Makindo Medical Notes

Trinucleotide repeat disorders are genetic conditions caused by abnormal expansions of DNA segments consisting of repeated sequences of three nucleotides (trinucleotides). These disorders often involve repeats of CAG, which codes for the amino acid glutamine, but other trinucleotide sequences are also implicated. These expansions typically arise from errors in DNA replication, particularly a process known as "slippage." During replication, the DNA polymerase can lose its place, leading to an abnormal number of trinucleotide repeats.

Mechanism of Disease

• Trinucleotide repeat expansions can occur in different parts of a gene, such as:
  • Coding regions: Repeats like CAG can result in elongated polyglutamine tracts in proteins, causing structural and functional disruptions (e.g., Huntington's disease).
  • Non-coding regions: Repeats in untranslated regions (e.g., CGG in Fragile X syndrome) can affect gene expression and result in toxic RNA species.
• The severity of the disorder is often related to the length of the repeat expansion, with longer repeats generally leading to earlier onset and more severe symptoms.
• Repeat instability can occur during meiosis, leading to variations in repeat length between generations.

Diseases Associated with Trinucleotide Repeats

• Huntington's disease (CAG repeat): Leads to toxic polyglutamine inclusions in neurons, causing progressive neurodegeneration.
• Fragile X syndrome (CGG repeat): Causes abnormal methylation of the FMR1 gene, leading to intellectual disability and developmental delays.
• Myotonic dystrophy (CTG repeat): Affects splicing and gene expression, leading to muscle weakness, cataracts, and multisystem involvement.
• Friedreich's ataxia (GAA repeat): Impairs mitochondrial function, leading to progressive ataxia and cardiomyopathy.
• X-linked spinobulbar muscular atrophy (Kennedy's disease, CAG repeat): Results in androgen receptor dysfunction and progressive muscle weakness.
• Spinocerebellar ataxia (CAG/CTG repeats): A group of disorders causing progressive cerebellar degeneration.
• Machado-Joseph disease (CAG repeat): Leads to ataxia, spasticity, and other neurological deficits.
• Dentatorubral-pallidoluysian atrophy (DRPLA, CAG repeat): Causes ataxia, chorea, and cognitive decline.

Understanding Anticipation

Anticipation is a key feature of many trinucleotide repeat disorders. It describes the phenomenon where symptoms worsen, and the age of onset decreases with each successive generation. This occurs because the number of trinucleotide repeats often increases during gametogenesis, particularly in paternal transmission for some disorders (e.g., Huntington's disease).

• Conditions showing anticipation include:
  • Huntington's disease: Earlier onset and more severe neurodegeneration with each generation.
  • Myotonic dystrophy: Progressive worsening of muscle weakness and systemic features.
  • Fragile X syndrome: Increased severity of intellectual disability in subsequent generations.
• Exception: Friedreich's ataxia (GAA repeat) does not exhibit anticipation because the repeats are typically stable during transmission.

Diagnostic Techniques

• Polymerase Chain Reaction (PCR): Used to amplify and measure the length of trinucleotide repeat expansions.
• Southern Blot Analysis: Useful for detecting very large repeat expansions that cannot be resolved by PCR.
• Molecular Sequencing: Can identify precise repeat lengths and associated mutations.

Therapeutic Approaches

• Symptomatic Management: Most current treatments address symptoms (e.g., tetrabenazine for Huntington's disease chorea, physical therapy for myotonic dystrophy).
• Gene Silencing: Experimental techniques such as antisense oligonucleotides (ASOs) and RNA interference (RNAi) aim to reduce expression of mutant genes.
• Gene Editing: CRISPR-Cas9 technology is being investigated as a potential tool to correct trinucleotide repeat expansions.
• Supportive Care: Multidisciplinary approaches involving neurologists, genetic counselors, and physiotherapists can improve quality of life.