Anticipation in myotonic dystrophy

Abstract

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.

Best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy types 1 and 2

“…15, 16, 17, 18, 19 An increasing number of CTG-repeat units within the DMPK gene in successive generations in a family is associated with an earlier onset of the disorder. This phenomenon is termed ‘anticipation'.…”

“…However, there is a large inter-individual variability and one should be very cautious with phenotypic predictions in individual cases. 15, 16, 17, 18, 19 Therefore, the boundaries in repeat lengths of the four groups in Table 1 should not be interpreted too rigidly.…”

Chronic Pain in Neuromuscular Disease

“…29,30 DM1 is caused by a polynucleotide (CTG) triplet expansion located on the 3′ untranslated region of chromosome 19q13.3. 31 This location results in a toxic gain of function of abnormally stored RNA in the nuclei of affected cells, leading to deregulation of RNA binding protein levels and mRNA splicing processes of multiple genes. 32,33 This action is presumed responsible for the multisystem features typical of DM1, with involvement of skeletal, cardiac, and smooth muscles, and the central nervous, endocrine, ocular, respiratory, and gastrointestinal systems to varying degrees.…”

Repeat expansion diseases

“…138,140). In contrast, the most severe form of myotonic dystrophy type I (DM1), congenital myotonic dystrophy, is almost always transmitted from the mother (6,141). Not all repeat expansions diseases show significant anticipation or a clear parent of origin effect.…”