A 35-year-old man presents with myotonia, cataracts, and frontal balding. His father had milder symptoms beginning at age 55. Muscle biopsy genetic testing shows expansion of a CTG repeat in the DMPK gene. The earlier onset and greater severity in successive generations is best explained by:

• A Somatic mosaicism increasing with age in affected tissue
• B Expansion of the repeat during gametogenesis, especially through maternal transmission
• C Accumulation of additional point mutations in the same gene over generations
• D Anticipation due to further intergenerational expansion of the unstable trinucleotide repeat ✓

Explanation

Myotonic dystrophy type 1 results from CTG repeat expansion in DMPK, and unstable repeats tend to enlarge when transmitted, producing anticipation: earlier onset and greater severity in descendants. Congenital cases classically follow maternal transmission, while the adult form here shows paternal transmission. Mosaicism and accumulating point mutations do not produce the characteristic generational pattern. Repeat instability during meiosis is the mechanistic basis of anticipation.

Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.