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

Types of Amyotrophic Lateral Sclerosis (ALS)

ALS is classified into two main clinical presentation types based on site of onset: bulbar-onset ALS (25-35% of cases) and limb-onset/spinal ALS (65-75% of cases), with further classification by etiology into sporadic ALS (85-90% of cases) and familial ALS (10-15% of cases). 1, 2

Clinical Classification by Site of Onset

Bulbar-Onset ALS

• Accounts for 25-35% of all ALS patients and presents with initial symptoms affecting speech and swallowing 1
• Approximately 80% of bulbar-onset patients develop dysarthria (speech difficulty) and dysphagia (swallowing difficulty) as primary manifestations 1, 3, 4
• Carries the worst prognosis, particularly when combined with older age at onset 1
• Degeneration of bulbar neurons manifests as difficulty in chewing, oral preparation, prolonged time to complete meals, and progressive dysphagia 1

Limb-Onset/Spinal ALS

• Represents the majority of ALS cases (65-75%) with initial symptoms in the extremities 1
• Primary manifestation is progressive muscle weakness in arms or legs 1
• Spinal motor neuron injury leads to peripheral muscle weakness and atrophy 1

Classification by Motor Neuron Involvement

Mixed Upper and Lower Motor Neuron ALS (Classical ALS)

• Most common presentation, with degeneration affecting both upper and lower motor neurons simultaneously 2, 3, 4
• Upper motor neuron signs include hypertonicity, hyperreflexia, and spasticity 1, 3
• Lower motor neuron signs include muscle fasciculations, weakness, and atrophy 1, 3

Upper Motor Neuron Predominant ALS

• Primarily affects corticospinal tracts with prominent spasticity as the dominant feature 2
• Less common variant with slower progression in some cases 2

Lower Motor Neuron Predominant ALS

• Primarily affects anterior horn cells with prominent muscle atrophy and minimal spasticity 2
• May present diagnostic challenges due to overlap with other motor neuron diseases 2

Etiologic Classification

Sporadic ALS

• Represents approximately 85-90% of all ALS cases 1, 2, 4, 5
• Occurs without known genetic mutation or family history 2
• Annual incidence of 1-2 per 100,000 people 1, 4
• Etiology is multifactorial, involving oxidative stress, glutamate toxicity, mitochondrial dysfunction, inflammation, and apoptosis 1, 3

Familial ALS

• Accounts for 10-15% of ALS cases with autosomal dominant inheritance pattern in most families 5, 6
• More than 20 genes have been associated with ALS, with the most common being C9orf72 (responsible for 30-50% of familial ALS and 7% of sporadic ALS), SOD1, FUS, and TARDBP 5, 7, 8
• Only distinguishing clinical feature from sporadic ALS is lower mean age of onset 7
• Many families show low disease penetrance, so genetic predisposition may remain unnoticed and patients may be misclassified as sporadic 7

Prognostic Classification

Typical Progressive ALS

• Mean survival of 3-5 years after symptom onset 1, 2, 3, 4, 5
• Respiratory failure and malnutrition with dehydration are primary causes of death 1

Slowly Progressive ALS

• Associated with longer survival of 5-10 years from symptom onset 2
• Only 5-10% of patients live longer than 10 years 1, 2, 3, 4

Important Clinical Considerations

Cognitive Involvement

• Cognitive dysfunction occurs in 20-50% of ALS cases, mainly frontotemporal dementia 1
• Up to 40-50% of patients have extra-motor manifestations including behavioral changes, executive dysfunction, and language problems 3, 5
• In 10-15% of patients, cognitive problems are severe enough to meet criteria for frontotemporal dementia (FTD), emphasizing the molecular overlap between ALS and FTD 5

Diagnostic Challenges

• Diagnostic delays are common due to heterogeneous presentation and overlap with other neurological conditions 2
• Definitive biomarkers for ALS are still lacking, complicating early diagnosis 2
• The only reliable way to distinguish familial from sporadic ALS is through genetic testing, as all clinical features reported in hereditary cases have also been observed in sporadic cases 7

Management Implications

• All ALS types require multidisciplinary approach with supportive and palliative care from time of diagnosis 3, 4
• Early diagnosis and intervention are crucial for improving outcomes and quality of life 2
• Nutritional support is essential, particularly for bulbar-onset patients with dysphagia and weight loss 3