Myotonic Disorders of Muscle

Disease/Disorder

Definition

Myotonic disorders are a group of genetic disorders, which can present with myotonia, weakness, and muscle wasting. Clinically, myotonia can be described as the inability to relax a muscle following activation, which may or may not be clearly evident. 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.^1,4-5

Etiology

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 being the most common autosomal recessive (AR) outlier. DM1 and type 2 myotonic dystrophy (DM2) result from genetic mutations that affect the DMPK and CNBP genes with CTG and CCTG repeats, respectively, which in turn result in a gain of function mutation.

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).⁴

Epidemiology including risk factors and primary prevention

DM1 is the most common form of myotonic dystrophy in adults and has an estimated prevalence of 9.27 per 100,000, with higher rates in populations of Northern European heritage.² 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.⁴

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.

Patho-anatomy/physiology

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.⁶ 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 Muscle⁶

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, sudden death), 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, and increased neonatal mortality may occur. There is also a notable intolerance to anesthetics which should lead to cardiac monitoring if ever used on these patients.^1,4-6

Essentials of Assessment

History

Myotonic dystrophy type 1 (DM1) is currently classified by the International Myotonic Dystrophy Consortium into five groups based on age of onset, CTG repeat size, and clinical manifestations.¹⁰ Congenital DM1 presents at birth (<1 year) with CTG expansions >1,000 and is associated with severe hypotonia (“floppy baby” syndrome), feeding difficulties (due to facial diplegia), cardiorespiratory complications, gastric hypomotility, and cognitive impairment (due to neuroanatomical abnormalities.¹¹ Childhood-onset DM1 (1–10 years) and juvenile-onset DM1 (11–20 years) are associated with CTG repeats ranging from 50 to 1,000 and may present with myotonia and cardiac conduction abnormalities, although motor involvement may be mild or delayed in juvenile cases.¹¹ Adult-onset DM1 (20–40 years), also with CTG repeats of 50–1,000, typically manifests with myotonia, muscle weakness, cataracts, cardiac conduction defects, insulin resistance, and respiratory involvement. Late-onset or asymptomatic DM1 (>40 years) is generally associated with smaller expansions (50–100 repeats) and a milder phenotype, often limited to cataracts and mild myotonia.

A 2024 factor analysis of 228 patients with adult-onset DM1 identified three principal symptom clusters: (1) facial weakness/myotonia, the most common presenting domain; (2) skeletal muscle weakness, more frequent in males and those with older age at onset; and (3) gastrointestinal distress/sleepiness, reflecting non-muscular involvement.¹² Over 63% of patients exhibited features from all three clusters, supporting the characterization of DM1 as a progressive, multisystem disorder with overlapping manifestations.

Increasing attention has also been directed toward the cognitive and behavioral manifestations of DM1.¹³ Contemporary literature describes characteristic neuropsychiatric features, including avoidance behaviors, reduced disease perception, mild cognitive impairment, and apathy, which may influence patient engagement with care and disease recognition. Furthermore, daytime sleepiness appears to be consistently present once physical disability develops, reinforcing the multisystem and neurobehavioral complexity of adult-onset DM1.

Myotonic dystrophy type 2 (DM2) is characterized by predominant proximal muscle weakness (neck, hip, and elbow flexors), in contrast to the distal pattern seen in DM1.¹⁴ Early manifestations often include proximal weakness, myalgia, mild myotonia, and cataracts before age 50. Additionally, calf hypertrophy may be present. Myalgia is a prominent feature and may lead to misdiagnosis as fibromyalgia.

The traditional concept of DM2 as an exclusively adult-onset disease now highlights a broader range of phenotypic presentations and multisystem involvement. Diabetes mellitus (particularly insulin-insensitive) appears to be more common in DM2 than in DM1.¹⁵ Additionally, cardiac involvement is increasingly recognized as clinically significant.¹⁴ Autoimmune disease has been identified in up to one-third of DM2 patients, suggesting that altered immune pathways may contribute to the multisystemic nature of the disorder.¹⁶

Physical examination

Patients often exhibit facial weakness and atrophy, frontal balding, and hypomimia. Weakness is typically distal, affecting finger flexors/extensors and ankle dorsiflexors, with possible sternocleidomastoid involvement and relative sparing of proximal shoulder muscles. Myotonia (grip or percussion) is common and may improve with repeated activity (warm-up phenomenon); tone is normal or decreased. Additional findings may include mild distal sensory loss, cataracts, hypogonadism in males, and abdominal distention due to gastrointestinal dysmotility.¹¹

Functionally, dorsiflexor weakness may produce a steppage gait and increased fall risk, while distal upper extremity involvement can impair fine motor tasks and activities of daily living.²⁸ Emerging evidence describes a childhood-onset phenotype, with reports of children presenting with foot deformities such as pes planovalgus.¹⁴ Finally, camptocormia and Drop Head Syndrome (DHS) have been documented in DM1 patients, presenting with flexible cervical and thoracic kyphosis.³⁵

Functional assessment

Several functional tests are commonly used to evaluate and monitor disease progression, including muscle strength tests with handheld dynamometry (HHD), the step test, Timed Up and Go test (TUG), and 10-meter walk test (10mWT), finding that both functional mobility tests were sufficiently reliable and valid, with the 10mWT being superior for reliability.¹⁷ Recent research has also supported the use of remote functional assessments in DM1. Remotely administered measures, including Handgrip strength via HHD, forced vital capacity (FVC), 10MWRT, TUG, and 9-Hole Peg Test (9HPT) demonstrate excellent reliability and sensitivity, making them appropriate for routine clinical assessment and longitudinal monitoring in DM1 via telehealth.¹⁸

In addition to performance-based measures, patient-reported outcome instruments have become increasingly important in evaluating functional status and participation. A systematic review assessing instruments used in muscular dystrophies identified the Myotonic Dystrophy Health Index (MDHI) and DM1-ActivC as validated tools for assessing multisystemic, functional, and quality of life impact in individuals with DM1.¹⁹

Laboratory studies

Laboratory findings in myotonic dystrophy are often nonspecific, though DM2 may present with normal to mildly elevated creatine kinase (CK) levels.²⁰ Definitive diagnosis is established through genetic testing, which is commercially available for both DM1 and DM2 and identifies the characteristic repeat expansions associated with each disorder.²¹ Muscle biopsy is rarely required for diagnosis, but when performed it may demonstrate type 1 fiber atrophy with centralized nuclei.¹¹

Imaging

Imaging studies are not required for the diagnosis of myotonic dystrophy. Brain MRI findings (white matter lesions) have been shown to correlate with the neuropsychiatric impairments observed in this condition.²⁰

Quantitative muscle MRI may be used as a sensitive marker of early muscle pathology in DM1. Research has shown that quantitative MRI can detect early muscle changes in muscles such as the gastrocnemius, even in patients who have not yet developed overt motor symptoms, suggesting a potential role for this technique in early disease detection and monitoring of disease progression.²²

Electrophysiological study

Electromyography (EMG) is a key tool in the evaluation of myotonic dystrophy. Although myotonic discharges are not entirely specific, they are highly prevalent in myotonic dystrophy, more frequently in DM1 than in DM2.¹¹ DM1 more commonly produces repetitive abnormal spontaneous muscle fiber discharges with Waxing and waning frequency and amplitude between 20-80Hz, (often heard as a “dive bomber” or “revving engine” sound), while in DM2 it tends to be waning only (less specific discharges).²⁴ Motor unit action potentials often demonstrate a myopathic pattern, characterized by low amplitude, short duration, and polyphasic morphology with early recruitment.¹¹ Nerve conduction studies are generally normal, although a reduction in compound motor action potential (CMAP) amplitude after exercise or repetitive nerve stimulation has been reported in myotonic dystrophy and related myotonic disorders.^25,26

The presence of “afterdischarges” has been described on EMG in patients with DM1. These findings reflect the muscle hyperexcitability that characterizes the disorder and may provide additional insight into the electrophysiological mechanisms underlying myotonia in these patients.²⁷

Early predictions of outcomes

A validated prognostic score using eight clinical variables accurately predicts 10-year survival, with higher scores associated with markedly increased mortality risk.²⁹ CTG repeat length remains a key determinant of disease severity and age of onset, correlating with muscle strength and respiratory function, while repeat interruptions are associated with milder phenotypes.¹¹ Cardiac predictors of adverse outcomes include severe ECG abnormalities and atrial arrhythmias, with electrophysiological study (HV interval ≥70 ms) improving risk stratification for sudden cardiac death.³⁰ Respiratory impairment is common and predicted by CTG expansion size and disease severity, with maximal voluntary ventilation potentially offering greater sensitivity than FVC for detecting clinically significant dysfunction.³¹

Environmental

Studies using the International Classification of Functioning, Disability and Health (ICF) framework show that environmental barriers are among the most significant unmet needs and are associated with reduced participation, highlighting the importance of environmental modification.³² Current recommendations support early evaluation for assistive devices (e.g., ankle-foot orthoses, wheelchairs) and multidisciplinary assessment by PM&R, PT, and OT as disease progresses. Fall risk is a key safety concern, with predictors including impaired mobility and reduced strength, underscoring the need for proactive fall prevention strategies.

Social role and social support system

Patients experience progressive decline in social participation over time, including reduced engagement in daily activities, employment, and community life, with high rates of unemployment and psychological distress. Social determinants such as low education, limited social support, and restricted access to transportation further contribute to participation limitations.³³

Professional issues

Professional management of DM1 and other related disorders requires a multidisciplinary, patient-centered approach.

Rehabilitation Management and Treatments

Current standard of care

Myotonia in myotonic dystrophy results from reduced muscle-specific chloride channel (ClC-1) expression due to aberrant ClC-1 pre-mRNA splicing, leading to membrane hyperexcitability.^46,47 Treatment focuses on reducing membrane excitability, while therapies targeting membrane stability continue to emerge.

Symptomatic pharmacologic management

Mexiletine is the gold standard for myotonia management.⁴⁸ Doses of 150–200 mg TID reduce myotonia in DM1 with good tolerability, though efficacy is greater in non-dystrophic forms. Lamotrigine is a well-tolerated alternative.⁴⁹ Baseline and serial EKGs are recommended due to QT prolongation risk.

Phenytoin, carbamazepine, benzodiazepines, and TCAs are not first-line.⁵⁰ Although historically used, they show poor tolerability and low-quality evidence compared with mexiletine.⁴⁶ Ranolazine and acetazolamide may be considered as off-label add-ons in refractory cases.^49,50

Pain management should prioritize acetaminophen or NSAIDs. Muscle relaxants are contraindicated. Opioids and sedating agents should be minimized due to respiratory risk. Cannabinoids have shown some benefit for myalgias.⁴⁴ Hypersomnolence may be treated with modafinil,⁴⁶ with pitolisant under investigation.

Non-pharmacologic management and rehabilitation interventions

Exercise and physical therapy are central, improving function and preventing deconditioning. Moderate-intensity aerobic and strength training improves strength, endurance, balance, and functional outcomes. Preclinical data suggest exercise may reduce CUG RNA foci, release MBNL1, and correct aberrant splicing without worsening muscle damage.

Gradual progression to moderate intensity is preferred; high-intensity exercise may worsen myotonia. Stretching preserves range of motion. Speech-language pathology supports communication and compensatory strategies.⁵

Assistive devices, orthoses, and energy conservation strategies should be considered. Include cardiac and respiratory screening when prescribing exercise. Orthopedic evaluation may be needed in congenital DM1 for foot and spinal deformities.

Multidisciplinary care and systems-based management

DM requires multidisciplinary care to optimize outcomes. Core teams include primary care, neurology or physiatry, and rehabilitation therapies, with additional specialties as needed. Prevention and monitoring of comorbidities are essential.

• Cardiac: Annual EKG and Holter monitoring; consider pacemaker or ICD in high-risk patients.
• Respiratory: Vaccination, prompt infection treatment, airway clearance techniques, and NIV for sleep-related breathing disorders; screen for hypoventilation.
• Metabolic/Endocrine: Annual screening for thyroid dysfunction, insulin resistance, and hypogonadism.
• Gastrointestinal: Screen for dysphagia, reflux, bowel dysfunction, and sphincter issues.
• Ophthalmic: Screen for cataracts; manage ptosis conservatively.
• Neuromuscular: Prevent contractures; prescribe orthoses; consider orthopedic referral.
• Reproductive: Monitor labor fatigue and postpartum hemorrhage risk; involve high-risk obstetrics and provide genetic counseling.
• Psychiatric: Baseline neuropsychological evaluation and early mental health support.

New Cutting-Edge Therapies

Emerging therapies target DM1 at the molecular level, including transcript inhibition, gene editing, and modulation of RNA toxicity. Approaches include antisense oligonucleotides (ASOs), siRNA, and rAAV vectors.⁵⁰

Disease modifying drugs

Tideglusib improves aberrant RNA splicing and cellular function. As of 2025, Phase 2 data show symptomatic improvement versus placebo.⁵³

Neuroplasticity

Studies using transcranial magnetic stimulation suggest CNS involvement, though small sample sizes limit conclusions. Robotic gait training with exoskeletons plus therapy may improve gait and strength, but evidence remains limited.⁵²

Gene therapy and editing

CRISPR/Cas9 and antisense approaches aim to silence CTG expansions and reduce toxic RNA, reversing myotonia in preclinical models.⁴³

Novel biologic delivery systems

Delpacibart etedesiran, an antibody-oligonucleotide conjugate targeting transferrin receptor 1, delivers siRNA to muscle. Phase 1–2 trials (MARINA) showed disease modification; Phase 3 (HARBOR) is ongoing.⁵⁴

Patient Resources and Support Systems

Myotonic Dystrophy Foundation: https://www.myotonic.org/
Muscular Dystrophy Association: https://mdaquest.org/understanding-myotonic-dystrophy-dm/
UR Medicine: https://www.urmc.rochester.edu/conditions-and-treatments/myotonic-dystrophy

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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, Cesar Astudillo, MD, Heakyung Kim, MD. Myotonic Disorders of Muscle. 12/21/2022

Author Disclosure

Edwardo Ramos, MD
Nothing to Disclose

Jan Garcia Rivera, MD
Nothing to Disclose

Sebastian Frontera, MD
Nothing to Disclose

Sofia Ojeda, MD
Nothing to Disclose