What are motor neuron disorders?

Motor Neuron Disorders: Definition and Classification

Motor neuron disorders (MNDs) are a group of neurodegenerative disorders characterized by the degeneration of upper motor neurons, lower motor neurons, or both, with amyotrophic lateral sclerosis (ALS) being the most common type, representing approximately 85% of all cases. 1

Classification of Motor Neuron Disorders

• Based on affected neurons:

  • Combined upper and lower motor neuron disorders: Amyotrophic Lateral Sclerosis (ALS) 1, 2
  • Pure lower motor neuron disorders: Spinal Muscular Atrophy, Progressive Muscular Atrophy, Multifocal Motor Neuropathies 1, 2
  • Pure upper motor neuron disorders: Primary Lateral Sclerosis, Hereditary Spastic Paraplegia 1, 2

• Major types of MNDs:

  • Amyotrophic Lateral Sclerosis (ALS): Characterized by degeneration of both upper and lower motor neurons with annual incidence of 1-2/100,000 and median survival of 3-4 years 1
  • Progressive Muscular Atrophy (PMA): Involves degeneration of only lower motor neurons 1, 3
  • Progressive Bulbar Palsy (PBP): Primarily affects bulbar muscles first 1, 3
  • Primary Lateral Sclerosis (PLS): Pure upper motor neuron disorder 2, 3

Clinical Features and Presentation

• Upper motor neuron signs: Hypertonicity, hyperreflexia, spasticity, and pathological reflexes 1, 4
• Lower motor neuron signs: Muscle fasciculations, weakness, atrophy, and hyporeflexia 1, 4
• Bulbar symptoms: Difficulties with speech, swallowing, and other functions controlled by lower cranial nerves 1
• Atypical variants: Include flail-leg syndrome, flail-arm syndrome, and facial-onset sensory and motor neuronopathy (FOSMN) 3

Diagnostic Features

• Electromyography (EMG): Cornerstone test for diagnosing motor neuron diseases, particularly for detecting lower motor neuron degeneration 1, 5

  • Characteristic findings include denervation with fibrillation potentials, positive sharp waves, and fasciculations 5, 4

• Neuroimaging:

  • MRI of the brain without IV contrast is the optimal initial imaging modality 1, 5
  • Common MRI findings include abnormal T2/FLAIR signal in the corticospinal tracts 1
  • Spine MRI may show abnormal T2/STIR signal in the anterior horns ("snake eyes" appearance) 1

• Genetic testing:

  • Recommended for familial cases, testing for ALS-associated genes (e.g., C9orf72, SOD1, FUS, TARDBP) 1, 6
  • Over 100 different mutant genes have been discovered in MNDs 6

Distinguishing Features from Other Neurological Disorders

• Anterior horn cell disorders vs. peripheral neuropathies:

  • Anterior horn cell disorders affect the cell bodies of lower motor neurons in the spinal cord 5
  • Peripheral neuropathies involve pathology of peripheral nerves outside the spinal cord 5
  • Peripheral neuropathies typically present with both sensory and motor symptoms, while MNDs are predominantly motor 5

• Biomarkers:

  • TAR DNA binding protein 43 (TDP-43) has been shown to be present in neuronal inclusions in ALS and may serve as a specific marker 7

Current Treatment Landscape

• FDA-approved drugs for ALS include riluzole, edaravone, AMX0035 (recently withdrawn), and tofersen 8
• Numerous clinical trials are investigating potential disease-modifying therapies 8

Clinical Monitoring and Management

• Motor and functional assessments are recommended at 3-6 month intervals for children under five years, and annually in older children and adults 5
• Submaximal, functional, and aerobic exercise is recommended while avoiding excessive resistive and eccentric exercise 5

Motor neuron disorders represent a complex group of neurodegenerative conditions with overlapping features but distinct pathophysiological mechanisms. Early and accurate diagnosis is crucial for appropriate management and potential enrollment in clinical trials for emerging therapies.