PROGRESSION OF SOMATIC CTG REPEAT LENGTH HETEROGENEITY IN THE BLOOD-CELLS OF MYOTONIC-DYSTROPHY PATIENTS

The genetic basis of myotonic dystrophy (DM) is the expansion of an un stable CTG repeat in the 3' UTR of the DM protein kinase gene on chrom osome 19, One of the principal features of the DM mutation is an extra ordinarily high level of somatic mosaicism, due to an extremely high d egree of somatic instability both within and between different tissues , This instability appears to be biased towards further expansion and continuous throughout the life of an individual, features that could b e associated with the progressive nature of the disease, Although incr easing measured allele size between patients clearly correlates with a n increased severity of symptoms and an earlier age of onset, this cor relation is not precise and measured allele length cannot be used as a n accurate predictor of age of onset, In order to further characterize the dynamics of DM CTG repeat somatic instability, we have studied re peat length changes over time in 111 myotonic dystrophy patients with varying clinical severity and CTG repeat size over time intervals of 1 -7 years. We have found a direct progression of the size heterogeneity over time related to initial CTG repeat size and the time interval an d always biased towards further expansion, Attempts to mathematically model the dynamics have proved only partially successful suggesting th at individual specific genetic and/or environmental factors also play a role in somatic mosaicism.