What are the main types of Amyotrophic Lateral Sclerosis (ALS)?

Main Types of Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic Lateral Sclerosis (ALS) is primarily classified into two main types: sporadic ALS (accounting for approximately 90% of cases) and familial ALS (accounting for 10% of cases), with each type having distinct genetic and clinical characteristics that affect disease progression, survival, and treatment approaches.

Classification by Etiology

• Sporadic ALS (sALS): Represents approximately 90% of all ALS cases, occurring without a known genetic mutation or family history 1, 2
• Familial ALS (fALS): Accounts for approximately 10% of cases, with an autosomal dominant inheritance pattern suggested by family history 3, 4

Genetic Classification

• C9orf72 hexanucleotide repeat expansion: Most common genetic cause, responsible for 30-50% of familial ALS and 7% of sporadic ALS cases, also frequently associated with frontotemporal dementia 3, 4
• SOD1 mutations: More common in Japanese populations than in Western populations, targeted by tofersen antisense oligonucleotide therapy 4
• FUS mutations: More prevalent in Japanese populations, associated with specific clinical features 4
• TARDBP (TDP-43) mutations: Associated with cytoplasmic mislocalization of TDP-43, a hallmark pathological finding in both ALS and frontotemporal dementia 5
• Other genetic mutations: Over 20 genes have been associated with ALS, with ongoing discovery of disease-modifying genes 3, 4

Clinical Classification

• Limb-onset ALS: Characterized by initial symptoms in the limbs, typically with asymmetric weakness 3
• Bulbar-onset ALS: Approximately 80% of patients with this type develop dysarthria and dysphagia as initial symptoms 6
• ALS with frontotemporal dementia (ALS-FTD): Up to 50% of ALS patients exhibit extra-motor manifestations such as behavioral changes, executive dysfunction, and language problems; in 10-15% of patients, these issues meet clinical criteria for frontotemporal dementia 3

Pathophysiological Classification

• Upper motor neuron predominant ALS: Primarily affects corticospinal tracts with prominent spasticity 6, 7
• Lower motor neuron predominant ALS: Primarily affects anterior horn cells with prominent muscle atrophy 6, 7
• Mixed upper and lower motor neuron ALS: The most common presentation, with degeneration of both upper and lower motor neurons 6, 5

Prognostic Considerations

• Rapidly progressive ALS: Associated with shorter survival (2-3 years from symptom onset) 3
• Slowly progressive ALS: Associated with longer survival (5-10 years from symptom onset), with 5-10% of patients living longer than 10 years 6, 3
• Respiratory-onset ALS: Often associated with poorer prognosis due to early respiratory involvement 3

Diagnostic Challenges

• ALS is diagnosed by exclusion, requiring evidence of both upper and lower motor neuron signs, progressive spread of symptoms, and compatible EMG findings 5
• Diagnostic delays are common due to the heterogeneous presentation and overlap with other neurological conditions 1, 5
• Definitive biomarkers for ALS are still lacking, complicating early diagnosis 1

Treatment Implications

• Different genetic forms may respond differently to emerging gene therapies, such as antisense oligonucleotide treatments targeting specific mutations 4
• Early diagnosis and intervention are crucial for improving outcomes and quality of life 1
• Multidisciplinary care remains the cornerstone of management, regardless of ALS type 1, 2