Walsh & Hoyt: Myotonic Muscular Dystrophies

Myotonic dystrophy (dystrophia myotonica 1 [DM1]) and the less severe proximal myotonic myopathy (PROMM [DM2]) are autosomal-dominant disorders associated with nucleotide repeat expansions in untranslated regions of the respective target genes. The genetic defect in DM1 is amplification of an unstable trinucleotide CTG repeat located in the 3? untranslated region of the gene that encodes dystrophia myotonica protein kinase (DMPK) on chromosome 19. DM1 is highly variable in severity and age of onset, and it exhibits ""anticipation,"" the phenomenon of increasing severity of inherited disease in successive generations of an affected family. The number of CTG repeats ranges from about 50 in patients who are mildly affected to thousands in severely affected patients. Amplification of the CTG repeat is the molecular basis for genetic anticipation. Although the mutation does not alter the protein-coding region of the DMPK gene, the CTG repeats can disrupt RNA splicing and cellular metabolism by interacting with RNA-binding proteins.