What are the main types of Spinocerebellar Ataxia (SCA) and their clinical implications, specifically for SCA3 (Machado-Joseph disease)?

Spinocerebellar Ataxia (SCA) Types with Focus on SCA3 (Machado-Joseph Disease)

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most common autosomal dominant ataxia worldwide, characterized by prominent cerebellar, pyramidal, extrapyramidal, and peripheral motor system degeneration with distinctive neuroimaging findings compared to other SCA types. 1, 2

Classification of Spinocerebellar Ataxias

Spinocerebellar ataxias are classified into several types based on genetic mutations and clinical presentations:

Major Types of SCAs:

1. SCA1:

   • Characterized by prominent pyramidal tract signs, pale optic discs, and dysphagia
   • Moderate cerebellar and brainstem atrophy on MRI
   • CAG trinucleotide repeat expansion in the ATXN1 gene 3

2. SCA2:

   • Characterized by slow saccadic eye movements (present in 100% of patients)
   • Severe olivopontocerebellar atrophy on MRI
   • CAG trinucleotide repeat expansion in the ATXN2 gene 3

3. SCA3/Machado-Joseph Disease:

   • Most common autosomal dominant ataxia globally
   • Milder cerebellar and brainstem atrophy compared to SCA1 and SCA2
   • CAG trinucleotide repeat expansion in the ATXN3 gene 1, 2

4. Other SCAs:

   • Include SCA6, SCA7, and SCA17, which also involve CAG trinucleotide repeat expansions
   • Various other types with different genetic mutations and clinical presentations 4

Clinical Features of SCA3 (Machado-Joseph Disease)

Neurological Manifestations:

• Progressive cerebellar ataxia (core feature)
• Parkinsonian features due to substantia nigra involvement
• Complex disturbance of ocular motility
• Weakness of the tongue
• Nystagmus in the horizontal direction
• Orbicularis oculi contractions
• Bilateral esotropia 1, 5

Neuropathological Features:

• Substantia nigra and dentate nucleus of cerebellum bear the brunt of the disease
• Cerebellar cortex remains relatively normal
• Dentate nucleus shows neuronal loss and "grumose regeneration" (proliferation of synaptic terminals)
• Atrophy of the basis pontis
• Polyglutamine-positive neuronal intranuclear inclusion bodies in pontine gray
• Variable involvement of basal ganglia, thalamus, spinal cord, dorsal root ganglia, and sensory peripheral nerves 1

Spinal Cord Involvement:

• Dorsal root ganglia show proliferation of satellite cells and active neuronal destruction
• Total or subtotal loss of neurons in dorsal nuclei
• Anterior horn cell atrophy
• Variable long tract degeneration 1

Diagnostic Approach

Imaging:

• MRI of the head without IV contrast is the preferred initial imaging modality for evaluating cerebellar ataxia 4
• Key findings in SCA3:
  • Mild cerebellar and brainstem atrophy (less severe than in SCA1 and SCA2)
  • Distinctive pattern distinguishable from typical olivopontocerebellar atrophy 3
  • Normal cerebellar cortex with affected dentate nucleus 1

Clinical Evaluation:

• Comprehensive neurological examination including:
  • Assessment of coordination, gait, and balance
  • Evaluation of eye movements (saccade velocity reduced in 30% of SCA3 patients)
  • Assessment of motor function and muscle tone
  • Evaluation of cranial nerve function 6, 3

Genetic Testing:

• Genetic studies with next-generation sequencing to identify CAG trinucleotide repeat expansion in the ATXN3 gene 6, 2

Differentiating SCA Types

Clinical Distinctions:

• SCA1: More frequent pyramidal tract signs, pale discs, and dysphagia
• SCA2: Universally slow saccadic eye movements (100% of patients)
• SCA3: Less frequent saccade velocity reduction (30% of patients) 3

Imaging Distinctions:

• SCA1: Moderate cerebellar and brainstem atrophy
• SCA2: Severe olivopontocerebellar atrophy
• SCA3: Mild cerebellar and brainstem atrophy, distinct from typical olivopontocerebellar atrophy 3

Diagnostic Pearls:

• Correlative plotting of saccade velocity and diameter of the middle cerebellar peduncle can help distinguish between SCA2 and SCA3
• SCA1 falls in an intermediate range that overlaps with both SCA2 and SCA3 3

Management Considerations

• Currently, there is no cure for SCA3/Machado-Joseph disease 2
• Management focuses on:
  • Symptomatic treatment of ataxia, Parkinsonian features, and other neurological manifestations
  • Rehabilitation strategies including teaching patients to avoid rapid multijoint movements
  • Encouraging slower movements limited to single joints
  • Reducing movement complexity
  • Stabilizing against inertial effects of limb movement 6

Prognosis

• SCA3/Machado-Joseph disease is a progressive neurodegenerative disorder
• The rate of progression and specific symptoms can vary based on the size of the CAG repeat expansion
• Prognosis varies widely depending on the specific etiology of cerebellar ataxia, with hereditary forms typically showing slow progression 6, 2

Clinical Pearls and Pitfalls

• SCA3 may be underdiagnosed in some regions; it was only recently reported in Eastern Europe (Poland) 7
• The remarkable clinical heterogeneity of SCA3 reflects the underlying unstable CAG trinucleotide repeat that varies in size among affected individuals 2
• Misfolding of ataxin-3 due to overly long polyglutamine stretches is a critical contributor to the pathogenesis of SCA3/MJD 1