trinucleotide repeat expansion
Summary
Trinucleotide repeat expansion disorders result from abnormal amplification of a 3-nucleotide sequence within a gene, leading to unstable, expandable repeats. These disorders often show anticipation (increasing severity/earlier onset in successive generations) and are classically remembered with the mnemonic 'Try hunting for my justice' or 'X-tra GAG's Fragile'. Examples include Huntington disease (CAG), Fragile X syndrome (CGG), myotonic dystrophy (CTG), and Friedreich ataxia (GAA).
Detail
Trinucleotide repeat expansion diseases are caused by an increase in the number of tandem repeats of a 3-base-pair sequence within or near a gene, beyond a normal threshold, leading to gene dysfunction. These repeats are unstable during DNA replication (especially meiosis), causing further expansion in subsequent generations—a phenomenon called genetic anticipation, most notably seen in paternal transmission of myotonic dystrophy and maternal transmission of Fragile X.
Mechanisms of pathology vary by disorder: - CAG repeats (e.g., Huntington disease) encode polyglutamine tracts, causing toxic gain-of-function protein aggregation (neurodegeneration in the striatum). - CGG repeats (Fragile X syndrome) occur in the 5' UTR of the FMR1 gene, leading to hypermethylation and transcriptional silencing (loss of function), causing intellectual disability, macroorchidism, and long face with large ears. - CTG repeats (myotonic dystrophy type 1) occur in the 3' UTR of the DMPK gene, causing myotonia, cataracts, testicular atrophy, and cardiac conduction defects. - GAA repeats (Friedreich ataxia) occur in an intron of the FXN gene (frataxin), leading to impaired mitochondrial iron metabolism; unusually, this is an autosomal recessive trinucleotide disorder without anticipation.
High-yield associations: - Huntington disease: CAG repeat, autosomal dominant, chromosome 4, chorea, dementia, caudate atrophy, anticipation with paternal transmission. - Fragile X: CGG repeat, X-linked dominant, FMR1 gene, most common cause of inherited intellectual disability, maternal transmission anticipation. - Myotonic dystrophy: CTG repeat, DMPK gene, autosomal dominant, muscle wasting and myotonia. - Friedreich ataxia: GAA repeat, FXN gene, autosomal recessive, ataxia, hypertrophic cardiomyopathy, diabetes mellitus, no anticipation.
Clinically, understanding repeat length correlates with disease severity and age of onset—the larger repeat expansions generally cause earlier onset and more severe phenotype, which is testable board knowledge for triplet repeat diseases and their modes of inheritance.
Sources
- First Aid for the USMLE Step 1
- Robbins Basic Pathology
- UpToDate: Trinucleotide repeat disorders
- Genetics in Medicine, Nussbaum et al.
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.