Myotonic dystrophy (MIM 160900) is the most frequent muscular dystrophy of adult life. It shows a characteristic pattern of progressive muscle weakness and wasting, together with myotonia, an electrophysiological disturbance resulting in delayed relaxation and muscle stiffness. Its progressive nature distinguishes it from other myotonic disorders. While it is the only form of muscular dystrophy showing myotonia, and even though it is a rare disorder, proximal myotonic myopathy (PROMM) (MIM 600109) was recently separated from myotonic dystrophy and is genetically, as well as clinically, distinct.
Myotonic dystrophy is a multisystem disorder, involving smooth and cardiac muscle, the central nervous system, and endocrine glands, and it causes cataracts. It is exceptionally variable in both severity and age at onset, the severe congenital form being frequently fatal in the neonatal period.
Myotonic dystrophy follows autosomal dominant inheritance, but with unusual features, notably anticipation between generations and parental origin effects; almost all congenital cases are maternally transmitted.
Positional cloning has isolated and characterized the myotonic dystrophy locus on chromosome 19q and has identified the responsible mutation as an expanded and unstable trinucleotide (CTG) repeat. The degree of expansion is very variable and correlates with phenotype, severe congenital cases showing several thousand repeats, while minimally affected individuals usually have less than 100 repeats. Anticipation within families also corresponds to enlargement of the molecular defect.
Instability of the expanded repeat sequence in germline transmission is affected by its size and by the sex of the transmitting parent, expansion being greater in male transmissions except for the largest repeats which are rarely male transmitted, agreeing with the observed parent of origin effects in the disorder. Somatic instability of the repeat is also seen in development and varies between tissues.
The prevalence of myotonic dystrophy varies considerably and is notably absent (with a single exception) in sub-Saharan Africa. Clinically significant mutations originate from symptomless individuals carrying expansions at the lower limit of the abnormal range; transmission through many generations with gradual increase in repeat number is likely to have preceded this and the prevalence of the disorder may be broadly related to the population frequency of alleles in the upper normal range.
All known cases of myotonic dystrophy show the same unstable CTG expansion, and all cases in European and Asian populations share a common haplotype, which suggests that a single original genetic event predisposing to future instability may have occurred around the time that the ancestors of present Caucasian and Asian ethnic groups migrated out of Africa. Study of the normal variation at the myotonic dystrophy locus is proving a powerful tool in understanding the process of human evolution.
Molecular analysis has become an essential element of clinical practice in relation to presymptomatic and prenatal detection as well as primary diagnosis. No specific pharmacologic or other therapy yet exists, but a range of important factors, notably in relation to anesthesia and the avoidance of cardiorespiratory risk factors, can help minimize morbidity and mortality. The production of transgenic animal models and other experimental approaches hold out promise for future more definitive therapy.