- Myotonic dystrophy (DM) is a multisystemic, inherited neuromuscular disorder and the most common form of adult-onset muscular dystrophy.
- It is characterized by progressive muscle weakness and wasting, prolonged muscle contractions (myotonia), and variable involvement of other organs, including the heart, eyes, endocrine system, and central nervous system.
- The condition belongs to the family of trinucleotide repeat disorders, and it exists in two main forms: type 1 (DM1) and type 2 (DM2). DM1, also known as Steinert’s disease, is the more common and severe form, while DM2, sometimes called proximal myotonic myopathy (PROMM), tends to have a milder clinical course. Both conditions share overlapping features but differ in genetic cause, age of onset, and pattern of muscle involvement.
- The genetic basis of myotonic dystrophy involves unstable repeat expansions in noncoding regions of specific genes. In DM1, the disorder is caused by an abnormal expansion of CTG trinucleotide repeats in the 3′ untranslated region of the DMPK (dystrophia myotonica protein kinase) gene on chromosome 19. Normal individuals have up to about 35 repeats, while patients with DM1 may have anywhere from 50 to several thousand. DM2 is caused by a CCTG tetranucleotide repeat expansion in the CNBP gene (also called ZNF9) on chromosome 3. These expansions do not disrupt protein coding directly; instead, they produce toxic RNA transcripts that accumulate in the nucleus. These mutant RNAs form abnormal foci that sequester RNA-binding proteins, particularly the muscleblind-like (MBNL) proteins, thereby impairing normal splicing of numerous genes. This mechanism of RNA toxicity explains why DM affects multiple organ systems.
- The clinical manifestations of myotonic dystrophy are broad and vary in severity. In DM1, symptoms typically include distal muscle weakness (affecting hands, forearms, and lower legs), facial muscle involvement leading to ptosis and a “hatchet face” appearance, and grip myotonia (delayed relaxation after handgrip). Severe congenital forms of DM1 can present at birth with hypotonia, respiratory failure, feeding difficulties, and developmental delay. DM2 usually presents later in life with milder, predominantly proximal muscle weakness (hips, thighs, shoulders) and less pronounced myotonia. Beyond skeletal muscle, both DM1 and DM2 can affect the cardiac conduction system, leading to arrhythmias and risk of sudden death. Cataracts are common and often appear early. Endocrine abnormalities include insulin resistance, thyroid dysfunction, and hypogonadism. Cognitive and psychiatric features, such as apathy, executive dysfunction, daytime sleepiness, and anxiety, are particularly associated with DM1.
- One of the hallmark features of DM1 is anticipation, in which symptoms appear earlier and with greater severity in successive generations due to progressive expansion of the CTG repeats. This is especially pronounced in congenital DM1, which typically arises when the expansion is transmitted maternally. By contrast, anticipation is less striking in DM2, as its repeat expansions are relatively more stable.
- Diagnosis of myotonic dystrophy is based on clinical features, family history, electromyography (EMG) showing myotonic discharges, and confirmatory genetic testing to detect the repeat expansions. Molecular analysis is essential, since DM1 and DM2 may overlap clinically but differ genetically.
- Currently, there is no cure for myotonic dystrophy, and management is supportive and multidisciplinary. Physical therapy, assistive devices, and exercise programs help maintain mobility. Cardiac surveillance is critical due to the risk of conduction defects, and pacemaker or defibrillator implantation may be required in high-risk patients. Ophthalmologic evaluation for cataracts, endocrine monitoring for diabetes and thyroid disease, and neuropsychiatric support are important components of care. Myotonia can be alleviated with medications such as mexiletine.
- Research into disease-modifying therapies is ongoing, with particular emphasis on targeting the toxic RNA mechanism. Experimental approaches include antisense oligonucleotides designed to degrade mutant RNA, small molecules that disrupt RNA-protein foci, and gene-editing technologies such as CRISPR/Cas9 aimed at removing or correcting the repeat expansion. These strategies offer hope that effective molecular treatments will eventually be developed.
Reliability Index *****
Note: If you notice any errors or inconsistencies, we welcome your feedback. Please share your observations in the comment box below — your input helps us improve.
Highest reliability: *****
Lowest reliability: *****
