Summary of molecular and clinical features of polyQ diseases
| Disease | Gene (locus) | Protein | Normal protein function | Normal (CAG)n | Pathogenic (CAG)n | Major clinical symptoms | Brain regions and cell types most affected | Essential literature |
|---|---|---|---|---|---|---|---|---|
| SBMA/Kennedy’s disease | AR (Xq11-q12) | Androgen receptor (AR) | Steroid hormone receptor and transcription factor | ≤34 | 35–37: reduced penetrancea, ≥38: pathogenic | Affects males; females can show very mild abnormalities. Progressive muscle weakness and atrophy, fasciculations, gynecomastia, testicular atrophy, and reduced fertility | Anterior horn of spinal cord (lower motor neurons) and brainstem | Arnold and Merry (2019) |
| HD | HTT (4p16.3) | Huntingtin (HTT) | Synaptic transmission, scaffolding protein for axonal transport | 6–35 | 36–39: reduced penetrance, ≥40: pathogenic | Chorea, progressive motor impairment, dystonia, cognitive deficits, dysarthria, dysphagia, and psychiatric disturbances | Striatum (MSNs) and cerebral cortex | Bates et al. (2015), Bunting et al. (2022) |
| SCA1 | ATXN1 (6p23) | Ataxin 1 (ATXN1) | Transcriptional corepressor | 4–39 uninterrupted or 39–44 if interrupted by CAT | >39 uninterrupted repeats, or ≥45 if interrupted by CAT: pathogenic | Progressive cerebellar ataxia, spasticity, dysarthria, and deterioration of bulbar functions | Cerebellum (PCs and dentate nucleus), brainstem, and spinocerebellar tracts | Tejwani and Lim (2020) |
| SCA2 | ATXN2 (12q24) | Ataxin 2 (ATXN2) | RNA metabolism, calcium regulation, and stress response | 14–31 | 32–34: reduced penetrancea, ≥35: pathogenic | Progressive cerebellar ataxia, dysarthria, nystagmus, slow saccadic eye movements, myoclonus, and parkinsonism | Cerebellum, brainstem, and spinal cord | Velázquez-Pérez et al. (2017), Egorova and Bezprozvanny (2019) |
| SCA3/Machado–Joseph disease | ATXN 3 (14q24.3-q31) | Ataxin 3 (ATXN3) | Deubiquitinase | 12–44 | 45–55: reduced penetrance, ∼60b–87: pathogenic | Progressive cerebellar ataxia, dystonia, spasticity, dysarthria, dysphagia, ophthalmoplegia, bulging eyes, and faciolingual fasciculations | Cerebellum (dentate nucleus and PCs), brainstem (vestibular, pontine and motor nuclei), basal ganglia, and spinal cord | Paulson (2012), McLoughlin et al. (2020) |
| SCA6 | CACNA1A (19p13) | CaV2.1 | Calcium channel | 4–18 | 19: reduced penetrancea, 20–33: pathogenic | Progressive cerebellar ataxia, dysphagia, dysarthria, and nystagmus | Cerebellum (PCs and dentate nucleus) | Du and Gomez (2018) |
| SCA7 | ATXN7 (3p12-p21.1) | Ataxin 7 (ATXN7) | Subunit of the SAGA complex | 4–33 | 34–36: reduced penetrance, ≥37: pathogenic | Progressive cerebellar ataxia, dysphagia, dysarthria, and retinal degeneration that leads to blindness | Cerebellum (PCs and dentate nucleus), brainstem, and retina (photoreceptors) | Niewiadomska-Cimicka and Trottier (2019) |
| SCA17 | TBP (6q27) | TATA box-binding protein (TBP) | Transcription factor | 25–40 CAG/CAA | 41–48 CAG/CAA: reduced penetrance, ≥49 CAG/CAA: pathogenic | Progressive cerebellar ataxia, dystonia, parkinsonism, chorea, dementia, psychiatric abnormalities, and seizures | Cerebellum (PCs), cortex, and striatum | Liu et al. (2019), Toyoshima and Takahashi (2018) |
| DRPLA | ATN1 (12p13) | Atrophin 1 (ATN1) | Transcriptional corepressor | 6–35 | 35–47: reduced penetrance or milder phenotype, 48–93: pathogenic | Progressive cerebellar ataxia, myoclonus, epilepsy, chorea, intellectual deterioration (juvenile), dementia (adults), and psychiatric symptoms | Cerebellum (dentate nucleus), basal ganglia (globus pallidus and subthalamic nucleus), and brainstem | Nowak et al. (2023) |
| Disease | Gene (locus) | Protein | Normal protein function | Normal (CAG)n | Pathogenic (CAG)n | Major clinical symptoms | Brain regions and cell types most affected | Essential literature |
|---|---|---|---|---|---|---|---|---|
| SBMA/Kennedy’s disease | Androgen receptor (AR) | Steroid hormone receptor and transcription factor | ≤34 | 35–37: reduced penetrance | Affects males; females can show very mild abnormalities. Progressive muscle weakness and atrophy, fasciculations, gynecomastia, testicular atrophy, and reduced fertility | Anterior horn of spinal cord (lower motor neurons) and brainstem | ||
| HD | Huntingtin (HTT) | Synaptic transmission, scaffolding protein for axonal transport | 6–35 | 36–39: reduced penetrance, ≥40: pathogenic | Chorea, progressive motor impairment, dystonia, cognitive deficits, dysarthria, dysphagia, and psychiatric disturbances | Striatum (MSNs) and cerebral cortex | ||
| SCA1 | Ataxin 1 (ATXN1) | Transcriptional corepressor | 4–39 uninterrupted or 39–44 if interrupted by CAT | >39 uninterrupted repeats, or ≥45 if interrupted by CAT: pathogenic | Progressive cerebellar ataxia, spasticity, dysarthria, and deterioration of bulbar functions | Cerebellum (PCs and dentate nucleus), brainstem, and spinocerebellar tracts | ||
| SCA2 | Ataxin 2 (ATXN2) | RNA metabolism, calcium regulation, and stress response | 14–31 | 32–34: reduced penetrance | Progressive cerebellar ataxia, dysarthria, nystagmus, slow saccadic eye movements, myoclonus, and parkinsonism | Cerebellum, brainstem, and spinal cord | ||
| SCA3/Machado–Joseph disease | Ataxin 3 (ATXN3) | Deubiquitinase | 12–44 | 45–55: reduced penetrance, ∼60 | Progressive cerebellar ataxia, dystonia, spasticity, dysarthria, dysphagia, ophthalmoplegia, bulging eyes, and faciolingual fasciculations | Cerebellum (dentate nucleus and PCs), brainstem (vestibular, pontine and motor nuclei), basal ganglia, and spinal cord | ||
| SCA6 | CaV2.1 | Calcium channel | 4–18 | 19: reduced penetrance | Progressive cerebellar ataxia, dysphagia, dysarthria, and nystagmus | Cerebellum (PCs and dentate nucleus) | ||
| SCA7 | Ataxin 7 (ATXN7) | Subunit of the SAGA complex | 4–33 | 34–36: reduced penetrance, ≥37: pathogenic | Progressive cerebellar ataxia, dysphagia, dysarthria, and retinal degeneration that leads to blindness | Cerebellum (PCs and dentate nucleus), brainstem, and retina (photoreceptors) | ||
| SCA17 | TATA box-binding protein (TBP) | Transcription factor | 25–40 CAG/CAA | 41–48 CAG/CAA: reduced penetrance, ≥49 CAG/CAA: pathogenic | Progressive cerebellar ataxia, dystonia, parkinsonism, chorea, dementia, psychiatric abnormalities, and seizures | Cerebellum (PCs), cortex, and striatum | ||
| DRPLA | Atrophin 1 (ATN1) | Transcriptional corepressor | 6–35 | 35–47: reduced penetrance or milder phenotype, 48–93: pathogenic | Progressive cerebellar ataxia, myoclonus, epilepsy, chorea, intellectual deterioration (juvenile), dementia (adults), and psychiatric symptoms | Cerebellum (dentate nucleus), basal ganglia (globus pallidus and subthalamic nucleus), and brainstem |
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