Myotonic dystrophy: A disease model of disorders with dynamic mutation

We correlated the myotonic dystrophy (DM) phenotype with the degree of [CTG](n) expansion in leukocytes and skeletal muscle in our patients. Analyzing our families we found often the anticipation phenomenon and clinical severity in family members correlated with [CTG](n) expansion. We have used a muscular disability scale (MDRS) and divided our series of DM patients in 3 phenotypic classes: minimal DM in old age, juvenile/adult DM and early child-hood DM. The distribution of the [CTG](n) expansions in leukocytes was analysed for each phenotype class and was found to have a log normal curve. Our results can be used to derive a prognostic index for each phenotypic class, although individual variations may be attributed to somatic mosaicism in different tissues, i.e. larger [CTG](n) expansions in skeletal muscle and other stable tissues. The ability of [CTG](n) mutation to alter the accumulation of poly (A) + RNA in trans in muscle tissue suggests that MD may be an example of a dominant negative mutation manifested at the RNA level. The expression of the DM-PK gene has been explored in skeletal muscle tissue: in muscle there is a selective expression at DM-PK gene product in type 1 fibers. We have observed biochemical and histochemical changes consistent with an altered modulatory mechanism of sarcoplasmic reticulum that may result in myotonia and atrophy of type 1 fibers and concurrent 'slow to fast' transformation. While this may explain the muscle alterations much remains to be studied to understand the multisystemic expression of this disorder.