Introduction to Repeat Expansions

• Definition: Repeat expansions refer to the abnormal increase in the number of tandem nucleotide repeats in specific regions of the genome.
  • Examples: CAG, CGG, CTG, GAA repeats.
• Significance: These expansions can disrupt gene function, resulting in a range of neurogenetic disorders.
• First discovered: The Fragile X Mental Retardation 1 (FMR1) gene was discovered in 1991.

Key Concepts

1. Mechanism of Repeat Expansion

   • Replication Slippage:
     • DNA polymerase dissociates temporarily, leading to misalignment and addition of extra repeats.
   • Mismatch Repair Defects:
     • Errors during repair of DNA loops in repetitive regions propagate repeats.
   • Recombination Errors:
     • Unequal crossing over during meiosis adds repeats to one allele.

2. Thresholds for Pathogenicity

   • Premutation: Repeats below pathogenic thresholds but prone to further expansion.
   • Full Mutation: Repeats exceed critical thresholds, impairing gene function.
   • Disease-specific thresholds:
     • Huntington’s disease: >40 CAG repeats.
     • Fragile X syndrome: >200 CGG repeats.

3. Types of Repeat Expansions

   • Coding Region Repeats:
     • Polyglutamine diseases (e.g., Huntington’s disease) result in toxic protein aggregates.
   • Non-Coding Region Repeats:
     • Disrupt transcription, splicing, or RNA function (e.g., Fragile X, Myotonic Dystrophy).

Key Examples of Repeat Expansion Disorders in Child Neurology

1. Fragile X Syndrome

   • Gene: FMR1.
   • Repeat: CGG (>200 for full mutation).
   • Clinical Features:
     • Intellectual disability, autistic features, hyperactivity.
     • Physical features: Large ears, long face, macroorchidism.
   • Pathogenesis: Hypermethylation leads to gene silencing.

2. Huntington’s Disease

   • Gene: HTT.
   • Repeat: CAG (>40).
   • Clinical Features:
     • Progressive motor dysfunction, cognitive decline, psychiatric disturbances.
     • Juvenile Onset: Often paternally inherited.
   • Pathogenesis: Toxic polyglutamine protein aggregates.

3. Myotonic Dystrophy Type 1

   • Gene: DMPK.
   • Repeat: CTG (>50).
   • Clinical Features:
     • Myotonia, progressive muscle weakness, cardiac conduction defects, cataracts.
     • Congenital form: Severe hypotonia, respiratory distress at birth.
   • Pathogenesis: RNA toxicity through sequestration of RNA-binding proteins.

4. Friedreich’s Ataxia

   • Gene: FXN.
   • Repeat: GAA (>66).
   • Clinical Features:
     • Ataxia, dysarthria, cardiomyopathy, diabetes.
   • Pathogenesis: Impaired transcription due to repeat-induced heterochromatin formation.

5. Spinocerebellar Ataxias (SCA)

   • Multiple subtypes caused by expanded CAG repeats in different genes.
   • Clinical Features:
     • Progressive ataxia, dysarthria, and eventual disability.

Diagnosis

1. Clinical Suspicion

   • Family history of similar symptoms, earlier onset in successive generations (anticipation).
   • Characteristic features: Ataxia, intellectual disability, or developmental regression.

2. Genetic Testing

   • PCR: Detects smaller repeat expansions.
   • Southern Blot: Identifies large expansions (>200 repeats).
   • Next-Generation Sequencing (NGS):
     • Long-read sequencing can map large or complex repeat regions.

3. Imaging and Biomarkers

   • MRI: Structural brain changes (e.g., caudate atrophy in Huntington’s).
   • Electromyography (EMG): Myotonia in Myotonic Dystrophy.

Treatment Options

1. Symptomatic Management

   • Antiepileptic drugs for seizures 
   • Physical therapy and occupational therapy for motor dysfunction.
   • Behavioral therapy for psychiatric or developmental issues.

2. Disease-Specific Interventions

   • Fragile X Syndrome: Early intervention programs, stimulants for ADHD symptoms.
   • Myotonic Dystrophy: Pacemaker for cardiac issues, respiratory support for neonatal onset.

3. Emerging Therapies

   • Antisense Oligonucleotides (ASOs):
     • Target RNA transcripts to reduce toxic RNA or protein levels.
     • Examples: Tofersen in SOD1-ALS.
   • Gene Editing (CRISPR):
     • Potential to correct repeat expansions.
   • RNA-Based Therapies:
     • Small molecules targeting RNA-protein interactions.

Clinical Implications

1. Anticipation

   • Expansions worsen with each generation, leading to earlier onset and severity.
   • Counseling families on inheritance patterns is critical.

2. Multisystem Impact

   • Many repeat expansion disorders involve multiple systems (e.g., cardiac in Myotonic Dystrophy, endocrine in Friedreich’s Ataxia).
   • Interdisciplinary care is essential.

3. Psychosocial Considerations

   • Support for families dealing with genetic disorders.
   • Address stigma and promote early intervention for better outcomes.

Recent Advancements

1. High-Throughput Sequencing:
   • Revolutionizing repeat detection, especially for mosaic or cryptic expansions.
2. Therapeutics in Development:
   • Expanded trials for ASOs in neuromuscular and neurodegenerative diseases.
3. Biomarker Discovery:
   • Improved prediction of disease onset (e.g., mutant huntingtin levels in HD).