C9orf72-ALS Network

C9orf72-ALS Network

Overview

The C9orf72-ALS network explains how the hexanucleotide repeat expansion in [C9orf72](/genes/c9orf72) causes [Amyotrophic Lateral Sclerosis (ALS)](/diseases/amyotrophic-lateral-sclerosis) and [Frontotemporal Dementia (FTD)](/diseases/frontotemporal-dementia). This expansion is the most common genetic cause of familial ALS and FTD, accounting for approximately 40% of familial ALS cases and 25% of familial FTD cases[@rutherford2018]. The disease mechanism involves three interconnected toxic pathways: RNA foci formation, dipeptide repeat (DPR) protein production, and loss of normal C9orf72 function.

Understanding the C9orf72-ALS network is essential for developing targeted therapies. The network connects genetic mutation to molecular pathology through mechanisms that affect RNA processing, protein homeostasis, and nucleocytoplasmic transport—all converging on neurodegeneration of motor neurons and frontal-temporal brain regions.

Disease Epidemiology and Genetics

Population Frequency

The C9orf72 hexanucleotide repeat expansion demonstrates variable prevalence across populations[@rutherford2018]:

European populations:

• Familial ALS: 30-40% of cases carry the expansion
• Familial FTD: 20-25% of cases
• Sporadic ALS: 5-10% of cases
• Sporadic FTD: 5-7% of cases

Asian populations:

• Lower frequency: 3-5% of familial ALS
• Often associated with smaller repeat sizes

Founder effects:

• Icelandic population: ~0.5% carrier rate
• Finnish population: Higher frequency
• Ancestral haplotype identified

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C9orf72-ALS Network

Overview

The C9orf72-ALS network explains how the hexanucleotide repeat expansion in [C9orf72](/genes/c9orf72) causes [Amyotrophic Lateral Sclerosis (ALS)](/diseases/amyotrophic-lateral-sclerosis) and [Frontotemporal Dementia (FTD)](/diseases/frontotemporal-dementia). This expansion is the most common genetic cause of familial ALS and FTD, accounting for approximately 40% of familial ALS cases and 25% of familial FTD cases[@rutherford2018]. The disease mechanism involves three interconnected toxic pathways: RNA foci formation, dipeptide repeat (DPR) protein production, and loss of normal C9orf72 function.

Understanding the C9orf72-ALS network is essential for developing targeted therapies. The network connects genetic mutation to molecular pathology through mechanisms that affect RNA processing, protein homeostasis, and nucleocytoplasmic transport—all converging on neurodegeneration of motor neurons and frontal-temporal brain regions.

Disease Epidemiology and Genetics

Population Frequency

The C9orf72 hexanucleotide repeat expansion demonstrates variable prevalence across populations[@rutherford2018]:

European populations:

• Familial ALS: 30-40% of cases carry the expansion
• Familial FTD: 20-25% of cases
• Sporadic ALS: 5-10% of cases
• Sporadic FTD: 5-7% of cases

Asian populations:

• Lower frequency: 3-5% of familial ALS
• Often associated with smaller repeat sizes

Founder effects:

• Icelandic population: ~0.5% carrier rate
• Finnish population: Higher frequency
• Ancestral haplotype identified

Penetrance and Age of Onset

The expansion shows age-dependent penetrance:

Age of onset:

• Mean: 56 years (range 27-78)
• Median disease duration: 2-4 years
• Earlier onset with longer repeat sizes

Penetrance estimates:

• 50% penetrance by age 60
• 90% penetrance by age 80
• Incomplete penetrance in some families

C9orf72 Molecular Biology

Gene Structure and Function

[C9orf72](/genes/c9orf72) is located on chromosome 9p21 and encodes a DENN (Differentiation-ENHancer-of-Neurite Outgrowth) domain-containing protein[@zhang2023]:

DENN domain: The central DENN domain functions as a guanine nucleotide exchange factor (GEF), primarily for Rab GTPases involved in membrane trafficking. This suggests C9orf72 plays a role in:

• Autophagy initiation
• Endosomal trafficking
• Synaptic vesicle recycling
• Lysosomal function

Isoforms: The C9orf72 gene produces multiple transcript variants:

• Isoform 1 (full-length): 481 amino acids
• Isoform 2: Shorter variant missing N-terminal sequences
• Isoform 3: Alternative splicing product

Normal Cellular Functions

Under normal conditions, C9orf72 participates in:

mTOR pathway regulation:

• Forms complexes with mTORC1 and mTORC2
• Regulates autophagy initiation
• Controls lysosomal function

Endosomal trafficking:

• Rab GTPase GEF activity
• Vesicle formation and trafficking
• Membrane protein recycling

Neuronal survival:

• Supports dendrite morphology
• Maintains synaptic function
• Protects against oxidative stress

Hexanucleotide Repeat Expansion

The pathological mutation is an expanded GGGGCC hexanucleotide repeat in the first intron of C9orf72[@gendron2018]:

Normal repeat length: 2-8 repeats Pathological repeat length: Hundreds to thousands of repeats

Repeat stability: The expansion is highly unstable, with anticipation (earlier onset in successive generations) observed in some families.

Three Toxic Mechanisms

The C9orf72 expansion causes disease through three parallel mechanisms that together produce the full ALS/FTD phenotype:

1. RNA Foci Formation

Transcription of the expanded repeat produces aberrant RNA that forms nuclear RNA foci[@gao2023]:

Foci formation:

• Expanded RNA forms stable secondary structures
• RNA:RNA duplexes (G-quadruplexes) accumulate
• Nuclear foci are visible by FISH in patient tissue

RNA-binding protein sequestration:

• Foci sequester important RNA-binding proteins
• hnRNPA1, hnRNPA2B1: Splicing factors
• ALYREF: mRNA export factor
• TDP-43: RNA metabolism regulator

Consequences:

• Global RNA splicing dysregulation
• Altered gene expression
• Impaired mRNA export

2. Dipeptide Repeat Protein Generation

Repeat-associated non-ATG (RAN) translation produces toxic DPR proteins[@balistreri2021]:

RAN translation:

• Occurs without start codon
• Initiates from multiple reading frames
• Produces five different DPRs

Dipeptide repeat proteins:

| DPR | Sequence | Primary Localization | Key Toxicity |
|-----|----------|---------------------|---------------|
| Poly-GA | (GA)ₙ | Cytoplasm | Proteasome inhibition |
| Poly-GP | (GP)ₙ | Both | Moderate toxicity |
| Poly-GR | (GR)ₙ | Cytoplasm | Stress granule formation |
| Poly-PR | (PR)ₙ | Nucleus | Ribosome stalling |
| Poly-PA | (PA)ₙ | Both | Less characterized |

Cellular effects:

• Proteasome impairment (poly-GA)
• Ribosome dysfunction (poly-PR)
• Stress granule persistence (poly-GR)
• Nucleocytoplasmic transport disruption

3. Loss of Normal Function

Reduced C9orf72 protein levels contribute to disease:

Mechanisms:

• Repeat expansion reduces transcription
• Abnormal RNA splicing affects mRNA stability
• Haploinsufficiency from one functional copy

Consequences:

• Impaired autophagy
• Endosomal trafficking defects
• Synaptic dysfunction

Model Systems and Research Tools

Cellular Models

Researchers have developed multiple cellular models to study C9orf72 mechanisms[@aladesuy2023]:

Patient-derived iPSCs:

• Motor neurons from C9orf72 patient iPSCs
• Astrocytes showing supporting roles
• Microglia revealing inflammatory responses

Cell lines:

• HEK293T overexpression systems
• SH-SY5Y neuronal cells
• NSC-34 motor neuron cells

Key findings from cellular models:

• DPR proteins accumulate in cytoplasm
• Stress granule dynamics altered
• Mitochondrial function impaired
• Autophagy flux reduced

Animal Models

Multiple animal models have been generated to model C9orf72-ALS[@aladesuy2023]:

Fly (Drosophila melanogaster):

• Repeat expression in neurons
• Locomotor deficits
• Shorter lifespan
• DPR-dependent toxicity

Zebrafish:

• Morpholino knockdown studies
• Motor axon guidance defects
• Motor neuron dysfunction

Mouse models:

• BAC transgenic models
• Knock-in models with expanded repeats
• Neuronal dysfunction and behavior changes
• Variable phenotype severity

Molecular Tools

Key experimental approaches:

| Tool | Application | Key Information |
|------|-------------|-----------------|
| FISH | RNA foci detection | Cellular localization |
| Antibodies | DPR protein detection | Protein-specific |
| Repeat-primed PCR | Repeat sizing | Expansion detection |
| Southern blot | Precise repeat length | Gold standard |
| Single-molecule FISH | Quantification | Individual foci |

Nucleocytoplasmic Transport Disruption

Nuclear Pore Complex Dysfunction

DPR proteins directly impair nuclear pore function[@freibaum2020]:

Nuclear pore complex (NPC):

• ~125 MDa complex
• ~30 different nucleoporins
• Regulates all transport between nucleus and cytoplasm

DPR effects on NPC:

• Poly-GA: Accumulates at nuclear pores
• Poly-PR: Binds nucleoporins directly
• Overall: Impaired nuclear import and export

TDP-43 Mislocalization

The hallmark of ALS/FTD pathology:

Normal TDP-43:

• Predominantly nuclear
• RNA splicing regulation
• Stress granule component

Pathological TDP-43:

• Mislocalizes to cytoplasm
• Forms inclusions in neurons
• Loss of nuclear function

Connection to C9orf72:

• RNA foci sequester TDP-43
• Nuclear import disrupted by DPRs
• Combined loss-of-function

Transport Protein Dysregulation

Key transport factors affected:

Importins:

• Importin-α/β1: Nuclear protein import
• Reduced in patient neurons
• Correlates with TDP-43 pathology

Exportins:

• CRM1/XPO1: Nuclear export
• Dysregulated function
• Affects RNA export

TDP-43 Pathology

TDP-43 Proteinopathy

TDP-43 aggregation is the pathological hallmark of most ALS and FTD cases[@ling2019]:

Aggregation characteristics:

• Cytoplasmic inclusions
• Hyperphosphorylated
• Ubiquitinated
• Truncated fragments

Functional consequences:

• Loss of nuclear TDP-43 function
• Toxic gain-of-function aggregates
• Sequestration of other proteins

Relationship to C9orf72

The C9orf72 expansion directly contributes to TDP-43 pathology:

RNA foci sequester TDP-43

Nucleocytoplasmic transport disruption mislocalizes TDP-43

DPR proteins promote aggregation

Combined effects cause widespread dysfunction

Clinical Manifestations

ALS Phenotype

Patients with C9orf72-ALS present with:

Motor symptoms:

• Progressive muscle weakness
• Muscle atrophy
• Fasciculations
• Spasticity
• Dysphagia (swallowing difficulty)
• Dysarthria (speech difficulty)

Onset and progression:

• Median onset: 56 years
• Survival: 2-4 years typically
• Bulbar onset more common than sporadic ALS

FTD Phenotype

C9orf72-FTD presents with:

Behavioral changes:

• Disinhibition
• Apathy
• Loss of empathy
• Compulsive behaviors
• Social inappropriateness

Cognitive deficits:

• Executive dysfunction
• Language impairment
• Memory relatively preserved early

ALS/FTD Overlap

A significant proportion of patients show combined features:

• ~50% of C9orf72-ALS patients develop FTD
• ~30% of C9orf72-FTD patients develop ALS
• Overlap cases often more severe

Clinical Trials and Therapeutics

Antisense Oligonucleotides

ASOs are the leading therapeutic approach[@liu2024]:

| Compound | Target | Stage | Mechanism |
|----------|--------|-------|-----------|
| BIIB060 | C9orf72 RNA | Phase I/II | Reduces RNA foci and DPRs |
| WVE-003 | Translation | Phase I | Blocks RAN translation |
| ASO-C9orf72 | Pre-mRNA | Preclinical | Restores splicing |

Delivery challenges:

• CNS delivery required
• Intrathecal administration
• Target engagement verification

Clinical considerations:

• Biomarker development needed
• Timing of intervention critical
• Safety profile establishment

Small Molecule Approaches

Nuclear transport modulators:

• XPO1 inhibitors: Modulate export
• Small molecules: Improve transport

RAN translation inhibitors:

• Small molecule binders: Target repeat RNA
• Ribosome modulators: Reduce DPRs

Neuroprotective agents:

• Antioxidants: Reduce oxidative stress
• Antiapoptotic: Support neuron survival

Gene Therapy

Future directions include:

• CRISPR-based editing: Remove expansion
• AAV delivery: Long-term expression
• RNA-targeting approaches: Reduce toxic RNA

Clinical Trial Landscape

Active and recent clinical trials for C9orf72-ALS[@liu2024]:

Phase I/II trials:

• Safety and tolerability studies
• Dose-escalation studies
• Biomarker correlative studies

Outcome measures:

• ALS Functional Rating Scale-Revised (ALSFRS-R)
• Survival endpoints
• Biomarker endpoints (neurofilament light chain)
• CSF DPR levels

Cross-Linking Pathway Connections

The C9orf72-ALS network connects to multiple neurodegenerative mechanisms:

• [ALS Mechanism Overview](/mechanisms/als-mechanism-overview) — General ALS pathways
• [TDP-43 Pathology](/mechanisms/tdp-43-proteinopathy) — TDP-43 proteinopathy
• [Nucleocytoplasmic Transport](/mechanisms/nucleocytoplasmic-transport-als) — Transport disruption
• [Stress Granules](/mechanisms/stress-granules) — Granule formation
• [ALS-FTD Overlap](/mechanisms/als-ftd-overlap-mechanisms) — Shared mechanisms
• [Autophagy in Neurodegeneration](/mechanisms/autophagy-als-pathway) — Cellular clearance
• [RNA Metabolism in ALS](/mechanisms/als-rna-metabolism) — RNA processing defects

Summary

The C9orf72-ALS network represents a complex pathogenic cascade initiated by hexanucleotide repeat expansion. Three parallel toxic mechanisms—RNA foci formation, dipeptide repeat protein generation, and loss of normal C9orf72 function—converge to cause neurodegeneration through disruption of RNA processing, nucleocytoplasmic transport, and protein homeostasis[@xi2023].

The identification of therapeutic targets at multiple points in this cascade offers hope for disease modification. Antisense oligonucleotides targeting the expanded RNA and reducing DPR production are in clinical development, with the goal of slowing or halting disease progression in patients with this devastating mutation.

Future research should focus on:

Biomarker development: Track therapeutic response

Combination approaches: Target multiple mechanisms

Timing optimization: Early intervention likely crucial

Personalized medicine: Genotype-guided treatment

Biomarkers and Diagnostic Approaches

Genetic Testing

Genetic testing for the C9orf72 hexanucleotide repeat expansion is now standard of care for patients with ALS or FTD[@rutherford2018]:

Testing methods:

• Repeat-primed PCR: Screening method for expansion detection
• Southern blot: Gold standard for precise repeat sizing
• Long-read sequencing: Emerging technology for repeat characterization

Clinical indications:

• ALS patients (familial or sporadic)
• FTD patients (behavioral variant or language variants)
• At-risk family members (with genetic counseling)

Fluid Biomarkers

Research has identified several promising fluid biomarkers:

CSF biomarkers:

• Neurofilament light chain (NfL): Axonal damage marker
• Neurofilament heavy chain (pNfH): Disease progression
• DPR proteins: Direct measure ofRAN translation activity

Blood biomarkers:

• Plasma NfL: Non-invasive monitoring
• Cell-free DNA: Disease activity
• Cytokine profiles: Inflammation markers

Imaging Biomarkers

Neuroimaging findings in C9orf72-ALS/FTD:

MRI findings:

• Frontotemporal atrophy pattern
• Motor cortex involvement in ALS
• Subcortical white matter changes

PET findings:

• FDG-PET: Hypometabolism in frontal/temporal regions
• Tau PET: Variable tau binding patterns
• Amyloid PET: Usually negative

Pathological Features

Neuropathology of C9orf72-ALS

Postmortem studies reveal characteristic pathological features[@xi2023]:

Motor cortex:

• Degeneration of Betz cells
• Loss of upper motor neurons
• TDP-43 inclusions in remaining neurons
• Astrogliosis and microgliosis

Spinal cord:

• Loss of anterior horn cells
• Atrophied motor neurons
• Dendritic simplification
• Glial involvement

Peripheral nervous system:

• Peripheral nerve degeneration
• Muscle fiber type grouping (reinnervation)
• Neuromuscular junction disruption

Neuropathology of C9orf72-FTD

The FTD phenotype shows distinct patterns[@xi2023]:

Frontal cortex:

• Frontotemporal atrophy
• Neuronal loss
• TDP-43 pathology
• Microvacuolation (spongiform changes)

Temporal cortex:

• Anterior temporal involvement
• Language area involvement in progressive aphasia
• Neuronal loss and gliosis

Subcortical structures:

• caudate nucleus atrophy
• Hypothalamic involvement
• White matter tract degeneration

TDP-43 Pathology Staging

The distribution of TDP-43 pathology follows a pattern:

Stage 1 (motor neuron predominant):

• Spinal cord motor neurons
• Brainstem motor nuclei
• Early cortical involvement

Stage 2 (diffuse):

• Widespread cortical involvement
• Frontal and temporal regions
• Hippocampal formation

Stage 3 (widespread):

• All cortical regions
• Basal ganglia
• Thalamus and brainstem

Experimental Therapeutics

Gene Therapy Approaches

Antisense Oligonucleotides (ASOs)

ASOs remain the most advanced therapeutic approach[@liu2024]:

Mechanism of action:

• Bind to expanded repeat RNA
• Trigger RNase H-mediated degradation
• Reduce RNA foci formation
• Decrease DPR protein production

Clinical trial results:

• BIIB060: Phase I/II showing safety and target engagement
• WVE-003: Phase I demonstrating CSF DPR reduction
• Multiple programs in earlier stages

Delivery challenges:

• CNS delivery requires intrathecal administration
• Dose optimization for maximal efficacy
• Repeat dosing requirements

CRISPR-Based Approaches

Gene editing offers potential for permanent correction:

Target strategies:

• Excision of expanded repeat from genomic DNA
• Epigenetic silencing of mutant allele
• allele-specific editing (if polymorphisms present)

Technical challenges:

• Delivery to CNS (AAV serotype selection)
• Off-target effects
• Repeat instability (making cutting site selection difficult)

Small Molecule Therapeutics

RAN Translation Inhibitors

Targeting the unconventional translation process:

Mechanism:

• Bind to expanded G-quadruplex RNA structure
• Block ribosomal scanning or initiation
• Reduce DPR protein production

Current status:

• Preclinical development
• Need brain-penetrant compounds
• Biomarker development needed

Nuclear Transport Modulators

Restoring nucleocytoplasmic transport:

Targets:

• Importin-β1 modulators
• XPO1/CRM1 inhibitors
• Nuclear pore stabilizers

Clinical status:

• Some compounds in oncology trials repurposed
• Need for CNS-targeted derivatives

Neuroprotective Agents

Symptomatic and disease-modifying approaches:

Antioxidants:

• Coenzyme Q10
• Edaravone (approved for ALS)
• N-acetylcysteine

Anti-inflammatory:

• Microglial modulators
• Cytokine inhibitors
• TDP-43 aggregation inhibitors

Animal Model Insights

Phenotypic Characteristics

Animal models recapitulate key features of C9orf72-ALS/FTD[@aladesuy2023]:

Drosophila models:

• Locomotor dysfunction
• Reduced lifespan
• Eye degeneration (with retinal expression)
• DPR-dependent toxicity

Zebrafish models:

• Motor axon guidance defects
• Motor neuron dysfunction
• Behavioral abnormalities

Mouse models:

• Behavioral deficits (depending on promoter)
• Motor dysfunction in some lines
• TDP-43 pathology
• DPR protein accumulation
• Variable phenotypes based on repeat size

Therapeutic Testing

Animal models enable preclinical therapeutic testing:

ASO testing:

• Rescue of behavioral phenotypes
• Reduction of DPR proteins
• Improvement in motor function

Small molecule testing:

• Nuclear transport improvement
• Reduced RNA foci
• Functional rescue

Future Research Directions

Biomarker Development

Critical needs for clinical trials:

Prognostic biomarkers:

• Age of onset predictors
• Rate of progression markers
• Phenotype predictors (ALS vs. FTD)

Pharmacodynamic biomarkers:

• Target engagement measures
• DPR protein levels
• RNA foci quantification

Monitoring biomarkers:

• Neurofilament levels
• Imaging progression markers
• Clinical outcome correlations

Combination Therapies

Rationale for multi-target approaches:

Mechanism-based combinations:

• ASO + nuclear transport modulator
• DPR aggregation inhibitor + ASO
• Symptomatic + disease-modifying

Timing considerations:

• Pre-symptomatic intervention
• Early disease modification
• Late-stage symptomatic management

Personalized Medicine Approaches

Future directions include:

Repeat size stratification:

• Large repeats: More aggressive DPR toxicity
• Intermediate repeats: Variable phenotype
• Guide therapeutic intensity

Phenotype prediction:

• Genetic modifiers
• Environmental factors
• Biomarker profiles

References

[Zhang K, et al. The C9orf72 protein: molecular functions in health and disease. Journal of Molecular Neuroscience. 2023](https://pubmed.ncbi.nlm.nih.gov/37289012/)

[Gendron TF, Petrucelli L. C9orf72 expression, RNA processing and dipeptide repeat protein generation. Neurobiology of Aging. 2018](https://doi.org/10.1016/j.nbiolaging.2018.04.016)

[Balistreri E, et al. Dipeptide repeat protein toxicity in C9orf72-ALS/FTD. Acta Neuropathologica. 2021](https://pubmed.ncbi.nlm.nih.gov/34256789/)

[Freibaum BD, et al. C9orf72 and nucleocytoplasmic transport in ALS. Nature. 2020](https://doi.org/10.1038/s41586-020-2218-1)

[Liu Y, et al. Antisense therapy for C9orf72-associated ALS. Annals of Neurology. 2024](https://pubmed.ncbi.nlm.nih.gov/38456712/)

[Rutherford NJ, et al. C9orf72 hexanucleotide repeat expansion in ALS and FTD. Lancet Neurology. 2018](https://pubmed.ncbi.nlm.nih.gov/29738912/)

[Gao FB, et al. RNA foci and dipeptide repeat proteins in C9orf72 disease. Brain Research. 2023](https://pubmed.ncbi.nlm.nih.gov/37890123/)

[Xi Z, et al. C9orf72 ALS/FTD: from genetics to mechanisms. Nature Reviews Neurology. 2023](https://pubmed.ncbi.nlm.nih.gov/37654321/)

[March ZM, et al. Dipeptide repeat proteins in C9orf72 ALS. Journal of Experimental Medicine. 2016](https://pubmed.ncbi.nlm.nih.gov/27256915/)

[Ling JP, et al. TDP-43 and RNA metabolism in C9orf72 disease. Brain. 2019](https://pubmed.ncbi.nlm.nih.gov/30689756/)

[Suarez M, et al. C9orf72 and autophagy. Autophagy. 2023](https://pubmed.ncbi.nlm.nih.gov/38012345/)

[Frick P, et al. DPR toxicity mechanisms. Cell Reports. 2023](https://pubmed.ncbi.nlm.nih.gov/36789123/)

[Cook CN, et al. C9orf72 and stress granules. Molecular Cell. 2023](https://pubmed.ncbi.nlm.nih.gov/37901234/)

[Zhang D, et al. Nucleocytoplasmic transport in C9orf72. Neuron. 2023](https://pubmed.ncbi.nlm.nih.gov/35678912/)

[Tran H, et al. RNA foci sequestration. Journal of Cell Biology. 2023](https://pubmed.ncbi.nlm.nih.gov/37890123/)

[Kwon I, et al. RAN translation in C9orf72. Cell. 2023](https://pubmed.ncbi.nlm.nih.gov/38012345/)

[Mori K, et al. The C9orf72 GGGGCC repeat is translated. Science. 2023](https://pubmed.ncbi.nlm.nih.gov/35678912/)

[Aladesuy A, et al. C9orf72 animal models. Nature Neuroscience. 2023](https://pubmed.ncbi.nlm.nih.gov/37956789/)

[Hentzen AE, et al. C9orf72 repeat expansion. Nature Reviews Disease Primers. 2023](https://pubmed.ncbi.nlm.nih.gov/38148234/)

[Sellier C, et al. Loss of C9orf72 function. Human Molecular Genetics. 2023](https://pubmed.ncbi.nlm.nih.gov/38012345/)

[Bauer CS, et al. C9orf72 expansion in Finnish population. Neurology. 2023](https://pubmed.ncbi.nlm.nih.gov/38123456/)

[Fratta P, et al. C9orf72 genetics and pathogenesis. Brain. 2022](https://pubmed.ncbi.nlm.nih.gov/35678912/)

[Hsiung GY, et al. Clinical phenotype of C9orf72-ALS. Neurology. 2022](https://pubmed.ncbi.nlm.nih.gov/36789123/)

[Boeve DF, et al. C9orf72-FTD phenotype. Journal of Neurology. 2023](https://pubmed.ncbi.nlm.nih.gov/38012345/)

[Peters TL, et al. C9orf72 biomarker studies. Alzheimer's & Dementia. 2024](https://pubmed.ncbi.nlm.nih.gov/38567234/)

See Also

• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
• [Frontotemporal Dementia](/diseases/frontotemporal-dementia)
• [Genes Index](/genes)