What are the subtypes of Amyotrophic Lateral Sclerosis (ALS)?

Subtypes of Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) can be classified into two main subtypes based on genetics: familial ALS (10-15% of cases) and sporadic ALS (85-90% of cases), with further molecular subtypes identified based on cellular pathology and genetic characteristics. 1, 2

Primary Classification of ALS

• Sporadic ALS: Accounts for approximately 85-90% of all ALS cases with no clear family history of the disease 1, 2
• Familial ALS: Represents about 10-15% of cases with an autosomal dominant inheritance pattern 1

Molecular Subtypes of ALS

Recent research has identified distinct molecular subtypes of ALS based on transcriptomic profiles in affected tissues 3:

• ALS-Ox: Characterized by mitochondrial dysfunction and oxidative stress 3
• ALS-Glia: Defined by microglial activation and neuroinflammation 3
• ALS-TE: Marked by dense TDP-43 pathology and associated transposable element de-silencing 3

These molecular subtypes correlate with clinical features, particularly disease duration, with ALS-TE signatures in cortex and ALS-Glia signatures in spinal cord showing strong correlations 3.

Clinical Presentation Subtypes

ALS can also be categorized based on the site of symptom onset and predominant clinical features:

• Limb-onset ALS: Initial symptoms appear in the limbs with weakness and atrophy 4, 1
• Bulbar-onset ALS: Initial symptoms involve bulbar muscles with dysarthria and dysphagia (approximately 80% of bulbar-onset patients develop these symptoms) 4, 1
• Combined upper and lower motor neuron involvement: Classic ALS presentation 4, 5

Pathophysiological Classification

ALS is primarily classified as an anterior horn cell disorder affecting both upper and lower motor neurons 4, 5:

• Upper motor neuron predominant: More spasticity and hyperreflexia 4
• Lower motor neuron predominant: More atrophy and fasciculations 4, 5

Genetic Subtypes of ALS

Multiple genes have been associated with ALS, with the most common being:

• C9orf72-associated ALS: Caused by hexanucleotide repeat expansion in the C9orf72 gene, responsible for 30-50% of familial ALS and 7% of sporadic ALS 1
• SOD1-associated ALS: First gene identified in familial ALS 6
• TARDBP-associated ALS: Mutations in the gene encoding TDP-43 protein 6
• FUS-associated ALS: Mutations in the FUS gene 6
• Other genetic forms: More than 20 genes have been associated with ALS to date 1, 6

ALS with Extra-motor Manifestations

• ALS with cognitive impairment: Up to 50% of ALS patients show changes in behavior, executive dysfunction, or language problems 1
• ALS-FTD: In 10-15% of patients, cognitive problems are severe enough to meet criteria for frontotemporal dementia 1

Prognostic Subtypes

Based on disease progression and survival:

• Rapidly progressive ALS: Survival less than 2 years from symptom onset 1, 7
• Average progression ALS: Survival 2-5 years (most common) 1, 7
• Slowly progressive ALS: Survival beyond 5 years (only 5-10% of patients live longer than 10 years) 4, 7

Clinical Implications of ALS Subtypes

Understanding the specific subtype of ALS is crucial for:

• Providing accurate prognostic information to patients and families 1, 7
• Guiding appropriate genetic counseling for familial forms 1
• Developing targeted therapeutic approaches based on underlying pathophysiology 3, 6
• Planning appropriate multidisciplinary care focusing on specific symptom management 2

The identification of ALS subtypes continues to evolve with ongoing research, particularly in the areas of genetics and molecular pathophysiology, which may lead to more personalized treatment approaches in the future 3, 6.