U01.01.055 Trinucleotide repeat expansion diseases

Trinucleotide repeat expansion diseases are genetic disorders caused by the abnormal repetition of three-nucleotide sequences within specific genes. These expansions disrupt gene function, leading to characteristic clinical features.

Key Features

Genetic anticipation: Worsening severity and earlier onset of symptoms in successive generations.
Mnemonic: Try (trinucleotide) hunting for my fragile cage-free eggs (X).

Common Diseases

Table of Diseases

Disease	Trinucleotide Repeat	Mode of Inheritance	Mnemonic	Key Clinical Features
Huntington disease	CAG	Autosomal dominant (AD)	Caudate has ↓ ACh and GABA	Progressive neurodegeneration, chorea, and psychiatric issues
Myotonic dystrophy	CTG	Autosomal dominant (AD)	Cataracts, Toupee, Gonadal atrophy	Muscle weakness, early balding, gonadal atrophy, cataracts
Fragile X syndrome	CGG	X-linked dominant (XD)	Chin (protruding), Giant Gonads	Intellectual disability, large ears, elongated face, macroorchidism
Friedreich ataxia	GAA	Autosomal recessive (AR)	Ataxic GAAit	Progressive ataxia, hypertrophic cardiomyopathy, scoliosis

Mnemonics

General mnemonic:
Try (trinucleotide) hunting for my fragile cage-free eggs (X).
Disease-specific mnemonics:
- Huntington’s disease: Caudate has ↓ ACh and GABA.
- Myotonic dystrophy: Cataracts, Toupee, Gonadal atrophy.
- Fragile X syndrome: Chin (protruding), Giant Gonads.
- Friedreich ataxia: Ataxic GAAit.

Points to Remember

Genetic anticipation: Trinucleotide repeat diseases often exhibit worsening symptoms and earlier onset with each generation.
Disease inheritance:
- Autosomal dominant (Huntington, myotonic dystrophy).
- Autosomal recessive (Friedreich ataxia).
- X-linked dominant (Fragile X syndrome).
Key trinucleotide repeats:
- CAG: Huntington’s disease (linked to neurodegeneration).
- CTG: Myotonic dystrophy (multi-system involvement).
- CGG: Fragile X syndrome (associated with intellectual disability).
- GAA: Friedreich ataxia (ataxia and cardiomyopathy).

Bibliography

Genetics Home Reference. “Trinucleotide repeat expansion disorders.”
First Aid for the USMLE Step 1 2024.

USMLE Step 1 Review Series

Curriculum