Myotonic Dystrophy

Written by: Dr Jeremy Steinberg – created: 6 March 2023; last modified: 12 March 2023

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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. Proximal and distal muscle weakness and myotonia in most. Variable age of onset
Diagnosis	Genetic testing
Treatment	Supportive
Prognosis	Slowly progressive disorder

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, proximal muscle pain, 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.

Pathogenesis

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. There is a lot of variability in the disorder.

History

Weakness can occur but usually only after years of myotonia. The weakness is usually both proximal and distal, however in DM2 the proximal weakness is worse than the distal weakness. Facial weakness can occur with mouth puckering and weak eye closure. The weakness usually starts in the hands and ankles with hand strength and foot drop.

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.

Cognitive impairment can be prominent in later years and the patient may have a severe personality disorder. Hypersomnolence can occur later in the disease. Cataracts are common. There may be insulin insensitivity with high sugar levels and hyperinsulinaemia.

Examination

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.

Myotonia is best tested in the hands and fingers. However it can also be demonstrated in the tongue.

• 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

The gold standard method of diagnosis is through genetic testing. However traditionally it could be made clinically especially with a positive family history.

Nerve conduction studies are usually normal. EMG is supportive if it shows a minimal increase in insertional activity of affected muscles. CK is often normal.

Muscle biopsy shows type 1 fibre atrophy, central nuclei, atrophied fibres mixed with hypertrophied fibres, and slight increase in endomysial connective tissue.

Differential Diagnosis

• Myotonia congenita
• Cold induced myotonia (paramyotonia)

Prognosis

The prognosis is variable even among individuals within the same family. When the onset is early that usually means poorer prognosis. It is overall rare to survive past 65.

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.

Treatment

There is no disease modifying treatment. ECG is used to monitor for cardiac disease looking for impending heart block to determine appropriateness for pacemaker placement. Medication such as methylphenidate can be used for the hypersomnolescence. Medications that may worsen symptoms include amitriptyline, digoxin, propranolol, quinine, and sedatives.

Resources

GeneReviews - DM1

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,