trinucleotide repeat
Summary
Trinucleotide repeat disorders are genetic diseases caused by expansion of three-nucleotide DNA sequences beyond a normal threshold, leading to unstable, expandable repeats. Many demonstrate genetic anticipation—increased repeat number and earlier/more severe disease onset in successive generations. Classic examples include Huntington disease, Fragile X syndrome, myotonic dystrophy, and Friedreich ataxia.
Detail
Trinucleotide repeat expansion disorders result from abnormal amplification of a repeated 3-nucleotide sequence within or near a gene, causing gain-of-function toxic protein/RNA effects (Huntington disease - CAG repeats in HTT gene, exon, causes toxic polyglutamine protein), loss-of-function (Fragile X syndrome - CGG repeats in FMR1 gene, 5' UTR, causes gene silencing via hypermethylation), or both (myotonic dystrophy - CTG repeats in DMPK gene, 3' UTR, causes toxic RNA gain-of-function with sequestration of splicing factors). Friedreich ataxia is unique as an autosomal recessive trinucleotide repeat disorder (GAA repeats in FXN gene, intron) causing frataxin deficiency and loss-of-function.
Key mechanism: 'Anticipation' refers to the phenomenon where repeat number increases with successive generations (due to instability during meiosis, especially in spermatogenesis for CAG/polyQ diseases and oogenesis for CGG in Fragile X), leading to earlier onset and increased severity in offspring. This is a hallmark testable feature.
Clinical associations for boards: - Huntington disease: CAG repeats, HTT gene, chromosome 4, autosomal dominant, chorea, dementia, psychiatric symptoms, caudate atrophy, paternal transmission worsens severity. - Fragile X syndrome: CGG repeats, FMR1 gene, X-linked, most common inherited cause of intellectual disability, macroorchidism, long face, large ears, mitral valve prolapse, autism spectrum features, maternal transmission increases instability. - Myotonic dystrophy: CTG repeats, DMPK gene, autosomal dominant, myotonia, cataracts, cardiac arrhythmias, testicular atrophy, frontal balding. - Friedreich ataxia: GAA repeats, FXN gene, autosomal recessive, ataxia, cardiomyopathy (common cause of death), diabetes, loss of vibration/proprioception sense (dorsal columns), hammer toes, scoliosis. - Spinocerebellar ataxias, spinal-bulbar muscular atrophy (Kennedy disease): CAG repeats, similar pattern to Huntington disease.
Diagnosis is typically via PCR-based repeat number analysis or Southern blot for large expansions. Understanding the location of repeat (exon vs UTR vs intron) helps predict mechanism (protein-coding expansion vs regulatory/RNA-mediated toxicity).
Sources
- First Aid for the USMLE Step 1
- Robbins Basic Pathology
- Thompson & Thompson Genetics in Medicine
- UWorld USMLE Step 1 Qbank
Reviewed by AnkiBoss editorial — medical student review. Information here is for study reference only and is not medical advice. Spotted an error? Let us know.