Myotonic Dystrophy

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

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Myotonic dystrophy patient.JPG
Individual with myotonic dystrophy showing prominent muscle wasting
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. Pain is often a prominent symptom in DM2 and hence is relevant to the Musculoskeletal Physician.

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

Patients may be unaware of or don't complain of their myotonia. Weakness can occur but usually only after years of myotonia. The weakness can be both proximal and distal, however in DM1 the distal weakness is worse, and in DM2 the proximal weakness is worse. 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, especially in DM2 where it can be disabling. The legs are usually the most painful where myotonia cannot typically be demonstrated. The pattern of pain in DM2 can cause the patient to be misdiagnosed with fibromyalgia,[1] however working backwards from fibromyalgia there may not be a relevant excess of undiagnosed cases among that group.[2]

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

The typical myotonic facies of a DM1 patient is frontal balding and temporal, jaw, and facial muscle atrophy. Cataracts may be visible.

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. Calf hypertrophy can occur in DM2

Myotonia is best tested in the hands and fingers. However it can also be demonstrated in the tongue. The myotonia is reduced with repeated muscle contractions.

  • 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.

Reflexes are reduced but sensory testing is normal.

Phenotypes

  • Congenital DM1 - Onset at birth. hypotonia, poor feeding, respiratory failure, premature death. CTG length is >1000.
  • Childhood DM1 - before 10 years old, cognitive and behavioural problems, then develop muscle symptoms and physical disability. CTG length is 50-1000.
  • Classic DM1 - presents between 10-30 years of age. Includes skeletal and respiratory muscle weakness, myotonia, cataracts, arrythmias, and excessive daytime sleepiness. Reduced lifespan. CTG length is 50-1000
  • Mild DM1 - Presents between 20 to 70 years, typically after 40. Mild weakness, myotonia, cataracts. Normal life expectancy. CTG length is 50-100.
  • DM2 - Presents between 2nd to 7th decades. Includes myotonia, proximal weakness especially the pelvic girdle, cataracts. DM2 is generally less severe than DM1. This is also known as proximal myotonic myopathy.

Summary features of DM1 vs DM2

Comparison of clinical manifestations between DM1 and DM2[3]
Clinical Features DM1 DM2
General features
Epidemiology Widespread European
Age of onset (years) 0 to adult 8-60
Anticipation Always present Exceptional
Congenital form Present Absent
Life expectancy Reduced Normal range
Core features
Clinical myotonia Evident in adult-onset Present in <50%
EMG myotonia Always present Absent or variable in many
Muscle weakness Disabling at age 50 Onset after age 50-70
Cataracts Always present Present in minority
Muscle symptoms
Facial and jaw weakness Always present Uusally absent
Bulbar weakness-dysphagia Always later Absent
Respiratory muscles weakness Always later Exceptional
Distal limb muscle weakness Always prominent Only flexor digitorium profundus, rare
Proximal limb muscle weakness May be absent Main disability in most patients, late
Sternocleidomastoid weakness Always prominent Prominent in few
Myalgic pain Absent or mild Most disabling symptom in many
Visible muscle atrophy Face, temporal, distal hands and legs Usually absent
Calf hypertrophy Absent Present in >50%
Systemic features
Tremors Absent Prominent in many
Behavioral change Early in most Not apparent
Cognitive disorders Prominent Not apparent
Hypersomnia Prominent Infrequent
Cardiac arrhythmias Always present From absent to severe
Male hypogonadism Manifest Subclinical in most
Manifest diabetes Frequent Infrequent

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 myotonic discharges. Multiple muscle samples are required to avoid false negatives. CK is often normal but can be mildly increased.

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 Differential Diagnosis
  • Myotonic dystrophy
    • DM type 1 (DMPK)
    • DM type 2 (CNBP)
  • Non-dystrophic myotonias
    • Chloride channelopathies (CLCN1)
    • Sodium channelopathies (SCN4A)
      • Sodium channel myotonia
      • Paramyotonia congenita
      • Hyperkalaemic periodic paralysis
    • Chondrodystrophic myotonia
  • Drug induced (statins, fibrates, cyclosporine, chloroquine, terbutaline, formoterol, propranolol)
  • Isolated electrical myotonia: Pompe Disease, Polymyositis, Myotubular congenital myopathy, hypothyroidism, malignant hyperpyrexia, severe denervation.

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.

Sudden cardiac death can occur but clinically significant cardiomyopathy is rare. Conduction abnormalities are very common. The cardiomyopathy severity does not necessarily correlate with the skeletal muscle weakness.

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 modafinil and methylphenidate can be used for the hypersomnolescence. Medications that may worsen symptoms include amitriptyline, digoxin, propranolol, quinine, and sedatives. Sleep apnoea and hypoventilation can occur and BiPAP can be used here.

Resources

GeneReviews - DM1

GeneReviews - DM2

Myotonic Dystrophy foundation - documents for health care providers and patients

References

  1. Auvinen, Satu; Suominen, Tiina; Hannonen, Pekka; Bachinski, Linda L.; Krahe, Ralf; Udd, Bjarne (2008-11). "Myotonic dystrophy type 2 found in two of sixty-three persons diagnosed as having fibromyalgia". Arthritis and Rheumatism. 58 (11): 3627–3631. doi:10.1002/art.24037. ISSN 0004-3591. PMC 2585600. PMID 18975316. Check date values in: |date= (help)
  2. van Vliet, J.; Verrips, A.; Tieleman, A. A.; Scheffer, H.; Cats, H. A.; den Broeder, A. A.; van Engelen, B. G. M. (2016-06). "No relevant excess prevalence of myotonic dystrophy type 2 in patients with suspected fibromyalgia syndrome". Neuromuscular disorders: NMD. 26 (6): 370–373. doi:10.1016/j.nmd.2016.03.009. ISSN 1873-2364. PMID 27132119. Check date values in: |date= (help)
  3. Clinical aspects, molecular pathomechanisms and management of myotonic dystrophies - Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Comparison-of-clinical-manifestations-between-DM1-and-DM2_tbl1_262112936 [accessed 8 Mar, 2023]

Literature Review