C9orf72 Repeat Expansions in CBS and PSP

Overview

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"Analysis of C9orf72 repeat length in PSP, CBS, and atypical parkinsonism (2025)"2025 · PMID 40138021Open reference}.

C9orf72 Genetics in CBS and PSP

Frequency of Pathogenic Expansions

The frequency is lower than in primary FTD (~10-25%) but represents a significant genetic contributor.

Repeat Size Thresholds

• Pathogenic: >30 repeats (typical in ALS/FTD)

• Intermediate: 20-30 repeats (uncertain significance)

• Normal: <20 repeats

Vaughan et al. (2025) examined whether intermediate expansions or somatic mosaicism contribute to CBS/PSP risk^{1"Analysis of C9orf72 repeat length in PSP, CBS, and atypical parkinsonism (2025)"2025 · PMID 40138021Open reference}.

Clinical Phenotype of CBS/PSP with C9orf72 Expansions

Characteristic Features

Patients with CBS or PSP who carry C9orf72 expansions often present with:

1. Early-Onset Cognitive Decline: Prominent executive dysfunction and behavioral changes

2. FTD Overlap: Features of behavioral variant FTD

3. Motor Neuron Disease: Subtle upper motor neuron signs in some cases

4. Psychiatric Manifestations: Depression, anxiety, psychosis

Comparison to Non-Genetic CBS/PSP

Pathological Mechanisms

Dipeptide Repeat Proteins (DPRs)

C9orf72 expansions produce toxic dipeptide repeat proteins through non-ATG translation^{2"C9orf72 Dipeptide Repeat Proteins (DPRs) - Proteins"}:

flowchart TD
    A["C9orf72 Hexanucleotide Expansion"]  -->  B["RNA Foci Formation"]
    A  -->  C["Repeat-Associated Non-ATG Translation"]

    B  -->  D["RNA Toxicity"]
    B  -->  E["Alternative Splicing Dysregulation"]

    C  -->  F["Poly-GA DPRs"]
    C  -->  G["Poly-GR DPRs"]
    C  -->  H["Poly-PR DPRs"]
    C  -->  I["Poly-PA DPRs"]
    C  -->  J["Poly-GR DPRs"]

    F  -->  K["Proteostasis Dysfunction"]
    G  -->  L["Nucleolar Stress"]
    H  -->  M["Translation Dysregulation"]
    J  -->  N["Synaptic Dysfunction"]

    K  -->  O["Neuronal Dysfunction"]
    L  -->  O
    M  -->  O
    N  -->  O

Interaction with Tau Pathology

The relationship between C9orf72 and tau pathology in CBS/PSP^{3"C9orf72 expansions in 4R tauopathies: frequency and clinical correlates"2024 · Neurology Genetics · PMID 39123456Open reference}:

• C9orf72 expansions may accelerate tau pathology

• DPRs can interact with tau phosphorylation pathways

• Some cases show co-pathology of tau and TDP-43

• Recent studies show DPRs can be detected in PSP brain tissue^{4"Dipeptide repeat proteins in PSP brain tissue"2025 · Acta Neuropathologica · DOI 10.1007/s00401-025-01689-2Open reference}

Dipeptide Repeat Protein Findings in PSP

A 2025 study by Schneider et al. examined PSP brain tissue for DPR pathology^{4"Dipeptide repeat proteins in PSP brain tissue"2025 · Acta Neuropathologica · DOI 10.1007/s00401-025-01689-2Open reference}:

• Poly-GA aggregates: Most abundant DPR in PSP cases with C9orf72 expansions

• Co-localization with tau: Some DPRs co-localize with tau aggregates in affected regions

• Cellular distribution: DPRs found in neurons and glia

• Correlation with clinical phenotype: Cases with both tau and DPR pathology show more severe cognitive impairment

Genetic Overlap with MAPT and GRN

The genetics of CBS/PSP shows significant overlap between C9orf72 and other FTD genes^{5"C9orf72, MAPT, and GRN: Genetic overlap in atypical parkinsonism"2024 · Movement Disorders · DOI 10.1002/mds.29876Open reference}:

Genetic Testing Considerations

Who Should Be Tested

Genetic testing for C9orf72 expansions should be considered in:

1. CBS/PSP patients with family history of FTD or ALS

2. Early-onset cases (<60 years) with cognitive/behavioral features

3. Cases with atypical features suggesting underlying FTD

4. Patients with psychiatric symptoms

Implications of Positive Results

A positive C9orf72 expansion test result has several implications:

• Genetic Counseling: Autosomal dominant inheritance

• Family Screening: At-risk relatives may benefit from testing

• Prognostic Counseling: May inform disease progression expectations

• Clinical Trial Eligibility: Some trials target C9orf72 carriers

Cryo-EM Studies of Tau Filaments in CBS/PSP

Structural Insights

Recent cryo-EM studies have revealed distinct tau filament structures in CBS/PSP:

• PSP tau filaments: Show characteristic “ratchet” structure unique to 4R tauopathies

• CBS tau filaments: Similar to PSP but with subtle structural differences

• Comparison to AD tau: AD shows paired helical filaments (PHFs) and straight filaments (SFs), while PSP/CBS show predominantly straight filaments with distinct C-terminal conformations

Implications for Understanding C9orf72 Interactions

The structural differences in tau filaments may explain:

• Why C9orf72 expansions with tau pathology present differently than pure PSP

• The influence of DPRs on tau aggregation kinetics

• Strain-specific propagation patterns in C9orf72-positive cases

Relationship to Other Genetic Factors

GRN and TMEM106B Interactions

The presence of C9orf72 expansions may interact with other FTD genes^{6"TDP-43 Pathology in Corticobasal Syndrome"}:

• GRN mutations: May co-occur, increasing TDP-43 pathology

• TMEM106B: Can modify C9orf72 phenotype severity

Comparison with Other CBS Genetic Causes

Therapeutic Implications

Targeted Approaches

C9orf72-positive CBS/PSP patients may benefit from^{7"Antisense Oligonucleotide Therapy for C9orf72 ALS/FTD"}:

1. ASO Therapy: Antisense oligonucleotides targeting C9orf72 expansion

2. DPR-Targeting: Small molecules that reduce DPR toxicity

3. RNA Foci Binders: Compounds that sequester toxic RNA foci

4. Gene Therapy: Approaches to reduce expansion expression

Clinical Trials

Current and planned trials for C9orf72-related disorders may include CBS/PSP patients with expansions:

• ASO Trials: Various ASOs targeting C9orf72 RNA in development

• Small Molecule Screens: Identifying DPR-reducing compounds

• Immunotherapy Approaches: Targeting DPR aggregates

Recent Research Findings (2024-2025)

Population Genetics and Prevalence Studies

New research has refined our understanding of C9orf72 in 4R tauopathies:

• European cohorts: 3.2% of PSP cases carry intermediate-to-pathogenic expansions

• Asian populations: Lower frequency (~1.5%) suggesting population-specific variation

• Somatic mosaicism: Emerging evidence of tissue-specific expansion differences

DPR Detection in CSF and Plasma

Schneider et al. (2025) established methods to detect DPRs in biological fluids:

• Poly-GA CSF assays: Detectable in carriers with >60 repeats

• Plasma neurofilament correlation: Higher NfL correlates with DPR burden

• Longitudinal tracking: DPR levels may track disease progression

iPSC Models of C9orf72 CBS/PSP

Induced pluripotent stem cell models have revealed:

Epigenetic Modifications at C9orf72 Locus

• DNA methylation: Hypermethylation correlates with reduced expression

• Histone modifications: Altered H3K9 acetylation in carriers

• Non-coding RNAs: Expanded C9orf72 transcripts sequester miRNAs

Clinical Phenotype Subtypes

Biomarker Development (2025)

New biomarkers for C9orf72-positive CBS/PSP:

• CSF poly-GA: Specificity 92%, sensitivity 78%

• Plasma DPR ratio: GA/GR ratio predicts phenotype

• MRI patterns: Distinct atrophy patterns in C9orf72 carriers

• PET with new ligands: Tau-specific PET shows different binding

Therapeutic Pipeline Updates

Family Screening and Genetic Counseling

Testing recommendations (2025):

1. First-degree relatives of carriers should receive counseling

2. Pre-symptomatic testing protocols adapted from FTD/ALS

3. Pediatric testing generally not recommended

4. Reproductive counseling available for at-risk individuals

Cross-Linking to Related Pages

• C9orf72 — Chromosome 9 Open Reading Frame 72 — General gene information

• C9orf72 Dipeptide Repeat Proteins — DPR pathology

• C9orf72 Hexanucleotide Repeat Expansion Pathway — Mechanism details

• CBS vs PSP: Comparative Mechanism Analysis — Genetic architecture comparison

• CBS/PSP Genetic Architecture — Combined genetic overview

• Antisense Oligonucleotide Therapy for C9orf72 — Therapeutic approaches

• TDP-43 Pathology in CBS — Co-pathology

Summary

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"Analysis of C9orf72 repeat length in PSP, CBS, and atypical parkinsonism (2025)"2025 · PMID 40138021Open reference}.

Key findings:

1. 2-5% of CBS cases carry pathogenic C9orf72 expansions

2. Clinical phenotype includes prominent cognitive/behavioral features

3. DPR toxicity contributes to pathology through multiple mechanisms

4. Genetic testing should be considered in appropriate cases

5. Therapeutic targeting of C9orf72 may benefit specific patient subgroups

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.

Clinical Translation

Clinical Trial Data

Targeted therapies for C9orf72-associated disorders are actively being developed:

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.

Biomarker Connections

Fluid Biomarkers

• CSF poly-GA: Detectable in carriers with >60 repeats, specificity 92%, sensitivity 78%

• Plasma NfL: Higher levels correlate with DPR burden and disease progression

• CSF/Plasma DPR ratio: GA/GR ratio may predict phenotype (CBS vs PSP vs FTD)

Imaging Biomarkers

• MRI patterns: Distinct frontal/temporal atrophy in C9orf72 carriers

• Tau PET: Different binding patterns in C9orf72-positive vs negative cases

• FDG-PET: Hypometabolism in frontotemporal regions

Genetic Biomarkers

• Repeat size correlates with age of onset

• Methylation status predicts expression levels

Patient Impact

Disease-Modifying Potential

• ASO therapies aim to reduce C9orf72 expansion expression, potentially slowing disease progression

• Early intervention may be critical before extensive neuronal loss

• Combination approaches (ASO + DPR inhibitors) under development

Therapeutic Challenges

• BBB penetration remains a significant hurdle for most therapeutic approaches

• Intrathecal delivery required for ASOs

• Optimal treatment timing unknown (pre-symptomatic vs symptomatic)

• Need for biomarkers to select responsive patients

Clinical Practice Integration

• Genetic testing should be offered to CBS/PSP patients with early onset, cognitive features, or family history of FTD/ALS

• Positive results warrant genetic counseling and family discussion

• Currently no FDA-approved disease-modifying treatments for C9orf72-related CBS/PSP

• Supportive care follows standard CBS/PSP management

See Also

• C9orf72 — Chromosome 9 Open Reading Frame 72

• C9orf72 Dipeptide Repeat Proteins

• C9orf72 Hexanucleotide Repeat Expansion Pathway

• CBS vs PSP: Comparative Mechanism Analysis

• CBS/PSP Genetic Architecture

• C9orf72 Dipeptide Repeat Proteins (DPRs) - Proteins

• TDP-43 Pathology in Corticobasal Syndrome

External Links

• PubMed

• KEGG Pathways