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Fragile X Associated Tremor Ataxia Syndrome (FXTAS)

Summary

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  • Late-onset neurodegenerative disorder associated with premutation in FMR1 gene
  • Characterised by intention tremor, cerebellar ataxia, and cognitive decline
  • MRI findings include T2 hyperintensities in middle cerebellar peduncles and cerebral white matter

Pathophysiology

  • Caused by expanded CGG trinucleotide repeat (55-200) in 5' UTR of FMR1 gene
  • RNA toxicity due to increased FMR1 mRNA levels
  • Intranuclear inclusions in neurons and astrocytes
  • Mitochondrial dysfunction and oxidative stress contribute to neurodegeneration

Demographics

  • Primarily affects males over 50 years old
  • Penetrance increases with age, reaching 75% in males by age 80
  • Female carriers have lower penetrance and milder symptoms
  • Prevalence estimated at 1 in 4,000 males over 55 years old

Diagnosis

  • Clinical criteria:
    • Major: intention tremor, cerebellar ataxia
    • Minor: parkinsonism, cognitive decline, neuropathy
  • Genetic testing: FMR1 CGG repeat expansion analysis
  • Family history of fragile X syndrome or premature ovarian insufficiency

Imaging

  • MRI findings:
    • T2 hyperintensities in middle cerebellar peduncles (MCP sign)
    • Generalised cerebral and cerebellar atrophy
    • Corpus callosum thinning
    • Cerebral white matter T2 hyperintensities
  • FDG-PET:
    • Hypometabolism in cerebellum and cerebral cortex
  • DTI:
    • Reduced fractional anisotropy in MCP and cerebral white matter

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  • A 50-year-old patient, with a family history for FXTAS, presented with worsening tremor.
  • MRI showed progressive hyperintensity and atrophy of the middle cerebellar peduncles.
  • There was non-progressive hyperintensity within the cerebellar peduncles.
  • DaTSCAN was normal and genetic testing confirmed the diagnosis of FXTAS.

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  • A 60-year-old patient presented with a tremor (few months) and longstanding nystagmus (many years).
  • MRI showed confluent hyperintensity within the middle cerebellar peduncles and atrophy of the pons and midbrain.
  • Genetic analysis confirmed the diagnosis of FXTAS.

Treatment

  • Symptomatic management:
    • Tremor: beta-blockers, primidone, or deep brain stimulation
    • Ataxia: physical therapy and occupational therapy
    • Cognitive decline: cholinesterase inhibitors
  • Neuroprotective strategies under investigation:
    • Allopregnanolone
    • Antioxidants and mitochondrial support
  • Genetic counselling for family members
  • Regular monitoring of symptoms and disease progression

Differential diagnosis

Differential Diagnosis Distinguishing Feature
Multiple System Atrophy (MSA-C) "Hot cross bun" sign in pons on T2; putaminal rim sign; more diffuse cerebellar and pontine atrophy
Spinocerebellar Ataxias Variable cerebellar and brainstem atrophy patterns depending on subtype; may show inferior olive, pons, or caudate involvement
Acquired hepatocerebral degeneration T1 hyperintensity in globus pallidus and striatum; MCP hyperintensity similar to FXTAS