Bergmann glial annotations. Subcellular compartments—GO:0005730 nucleolus, GO:0005634 nucleus, GO:0030529 intracellular ribonucleoprotein complex, and GO:0005840 ribosome.

No disease-specific metabolomic, lipidomic, proteomic, single-cell, spatial-transcriptomic, or integrated multi-omic signature has been validated. RNA-seq was used to characterize iPSC clones, but not to establish a clinical molecular signature. (matsuzono2017antisenseoligonucleotidesreduce pages 1-2)

7. Anatomical structures affected

The primary system is the nervous system. The cerebellum—vermis and hemispheres—is central; MRI showed cerebellar atrophy in all 14 examined participants in one study, with brainstem atrophy in 28.6% and cerebral atrophy in 14.3%. FDG-PET abnormalities may precede symptoms and progress from vermis/right cerebellum toward hemispheres and brainstem, but PET is not a validated screening biomarker. (lopez2022spinocerebellarataxia36 pages 3-5, obayashi2015spinocerebellarataxiatype pages 3-4)

Other affected structures include the inferior olivary nucleus, hypoglossal nucleus, spinal cord/motor system, peripheral sensory nerves, auditory pathways, tongue, and limb skeletal muscle secondary to denervation. Disease is generally bilateral/systemic rather than unilateral. (lopez2022spinocerebellarataxia36 pages 3-5, obayashi2015spinocerebellarataxiatype pages 4-5)

Suggested anatomy terms: cerebellum UBERON:0002037; cerebellar cortex UBERON:0002129; Purkinje cell layer UBERON:0002956; brainstem UBERON:0002298; spinal cord UBERON:0002240; tongue UBERON:0001723; skeletal muscle tissue UBERON:0001134.

8. Temporal development

Onset is usually insidious in the fifth to sixth decade, although the British range extended from 28 to 62 years. Initial gait/truncal ataxia slowly expands to limb incoordination and dysarthria; auditory and pyramidal manifestations may coexist, whereas lower-motor-neuron signs become more evident with longer duration. (lee2016spinocerebellarataxiatype pages 1-2, lam2023repeatexpansionsin pages 1-3, lam2023repeatexpansionsin pages 3-4)

The course is chronic, lifelong, and progressive rather than episodic or relapsing. In the British series, duration was 9–29 years and all patients retained mobility at least nine years after onset; a patient with 29 years of disease continued walking. A fastest reported interval to wheelchair dependence was five years, demonstrating occasional faster progression. (lam2023repeatexpansionsin pages 1-3, lam2023repeatexpansionsin pages 3-4)

No spontaneous remission is expected. Preclinical PET changes in asymptomatic carriers suggest a presymptomatic biological phase and a potential future intervention window, but neither PET screening nor presymptomatic treatment has been validated. (lopez2022spinocerebellarataxia36 pages 3-5)

9. Inheritance and population

Inheritance is autosomal dominant. Each child of a heterozygous affected individual has a theoretical 50% chance of inheriting the expansion. Penetrance appears strongly age dependent; precise lifetime penetrance has not been estimated. Expressivity is variable, particularly for hearing loss, cognition, neuropathy, and motor-neuron involvement. (obayashi2015spinocerebellarataxiatype pages 2-3, lam2023repeatexpansionsin pages 1-3)

Anticipation has been described clinically, but massive repeat size, somatic mosaicism, and assay limitations prevent a robust expansion-size/onset model. Three reported short-expansion cases were maternally transmitted, but evidence is insufficient to establish a general parent-of-origin rule. Germline mosaicism and carrier frequency have not been quantified. Consanguinity is not etiologically relevant to this dominant disorder. (obayashi2015spinocerebellarataxiatype pages 3-4, lopez2022spinocerebellarataxia36 pages 2-3, obayashi2015spinocerebellarataxiatype pages 7-9)

Founder effects are documented in Galicia, western Japan, Han Chinese/Taiwanese families, and possibly Britain. Three Taiwanese pedigrees shared a 5.3-kb haplotype. In Britain, five unrelated families shared a 72.2–87-kb region around NOP56. (lee2016spinocerebellarataxiatype pages 1-2, lam2023repeatexpansionsin pages 1-3, lam2023repeatexpansionsin pages 3-4)

Reported proportions among selected ataxia cohorts are 6.3% in Galicia, 1.9% in France, 1.5% in Japan, 0.6% (3/512 pedigrees) in Han Chinese SCA, and 0.7% (4/577 index cases) in a US undiagnosed-ataxia cohort. The 2023 British study found five families/seven patients among 1,257 hereditary-ataxia patients. These are not incidence or general-population prevalence estimates. Sex-specific risk has not been demonstrated. (lee2016spinocerebellarataxiatype pages 1-2, obayashi2015spinocerebellarataxiatype pages 4-5, lopez2022spinocerebellarataxia36 pages 2-3, lam2023repeatexpansionsin pages 1-3)

10. Diagnostics

Recommended workflow

Clinical assessment: document three-generation pedigree; onset and progression; gait, limb, ocular, speech, pyramidal and lower-motor-neuron signs; cognition; hearing; sensory neuropathy; and acquired exposures.
Exclude treatable acquired ataxias: basic metabolic, nutritional, immune/paraneoplastic, toxic, infectious, and structural evaluation tailored to presentation.
MRI brain: look for predominantly cerebellar atrophy; a normal early MRI does not molecularly exclude disease.
Audiology: pure-tone testing, especially high frequencies; useful phenotyping, not diagnostic.
Electrophysiology: EMG/nerve-conduction testing when fasciculation, weakness, atrophy, or sensory loss is present.
Molecular testing: use a repeat-expansion panel or NOP56-specific repeat-primed PCR (RP-PCR). A characteristic 6-bp sawtooth/decremental peak pattern supports expansion.
Orthogonal characterization: Southern blot estimates very large and mosaic alleles; long-range PCR may characterize short expansions. Segregation testing strengthens interpretation.
Genome approaches: short-read WGS with ExpansionHunter or comparable callers can screen the locus, but manual review and molecular confirmation remain advisable. Long-read WGS/targeted nanopore sequencing can directly span, size, phase, and assess methylation of complex expansions. (obayashi2015spinocerebellarataxiatype pages 4-5, lee2016spinocerebellarataxiatype pages 2-3, lam2023repeatexpansionsin pages 1-3, lam2023repeatexpansionsin pages 3-4, rafehi2023detectionanddiscovery pages 1-2, stevanovski2022comprehensivegeneticdiagnosis pages 1-3)

The 2023 review states that the current gold standard remains “repeat-primed PCR assays or Southern blots, neither of which are scalable nor readily available for all STR loci.” WGS repeat-calling is increasingly practical, while long-read sequencing is the likely future comprehensive assay. (rafehi2023detectionanddiscovery pages 1-2)

WES: generally unsuitable for directly detecting this deep intronic expansion. Apparent exome-based clues require dedicated confirmation. CMA, karyotype, FISH, and mitochondrial testing do not diagnose the repeat and are reserved for alternative hypotheses. No blood, CSF, enzyme, transcriptomic, proteomic, metabolomic, epigenomic, or liquid-biopsy diagnostic biomarker is validated.

Differential diagnosis

Important genetic alternatives include SCA1/2/3/6/7/8/10/12/17/31, SCA27B/FGF14, SCA4/ZFHX3, DRPLA, RFC1-CANVAS, Friedreich ataxia, FXTAS, and other dominant ataxias. Motor-neuron disease with ataxia raises C9ORF72 ALS/FTD and ATXN2-associated disease; preserved swallowing and slowly progressive cerebellar disease may favor SCA36 over classic ALS. Multiple-system atrophy–cerebellar type is usually sporadic and accompanied by prominent autonomic failure. Acquired immune, toxic, nutritional, infectious, neoplastic, and structural causes must also be excluded.

Screening

There is no newborn or population screening. Cascade testing is appropriate after a familial expansion is identified. Predictive testing of asymptomatic adults should occur with genetic counseling and informed consent. Prenatal diagnosis and preimplantation genetic testing are technically possible when the familial expansion and laboratory method are established.

11. Outcome and prognosis

SCA36 causes progressive neurological disability but generally advances more slowly than aggressive motor-neuron disease. Long-term morbidity includes falls, impaired ambulation, dysarthria, hearing-related communication difficulty, tremor, sensory loss, muscle wasting, and eventual dependence. (lee2016spinocerebellarataxiatype pages 1-2, obayashi2015spinocerebellarataxiatype pages 3-4, lam2023repeatexpansionsin pages 3-4)

Disease-specific five- or ten-year survival, mortality rates, and treatment-adjusted life expectancy have not been established. Deaths in the British series after shorter observed durations were reported as unrelated to SCA36. Aspiration, immobility, falls, and respiratory weakness are clinically plausible late complications, but SCA36-specific rates are unavailable. Recovery of lost neurons is not expected; rehabilitation can preserve function and safety.

Potential prognostic factors include age at onset, baseline ataxia severity, disease duration, and emergence of motor-neuron involvement. Repeat length is not sufficiently validated for individual prediction. No accepted molecular prognostic biomarker exists.

12. Treatment

Current clinical management

No drug, gene therapy, RNA therapy, cell therapy, surgery, or immunotherapy is approved to alter SCA36 progression. Management should be coordinated by neurology/ataxia specialists:

physical therapy, balance and gait training, home-safety assessment, walking aids, and fall prevention;
occupational therapy and adaptive equipment;
speech-language therapy and communication aids;
swallow evaluation if dysphagia develops, with nutritional support as needed;
audiology and hearing aids/cochlear evaluation where appropriate;
EMG-guided assessment and respiratory monitoring when motor-neuron weakness is substantial;
symptomatic treatment of tremor, spasticity, cramps, mood, sleep, pain, and bladder symptoms using standard individualized practice;
genetic counseling and psychosocial support.

Suggested NCIT intervention concepts include Physical Therapy (C15308), Occupational Therapy, Speech Therapy, Genetic Counseling (C15241), Hearing Aid, and Assistive Device; terminology/version should be validated against the current NCIT release.

Experimental therapies

Antisense oligonucleotides: ENA-modified ASOs reduced RNA-foci-positive cells to approximately 50% in SCA36 iPSCs and derived neurons; one candidate did so without further lowering NOP56 mRNA. This is proof of molecular target engagement, not clinical efficacy. (matsuzono2017antisenseoligonucleotidesreduce pages 1-2, matsuzono2017antisenseoligonucleotidesreduce pages 6-7)

Transcription/RNA-pathway modulation: Supt4a knockdown and erythromycin reduced repeat RNA, foci/DPR production, and cytotoxicity in Neuro2A models. Erythromycin is not an established SCA36 therapy and should not be used off-label on this evidence. (furuta2019suppressionofthe pages 1-2)

DPR targeting: repeat-targeting ASOs robustly reduced poly(GP) in experimental systems, but uncertainty over the pathogenic DPR species and CNS delivery remains. (mceachin2020chimericpeptidespecies pages 1-3)

No SCA36-specific therapeutic trial was identified. NCT06467175 (ALICA) is a recruiting diagnostic study—not treatment—planning 210 participants with unresolved cerebellar ataxia to assess Oxford Nanopore long-read genome sequencing after nondiagnostic short-read GS. It began December 11, 2024; estimated completion is June 2028. ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT06467175. (NCT06467175 chunk 1)

13. Prevention

Primary prevention through lifestyle modification or vaccination is not applicable to a germline dominant expansion. Reproductive risk reduction may include informed family planning, donor gametes, prenatal diagnosis, or preimplantation genetic testing after nondirective counseling.

Secondary prevention consists of cascade identification of at-risk relatives, predictive testing of consenting adults, baseline neurologic/audiologic assessment, and early rehabilitation. There is no evidence supporting presymptomatic medication.

Tertiary prevention includes fall reduction, exercise within safe limits, hearing rehabilitation, aspiration surveillance, mobility maintenance, vaccination according to general recommendations, and prompt management of respiratory or nutritional complications. No prophylactic drug is established.

14. Other species and natural disease

No naturally occurring SCA36-equivalent veterinary disorder or zoonotic transmission was identified. SCA36 is not infectious and has no zoonotic potential. NOP56 is evolutionarily conserved; zebrafish nop56 has approximately 70% homology to the human gene, supporting comparative functional studies. (quelleregaldie2022anop56zebrafish pages 1-2)

Relevant experimental taxa include Homo sapiens (NCBI Taxon 9606), Mus musculus (10090), Danio rerio (7955), and Saccharomyces cerevisiae (4932). Specific ortholog NCBI Gene IDs and VBO breed terms should be drawn directly from current organism databases during knowledge-base loading; no breed-specific natural disease applies.

15. Model organisms and experimental systems

Patient-derived cells

SCA36 iPSCs and iPSC-derived neurons reproduce repeat retention and RNA foci and permit ASO testing. Their advantages are patient genotype and human neuronal context; limitations include immature cellular age, short culture duration, and incomplete modeling of decades-long cerebellar degeneration. (matsuzono2017antisenseoligonucleotidesreduce pages 1-2, matsuzono2017antisenseoligonucleotidesreduce pages 6-7)

Neuro2A/cellular repeat-expression models

Expanded GGCCTG constructs produce predominantly nuclear sense GGCCUG foci and cytotoxicity. RAN translation was rare in one construct system, whereas human tissue showed multiple DPRs, illustrating dependence on genomic context, repeat length, intron retention, and upstream initiation sequences. These models are useful for high-throughput mechanistic and therapeutic screening but do not capture anatomy or natural expression. (mceachin2020chimericpeptidespecies pages 1-3, furuta2019suppressionofthe pages 1-2)

Mouse

Transient/transgenic TG3C2 repeat-expression mice model RNA foci, DPR biology, gliosis, Purkinje-cell loss, and cerebellar degeneration. Todd et al. used behavioral cohorts of roughly 12–20 animals per genotype at selected ages and pathological groups of approximately 5–8. Limitations include artificial expression, incomplete motor-neuron/hearing phenotype, and failure to reproduce all human DPR pathology. (todd2020hexanucleotiderepeatexpansions pages 8-9, todd2020hexanucleotiderepeatexpansions pages 16-17)

Zebrafish loss-of-function model

The 2022 nop56 mutant showed absent cerebellum, reduced spinal neurons, extensive CNS apoptosis, impaired movement, altered expression of C/D-box and CNS-development genes, and death before seven days post-fertilization. The abstract states: “We observed a severe neurodegenerative phenotype … resulting in death before 7 days post-fertilization.” This strongly demonstrates that Nop56 is essential for neural development, but the severe embryonic knockout is not a faithful model of heterozygous, late-onset repeat toxicity. DOI: https://doi.org/10.3390/biomedicines10081814; published July 28, 2022. (quelleregaldie2022anop56zebrafish pages 1-2)

Yeast and Drosophila

Yeast/Spt4-related systems and repeat-transfected cells support transcriptional-modifier screening. Drosophila Nop56 perturbation causes optic-lobe/cell-cycle defects, informing conserved NOP56 biology rather than faithfully reproducing SCA36. (quelleregaldie2022anop56zebrafish pages 1-2, furuta2019suppressionofthe pages 1-2)

Recent developments and expert assessment

The most important recent disease-specific development is the 2023 demonstration of SCA36 in White British families. Analysis of 1,257 hereditary-ataxia patients and 7,506 controls found pathogenic expansions in five families/seven patients and showed that disease should be considered even without hearing loss or tongue fasciculation. DOI: https://doi.org/10.1093/braincomms/fcad244; advance publication September 14, 2023. (lam2023repeatexpansionsin pages 1-3, lam2023repeatexpansionsin pages 3-4)

The broader 2023–2024 diagnostic consensus is that repeat-expansion testing must be integrated with genome analysis: RP-PCR/Southern blot remain reference methods, short-read WGS can efficiently screen known loci, and long-read sequencing offers direct sizing, phasing, interruption detection, and methylation analysis. The recruiting ALICA study is evaluating whether long-read GS can serve as a real-world second-line diagnostic test. (NCT06467175 chunk 1, rudaks2024anupdateon pages 14-15, rafehi2023detectionanddiscovery pages 1-2, stevanovski2022comprehensivegeneticdiagnosis pages 1-3)

Expert interpretation should remain cautious in three areas. First, short and classic massive expansions complicate a single universal pathogenic cutoff. Second, hearing loss and motor-neuron signs are neither necessary nor uniformly early. Third, RNA foci, DPR production, and partial NOP56 deficiency may coexist; current evidence does not establish which downstream lesion is necessary and sufficient for human neurodegeneration. (obayashi2015spinocerebellarataxiatype pages 2-3, mceachin2020chimericpeptidespecies pages 1-3, matsuzono2017antisenseoligonucleotidesreduce pages 1-2, lam2023repeatexpansionsin pages 1-3)

Key evidence gaps

Population incidence and prevalence per 100,000, lifetime penetrance, sex effects, longitudinal SARA progression, survival, respiratory and aspiration complication rates, validated fluid/imaging biomarkers, patient-reported quality of life, modifier genes, epigenetic signatures, single-cell/spatial omics, natural veterinary disease, and treatment response rates remain unknown or inadequately studied. Multicenter prospective natural-history cohorts and assay-standardized repeat characterization are prerequisites for genotype–phenotype modeling and future SCA36 therapeutic trials.

References

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(todd2020hexanucleotiderepeatexpansions pages 8-9): Tiffany W. Todd, Zachary T. McEachin, Jeannie Chew, Alexander R. Burch, Karen Jansen-West, Jimei Tong, Mei Yue, Yuping Song, Monica Castanedes-Casey, Aishe Kurti, Judith H. Dunmore, John D. Fryer, Yong-Jie Zhang, Beatriz San Millan, Susana Teijeira Bautista, Manuel Arias, Dennis Dickson, Tania F. Gendron, María-Jesús Sobrido, Matthew D. Disney, Gary J. Bassell, Wilfried Rossoll, and Leonard Petrucelli. Hexanucleotide repeat expansions in c9ftd/als and sca36 confer selective patterns of neurodegeneration in vivo. Cell Reports, 31(5):107616, May 2020. URL: https://doi.org/10.1016/j.celrep.2020.107616, doi:10.1016/j.celrep.2020.107616. This article has 58 citations and is from a highest quality peer-reviewed journal.
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(matsuzono2017antisenseoligonucleotidesreduce pages 6-7): Kosuke Matsuzono, Keiko Imamura, Nagahisa Murakami, Kayoko Tsukita, Takuya Yamamoto, Yuishin Izumi, Ryuji Kaji, Yasuyuki Ohta, Toru Yamashita, Koji Abe, and Haruhisa Inoue. Antisense oligonucleotides reduce rna foci in spinocerebellar ataxia 36 patient ipscs. Sep 2017. URL: https://doi.org/10.1016/j.omtn.2017.06.017, doi:10.1016/j.omtn.2017.06.017. This article has 47 citations.
(lee2016spinocerebellarataxiatype pages 2-3): Yi-Chung Lee, Pei-Chien Tsai, Yuh-Cherng Guo, Cheng-Tsung Hsiao, Guan-Ting Liu, Yi-Chu Liao, and Bing-Wen Soong. Spinocerebellar ataxia type 36 in the han chinese. Jun 2016. URL: https://doi.org/10.1212/nxg.0000000000000068, doi:10.1212/nxg.0000000000000068. This article has 43 citations.
(rudaks2024anupdateon pages 14-15): Laura Ivete Rudaks, Dennis Yeow, Karl Ng, Ira W. Deveson, Marina L. Kennerson, and Kishore Raj Kumar. An update on the adult-onset hereditary cerebellar ataxias: novel genetic causes and new diagnostic approaches. Cerebellum (London, England), 23:2152-2168, May 2024. URL: https://doi.org/10.1007/s12311-024-01703-z, doi:10.1007/s12311-024-01703-z. This article has 59 citations.

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	12
Resolved	12
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	12
On topic	5
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	39
Resolved	36
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	2

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0030529 (GO_0030529) (1 mention) - replaced by GO:1990904

Prefixes with no resolver

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

36 of 39 terms resolved to a current term; the rest could not be looked up either way.

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OpenScientist Report

Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Imaging Findings

Progression

Prevalence

Clinical Burden

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Spinocerebellar Ataxia Type 36 (SCA36): Disease-Characteristics Report

Executive summary

1. Disease information

Definition and identifiers

2. Etiology

Causal and genetic factors

Risk, modifiers, and protection

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Mechanistic detail and evidence grading

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Recommended workflow

Differential diagnosis

Screening

11. Outcome and prognosis

12. Treatment

Current clinical management

Experimental therapies

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Patient-derived cells

Neuro2A/cellular repeat-expression models

Mouse

Zebrafish loss-of-function model

Yeast and Drosophila

Recent developments and expert assessment

Key evidence gaps

Artifacts

Reference Validation

Term Validation

Obsolete terms

Prefixes with no resolver