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Anticipation in myotonic dystrophy

II. Complex relationships between clinical findings and structure of the GCT repeat

Departments of Neurology (Drs. Ashizawa, Dubel, and P.W. Dunne; Mrs Dunne; and Dr. Epstein) and Medicine (Section of Cardiology) (Dr. Perryman), and the Institute for Molecular Genetics (Drs. Fu, Pizzuti, and Caskey), Baylor College of Medicine; Veterans Affairs Medical Center (Drs. Ashizawa and Dubel); Genetic Centers (Dr. Boerwinkle), University of Texas Health Science Center, Houston, TX, and National Eye Institute (Dr. Hejtmancik), National Institutes of Health, Bethesda, MD.

We studied the expansion of the GCT repeats within the myotonic dystrophy protein kinase gene in nine myotonic dystrophy (DM) kindreds. Southern blot and polymerase chain reaction analyses of the repeat region demonstrated the expansion in all 62 patients with the diagnosis of DM. Among 43 DM parent-child pairs, age of onset in the child was earlier than in the parent in 36 pairs, in the same decade as the parent in five, and undetermined in two. The clinical anticipation observed in the 36 pairs accompanied an increase in the fragment size in 32, a decrease in two, and no apparent change in two pairs. In the remaining pairs without documented clinical anticipation, the fragment size increased in four, decreased in two, and was apparently unchanged in one. Overall, the size of expansion showed an inverse correlation with the age of onset (p < 0.001). In all seven pairs in which the fragment did not increase in size, the affected parent was male. Two congenital DM children born to affected mothers had expanded DNA greater than 4.5 kb. The differences between parent and child in age of onset significantly correlated with the differences in the expansion size among father-child pairs (p < 0.001) but not mother-child pairs (p > 0.5). Our data suggest that the expansion of the GCT repeats plays an important role in anticipation although other factors, including the sex of the affected parent, may have significant effects on molecular mechanisms of anticipation.

Address correspondence and reprint requests to Dr. T. Ashizawa, Department of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.

Supported by the VA Merit Review (T.A.) and the Task Force on Genetics of the Muscular Dystrophy Association (H.F.E.).

Received May 19, 1992. Accepted for publication in final form August 10, 1992.

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