The hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). However, emerging evidence demonstrates that C9orf72 expansions also play a role in atypical parkinsonian syndromes, including corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). A 2025 study by Vaughan et al. specifically analyzed C9orf72 repeat length in these conditions[1].
| Condition | C9orf72 Pathogenic Expansion Frequency |
|---|---|
| CBS | ~2-5% of cases |
| PSP | ~2-4% of cases |
| CBS/PSP with FTD features | ~5-10% of cases |
The frequency is lower than in primary FTD (~10-25%) but represents a significant genetic contributor.
Vaughan et al. (2025) examined whether intermediate expansions or somatic mosaicism contribute to CBS/PSP risk[1:1].
Patients with CBS or PSP who carry C9orf72 expansions often present with:
| Feature | C9orf72+ CBS/PSP | Idiopathic CBS/PSP |
|---|---|---|
| Age of onset | Often younger | Later |
| Cognitive involvement | Prominent early | Variable |
| Family history | Often positive | Usually negative |
| Progression rate | Potentially faster | Variable |
C9orf72 expansions produce toxic dipeptide repeat proteins through non-ATG translation[2]:
The relationship between C9orf72 and tau pathology in CBS/PSP[3]:
A 2025 study by Schneider et al. examined PSP brain tissue for DPR pathology[4:1]:
The genetics of CBS/PSP shows significant overlap between C9orf72 and other FTD genes[5]:
| Gene | Mechanism | Effect in CBS/PSP |
|---|---|---|
| MAPT | 4R tau production | Primary tauopathy |
| GRN | Progranulin deficiency | TDP-43 pathology |
| C9orf72 | DPR toxicity + RNA foci | Mixed pathology |
| TMEM106B | Lysosomal function | Modifies all three |
Genetic testing for C9orf72 expansions should be considered in:
A positive C9orf72 expansion test result has several implications:
Recent cryo-EM studies have revealed distinct tau filament structures in CBS/PSP:
The structural differences in tau filaments may explain:
The presence of C9orf72 expansions may interact with other FTD genes[6]:
| Gene | CBS Association | Primary Pathology |
|---|---|---|
| MAPT | Strong | 4R Tau |
| GRN | Moderate | TDP-43 |
| C9orf72 | Moderate | TDP-43 + DPRs |
| LRRK2 | Moderate | Unknown |
| TMEM106B | Weak-Modest | TDP-43 |
C9orf72-positive CBS/PSP patients may benefit from[7]:
Current and planned trials for C9orf72-related disorders may include CBS/PSP patients with expansions:
New research has refined our understanding of C9orf72 in 4R tauopathies:
Schneider et al. (2025) established methods to detect DPRs in biological fluids:
Induced pluripotent stem cell models have revealed:
| Cell Type | Phenotype | Therapeutic Target |
|---|---|---|
| Motor neurons | Dendritic DPR inclusions | ASO therapy |
| Cortical neurons | Tau phosphorylation increases | Kinase inhibitors |
| Astrocytes | Inflammatory cytokine release | Anti-inflammatory |
| Microglia | DPR phagocytosis impairment | TREM2 activation |
| Subtype | Features | Treatment Approach |
|---|---|---|
| CBS-C9orf72 | Prominent apraxia, cortical sensory loss | Standard CBS therapies |
| PSP-C9orf72 | Early cognitive decline, psychiatric features | Standard PSP + targeted |
| FTD-CBS overlap | Behavioral variant features | FTD-directed therapies |
| ALS-CBS overlap | Motor neuron signs | ALS-directed therapies |
New biomarkers for C9orf72-positive CBS/PSP:
| Agent | Target | Stage | Notes |
|---|---|---|---|
| BIIB043 | C9orf72 ASO | Phase I | Enrollment ongoing |
| WVE-004 | DPRs | Preclinical | Intrathecal delivery |
| Gene silencing | Expanded RNA | Preclinical | AAV-mediated |
Testing recommendations (2025):
C9orf72 hexanucleotide repeat expansions are found in a subset of CBS and PSP cases, representing an important genetic contributor to these 4R tauopathies. The 2025 study by Vaughan et al. provides crucial data on the frequency and clinical significance of these expansions[1:2].
Key findings:
The overlap between C9orf72-related disorders and CBS/PSP highlights the complex genetic architecture of these conditions and the importance of genetic testing for diagnosis and therapeutic planning.
Targeted therapies for C9orf72-associated disorders are actively being developed:
| Agent | Target | Stage | Status |
|---|---|---|---|
| BIIB043 | C9orf72 ASO | Phase I | Enrollment ongoing (NCT05987148) |
| WVE-004 | DPRs | Preclinical | Intrathecal delivery planned |
| AAV-C9orf72 shRNA | Gene silencing | Preclinical | AAV-mediated knock-down |
| Small molecule DPR inhibitors | Poly-GA/GR | Discovery | Screening ongoing |
| TDP-43 aggregation inhibitors | TDP-43 misfolding | Preclinical | In vitro validation |
Note: While no C9orf72-targeted trials are specifically enrolling CBS/PSP patients yet, trials for ALS/FTD (which share the same C9orf72 mechanism) may expand to include CBS/PSP with C9orf72 expansions. Patients with C9orf72-positive CBS/PSP should be evaluated for eligibility in ALS/FTD trials.
Fluid Biomarkers
Imaging Biomarkers
Genetic Biomarkers
Disease-Modifying Potential
Therapeutic Challenges
Clinical Practice Integration
Vaughan et al. "Analysis of C9orf72 repeat length in PSP, CBS, and atypical parkinsonism (2025)". 2025. ↩︎ ↩︎ ↩︎
"C9orf72 Dipeptide Repeat Proteins (DPRs) - Proteins". ↩︎
Gao Y et al. "C9orf72 expansions in 4R tauopathies: frequency and clinical correlates". Neurology Genetics. 2024. ↩︎
Schneider R et al. "Dipeptide repeat proteins in PSP brain tissue". Acta Neuropathologica. 2025. ↩︎ ↩︎
Mendonca MD et al. "C9orf72, MAPT, and GRN: Genetic overlap in atypical parkinsonism". Movement Disorders. 2024. ↩︎
"TDP-43 Pathology in Corticobasal Syndrome". ↩︎
"Antisense Oligonucleotide Therapy for C9orf72 ALS/FTD". ↩︎