Myotonic dystrophy 1 is the most common inherited neuromuscular disease in adults, with incidence rates that may reach as high as 1 in 7,400 live births in certain parts of Europe. The dominantly inherited disorder shows a very wide range of presentations and progressions, from the adult onset form, which typically presents with distal dystrophy and myotonia after 20 years of age. The disease is progressive and often leads to significant disability. Characteristic facial changes are also common: low-set ears, a hatchet chin and drooping of the lips and ptosis. Severe cases of adult-onset myotonic dystrophy also show a high incidence of presenile cataracts, testicular atrophy, diabetes, kidney failure and early frontal balding in males. Intellectual disability and personality disorders can also be seen.
Myotonic dystrophy 1 is caused by the expansion of an unstable CTG repeat located in the 3' untranslated region of the dystrophia myotonica protein kinase gene, DMPK, on 19q13.3. The myotonic dystrophy 1 gene is 14 kb and encodes 2.3 kb of mRNA with 15 exons and a protein of 624 amino acids. The consequence of the repeat expansion includes abnormal splicing and transport of DMPK transcripts, which result in a decrease in DMPK protein levels and sequestration or induction of RNA-binding proteins by transcribed, expanded CUG repeats. In addition, the repeat lies immediately 5' to the regulatory region of the homeobox gene SIX5, and repeat expansion causes the loss of a DNase I-hypersensitive site in the region and suppression of SIX5 expression.