What is spinocerebellar ataxia?

Spinocerebellar Ataxia

Spinocerebellar ataxia (SCA) is a genetically heterogeneous group of autosomal dominantly inherited progressive neurological disorders characterized by degeneration of the cerebellum and its connections, resulting in impaired coordination of voluntary movements that persists regardless of visual feedback. 1

Clinical Characteristics

• SCAs manifest with progressive deterioration of cerebellar function including unsteadiness of gait, incoordination of limb movements, impairment of skilled movements (like handwriting), and distinctive dysarthria 2
• Truncal ataxia (difficulty maintaining posture) is particularly common with cerebellar vermian pathology 1
• Unlike sensory ataxia, cerebellar ataxia shows unsteadiness that does not significantly worsen with eye closure (negative Romberg test) 1
• Many SCAs involve additional neuronal systems beyond the cerebellum, including corticospinal pathways, basal ganglia, and autonomic nuclei of the brain stem and spinal cord 2
• Onset is most often in adult life, and many SCAs lead to premature death 3

Genetic Classification

• SCAs are genetically classified into two main groups: 3
  • Repeat expansion SCAs (most common), such as SCA3/Machado-Joseph disease
  • Rare SCAs caused by non-repeat mutations, such as SCA5
• Up to 48 recognized genetic subtypes have been identified 4
• Recent advances in next-generation sequencing have identified numerous novel genes associated with SCAs 5

Pathophysiological Mechanisms

• Main disease mechanisms include: 5
  • Toxic RNA gain-of-function
  • Mitochondrial dysfunction
  • Channelopathies
  • Autophagy dysfunction
  • Transcription dysregulation
• DNA repair pathways play an important role in modifying SCAs with CAG expansions 5
• Most SCA mutations cause prominent damage to cerebellar Purkinje neurons with consecutive cerebellar atrophy 3

Diagnostic Approach

• MRI of the head without IV contrast is the preferred initial imaging modality for evaluating cerebellar ataxia 6
• MRI can detect morphologic changes (atrophy) and signal alterations primarily involving the cerebellum and brainstem 6
• If inflammatory or neoplastic causes are suspected, contrast-enhanced MRI should be included 6
• Advanced MRI techniques such as diffusion-weighted imaging and spectroscopy may help detect early changes and distinguish between ataxia subtypes 6
• Spinal cord atrophy on MRI has been described in certain SCA types (SCA1, SCA7) and correlates with symptom severity and disease duration 6

Management

• Currently, there are no FDA-approved drugs specifically for SCA treatment 7
• Only two therapies have Level A recommendations for managing ataxia symptoms: 4
  • Riluzole
  • Immediate in-patient neurorehabilitation
• Therapies with Level B recommendations include: 4
  • High-dose valproic acid
  • Branched-chain amino acids
  • Intravenous trehalose
  • Restorative rehabilitation using cycling regimens and videogames
  • Cerebellar stimulations (transcranial direct current stimulation and transcranial magnetic stimulation)
• Balance training programs can improve stability 1
• Task-oriented upper limb training can improve reaching and fine motor control 1
• Appropriate assistive devices and orthoses can improve balance and mobility 1

Future Therapeutic Directions

• Antisense oligonucleotides and RNA-based therapies are being investigated as potential treatments 5
• Development of effective therapies is hampered by the heterogeneity of SCAs; specific therapeutic approaches may be required for each disease 3

Common Pitfalls and Caveats

• SCAs are often misdiagnosed due to their rarity and clinical overlap with other neurological conditions 6
• The Romberg test cannot be properly performed in cerebellar ataxia as unsteadiness is present regardless of visual input 1
• Heterogeneous study designs, different genotypes, and non-standardized clinical measures alongside short duration and small sample sizes hamper meaningful clinical translation of research findings 4
• Some patients with cerebellar ataxia may have coexisting symptoms of central or peripheral vestibulopathy, which can further complicate the clinical picture 1