¶ Amyotrophic Lateral Sclerosis (ALS)
¶ Introduction
Amyotrophic Lateral Sclerosis (Als) is a progressive neurodegenerative disorder characterized by the gradual loss of neuronal function. This page provides comprehensive information about the disease, including its pathophysiology, clinical presentation, diagnosis, and current therapeutic approaches.
Histopathology showing Bunina bodies in the anterior horn cell in sporadic ALS. Image: Wikimedia Commons (CC BY-SA 3.0).
¶ Overview
Amyotrophic lateral sclerosis (ALS)[1], also known as Lou Gehrig's disease, is a progressive neurodegenerative disorder that affects motor neurons in the brain and spinal cord. The disease leads to gradual loss of muscle control, ultimately affecting breathing, speaking, and movement. ALS is part of a spectrum of overlapping disorders that includes Frontotemporal Dementia (FTD), with which it shares genetic, pathological, and clinical features.1
Approximately 30,000 people in the United States have ALS, with about 5,000 new cases diagnosed each year. The average life expectancy after diagnosis is 2-5 years, though some patients live longer with modern interventions.2
¶ Epidemiology
- Incidence: 1-2 per 100,000 people annually
- Prevalence: Approximately 5-10 per 100,000
- Age of onset: Most commonly 55-75 years
- Sex distribution: Slightly more common in men (1.2-1.5:1 ratio)
- Sporadic ALS: 90-95% of cases with no known family history
- Familial ALS: 5-10% of cases with inherited genetic mutations
¶ Causes and Risk Factors
¶ Genetic Factors
Approximately 5-10% of ALS cases are familial, with over 30 genes identified as causative:3
| Gene | Inheritance | Percentage of FALS | Protein Function |
|---|---|---|---|
| C9orf72[3] | Autosomal dominant | ~40% | Guanine nucleotide exchange factor |
| SOD1 | Autosomal dominant/recessive | ~15-20% | Superoxide dismutase |
| TARDBP | Autosomal dominant | ~5% | RNA-binding protein |
| FUS | Autosomal dominant | ~5% | RNA-binding protein |
| TBK1 | Autosomal dominant | ~3% | Kinase |
| OPTN | Autosomal dominant | ~2% | Autophagy receptor |
| FBXO7 | Autosomal recessive | ~1% | Mitochondrial quality control, mitophagy |
| CTSD | Autosomal dominant | <1% | Lysosomal protease, protein degradation |
| HSP90AB1 | Complex | <1% | Molecular chaperone, protein folding |
¶ Environmental and Lifestyle Factors
- Smoking: Consistent risk factor
- Physical trauma: Military service and professional sports associated with increased risk
- Heavy metal exposure: Limited evidence for lead, mercury, selenium
- Pesticide exposure: Some association observed in agricultural workers
- Diet: No definitive dietary risk factors identified
¶ Pathophysiology
¶ Motor Neuron Degeneration
ALS is characterized by progressive degeneration of both upper motor neurons (corticospinal neurons) and lower motor neurons (anterior horn cells and brainstem motor nuclei). The degeneration leads to muscle weakness, atrophy, and spasticity.4
¶ Key Molecular Mechanisms
¶ TDP-43[2] Proteinopathy
- TDP-43[2] (encoded by TARDBP) is the primary pathological protein in ~97% of ALS cases
- Abnormal cytoplasmic inclusions in motor neurons
- Loss of normal nuclear TDP-43[2] function disrupts RNA metabolism
- TDP-43[2] aggregates also found in ~50% of FTD cases (ALS-FTD spectrum)
¶ RNA Metabolism Defects
ALS-associated proteins (TDP-43[2], FUS, C9orf72[3]) are all involved in RNA processing:5
- Abnormal RNA splicing
- Disrupted transport
- Impaired stress granule dynamics
- Defective nuclear import/export
¶ C9orf72[3] Hexanucleotide Repeat Expansion
The most common genetic cause of familial ALS:
- Abnormal GGGGCC repeat expansion in first intron
- Leads to:
- Toxic gain-of-function from repeat-containing RNA
- Translation of dipeptide repeat proteins (DPRs)
- RNA foci sequestering RNA-binding proteins
- Nucleolar stress
¶ Proteostasis Failure
- Impaired autophagy-lysosomal pathway
- Ubiquitin-proteasome system dysfunction
- Protein aggregation (SOD1, TDP-43[2], FUS)
- ER stress response activation
¶ neuroinflammation
- Activated microglia and astrocytes
- Pro-inflammatory cytokine release (IL-1β, TNF-α, IL-6)
- Non-neuronal cell contribution to disease progression
- Complement system activation
¶ Excitotoxicity
- Glutamate-mediated excitotoxicity
- Impaired glutamate transport (EAAT2)
- AMPA/kainate receptor involvement
- Riluzole targets this mechanism
¶ Clinical Presentation
¶ Core Symptoms
- Muscle weakness (most common presenting symptom)
- Muscle atrophy
- Fasciculations (muscle twitches)
- Spasticity (upper motor neuron involvement)
- Hyperreflexia
- Fatigue
¶ Disease Progression
- Typically begins in focal muscle group
- Spreads contiguously to adjacent regions
- Eventually affects respiratory muscles
- Cognitive function usually preserved (10-15% develop FTD)
¶ Bulbar Onset
- ~25-30% present with bulbar symptoms
- Dysarthria (slurred speech)
- Dysphagia (swallowing difficulty)
- Tongue atrophy and fasciculations
- Poorer prognosis (median survival 2 years)
¶ Limb Onset
- ~65-70% present with limb weakness
- Typically begins in distal muscles
- Hand weakness common (grip, dexterity)
- Foot drop
¶ Diagnosis
¶ El Escorial and Awaji Criteria
Clinical diagnosis uses established criteria:
- Definite ALS: Combined upper and lower motor neuron signs in three regions
- Probable ALS: Upper and lower motor neuron signs in two regions
- Possible ALS: Upper and lower motor neuron signs in one region
- Laboratory-supported probable: Progressive spread within regions with genetic mutation
¶ Diagnostic Tests
| Test | Purpose |
|---|---|
| Electromyography (EMG) | Confirms lower motor neuron involvement |
| Nerve conduction studies | Excludes peripheral neuropathy |
| MRI brain/spine | Excludes structural lesions |
| Genetic testing | Identifies causal mutations |
| CSF analysis | Excludes inflammatory conditions |
¶ Biomarkers
- Neurofilament light chain (NfL): Elevated in blood and CSF
- pNfH: Phosphorylated neurofilament heavy chain
- TDP-43[2]: CSF levels may correlate with disease
- Genetic panels: C9orf72[3], SOD1, TARDBP, FUS, and others
¶ Emerging Biomarkers
- 14-3-3 Proteins (CSF): Neuronal damage markers
- Cell-Free DNA Biomarkers: Blood-based neuronal death markers
- Complement C3: Inflammatory biomarker
- GFAP: Astrocyte activation marker
¶ Treatment
¶ Disease-Modifying Therapies
¶ Riluzole (Rilutek)
- First FDA-approved ALS drug (1995)
- Reduces glutamate excitotoxicity
- Extends survival by 2-3 months
- Dose: 50 mg twice daily
¶ Edaravone (Radicava)
- FDA approved in 2017
- Free radical scavenger
- Selective for slower progression patients
- Monthly IV infusions
¶ Tofersen (Qalsody)
- FDA approved in 2023 for SOD1-ALS
- Antisense oligonucleotide
- Targets SOD1 mRNA
- First gene-specific therapy
¶ AMX0035 (Albrioza)
- FDA approved in 2024
- Combination of sodium phenylbutyrate and taurursodiol
- Targets ER stress and mitochondrial dysfunction
- Extends survival by 4.8 months
¶ Symptomatic Management
| Symptom | Treatment |
|---|---|
| Spasticity | Baclofen, tizanidine, benzodiazepines |
| Muscle cramps | Quinine, mexiletine, physical therapy |
| Dysphagia | Feeding tube (PEG), dysphagia therapy |
| Dysarthria | Speech therapy, assistive devices |
| Salivation | Glycopyrrolate, botulinum toxin |
| Pain | NSAIDs, opioids, multidisciplinary care |
| Depression/anxiety | SSRIs, counseling |
¶ Respiratory Support
- Non-invasive ventilation (BiPAP)
- Mechanical insufflation/exsufflation
- Tracheostomy for advanced disease
- Cough-assist devices
¶ Multidisciplinary Care
Standard of care involves:
- Neurology
- Pulmonology
- Physical therapy
- Occupational therapy
- Speech therapy
- Nutrition
- Psychology/social work
¶ Clinical Trials
¶ Active Areas of Investigation
- Gene therapies: AAV-based delivery, ASOs for additional targets
- Anti-aggregation drugs: Small molecules targeting protein aggregates
- Neuroprotective agents: Mitochondrial protectors, anti-excitotoxic
- Cell therapy: Stem cell transplantation
- Repurposing trials: Existing drugs with neuroprotective properties
¶ Pipeline Overview
- Over 100 clinical trials in various phases
- Focus on C9orf72[3], sporadic ALS, and broad-spectrum approaches
- Biomarker development for patient stratification
¶ Recent Research
- 2025: Phase 3 trials of tofersen showed significant slowing of disease progression in SOD1-ALS6
- 2024: C9orf72[3]-targeted therapies entering clinical trials7
- 2024: TDP-43[2] liquid-liquid phase separation studies revealing new therapeutic targets8
- 2025: Biomarker studies using neurofilament levels for trial enrichment9
¶ Recent Publications (ALS)
Updated: 2026-03-02 06:03 (UTC)
- Source: PubMed
- Window: last 7 days
¶ Highlighted Papers
- Voxel-mirrored homotopic connectivity in upper motor neuron-dominant amyotrophic lateral sclerosis is associated with different spread directions. (Brain imaging and behavior; 2026 Mar 1). DOI: 10.1007/s11682-026-01089-y.
- A role for the cholinergic neuron circadian clock in RNA metabolism and mediating neurodegeneration. (Life science alliance; 2026 Mar). DOI: 10.26508/lsa.202503508.
- The Tuesday lessons of ALS. (The Lancet. Neurology; 2026 Mar). DOI: 10.1016/S1474-4422(26)00048-7.
- Natural Killer Cell Dysregulation During ALS Disease Progression: A Gene Expression Analysis. (Neurology open access; 2026 Mar). DOI: 10.1212/wn9.0000000000000067.
¶ Related NeuroWiki Pages
¶ See Also
- ALS-FTD Spectrum
- TDP-43[2]
- C9orf72[3]
- SOD1
- FUS
- Motor Neurons
- ALS RNA Metabolism and Proteostasis Failure
- ALS Biomarkers and Disease Monitoring
- Proteins/TIA1
¶ External Links
¶ Recent Publications (Last 30 Days)
Auto-updated from bioRxiv/medRxiv ingest pipeline for papers published since 2026-01-31.
- Plasma and CSF proteomic signatures related to Alzheimer's, α-synuclein, or vascular pathologies and clinical decline (medrxiv, published 2026-02-04; DOI:
10.64898/2026.02.04.26345534)
These entries are preprints and should be interpreted alongside peer-reviewed evidence on Amyotrophic Lateral Sclerosis (ALS).
¶ Recent Research Developments (2026)
Recent advances in ALS research (2026):
¶ SOD1 and Tofersen
- Long-term tofersen: "Long-Term Tofersen in SOD1 Amyotrophic Lateral Sclerosis." JAMA Neurology 2026 Feb. PMID:41661214 - Shows that earlier initiation of tofersen (compared to later initiation) was associated with better outcomes. Approximately 2% of ALS cases are linked to SOD1 gene variants.
¶ C9orf72[3]
- Microglia in C9orf72[3]-associated ALS: "Microglia in C9orf72[3]-associated amyotrophic lateral sclerosis: More or less active?" Neural Regen Res 2026 Jan. PMID:41495602
¶ Regulatory T Cells
- Treg therapy: "Next steps in regulatory T cells: Biology and clinical application." Cell 2026 Jan. PMID:41512846 - Discusses low-dose interleukin-2 therapy showing promising results in trials for ALS.
¶ Biomarkers
- Skeletal muscle biomarkers: "Skeletal Muscle Biomarkers of Amyotrophic Lateral Sclerosis: A Large-Scale, Multi-Cohort Proteomic Study." Ann Neurol 2026 Feb. PMID:41020397
¶ Therapeutic Approaches
- Alpha-lipoic acid: "ALSUntangled #79: alpha-lipoic acid." Amyotroph Lateral Scler Frontotemporal Degener 2026 Feb. PMID:40411245 - Reviews alpha-lipoic acid as a potential therapy, noting it serves as an essential cofactor for enzymatic reactions in mitochondrial energy production.
¶ Background
The study of Amyotrophic Lateral Sclerosis (Als) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
¶ References
-
Taylor JP, Brown RH Jr, Cleveland DW. Decoding ALS: from genes to mechanism. Nature. 2016
-
Ling JP, Pletnikova O, Troncoso JC, Wong PC. TDP-43[2] neurodegeneration. Nat Rev Neurosci. 2015
-
Miller TM et al. Phase 3 trial of tofersen in SOD1-ALS. N Engl J Med. 2023
-
Wang A et al. TDP-43[2] phase separation in ALS pathogenesis. Cell. 2024
-
Benatar M et al. Neurofilament light chain as ALS biomarker. Lancet Neurol. 2025
-
Gaur N et al., Chitinases in Amyotrophic Lateral Sclerosis. Brain (2026)