Reverse Mutation in Myotonic Dystrophy

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Abstract
Myotonic dystrophy is a multisystem disorder that is transmitted in an autosomal dominant fashion and is characterized by muscular weakness and atrophy, clinical and electromyographic evidence of myotonia, ocular cataract, and various other abnormalities, such as cardiac conduction disturbances, testicular atrophy in males, premature balding, increased risk from anesthesia, and mental retardation in cases with early onset1. It is the most common inherited muscular dystrophy of adulthood, with an incidence of approximately 1 per 7500 people. The clinical expression of myotonic dystrophy is variable, ranging from neonatal mortality to a complete absence of symptoms. Recently, the disorder has been shown to be caused by an increased number of cytosine-thymidine-guanine (CTG) trinucleotide repeats in the 3' untranslated region of a protein kinase gene located in the q13.3 band of chromosome 192-8. The normal gene has between 5 and 40 CTG trinucleotide repeats, whereas myotonic dystrophy alleles have from approximately 50 to several thousand such repeats. The severity of the clinical symptoms of myotonic dystrophy usually increases with transmission to subsequent generations, a phenomenon that has been termed “anticipation”9. This is paralleled by an increase in the length of the CTG repeat sequence2,5,7. It has been suggested that the progressively increasing severity of myotonic dystrophy eventually leads to the extinction of the disease from a given pedigree10.