Trinucleotide Repeat Expansion Diseases

Trinucleotide Repeat Expansion Diseases

• These are a group of genetic disorders arising from mutations characterized by an increased number of three-base-pair repeats (e.g., C, G nucleotides) at specific locations in genes.
• The mechanism of these diseases often involves either a loss-of-function effect, where the gene's normal function is diminished, or a gain-of-function effect, where the gene produces an altered protein with toxic impacts.

Fragile X Syndrome

• This is an X-linked genetic disease causing intellectual disability and characteristic physical features.
• It arises from an inherited defect in the 5' untranslated region of the FMR1 gene.
• This defect leads to an abnormal expansion of trinucleotide repeats within the gene and subsequent methylation, significantly reducing the production of the FMR1 protein.
• This results in distinctive behavioral and physical characteristics, such as intellectual disability, a long face, large ears, and macroorchidism in males.
• Anticipation, meaning the severity and age of onset of the disease often worsen in succeeding generations, is a key issue in fragile X syndrome.

Huntington's Disease

• This is an autosomal dominant neurodegenerative disorder often presenting with involuntary movements (chorea), alongside dementia.
• It involves an excessive expansion of CAG trinucleotide repeats within the HTT gene.
• This repeat expansion results in a protein with an abnormally elevated number of glutamine amino acids (elongated polyglutamine tract), leading to abnormal aggregation and cellular dysfunction in the brain.
• Increased repeat numbers correlate with an earlier age of onset and greater severity of the disease.
• The disease progressively impacts motor control, cognitive abilities, and psychiatric well-being.