Myotonic disorders are a group of genetic disorders, characterized by the presence of myotonia. Clinically, myotonia can be described as the inability to relax a muscle following activation, which may or may not be clearly evident. Electromyographically, it appears as repetitive abnormal spontaneous muscle fiber discharges with waxing and waning frequency and amplitude between 20-80Hz, heard as a “dive bomber” sound. Of note, not all electrical myotonia is indicative of myotonic disorders and may be seen in other circumstances such as hypothyroidism or with the administration of certain drugs. This review will describe the clinical presentation and pathophysiology of select myotonic disorders with a focus on type 1 myotonic dystrophy (DM1), as well as the diagnosis via laboratory and electrophysiologic findings and the rehabilitation management of such disorders.1,2
Myotonic disorders are classified as either dystrophic or non-dystrophic. Both dystrophic and non-dystrophic forms can be inherited or acquired. Autosomal dominant (AD) inheritance is most common, with Becker myotonia congenita the most common autosomal recessive (AR) outlier. DM1 and type 2 myotonic dystrophy (DM2) result from a cytosine-thymine-guanine (CTG) and cytosine-cytosine-thymine-guanine (CCTG) repeats on the DM1 protein kinase (DMPK) and CCHC-type zinc finger nucleic acid binding protein (CNBP) genes respectively. This leads to overexpression of toxic gain of function proteins with resulting disruption in normal splicing mechanisms of their target mRNA in all tissue types. The repeat expansion mutations are highly unstable, changing in length among generations (anticipation phenomenon seen in DM1) and within different tissue types of an individual (leading to variable multisystem involvement).1
Epidemiology including risk factors and primary prevention
DM1 is the most common form of myotonic dystrophy in adults and has an estimated prevalence of 4.8 per 100,000, with higher rates in populations of Northern European heritage. Classically, DM1 onset is in the second through fourth decades of life, although may present from birth through advanced age. Age of onset and disease severity correlate to length of CTG expansion.1
DM2, or proximal myotonic myopathy (PROMM), is a disease primarily of adulthood, presenting in the second through sixth decades of life. There is no clear correlation between length of CCTG repeat expansion and severity of disease.
Muscle contraction is achieved via activation of voltage-gated sodium channels that depolarize the sarcolemmal membrane, and muscle relaxation via stabilization of the sarcolemmal membrane by combined sodium and potassium channel activity causing repolarization. Reduced conductance of chloride or sodium leads to difficulty with skeletal muscle repolarization and thus relaxations.3 DM1 results from a volitional contraction or mechanical stimulation, such as needle insertion or muscle percussion, will trigger both clinical and electrical myotonia. (Table 1)
TABLE 1: MYOTONIC DISORDERS OF MUSCLE3
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
- New onset/acute: Early presentation may be limited (e.g., isolated finger weakness, difficulty lifting head off a pillow, amenorrhea, or cataracts without other symptoms).
- Subacute: Women may have problems with labor due to poor uterine contractions. Anesthesia complications can occur.
- Chronic: Difficulty walking, worsening function, difficulty climbing stairs, dysarthria, dysphagia, constipation, dyspnea, sleep apnea, cardiac conduction defects, vision problems due to cataracts/retinal degeneration.
- Pre-terminal: Death occurs from sudden cardiac events or respiratory complications. Infants with congenital DM may have poor feeding and respiratory involvement.
TABLE 2: MYOTONIC DYSTROPHY
Specific secondary or associated conditions and complications
Myotonic dystrophy is characterized by multisystem involvement with muscle predominance. In order of prevalence, these include respiratory dysfunction (hypoventilation, respiratory failure, recurrent aspiration pneumonia), cardiovascular abnormalities (syncope, palpitations, asymptomatic cardiac conduction defects), central nervous system involvement (mild cognitive dysfunction, affective disorders, disordered sleep, pain), gastrointestinal involvement (dysmotility leading to constipation, gastroesophageal reflux disease (GERD), dysphagia, chronic pseudo-obstruction), endocrine dysfunction (pituitary, growth, pancreatic), and vision and hearing issues (early cataracts, retinal degeneration, ocular weakness, early hearing loss) due to overexpression of mutant mRNA in those tissues. There is an increased risk of tumors and malignancy in those with DM for unclear reasons. Complications in pregnancy including prolonged labor, weakness, increased neonatal mortality may occur. There is also a notable intolerance to anesthetics.1, 4-6
Essentials of Assessment
Unlike in the congenital form of DM, the natural history of adult-onset DM is slow and progressive, with maintenance of ambulation nearly twenty years after the onset. Typically, in DM1, muscle weakness and myotonia progress in a distal to proximal fashion with initial weakness of the face, forearms/hands and calves, particularly with finger flexors, finger extensors, and ankle dorsiflexors. Temporal balding, atrophy of the temporalis, jaw muscles, and other facial muscles contribute to the characteristic “myotonic facies” or “hatchet facies”. There may be ptosis, weakness in neck flexion and extension, dysphagia, and dysarthria with varying intelligibility.2,7 There also may be mild peripheral neuropathy. There often are mild cognitive impairments, with a marked impassivity toward their symptoms, which may contribute to the often late presentation and diagnosis. There also may be visual deficits, notably pathognomic cataracts with bilateral iridescent cortical lens opacities. Due to smooth muscle dysfunction, gastrointestinal dysmotility resulting in GERD, diarrhea, constipation, or chronic pseudo-obstruction is common. For unknown reasons, there is also a higher incidence of endocrine dysfunction and increased malignancy. Myalgia and chronic muscle pain are common and contribute significantly to morbidity.1,6
DM2 typically presents as a milder form of DM1. Proximal weakness (rather than distal in DM I), myotonia and early cataracts before 50 years of age are often presenting symptoms. Myotonia is frequently, but not universally, present with a more “jerky” quality. Patients may report difficulty standing from squatting and calf muscle hypertrophy may be seen. There is a higher incidence of myalgias, which frequently leads to an incorrect diagnosis of fibromyalgia. Facial weakness and muscle atrophy, along with actual myotonia, are less common in DM2.4,6
Congenital DM, the disease’s most severe form, may initially present with hypotonia in a “floppy baby,” which may result in a search for DM1 in the baby’s parents. It can be associated with foot deformity, impaired feeding, intracerebral hemorrhage, or respiratory failure.4 They may also be noted to have issues with ventilation, gastric hypomotility, and facial diplegia. It has also been reported to present as intermittent episodes of acute respiratory distress with spontaneous resolution due to transient inappropriate adduction of the vocal folds during inspiration.8 If the child survives past birth, they may develop significant intellectual disability or communication difficulties. Decreased facial strength causes speech and articulation to be negatively affected with hypernasality and reduced intelligibility.2 Muscle strength can improve over time with rehabilitation intervention.
There is typically visible facial atrophy and weakness, frontal balding, and flat affect on initial encounter. With assessment of functional strength, weakness may be noted particularly distally in the finger flexors and extensors as well as in the ankle dorsiflexors. Grip or percussion myotonia of thenar of finger extensor muscles is seen and may improve with repetitive activity. Tone may be normal to decreased. There may be sternocleidomastoid weakness with relative sparing of shoulder girdle muscles. On sensory examination, there may be mild distal sensory loss. On further examination, cataracts may be noted, as well as hypogonadism in males, and abdominal distention secondary to bloating from diminished intestinal motility.4
Due to the predilection for dorsiflexor weakness, there may be a steppage gait pattern and increased incidence of falls due to weakness rather than neuropathy. As a result of the distal upper extremity weakness frequently seen, fine motor coordination and grip may be impaired, which may lead to impairments in ADLs. Due to its slow progression and years of compensatory strategies, ambulation and independence is maintained until late in the course.4 Assessments commonly used for evaluation and monitoring include the 6-minute walk test, 10 meter walk test, the timed up and go test, the timed stands test, grip strength test and the nine-hole peg test.9 Assessment of the extra-muscular features must also be considered with specialized testing outside of the scope of this review.1,4
DM2 may present with normal to mildly elevated CK levels. Diagnosis is confirmed by genetic testing which is commercially available for both DM1 and DM2. Muscle biopsy is rarely used, though may demonstrate type 1 fiber atrophy with centralized nuclei.5
Imaging studies are not required for diagnosis. Brain MRI findings correlate with neuropsychiatric impairments seen in this condition. The range of abnormalities include white matter lesions in a variety of locations; reduced myelin; enlarged hippocampus; atrophy of corpus callosum, thalamus, and putamen; white and gray matter decrease of volume; and enlarged ventricles 10-13. Functional brain imaging has also shown hypometabolism, hypoperfusion and abnormal connectivity in a variety of regions.14-16
While myotonic discharges on electromyography (EMG) are nonspecific and may be seen in inflammatory myopathies, hypothyroidism, and drug induced myopathies, myotonic discharges will be present in 100% of DM1 cases and 90-100% of all DM2 cases. It has a characteristic sound of a “revving engine” and can be seen as a brief spike potential that waxes and wanes generated by moving the EMG needle. This motor unit action potentials have low amplitude, short duration and is polyphasic (myopathic pattern) with early recruitment. Decreasing the temperature of the limb to 20oC might be needed to bring out the discharges. Nerve conduction studies are typically normal, except for a possible decreased amplitude compound motor action potential (CMAP) after exercise and repetitive nerve stimulation seen in myotonic dystrophy and myotonia congenita.17
Early predictions of outcomes
Given the variability in severity of DM1 in particular, it is essential that an early diagnosis be made to prevent adverse outcomes. Unfortunately, some studies have identified a higher risk of certain malignancies in the DM population. However, knowing this at the time of diagnosis, proper cancer screening can be initiated earlier. Patients with DM1 have a higher incidence of cardiac conduction abnormalities, as well as respiratory depression, both of which can lead to mortality if not addressed in a timely manner. Additionally, with proper early therapeutic intervention, those with a diagnosis in infancy may regain muscle function and avoid further complications later in life.
Patients may require accessibility modifications and adaptive equipment both at home and at work.
Social role and social support system
As a result of the variable nature of this disorder, a new diagnosis may be met with denial by other family members. Symptoms such as fatigue or frontal balding are relatively vague in nature, and it may be difficult for family members to associate them with a genetic and potentially fatal condition. Alternatively, having an infant with severe cognitive and physical impairments is also very difficult for families. Behavioral disturbances are common, which can add to the challenges of completing an education and been employed. The initiation of accessibility modifications in the home or for transportation services have an effect on the patient’s family as well.
Consider genetic counseling and testing of family members, particularly given asymptomatic cardiac conduction defects in those yet undiagnosed.
Rehabilitation Management and Treatments
Available or current treatment guidelines
Current clinical trials have taken us closer to the development of targeted therapies. Small-molecule drugs like Tideglusib have shown improvement in clinical neuromuscular symptoms, Metformin has shown improvement in mobility and mechanical power, Mexiletine and Ranolazine improves myotonia, Cannabinoids have improved myalgias, Pitolisant and Theobromine with Caffeine has improved hypersomnia. Oligonucleotide-based therapies like ISIS 486178 has been able to alter cardiac conduction defects, improve weight and strength, FORCE-DMPK and Pip6a-PMO-CAG7 have shown to reverse myotonia and splicing defects. Gene therapy approaches like using adeno-associated viruses to promote endogenous expression of antisense oligonucleotides and CRISPR/Cas9 to regulate gene expression could lower the levels of toxic DMPK RNA and diminish myotonia.18,19 Speech language pathologist (SLP) can be helpful to work on speech intelligibility, compensatory strategies, and consideration of augmentative assisted communication.2
At different disease stages
Congenital DM1 are usually able to wean off the ventilator and walk without assistance.20 Stretching, submaximal strengthening, NSAIDs, and modalities are useful for myalgias and stiffness. Compensate for home and work accessibility and provide patient education as appropriate. During acute attacks in sodium channel disorders, ingestion of simple carbohydrates is an option.21 In hyperkalemic periodic paralysis acute attacks, inhalation of beta-adrenergic agents and ingestion of carbohydrates can help.17 Provide a link to resources such as Myotonic Dystrophy Foundation, Muscular Dystrophy Association, Parent Project Muscular Dystrophy or a local clinic for support and information.
Manage blood glucose as needed. Provide mexiletine for function-limiting myotonia and screen for QT prolongation with EKG during therapy. In congenital myotonic muscular dystrophy, carbamazepine and phenytoin are also options along with magnesium and tonic water.21 NSAIDs are a good option for muscle pain. Hypersomnolence can be treated with modafinil.21 Coordinate thorough screening and treatment for cardiac, cancer, endocrine, ophthalmological, GI, and respiratory complications. Address nutritional concerns if dysphagia, difficulty with self-feeding, or jaw dislocation are present. A modified diet might be required and if needed, a G-tube should be placed. Referrals must be provided to address neuropsychiatric conditions. Monitor and prevent development of contractures, educate on passive range of motion exercises. Orthopedic surgery evaluation might be needed in congenital DM1 for club foot, talipes equinovarus and spinal deformities. Provide lower limb orthoses to improve balance and gait pattern. Devices for energy conservation, assisted breathing, assisted coughing, upper limb functional or resting orthoses, adaptive equipment, or communication may be needed. Low intensity, low impact, low resistance aerobic training should be encouraged with caution to avoid muscle fatigue and pain.21 Ensure understanding of advanced directives during end-of-life conversations.
Pre-terminal or end of life care
Continue symptomatic care and understand patient wishes; develop a plan agreed upon by the entire family.
Coordination of care
Since DM is a multi-system disorder, it’s only reasonable that the care of DM requires a multi-disciplinary clinic to improve outcomes and survival. Management typically involves, at the very least, primary care, neuromuscular disease trained neurologist or physiatrist, and physical and occupational therapy. Depending on the severity of the disease, neuropsychology, speech therapy, nutrition, cardiology, pulmonology, endocrinology, ophthalmology, orthopedic surgery, gastroenterology, or oncology may also be involved. A focus should also be placed on the prevention of common comorbidities. Equipment may include assistive devices (neck braces, arm and foot braces, canes, walkers, scooters, or wheelchairs) to ensure safe mobility, eye crutches for ptosis, pacemaker or implantable cardioverter defibrillator (ICD) for arrhythmias, incentive spirometry, cough assist devices, or bilevel positive airway pressure (BiPAP) to ensure respiratory sufficiency 21. Surgical intervention is rare (eyelid procedures, contracture release) and requires careful communication of surgical and anesthesia risks, especially with the use of succinylcholine and anticholinesterase agents 17. Geneticists and counselors are also vital members of the team. Obstetricians also need education about this special need population, given that labor may be difficult due to poor uterine contractions. An individualized educational plan needs to be established and followed up with vocational training to ensure active participation in the society.
Cutting Edge/ Emerging and Unique Concepts and Practice
Cutting edge concepts and practice
The mechanism of myotonia production in myotonic dystrophy has been attributed to reduced muscle-specific chloride channel (ClC-1) expression due to aberrant splicing of the ClC-1 pre-mRNA leading to membrane hyperexcitability.22,23
Therapeutic strategies in DM1 include small-molecule drugs that act on DMPK gene expression by transcript inhibition, gene editing, inactivation of toxic mutant transcript, modulation of its RNA products, modulation of downstream signaling pathways. The classes of molecules include antisense oligonucleotides (ASOs), small interfering RNA (siRNA) and recombinant adeno-associated virus (rAAV).24 This is a promising area of gene therapy in which preclinical and clinical studies are underway. Some have shown improvement in body weight, fatigue, muscle strength, muscle histology, cardiac conduction defects and myotonia in mice.25-28
Recently, studies have also begun to look at neuroplasticity in subjects with DM1 through the use of transcranial magnetic stimulation in order to determine a more personalized approach to rehabilitation. While variations in CNS abnormalities have been noted, the sample sizes have been very small, and the significance of the findings remain unclear.29
Gaps in the Evidence-Based Knowledge
A firm understanding of the advantages/disadvantages of strengthening and the role of stretching in the muscular dystrophies remains elusive and requires a more consistent approach to research.
- Montagnese F, Schoser B. New developments in myotonic dystrophies from a multisystemic perspective. Curr Opin Neurol. 2021;34(5):738-747.
- Sjogreen L, Martensson A, Ekstrom AB. Speech characteristics in the congenital and childhood-onset forms of myotonic dystrophy type 1. Int J Lang Commun Disord. 2018;53(3):576-583.
- Stunnenberg BC, LoRusso S, Arnold WD, et al. Guidelines on clinical presentation and management of nondystrophic myotonias. Muscle Nerve. 2020;62(4):430-444.
- Heatwole CR, Statland JM, Logigian EL. The diagnosis and treatment of myotonic disorders. Muscle Nerve. 2013;47(5):632-648.
- Matthews E, Holmes S, Fialho D. Skeletal muscle channelopathies: a guide to diagnosis and management. Pract Neurol. 2021;21(3):196-204.
- Amato AA, Russell JA. Myotonic Dystrophies. Neuromuscular Disorders, 2e. New York, NY: McGraw-Hill Education 2015.
- Hanoun S, Sun Y, Ebrahimi F, et al. Speech and language abnormalities in myotonic dystrophy: An overview. J Clin Neurosci. 2022;96:212-220.
- Purkey MR, Valika T. A unique presentation and etiology of neonatal paradoxical vocal fold motion. Int J Pediatr Otorhinolaryngol. 2019;125:199-200.
- Kierkegaard M, Petitclerc E, Hebert LJ, et al. Is one trial enough for repeated testing? Same-day assessments of walking, mobility and fine hand use in people with myotonic dystrophy type 1. Neuromuscul Disord. 2017;27(2):153-158.
- Leddy S, Serra L, Esposito D, et al. Lesion distribution and substrate of white matter damage in myotonic dystrophy type 1: Comparison with multiple sclerosis. Neuroimage Clin. 2021;29:102562.
- Langbehn KE, van der Plas E, Moser DJ, et al. Cognitive function and its relationship with brain structure in myotonic dystrophy type 1. J Neurosci Res. 2021;99(1):190-199.
- Cabada T, Díaz J, Iridoy M, et al. Longitudinal study in patients with myotonic dystrophy type 1: correlation of brain MRI abnormalities with cognitive performances. Neuroradiology. 2021;63(7):1019-1029.
- Serra L, Bianchi G, Bruschini M, et al. Abnormal Cortical Thickness Is Associated With Deficits in Social Cognition in Patients With Myotonic Dystrophy Type 1. Front Neurol. 2020;11:113.
- Meola G, Sansone V, Perani D, et al. Executive dysfunction and avoidant personality trait in myotonic dystrophy type 1 (DM-1) and in proximal myotonic myopathy (PROMM/DM-2). Neuromuscul Disord. 2003;13(10):813-821.
- Romeo V, Pegoraro E, Squarzanti F, et al. Retrospective study on PET-SPECT imaging in a large cohort of myotonic dystrophy type 1 patients. Neurol Sci. 2010;31(6):757-763.
- Serra L, Mancini M, Silvestri G, et al. Brain Connectomics’ Modification to Clarify Motor and Nonmotor Features of Myotonic Dystrophy Type 1. Neural Plast. 2016;2016:2696085.
- Preston D, Shapiro B. Myotonic muscle disorders and periodic paralysis syndromes. In Preston D, (Ed). Electromyography and Neuromuscular Disorder. Philadelphia, PA: Elsevier 2021:693-706.
- Pascual-Gilabert M, López-Castel A, Artero R. Myotonic dystrophy type 1 drug development: A pipeline toward the market. Drug Discov Today. 2021;26(7):1765-1772.
- Meola G. Myotonic dystrophy type 2: the 2020 update. Acta Myol. 2020;39(4):222-234.
- McDonald C. Neuromuscular diseases. In Alexander M, (Ed). Pediatric Rehabilitation Principles and Practice. New York, NY: Demos Medical Publishing 2015:485-490.
- Williams L, McDonald C. Myopathic disorders. In Cifu D, (Ed). Braddom’s Physical Medicine and Rehabilitation. Philadelphia, PA: Elsevier 2021:901-905, 910-914.
- Mankodi A, Takahashi MP, Jiang H, et al. Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell. 2002;10(1):35-44.
- Charlet-B N, Savkur RS, Singh G, et al. Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Mol Cell. 2002;10(1):45-53.
- Izzo M, Battistini J, Provenzano C, et al. Molecular Therapies for Myotonic Dystrophy Type 1: From Small Drugs to Gene Editing. Int J Mol Sci. 2022;23(9).
- Jauvin D, Chrétien J, Pandey SK, et al. Targeting DMPK with Antisense Oligonucleotide Improves Muscle Strength in Myotonic Dystrophy Type 1 Mice. Mol Ther Nucleic Acids. 2017;7:465-474.
- Hu N, Kim E, Antoury L, et al. Antisense oligonucleotide and adjuvant exercise therapy reverse fatigue in old mice with myotonic dystrophy. Mol Ther Nucleic Acids. 2021;23:393-405.
- Wheeler TM, Leger AJ, Pandey SK, et al. Targeting nuclear RNA for in vivo correction of myotonic dystrophy. Nature. 2012;488(7409):111-115.
- Yadava RS, Yu Q, Mandal M, et al. Systemic therapy in an RNA toxicity mouse model with an antisense oligonucleotide therapy targeting a non-CUG sequence within the DMPK 3’UTR RNA. Hum Mol Genet. 2020;29(9):1440-1453.
- Portaro S, Naro A, Chillura A, et al. Toward a more personalized motor function rehabilitation in Myotonic dystrophy type 1: The role of neuroplasticity. PLoS One. 2017;12(5):e0178470.
Original Version of the Topic
Kathryn Stolp, MD. Myotonic Disorders of Muscle. 12/27/2012.
Previous Revision(s) of the Topic
Kaile Eison, DO, Heakyung Kim, MD. Myotonic Disorders of Muscle. 6/28/2018.
Kayla Williams, MD
Nothing to Disclose
Cesar Astudillo, MD
Nothing to Disclose
Heakyung Kim, MD
Nothing to Disclose