• Hereditary ataxias are caused by repeat expansions in specific genes.
• Testing for repeat expansions is recommended before Next-Generation Sequencing (NGS) analysis.
• Key clinical features often include cerebellar ataxia and other systemic manifestations.
• MRI findings can assist in the diagnosis by revealing characteristic patterns of atrophy.
• The spectrum of spinocerebellar ataxias (SCAs) varies widely in clinical features, onset age, and genetic causes.
• Repeat expansion size influences severity and associated systemic manifestations.

Friedreich's Ataxia (FA)

• Gene: FXN
• Pathological Expansion:
  • FA: >700 GAA repeats
  • LOFA (Late-Onset FA): <500 GAA
• Protein: Frataxin
• Transmission: Recessive (isolated cases or ≥2 siblings in the same generation, unaffected parents)
• Age at Onset:
  • FA: 7–25 years
  • LOFA: 25–40 years
  • VLOFA (Very Late-Onset FA): >40 years
• Clinical Phenotype:
  • FA: Sensory neuropathy, cerebellar ataxia, absent tendon reflexes, Babinski sign, scoliosis, pes cavus, impaired position and vibratory senses, hearing loss, optic neuropathy, diabetes, cardiomyopathy.
  • LOFA & VLOFA: Normal tendon reflexes, Babinski sign, spastic ataxia.
• MRI Findings: Spine atrophy.

Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome (CANVAS)

• Gene: RFC1
• Pathological Expansion: 400–2000 AAGGG repeats
• Protein: Replication Factor C
• Transmission: Recessive (isolated cases or ≥2 siblings in the same generation, unaffected parents)
• Age at Onset: Median 54 years (range: 35–73 years)
• Clinical Phenotype:
  • Cerebellar ataxia, sensory neuropathy, vestibular areflexia, chronic cough.
• MRI Findings: Cerebellar vermis atrophy.

Spinocerebellar Ataxia Type 3 (SCA3)

• Gene: ATXN3
• Pathological Expansion: >51 CAG repeats
• Protein: ATXN3
• Transmission: Dominant (founder mutations: Portugal, Germany, Japan)
• Age at Onset:
  • 0–20 years: 11%
  • 21–40 years: 43%

  • 40 years: 46%

• Clinical Phenotype:
  • Small Repeat: Axonal neuropathy, dopa-responsive parkinsonism.
  • Medium Repeat: Cerebellar ataxia, pyramidal signs, diplopia.
  • Large Repeat: Dystonia, pyramidal signs, gaze-evoked nystagmus, hypometric saccades.
• MRI Findings: Cerebellar, brainstem, and spine atrophy.

Spinocerebellar Ataxia Type 2 (SCA2)

• Gene: ATXN2
• Pathological Expansion: >32 CAG repeats
• Protein: ATXN2
• Transmission: Dominant (founder mutations: Cuba, West Indies)
• Age at Onset:
  • 0–20 years: 17%
  • 21–40 years: 45%

  • 40 years: 38%

• Clinical Phenotype:
  • Small Repeat: Postural tremor.
  • Medium Repeat: Cerebellar ataxia, decreased reflexes.
  • Large Repeat: Cerebellar ataxia, chorea, dementia, myoclonus, dystonia.
  • Very Large Repeat: Cardiac failure, retinal degeneration.
• MRI Findings: Slow saccades.

Spinocerebellar Ataxia Type 6 (SCA6)

• Gene: ATX-CACNA1A
• Pathological Expansion: >19 CAG repeats
• Protein: α1A-Subunit of voltage-dependent calcium channel of P/Q type
• Transmission: Dominant (can be under-reported due to late onset)
• Age at Onset: Median 45 years (range: 19–73 years)
• Clinical Phenotype:
  • Small Repeat: Episodic ataxia, downbeat nystagmus.
• MRI Findings: Cerebellar atrophy.

Spinocerebellar Ataxia Type 1 (SCA1)

• Gene: ATX-ATXN1
• Pathological Expansion: >38 CAG repeats (without CAT interruption)
• Protein: ATXN1
• Transmission: Dominant (several cases in successive generations)
• Age at Onset:
  • 0–20 years: 15%
  • 21–40 years: 42%

  • 40 years: 43%

• Clinical Phenotype:
  • Medium Repeat: Cerebellar ataxia, pyramidal syndrome.
  • Large Repeat: ALS-like disorder.
  • Very Large Repeat: Developmental delay.
• MRI Findings: Hypermetric saccades, cerebellar (vermis) and brainstem atrophy.

Spinocerebellar Ataxia Type 7 (SCA7)

• Gene: ATX-ATXN7
• Pathological Expansion: >36 CAG repeats
• Protein: ATXN7
• Transmission: Dominant (founder mutations: Scandinavian countries, South Africa, Mexico)
• Age at Onset:
  • 0–20 years: 25%
  • 21–40 years: 48%

  • 40 years: 27%

• Clinical Phenotype:
  • Small Repeat: Cerebellar ataxia without visual loss.
  • Medium Repeat: Cerebellar ataxia, cone-rod dystrophy.
  • Large Repeat: Visual loss (cone-rod dystrophy) before cerebellar syndrome.
  • Very Large Repeat: Cardiac and renal failure.
• MRI Findings: Cerebellar and brainstem atrophy.

Spinocerebellar Ataxia Type 8 (SCA8)

• Gene: ATX-ATXN8
• Pathological Expansion: CTA/CTG repeat in 3′ untranslated region
• Protein: ATXN8
• Transmission: Dominant
• Clinical Phenotype:
  • Cerebellar ataxia, pyramidal syndrome, sensory neuropathy, cognitive impairment, depression.
• MRI Findings: Cerebellar atrophy.

Spinocerebellar Ataxia Type 36 (SCA36)

• Gene: ATX-NOP56
• Pathological Expansion: >650 GGCCTG repeats (normal: 3–14 repeats)
• Protein: Nucleolar protein 56
• Transmission: Dominant
• Age at Onset:
  • 0–20 years: 21%
  • 21–40 years: 10%
  • 40 years: 69%
• Clinical Phenotype:
  • Cerebellar ataxia, amyotrophy, hearing loss.
• MRI Findings: Cerebellar atrophy.

Dentatorubral-Pallidoluysian Atrophy (DRPLA)

• Gene: ATX-ATN1
• Pathological Expansion: >47 CAG repeats
• Protein: DRPLA
• Transmission: Dominant
• Age at Onset: Median 31 years (range: 1–67 years)
• Clinical Phenotype:
  • Small Repeat: Chorea, ataxia, psychiatric manifestations.
  • Large Repeat: Progressive myoclonus, epilepsy, developmental delay, mild ataxia.
  • Very Large Repeat: Myoclonic epilepsy, chorea, cognitive impairment.
• MRI Findings: Cerebellar and brainstem atrophy, white matter lesions in the cerebrum, thalamus, globus pallidus.

Spinocerebellar Ataxia Type 12 (SCA12)

• Gene: PPP2R2B
• Pathological Expansion: CAG repeat in 5′ untranslated region
• Protein: Protein phosphatase 2, regulatory subunit B
• Transmission: Dominant
• Age at Onset: 10–55 years
• Clinical Phenotype:
  • Cerebellar ataxia, tremor, dystonia, dementia, polyneuropathy.
• MRI Findings: Cerebellar atrophy.

Spinocerebellar Ataxia Type 31 (SCA31)

• Gene: BEAN–TK2
• Pathological Expansion: Intronic TGGAA repeat insertion
• Protein: Brain-expressed protein associating with NEDD4 homologue
• Transmission: Dominant
• Age at Onset: Median 56 years (range: 45–72 years)
• Clinical Phenotype:
  • Pure cerebellar ataxia.
• MRI Findings: Cerebellar atrophy.

Spinocerebellar Ataxia Type 17 (SCA17)

• Gene: TBP
• Pathological Expansion: >48 CAG repeats
• Protein: TATA-box-1-binding protein
• Transmission: Dominant with incomplete penetrance
• Age at Onset: Median 34 years (range: 3–75 years)
• Clinical Phenotype:
  • Small Repeat: Huntington’s disease-like phenotype, parkinsonism.
  • Medium Repeat: Ataxia, dementia, chorea, dystonia, pyramidal signs.
  • Large Repeat: Ataxia, dementia, spasticity, epilepsy.
  • Very Large Repeat: Growth retardation.
• MRI Findings: Diffuse cerebral atrophy.

Spinocerebellar Ataxia Type 10 (SCA10)

• Gene: ATXN10
• Pathological Expansion: Intronic ATTCT repeat insertion
• Protein: ATXN10
• Transmission: Dominant
• Age at Onset: 10–40 years
• Clinical Phenotype:
  • Cerebellar ataxia, epilepsy.
• MRI Findings: Cerebellar atrophy.

Spinocerebellar Ataxia Type 37 (SCA37)

• Gene: DAB1
• Pathological Expansion: ATTTC insertion in 5′ untranslated region (31–75 repeats)
• Protein: Disabled homologue 1
• Transmission: Dominant
• Age at Onset: Median 48 years (range: 18–64 years)
• Clinical Phenotype:
  • Cerebellar ataxia, saccadic pursuit (vertical > horizontal).
• MRI Findings: Cerebellar atrophy.

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)

• Gene: FMR1
• Pathological Expansion: 55–200 CGG repeats
• Protein: Fragile X mental retardation protein
• Transmission: X-linked
• Age at Onset: >50 years
• Clinical Phenotype:
  • Intention tremor, cerebellar ataxia, parkinsonism, axonal neuropathy, cognitive impairment.
• MRI Findings:
  • White matter lesions in the middle cerebellar peduncle, splenium of the corpus callosum, and cerebrum.
  • Cerebral atrophy.

Reference

Coarelli, G., Wirth, T., Tranchant, C., Koenig, M., Durr, A., & Anheim, M. (2023). The inherited cerebellar ataxias: an update. Journal of Neurology, 270(1), 208–222. doi:10.1007/s00415-022-11383-6