Myotonic dystrophy 1 is an autosomal dominant disorder caused by a trinucleotide (CTG) repeat expansion in a region of the DMPK gene (19q13.2-q13.3). The number of repeats varies widely and is roughly correlated with severity of disease. Infants with congenital myotonia usually have the highest number of repeats and have the most severe cognitive deficits. The number can expand during gametogenesis each generation (resulting in the phenomenon of anticipation) and females generally transmit larger numbers. Most infants with congenital myotonia are offspring of affected mothers. Reduced fetal movement and hydramnios are often noted during such pregnancies.
Affected males have few offspring secondary to gonadal atrophy. Affected heterozygous females, however, do not have the expected ratio of affected offspring because of the dynamic nature of the number of repeats. The risk of an affected offspring for a nulliparous afflicted female is only 3-9% and she has a 20-40% risk of recurrence after the birth of an affected child.
In a study of sibships with myotonic dystrophy, 58% of offspring were affected when the transmitting parent was male and 63% when the transmitting parent was female.
At least some of the variable transmission risks and clinical heterogeneity may be explained by somatic instability of the CTG repeat numbers. The degree of instability, moreover, may also be heritable. Age of onset, for example, is modified by the level of somatic instability. Further, patients in whom the repeat expands more rapidly develop symptoms earlier.
A similar disorder, myotonic dystrophy 2 (602668), is caused by a tetranucleotide repeat expansion in the CNBP gene.