What is Dentatorubral-Pallidoluysian Atrophy (DRPLA)?

Dentatorubral-Pallidoluysian Atrophy (DRPLA): A Rare Neurodegenerative Disorder

Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, autosomal dominant neurodegenerative disorder characterized by a combination of cerebellar ataxia, myoclonus, epilepsy, dementia, and choreoathetosis, caused by CAG repeat expansion in the ATN1 gene. 1, 2

Clinical Presentation

DRPLA presents with marked clinical heterogeneity that varies primarily by age of onset:

• Early-onset (juvenile) presentation:

  • Progressive myoclonic epilepsy (predominant feature)
  • Intellectual deterioration
  • Ataxia
  • Mean age of onset: 31 years 1

• Late-onset (adult) presentation:

  • Cerebellar ataxia (predominant feature)
  • Choreoathetosis
  • Dementia
  • Psychiatric disturbances
  • May resemble Huntington's disease 3

Genetics and Pathophysiology

• Genetic basis: Expansion of CAG trinucleotide repeats in the ATN1 gene (chromosome 12)
• Inheritance: Autosomal dominant with prominent genetic anticipation
  • Paternal transmission results in more prominent anticipation than maternal transmission 4
• Pathology:
  • Diffuse accumulation of mutant atrophin-1 protein in neuronal nuclei
  • Variable neuronal loss and astrocytosis primarily in:
    • Globus pallidus
    • Dentate nucleus
    • Red nucleus
  • Widespread effects beyond these primary regions 4

Epidemiology

• Most common in Japanese populations
• Increasing global recognition
• Previously thought to be rare in Caucasian populations, but may be underdiagnosed
• Notable clusters reported in South Wales and Brazil 5, 3

Diagnostic Approach

1. Clinical assessment:

   • Evaluate for combination of ataxia, dementia, chorea, myoclonus, and epilepsy
   • Document family history (autosomal dominant pattern)

2. Neuroimaging:

   • MRI findings:
     • Cerebellar atrophy (most common)
     • Brainstem atrophy
     • Leukoencephalopathy (less common) 5

3. Genetic testing:

   • Molecular analysis of ATN1 gene for CAG repeat expansion
   • Normal: 6-35 repeats
   • Disease-causing: >48 repeats
   • Reduced penetrance: 35-48 repeats 6

Differential Diagnosis

DRPLA can be confused with:

• Huntington's disease (especially in late-onset cases)
• Other spinocerebellar ataxias
• Progressive myoclonic epilepsies
• Frontotemporal dementia

When evaluating patients with a clinical diagnosis of Huntington's disease who test negative for HTT gene expansion, DRPLA should be considered as an alternative diagnosis (HD phenocopy) 6.

Management

Currently, there are no disease-modifying or curative treatments available for DRPLA 1. Management focuses on:

• Symptomatic treatment of movement disorders
• Anticonvulsants for seizure control
• Cognitive support
• Genetic counseling for at-risk family members

Prognosis

DRPLA is a progressive, intractable neurodegenerative disorder. The rate of progression correlates with age of onset and CAG repeat length, with earlier onset typically associated with more rapid progression 1, 4.

Key Considerations for Clinicians

• Consider DRPLA in patients with combinations of ataxia, dementia, chorea, and myoclonus
• Genetic testing is essential for definitive diagnosis
• Early recognition facilitates appropriate genetic counseling
• DRPLA may be underdiagnosed in non-Japanese populations
• Genetic anticipation means that subsequent generations may have earlier onset and more severe disease