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
• Synonyms
  • Naito-Oyanagi disease 
  • Haw River syndrome
  • ATN1-related dentatorubral-pallidoluysian atrophy
• Onset & Progression:
  • 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)

Clinical Features

• 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)
  • Seizure Characteristics
    • Resistant to anti-seizure medications
    • Types evolve over time:
      • Early: Partial and brief generalized seizures (atypical absence, myoclonic)
      • Later: Generalized tonic-clonic seizures
    • Photosensitivity and reflex seizures common
  • Ataxia may develop early or later in the disease.
  • Later stages: Chorea and psychiatric symptoms.
• Adult Onset (after age 20 years):

• 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
• Rare features:
  • Seizures (in younger adults)
  • Isolated ataxia in older adults (age >60 years)
• Sleep disturbances:
  • REM sleep behavior disorder (RBD), insomnia, circadian rhythm disruption

Additional Clinical Manifestations

• All ages:
  • Dysphagia (late stages)
  • Choreoathetosis, dystonia, myoclonus, oculomotor impairments
  • Postural instability, optic atrophy, corneal endothelial degeneration
• Rare findings:
  • Parkinsonism, tremors, hyperreflexia, posterior column sensory loss

Family History

• Inheritance Pattern:
  • Autosomal dominant inheritance
  • Affected males and females in multiple generations
• Geographic & Ethnic Association:
  • Predominantly in Japanese populations
  • Extremely rare outside Japanese populations

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

Molecular Genetics

• Diagnostic Marker: Heterozygous abnormal CAG repeat expansion in the ATN1 gene
• Emerging Methods:
  • Genome sequencing tools for nucleotide repeat expansions but has limitations
    • May detect expanded repeat but not determine exact repeat number
    • Pathogenic CAG repeat expansions may not be reliably detected by standard next-generation sequencing (NGS) methods, Multigene panels & Exome sequencing

• Repeat Sizes in ATN1 Gene

• Normal: 6 to 35 CAG repeats
• Intermediate: 35 to 47 CAG repeats
  • Incompletely penetrant, usually milder clinical phenotype
  • Potential for expansion in transmission to next generation (rare)
  • Higher prevalence in Japanese individuals
• Pathogenic (Full Penetrance): 48 to 93 CAG repeats

Genotype-Phenotype Correlations in DRPLA

• Heterozygotes
  • Inverse Correlation: Age at onset inversely correlates with the size of the expanded ATN1 CAG repeat.
  • Age at Onset and Repeat Range:
    • <21 years: 63-79 repeats
    • 21-40 years: 61-69 repeats
    • >40 years: 48-67 repeats
    • Note: Overlap exists, and distinctions between ranges are not clearly defined.
  • Clinical Presentation and Repeat Size
    • <65 CAG repeats: Associated with non-PME phenotype (adult-onset features: ataxia, chorea, and neuropsychiatric symptoms).
    • ≥65 CAG repeats:Associated with PME phenotype (juvenile-onset features: myoclonus, epilepsy, intellectual deterioration).
    • Extreme Repeat Expansions (90-93 CAG): Associated with severe infantile onset.
      • Example: c.1462CAG[90_93] reported in cases of severe disease.
• Homozygotes
  • Rare cases suggest a dosage effect:
    • Biallelic expanded repeats (onset at age 14 years, indicating increased severity) [Sato et al. 1995].
    • Homozygosity for 57 CAG repeats in a consanguineous family (onset at 18 years, more severe manifestations) [Ikeuchi et al. 1995].
• Penetrance
  • Pathogenic CAG repeats (48-93 repeats) are fully penetrant, with rare exceptions:
    • Example: An individual with 51 CAG repeats was asymptomatic at age 81 years [Hattori et al. 1999].
• Anticipation
  • Marked Expansion: ATN1 CAG repeat expands significantly when transmitted to offspring.
    • Results in earlier onset:
      • 26-29 years earlier than affected fathers
      • 14-15 years earlier than affected mothers

Neuroimaging

• MRI Findings:
  • Cerebellar and brainstem atrophy (pontine tegmentum)
  Mid-sagittal T1-weighted image illustrating cerebellar atrophy and central pontine hypointensity
  • Cerebellar white matter lesions (paravermal areas on FLAIR images)
  • Diffuse high-intensity areas in deep white matter (T2-weighted MRI, late adult-onset)
• 18F-FDG-PET:
  • Bistriatal glucose hypometabolism in juvenile-onset DRPLA
• Neuropathology:
  • Degeneration of dentatorubral and pallidoluysian systems
  • Diffuse myelin pallor with axonal preservation
  • Neuronal intranuclear inclusions (common in polyglutamine diseases)
    (References: Sugiyama et al. 2018, Mori et al. 2012)

Prevalence of DRPLA

• Higher prevalence in Japan: Affects 0.2-0.7 per 100,000 people.
  • Higher proportion of individuals with 20-35 CAG repeats in the population (Takano et al. 1998).
  • Third most common autosomal dominant ataxia, accounting for 9.7% of cases (Tsuji et al. 2008).
  • Most common cause of childhood-onset cerebellar ataxia (Ono et al. 2019).
• Non-Japanese Populations
  • DRPLA is rarer but reported globally, including North and South America, Europe, and Australia (Chaudhry et al. 2021).
  • Regional prevalence estimates among cerebellar ataxia cohorts with autosomal dominant inheritance:
    • Brazil: 0.2%-0.92% (Braga-Neto et al. 2017, Pinto et al. 2021).
    • China: 1% (Lee et al. 2001).
    • France: 0.25% (Le Ber et al. 2003).
    • Italy: 1% (Filla et al. 2000). The largest Northern European pedigree originated in Italy (1500s) (Grimaldi et al. 2019).
    • Korea: 3.4% (Jin et al. 1999).
    • Portugal: 2%-11.2% (Silveira et al. 2002, Vale et al. 2010).
      • Prevalence: 0.33 per 100,000.
      • Second most frequent autosomal dominant ataxia.
      • Shared haplotype with Japan may explain higher prevalence (Martins et al. 2003).
    • Singapore: 3.4% (Zhao et al. 2002).
    • South Wales: 11.4% (Wardle et al. 2008).
      • High prevalence partially explained by a founder effect and spontaneous repeat expansions.
    • Spain: 1.4%-3.3% (Pujana et al. 1999, Infante et al. 2005).
    • Venezuela: 3.1% (Paradisi et al. 2016).

Genetically Related Disorders

• ATN1-Related Neurodevelopmental Disorder (ATN1-NDD)

  • Features:
    • Developmental delay/intellectual disability.
    • Neurologic findings: Hypotonia, brain malformations, epilepsy, cortical visual impairment, and hearing loss.
    • Distinctive facial features and hand/foot differences.
  • Cause: Heterozygous pathogenic variant in a 16-amino-acid sequence of exon 7 in ATN1.
  • Inheritance: De novo pathogenic variants in all reported cases where parents were tested.
• Pallister-Killian Syndrome (PKS)

• Features:
  • Tissue-limited mosaicism of tetrasomy 12p, including ATN1.
• Diagnosis:
  • Requires chromosome analysis of specific tissues (e.g., fibroblasts).
  • Routine molecular testing of blood samples may not detect PKS.

Differential Diagnosis of Early-Onset DRPLA

1. Neuronal Ceroid Lipofuscinosis (NCL)

   • Genes: CLN3, CLN5, CLN6, CLN8, CTSD, CTSF, DNAJC5 (AD), GRN, KCTD7, MFSD8, PPT1, TPP1
   • Disorder: Neuronal ceroid lipofuscinosis (OMIM PS256730).
   • Mode of Inheritance (MOI): Autosomal Recessive (AR), except for DNAJC5 (Autosomal Dominant - AD).
   • Key Features: Progressive cognitive decline, visual impairment, and seizures.

2. Benign Adult Familial Myoclonus Epilepsy

   • Genes: CNTN2, MARCHF6, RAPGEF2, SAMD12, STARD7, TNRC6A, YEATS2.
   • Disorder: Benign adult familial myoclonus epilepsy (OMIM PS601068).
   • MOI: Autosomal Dominant (AD).
   • Key Features: Adult-onset myoclonic seizures without progressive neurological decline.

3. EPM1 (Unverricht-Lundborg Disease)

   • Gene: CSTB.
   • Disorder: Progressive myoclonus epilepsy (EPM1).
   • MOI: Autosomal Recessive (AR).
   • Key Features: Myoclonus, ataxia, and progressive neurological deterioration.

4. Progressive Myoclonus Epilepsy (Lafora Type)

   • Genes: EPM2A, NHLRC1.
   • Disorder: Lafora disease.
   • MOI: Autosomal Recessive (AR).
   • Key Features: Myoclonic seizures, cognitive decline, and visual hallucinations.

5. Neuroferritinopathy

   • Gene: FTL.
   • Disorder: Neuroferritinopathy.
   • MOI: Autosomal Dominant (AD).
   • Key Features: Movement disorders and cognitive impairment.

6. Gaucher Disease Type 3

   • Gene: GBA1 (GBA).
   • Disorder: Gaucher disease type 3 (primary neurologic disease).
   • MOI: Autosomal Recessive (AR).
   • Key Features: Neurological symptoms, hepatosplenomegaly, and bone involvement.

7. EPM6

   • Gene: GOSR2.
   • Disorder: EPM6 (OMIM 614018).
   • MOI: Autosomal Recessive (AR).
   • Key Features: Early-onset myoclonus and epilepsy.

8. Late-Onset Tay-Sachs Disease

   • Gene: HEXA.
   • Disorder: Late-onset Tay-Sachs disease.
   • MOI: Autosomal Recessive (AR).
   • Key Features: Progressive neurodegeneration with motor and cognitive decline.

9. MERRF Syndrome (Myoclonus Epilepsy Associated with Ragged Red Fibers)

   • Genes: MT-TF, MT-TH, MT-TI, MT-TK, MT-TL1, MT-TP, MT-TS1, MT-TS2.
   • Disorder: MERRF syndrome.
   • MOI: Maternal inheritance.
   • Key Features: Myoclonic epilepsy, ataxia, and mitochondrial dysfunction.

10. Neuraminidase Deficiency

    • Gene: NEU1.
    • Disorder: Neuraminidase deficiency (OMIM 256550).
    • MOI: Autosomal Recessive (AR).
    • Key Features: Developmental delay and neurodegeneration.

11. Pantothenate Kinase-Associated Neurodegeneration

    • Gene: PANK2.
    • Disorder: Pantothenate kinase-associated neurodegeneration.
    • MOI: Autosomal Recessive (AR).
    • Key Features: Movement disorders and iron accumulation in the brain.

12. Infantile Neuroaxonal Dystrophy

    • Gene: PLA2G6.
    • Disorder: PLA2G6-associated neurodegeneration.
    • MOI: Autosomal Recessive (AR).
    • Key Features: Developmental regression and motor deficits.

13. Progressive Myoclonic Epilepsy with Ataxia (EPM1B)

    • Gene: PRICKLE1.
    • Disorder: PRICKLE1-related disorders.
    • MOI: Autosomal Recessive (AR).
    • Key Features: Myoclonus, ataxia, and progressive motor decline.

14. SCARB2-Related Action Myoclonus – Renal Failure Syndrome (EPM4)

    • Gene: SCARB2.
    • Disorder: EPM4.
    • MOI: Autosomal Recessive (AR).
    • Key Features: Myoclonic seizures and renal involvement.

Key Points

• Mode of Inheritance:
  • Most disorders listed are Autosomal Recessive (AR).
  • Some exceptions include Autosomal Dominant (AD) and Maternal inheritance (MERRF).
• Clinical Approach:
  • Thorough genetic testing is critical for accurate diagnosis.
  • Multidisciplinary management for associated neurological and systemic symptoms.

Differential Diagnosis of Adult-Onset DRPLA

• Huntington Disease (HD)
  • Gene: HTT
  • Differentiation from Huntington Disease (HD)
    • DRPLA: Early ataxia; Imaging: Cerebellar/brainstem atrophy (pontine tegmentum).
    • HD: Caudate nucleus atrophy.
    • Similarities: Involuntary movements; Dementia masking other symptoms.
    • Key Differences:
    • Diagnostic Approach:
      • Imaging studies (MRI).
      • Molecular genetic testing for HTT and DRPLA-specific mutations.
• Huntington Disease-like 2
  • Gene: JPH3
  • Similar clinical presentation necessitates genetic testing to distinguish from DRPLA
• Genetic Prion Disease
  • Gene: PRNP
  • Progressive dementia and movement disorders overlap; prion testing may be required
• Autosomal Dominant Cerebellar Ataxias
  • Gene: ATXN1, ATXN2, ATXN3, ATXN7, ATXN8, ATXN10, CACNA1A, TBP
  • Early stages of DRPLA with mild CAG expansions (49-55 repeats) may mimic pure cerebellar ataxias
  • Differentiation requires identifying additional features like dementia, choreoathetosis, or character changes.
• Overlap of DRPLA with Other Autosomal Dominant Cerebellar Ataxias
  • Mild DRPLA CAG Expansions (49-55 repeats):
    • Present primarily as pure cerebellar symptoms without dementia, chorea, or character changes.
    • Clinical Differentiation: Requires identifying hallmark DRPLA features that evolve over time.

Management

• Evaluation and regular surveillance of:
  • Myoclonus:
    • Assessment includes at rest, with action, and in response to stimuli.
    • Use the Unified Myoclonus Rating Scale (UMRS) for standardized evaluation.
  • Seizures
  • Cerebellar Motor Dysfunction:
    • Evaluate gait, postural ataxia, dysmetria, dysdiadochokinesis, tremor, dysarthria, nystagmus, saccades, and smooth pursuit.
    • Use standardized scales such as SARA, ICARS, or BARS.
  • Chorea:
    • Rare in juvenile-onset DRPLA

  • Standardized Tools

    • UMRS: Unified Myoclonus Rating Scale (myoclonus assessment).
    • SARA: Scale for the Assessment and Rating of Ataxia.
    • ICARS: International Cooperative Ataxia Rating Scale.
    • BARS: Brief Ataxia Rating Scale.
    • MDS-UPDRS: Movement Disorder Society’s Unified Parkinson's Disease Rating Scale.
  • Developmental and Cognitive Assessments
  • Psychiatric Assessment
  • Musculoskeletal and Functional Evaluations
  • Genetic Counseling: Genetic counseling and testing are recommended to inform at-risk relatives
  • Sleep Disturbances
• Family and Community Support
• Palliative care
• Educational and Family Support Services
• Transition planning

Symptomatic treatment

• Multidisciplinary Care:
  • Involves neurologists, PT/OT, SLPs, dieticians, and social workers.
  • Adaptive Interventions:
    • Regular assessment for devices and environmental modifications to improve quality of life.
    • Proactive Management: Early intervention for symptoms and ongoing evaluation for emerging issues.
• Myoclonus
  • Pharmacologic: Carbamazepine, phenytoin, levetiracetam, other standard drugs.
  • Other Considerations: Avoid extreme stimuli (lights, noises, stress).
• Epilepsy: Anti-seizure medications (ASM): Sodium valproate, perampanel, zonisamide.
• Cerebellar Ataxia
  • Physical Therapy (PT): Balance exercises, gait training, muscle strengthening.
  • Occupational Therapy (OT): Optimize ADLs using adaptive devices (e.g., weighted utensils, dressing hooks).
  • Pharmacologic Treatment: Riluzole may benefit ataxia in adults
  • Adaptive devices for mobility (canes, walkers, motorized chairs)
  • Home adaptations to prevent falls (e.g., grab bars, ramps)
  • Weight control to avoid obesity
• Activities of Daily Living (ADLs)
  • PT and OT to maintain independence.
  • Adaptive devices and home modifications as above
• Choreoathetosis and Dystonic Movements: Pharmacologic Treatment: Tetrabenazine, risperidone, bromazepam, gabapentin.
• Developmental Delay / Intellectual Disability
  • Refer to specialized management programs for cognitive and developmental support.
• Dysarthria: Speech and language therapy; alternative communication methods (e.g., digital devices).
• Dysphagia
  • Feeding therapy programs
  • videoflouroscopy
  • gastrostomy
• Psychiatric Comorbidities
  • Pharmacologic and psychological therapy as needed.
  • Quetiapine for psychosis (adults).
• Cognitive and behavioral therapy for neuropsychological rehabilitation.
• Weight Management; Nutritional assessment, avoid obesity; Consider vitamin supplementation.

Agents/Circumstances to Avoid

• General Anesthesia: Increases the risk of intra- and postoperative seizures.

Pregnancy Management

• Anti-Seizure Medications (ASMs):
  • Use of ASMs during pregnancy reduces maternal seizure risk but may increase fetal risks.
  • Safer ASM options: Carbamazepine, phenytoin, and levetiracetam.
  • Caution: Limited data on piracetam, brivaracetam, perampanel, and riluzole during pregnancy.
  • Pre-Conception Planning:
    • Transition to lower-risk medications prior to pregnancy if possible.
    • Discuss risks/benefits with healthcare providers.
• Alternative Therapies:
  • N-acetylcysteine: No significant increase in fetal malformations reported.
  • Riluzole: Limited data, mixed outcomes in case studies.

Therapies Under Investigation

• Clinical Trials:
  • https://www.ucl.ac.uk/ion/research/research-centres/ataxia-centre/research/clinical-studies

Key Points

• DRPLA is a rare, autosomal dominant neurologic disorder with variable onset and progression.
• Age of onset and clinical severity correlate strongly with CAG repeat size.
• Diagnosis relies on molecular genetic testing of ATN1.
• Clinical manifestations evolve over time and vary significantly by age of onset.
• DRPLA is most prevalent in Japanese populations but has significant variability worldwide.
• Certain populations, like Portugal and South Wales, show unexpectedly high prevalence due to shared haplotypes or founder effects.
• Molecular genetic testing, particularly targeted analysis, is crucial for diagnosis.
• Intermediate repeat sizes require careful evaluation due to transmission instability.
• Genotype-phenotype correlations in DRPLA are primarily dictated by CAG repeat size in the ATN1 gene.
• Juvenile-onset and adult-onset forms exhibit distinct clinical patterns, with anticipation playing a significant role in earlier onset across generations.
• Homozygosity and extreme repeat expansions result in more severe phenotypes.
• Related disorders, such as ATN1-NDD and PKS, highlight the complexity of conditions associated with ATN1, requiring specialized genetic testing for diagnosis
• Surveillance: Tailored to age of onset and symptom progression.
• Multidisciplinary Care: Essential for managing complex, progressive symptoms
• Pregnancy Management: Requires careful balancing of maternal and fetal risks with ASMs. 

References

Prades, S., Melo de Gusmao, C., Grimaldi, S., Shiloh-Malawsky, Y., Felton, T., & Houlden, H. (2023). Dentatorubral-Pallidoluysian Atrophy. GeneReviews® [Internet]. University of Washington, Seattle. Available from https://www.ncbi.nlm.nih.gov/books/NBK1491/

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