Lecture Notes

DRPLA (dentatorubral-pallidoluysian atrophy) is a progressive neurologic disorder characterized by ataxia, cognitive decline, myoclonus, chorea, epilepsy, and psychiatric manifestations.

Overview

• Hallmark features
  • Ataxia
  • Cognitive decline
  • Myoclonus
  • Chorea
  • Epilepsy and psychiatric manifestations

  Clinical Features

  • Naito-Oyanagi disease 
  • Haw River syndrome
  • ATN1-related dentatorubral-pallidoluysian atrophy
  • Age of onset: 0-72 years (mean: 31.5 years)
  • Inversely related to CAG repeat size in the ATN1 gene
  • Disease duration: ~8 years (range: 0-35 years)
  • Mean age at death: 49 years (range: 18-80 years)

  Additional Clinical Manifestations

  • Juvenile Onset (before age 20 years):
    • Associated with ≥65 CAG repeats
    • Key features:
      • Developmental delay and progressive intellectual disability
      • Myoclonus and epilepsy (progressive myoclonic epilepsy phenotype)
      • Developmental regression, ADHD, autism spectrum disorder, microcephaly (variable findings)

      Family History

      • Resistant to anti-seizure medications
      • Types evolve over time:
        • Early: Partial and brief generalized seizures (atypical absence, myoclonic)
        • Later: Generalized tonic-clonic seizures

        Note: Absence of a known family history does not rule out diagnosis.

        Molecular Genetics

        • Associated with <65 CAG repeats
        • Mean age of onset: 48 years
        • Prominent features:
          • Ataxia, choreoathetosis
          • Personality changes (e.g., delusions, hallucinations, aggression)
          • Cognitive decline affecting attention, executive function, visuoconstruction; memory relatively preserved
          • Seizures (in younger adults)
          • Isolated ataxia in older adults (age >60 years)
          • REM sleep behavior disorder (RBD), insomnia, circadian rhythm disruption

          Genotype-Phenotype Correlations in DRPLA

          • All ages:
            • Dysphagia (late stages)
            • Choreoathetosis, dystonia, myoclonus, oculomotor impairments
            • Postural instability, optic atrophy, corneal endothelial degeneration

            Neuroimaging

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