Trinucleotide repeat disorders
Also known as: triplet repeat disorders, trinucleotide repeat expansion disorders
Trinucleotide repeat disorders are genetic diseases caused by an abnormally expanded three-nucleotide sequence within a gene. The repeat count grows across generations, so the disease often appears earlier and more severely in each successive generation.
A trinucleotide repeat disorder arises when a short three-base sequence — CAG, CGG, GAA, or CTG — is repeated far more times than normal within or near a gene. Small numbers of repeats are present in healthy individuals; disease follows once the count crosses a threshold. The expansion either produces a toxic protein or RNA product or silences the gene entirely, depending on where in the gene the repeat sits.
The defining clinical feature is anticipation: because expanded repeats are unstable during meiosis, offspring frequently inherit more repeats than the parent carried, so symptoms begin at a younger age and progress more severely in each generation. Repeat length generally correlates with severity and with age of onset.
Four classic examples anchor this topic. Huntington disease is autosomal dominant, caused by CAG expansion in the HTT gene on chromosome 4, presenting in mid-adulthood with chorea, behavioral change, and dementia, with caudate atrophy on imaging. Fragile X syndrome is X-linked, caused by CGG expansion in FMR1, producing intellectual disability, a long face with large ears, macroorchidism, and mitral valve prolapse. Friedreich ataxia is autosomal recessive, caused by GAA expansion in the frataxin gene, causing ataxia, kyphoscoliosis, and hypertrophic cardiomyopathy. Myotonic dystrophy type 1 is autosomal dominant, caused by CTG expansion in DMPK, causing myotonia, muscle wasting, cataracts, frontal balding, and arrhythmias.
USMLE Step 1 tests this cluster as a set. Expect vignettes that give a family history showing progressively earlier onset and ask you to name the mechanism, or that describe the classic phenotype and ask for the repeat sequence, gene, chromosome, and inheritance pattern — the mnemonic "Try hunting for my fried eggs" maps X to fragile X, H to Huntington, M to myotonic dystrophy, and F to Friedreich ataxia.
Key takeaways
- Trinucleotide repeat disorders result from expansion of a three-base sequence beyond a pathologic threshold.
- Anticipation means the repeat expands between generations, producing earlier onset and greater severity in offspring.
- Huntington disease (CAG, HTT) is autosomal dominant with chorea and caudate atrophy.
- Fragile X syndrome (CGG, FMR1) is X-linked with intellectual disability, large ears, and macroorchidism.
- Friedreich ataxia (GAA, frataxin) is autosomal recessive; myotonic dystrophy type 1 (CTG, DMPK) is autosomal dominant.