Myotonic Dystrophy
| Myotonic Dystrophy | |
|---|---|
| Epidemiology | Most common muscular dystrophy among Europeans. |
| Inheritance | Autosomal dominant |
| Genetics | DMPK (DM1), CNBP/ZNF9 (DM2) |
| Pathophysiology | RNA toxicity from expanded repeats |
| Clinical Features | Multi-system disease. Muscle weakness and myotonia in most. |
Myotonic dystrophy is a clinically and genetically heterogenous disorder with two major forms being myotonic dystrophy 1 (DM1) and myotonic dystrophy 2 (DM2). They are multisystem disorders characterised by skeletal muscle weakness, myotonia, arrythmias, cataracts, and other abnormalities.
Epidemiology
In Europe, myotonic dystrophy type 1 occurs in approximately 1 in 7000 people. Myotonic dystrophy type 2 is less frequent and less severe than type 1. Overall DM is the most common muscular dystrophy amongst adults with European ancestry.
Genetics
Both DM1 and DM2 have an autosomal dominant pattern of inheritance.
DM1 results from CTG repeat expansion in the DMPK gene's 3' untranslated region. Normally there are 5 to 34 repeats, while pathogenic variants have hundreds to thousands. A maternally inherited mutant allele is almost always the cause of a severe congenital form of the disease, which is linked to over 1000 CTG repeats.
DM1 demonstrates anticipation, as is common in other trinucleotide repeat disorders, where the size of the repeat is linked to an earlier age of onset. Contraction of repeats can also occur across generations. Somatic mosaicism can also contribute to variable clinical features.
DM2 is characterised by expanded CCTG repeats on intron 1 of the ZNF9 (also called CNBP) gene. Normally there are 11 to 26 repeats, but on pathogenic variants there are 75 to more than 11,000, with a mean of 5,000. DM2 doesn't clearly display anticipation.
Pathophysiology
DM demonstrates a unique disease mechanism called RNA toxicity that arises from the enlarged repeat in the transcripts from the mutant DM alleles. In each of DM1 and DM2, the gene is transcribed to RNA but isn't translated. The mutant RNA then interferes with other genes that are not affected by the mutation. This happens because the mutant RNA accumulates in the nucleus, changing the activity of RNA-binding proteins and causing abnormal splicing of several genes. The result is a range of symptoms, including muscle weakness, myotonia, and cardiac conduction issues.
Clinical Features
DM is a multisystem disorder and so may present to a variety of different specialists before receiving a diagnosis.
Other than weakness, patients may also complain of muscle pain. The legs are usually the most painful where myotonia cannot typically be demonstrated. The pain is usually proximal. The pattern of pain can cause the patient to be misdiagnosed with fibromyalgia.
Finger flexion and ankle dorsiflexion weakness in the distal muscles are typical, as is ptosis, facial weakness with frontal balding, and a distinct facial appearance.
Although clinically significant cardiomyopathy is rare, respiratory issues are the most prevalent cause of early mortality, brought on by neuromuscular respiratory weakness, dysphagia, and primary central apnea. In addition, DM1 may affect bowel and bladder function and cause a specific cognitive phenotype that is poorly defined.
Myotonia is best tested in the hands and fingers.
- To demonstrate grip myotonia ask the patient to grip their fingers tightly and then release them quickly. If myotonia is present, the fingers will relax slowly.
- To demonstrate percussion myotonia, the doctor taps firmly on a specific muscle, such as the thenar eminence or the extensor digitorum. In the presence of myotonia, the muscle will contract and then relax slowly. This can be tested in other muscles as well.
Phenotypes
- Congenital DM1 - hypotonia, poor feeding, respiratory failure, premature death
- Childhood DM1 - before 10 years old, cognitive and behavioural problems, then develop muscle symptoms and physical disability
- Classic DM1 - presents between 2nd to 4th decades. Includes skeletal and respiratory muscle weakness, myotonia, cataracts, arrythmias, and excessive daytime sleepiness. Reduced lifespan
- Mild DM1 - Presents between 20 to 70 years, typically after 40. Mild weakness, myotonia, cataracts. Normal life expectancy
- DM2 - Presents between 2nd to 7th decades. Includes myotonia, proximal weakness especially the pelvic girdle, cataracts. DM2 is generally less severe than DM1.
Diagnosis
It can be made clinically with a positive family history. However often genetic testing is required. EMG is supportive.
Treatment
There is no disease modifying treatment.
Resources
GeneReviews - DM2== Literature Review ==
Literature Review
- Reviews from the last 7 years: review articles, free review articles, systematic reviews, meta-analyses, NCBI Bookshelf
- Articles from all years: PubMed search, Google Scholar search.
- TRIP Database: clinical publications about evidence-based medicine.
- Other Wikis: Radiopaedia, Wikipedia Search, Wikipedia I Feel Lucky, Orthobullets,
