Myotonic dystrophy (DM) is a progressive genetic disorder that affects an estimated 1 in 8,000 people. However, estimates of prevalence are based on studies of a relatively small number of cases and it is suspected that the prevalence may be much higher. One of the nine muscular dystrophies, myotonic dystrophy is the most common form of adult-onset muscular dystrophy and one of the most common forms of childhood-onset. However, classifying myotonic dystrophy as a muscle disease is misleading - myotonic dystrophy is considered the most variable neuromuscular disorder in terms of severity, age at onset, and different body systems affected.
Although the most pronounced characteristic of myotonic dystrophy is skeletal and smooth muscle dysfunction (weakness, stiffness, and pain), the condition can be present with issues such as reduced cognitive function, vision impairment, gastrointestinal disturbances, endocrine deficiency, fertility issues, cardiovascular dysfunction, personality abnormalities, and respiratory insufficiency, in addition to muscle complains.
The range of systems affected and the severity of symptoms seen can vary greatly between patients, even in the same family. However, an affected person does not typically exhibit all, or even most, of the possible symptoms. Often the disorder is mild and only minor muscle weakness or cataracts are seen late in life. At the opposite end of the spectrum, life-threatening neuromuscular, cardiac, and pulmonary complications can occur in the most severe cases when children are born with the congenital form of the disorder.
Myotonic dystrophy is a triplet repeat disease caused by an autosomal dominant mutation.
Myotonic dystrophy type 1 (DM1), also known as Steinert's disease, has three subtypes that vary based on age at onset: a severe congenital form with life-threatening issues at birth, a childhood onset form which typically first presents with intellectual disability and learning disabilities, and an adult onset form characterized by distal muscle weakness, atrophy, and myotonia. DM1 is caused by an expanded and unstable (CTG) trinucleotide repeat, located in the 3’ untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene on chromosome 19.
The mutation involved in DM1 does not arise spontaneously. It appears that all affected individuals share a common ancestor. With the exception of one sub-Saharan family, the presence of DM1 has been associated with a single haplotype within and flanking the DMPK gene. This suggests predisposition for CTG instability has resulted from a single mutation event, which occured after the migration from Africa to Europe.
A second alternative exists, where predisposition to CTG instability is due to elements within the haplotype. Individuals who do not possess this specific set of genetic alleles would have a stable number of repeats and not develop the disease.
Myotonic dystrophy type 2 (DM2), also known as proximal myotonic myopathy (PROMM), is a milder form of myotonic dystrophy where transient muscle pain is the most common complaint. Only adult-onset forms of DM2 have been recognized. DM2 is caused by a mutation in the first intron of the zinc finger 9 (Cnbp also known as Znf9) gene on chromosome 3.
Additional forms (DM3, DM4) have been suggested, as a small number of individuals have been seen who have the characteristic symptoms of myotonic dystrophy, but who do not have the genetic mutations which cause these disroders. Considerable debate exists as to whether these individuals truly represent a new form of myotonic dystrophy or whether they simply present unique diagnostic challenges.
Further detail on the genetic cause and molecular basis of myotonic dystrophy is available by clicking here.