| 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. (pqac-00000000, pqac-00000011, pqac-00000016) | Disease database + human cohort + review | Open Targets links SCA36 to **NOP56**; British paper screened 1257 hereditary ataxia patients and 7506 controls. (pqac-00000000, pqac-00000016) | 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. (pqac-00000002, pqac-00000003, pqac-00000008, pqac-00000016) | 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**. (pqac-00000002, pqac-00000003, pqac-00000016) | 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. (pqac-00000002, pqac-00000004, pqac-00000016, pqac-00000017) | 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%**. (pqac-00000002, pqac-00000004, pqac-00000017) | 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. (pqac-00000016) |
| 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. (pqac-00000002, pqac-00000005, pqac-00000007, pqac-00000016) | 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. (pqac-00000002, pqac-00000005, pqac-00000007, pqac-00000016) | 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. (pqac-00000001, pqac-00000012, pqac-00000013, pqac-00000015) | 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. (pqac-00000001, pqac-00000012, pqac-00000013, pqac-00000015) | 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. (pqac-00000002, pqac-00000005, pqac-00000016, pqac-00000021, pqac-00000022) | 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. (pqac-00000005, pqac-00000016, pqac-00000021, pqac-00000022) | 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. (pqac-00000007, pqac-00000013, pqac-00000015) | 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. (pqac-00000013, pqac-00000015) | 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. (pqac-00000018) |
| 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. (pqac-00000009, pqac-00000011, pqac-00000013, pqac-00000015) | 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. (pqac-00000010, pqac-00000011) | 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.*