Myotonic Dystrophy

Myotonic dystrophies (DM) are the most common muscular dystrophies in adults, characterized by the triad of progressive muscle weakness, myotonia (delayed muscle relaxation after contraction), and broad multisystem involvement affecting the heart, brain, eyes, endocrine system, and gastrointestinal tract. Two genetically distinct forms are recognized: myotonic dystrophy type 1 (DM1, Steinert disease), caused by a CTG trinucleotide repeat expansion in the DMPK gene, and myotonic dystrophy type 2 (DM2, proximal myotonic myopathy/PROMM), caused by a CCTG tetranucleotide repeat expansion in the CNBP gene. Despite different genetic variants, DM1 and DM2 share a common pathogenic mechanism in which expanded RNA transcripts sequester splicing regulators, producing widespread downstream effects. Life-threatening cardiac arrhythmias and respiratory complications can occur at any disease stage—even in patients with mild skeletal muscle symptoms—making recognition and proactive surveillance essential.

Genetics

DM1: DMPK CTG Repeat Expansion

DM1 is caused by a heterozygous, unstable CTG trinucleotide repeat expansion within the 3′ untranslated region of the DMPK gene on chromosome 19q13.32. The expansion is meiotically and mitotically unstable, producing two clinically relevant phenomena:

• Anticipation: Successive generations inherit progressively longer expansions, leading to earlier onset and more severe disease in offspring than in parents
• Somatic mosaicism: Different tissues and cells within a single patient carry different expansion lengths, contributing to phenotypic variability

CTG repeat length correlates with phenotype severity:

DM2: CNBP CCTG Repeat Expansion

DM2 is caused by a heterozygous CCTG tetranucleotide repeat expansion within intron 1 of the CNBP gene (formerly ZNF9) on chromosome 3q21.3. Expansions can reach up to 11,000 repeats, and their large size makes precise measurement technically challenging, limiting genotype-phenotype correlation. Unlike DM1, no clear anticipation or congenital form has been identified, although the expansion is somatically unstable and may increase over a patient’s lifetime. Diagnosis is generally confirmed when the expansion exceeds 75 CCTG repeats.

Pathogenic Mechanism

Despite distinct genetic variants, DM1 and DM2 share a common RNA gain-of-function mechanism. Expanded CTG or CCTG DNA is transcribed into toxic CUG or CCUG RNA molecules that accumulate in the nucleus as hairpin-shaped aggregates called RNA foci. These foci sequester muscleblind-like (MBNL) family proteins, which normally regulate alternative splicing of downstream effector genes. When MBNL proteins are trapped, abnormal splicing produces aberrant protein products responsible for the multiorgan manifestations of DM:

• CLCN1 (chloride channel) missplicing → myotonia (strongest known association)
• INSR (insulin receptor) missplicing → insulin resistance
• CACNA1S (calcium channel) missplicing → muscle weakness
• SCN5A (sodium channel) missplicing → cardiac arrhythmia

These abnormally spliced transcripts in muscle biopsy specimens are molecular signatures of DM and are under investigation as biomarkers for disease progression. Research into measuring these splicing abnormalities in biofluids (urine, blood, cerebrospinal fluid) is yielding promising results as less invasive alternatives to repeated muscle biopsy.

DM1 vs. DM2: Comparison

Clinical Presentation: DM1

Classic Adult DM1

The classic adult phenotype is the most common presentation, typically manifesting in the second to fourth decades. Patients develop relatively symmetric, progressive distal upper and lower extremity weakness and wasting, particularly of finger flexors and ankle dorsiflexors, resulting in weak grip and a steppage gait. In contrast to neurogenic causes of foot drop, toe extensors may be relatively spared. The characteristic DM1 facies includes a long, thin face with temporalis and masseter atrophy, ptosis, frontal balding, nasal speech, and dysphagia. Neck flexor weakness is common.

Congenital DM1

Congenital DM1 represents 15–20% of DM1 cases and is the most severe form. It is almost exclusively maternally transmitted—the mother is often a premutation carrier or has mild, undiagnosed DM1. Infants present with severe generalized hypotonia, muscle weakness, and respiratory and feeding difficulties frequently requiring NICU admission. Mortality approaches 30% within the first year of life for infants requiring more than 3 months of ventilatory support. Facial weakness and a tented upper lip at birth are highly suggestive clinical findings. Talipes equinovarus (clubfoot) may be present from reduced fetal movement in utero.

Clinical myotonia is absent in the neonatal period but typically develops in childhood. Although motor milestones improve over time, neurobehavioral impairment frequently emerges, including intellectual disability, executive dysfunction, features of autism spectrum disorder, and high rates of unemployment in adulthood.

Late-Onset DM1

Patients with late-onset DM1 (50–100 CTG repeats) typically develop symptoms in the fifth decade or later, presenting with mild distal weakness, early-onset cataracts, and myotonia. These patients may remain undiagnosed due to their mild phenotype. Despite mild symptoms, they still require cardiac monitoring and adherence to DM1 management guidelines, as life-threatening arrhythmias can occur at any disease stage.

Clinical Presentation: DM2

DM2 is a predominantly adult DM form characterized by proximal and sometimes axial weakness, primarily affecting hip and neck flexor muscles. Many patients describe prominent muscle pain or stiffness, which can be the sole skeletal muscle manifestation—misdiagnosis as fibromyalgia is common. Symptom onset varies from the second to sixth decades.

• Despite proximal weakness distribution, percussion myotonia is more easily elicited in distal muscles (finger extensors, thenar eminence)
• Myotonia is usually milder and more variable than in DM1, and its absence does not exclude DM2
• Neck extensor and paraspinal weakness may produce head drop or camptocormia
• Calf hypertrophy has been reported as a common but nonspecific finding
• Cataracts occur (including characteristic “Christmas tree” cataracts), though facial features and ptosis are rare
• Autoimmune disorders are more frequent (~30%) in DM2 compared to DM1 and the general population

Myotonia

Myotonia is the clinical hallmark of adult DM, resulting from missplicing of CLCN1, which produces a defective chloride channel that impairs normal muscle fiber repolarization. Two important clinical features should guide examination:

• Myotonia is often not bothersome to patients and may not be the presenting complaint
• It is variably present on examination and is best tested after a period of rest (before strength testing), as it may dissipate with repetitive movement

Types of Myotonia

• Grip myotonia: Delayed hand opening after forceful grip for several seconds; improves with repeated hand opening (warm-up phenomenon)
• Eyelid myotonia: Delayed eyelid opening after forceful eye closure; also demonstrates warm-up
• Percussion myotonia: Delayed muscle relaxation after tapping with a reflex hammer; tested at the thenar eminence and extensor digitorum communis; may be present even when spontaneous myotonia is absent
• Electrical myotonia (EMG): Myotonic discharges on needle EMG at rest—trains of positive sharp waves with characteristic sound; DM1 shows waxing and waning pattern; DM2 shows waning pattern; electrical myotonia is usually present in all adult DM1 patients but may be absent in DM2

Exacerbating factors include rest, cold temperature, and pregnancy. Myotonic discharges are not specific for DM and can occur in other myopathies, neuropathies, and even MuSK myasthenia gravis.

Multisystem Involvement

Cardiovascular Complications

Cardiac involvement is the second most common cause of death in DM (after respiratory complications) and demands proactive surveillance. Any cardiac rhythm abnormality may occur in up to 25% of patients with DM1 and less frequently in DM2:

• Atrioventricular blocks and ventricular tachyarrhythmias are the most common causes of sudden cardiac death
• Sudden death can be the initial cardiac manifestation or even the first disease manifestation of DM
• Prolongation of the PR interval (>200 ms) or QRS complex may be the earliest ECG abnormalities
• Annual incidence of sudden death in DM1 and DM2 is 0.53–1.16%
• Metabolic syndrome and vascular risk factors are common, particularly in DM2

Respiratory Complications

Respiratory complications are the leading cause of death in DM1. Weakness and myotonia of the diaphragm, intercostal, and abdominal muscles lead to restrictive physiology, hypoventilation (particularly nocturnal), and impaired cough. Aspiration pneumonia occurs in patients with dysphagia. Sleep apnea—obstructive, central, or mixed—is frequent and contributes to daytime sleepiness.

Other Systemic Manifestations

Diagnostic Evaluation

Genetic Testing

Genetic testing is the gold standard for diagnosis. When clinical history and examination suggest DM (distal weakness with myotonia in DM1; proximal weakness with pain in DM2), confirmatory genetic testing should be sent after appropriate genetic counseling. Key considerations:

• DM1 testing uses PCR-based methods for smaller expansions and Southern blot or repeat-primed PCR for larger expansions
• DM2 testing is technically challenging due to very large repeat sizes (up to 11,000 CCTG repeats); repeat-primed PCR is the preferred method
• CTG repeat length should not be used for prognosis despite being an indicator of severity—somatic mosaicism limits predictive value
• Genetic counseling must address anticipation (DM1), reproductive implications, and cascade testing of at-risk family members
• DM1 genetic testing is not currently included in newborn screening programs

Electrodiagnostic Studies

Needle EMG demonstrates myotonic discharges—trains of positive sharp waves or brief motor unit potentials with characteristic waxing and waning of amplitude and frequency in DM1 and a waning pattern in DM2. Myotonic discharges are more likely in distal muscles of the upper and lower extremities in both types. In DM2, the vastus lateralis and tensor fascia latae are particularly sensitive muscles. Additional EMG findings include short-duration, low-amplitude motor unit potentials with early recruitment, reflecting the underlying myopathic process.

Muscle Biopsy

Biopsy is not required for diagnosis when genetic testing is available but may be performed during the workup of undiagnosed weakness. Characteristic findings include abundant internally and centrally located nuclei, type 1 fiber atrophy (DM1) or type 2 fiber atrophy (DM2), nuclear clumps, ring fibers, and sarcoplasmic masses. These histopathologic features may provide the first clue to a DM diagnosis in patients undergoing biopsy for unexplained myopathy.

Anesthesia and Perioperative Risk

Treatment and Management

No disease-modifying therapy is currently available for DM. Management is symptomatic, preventive, and multidisciplinary.

Myotonia Management

• Mexiletine: First-line antimyotonia agent; effective at reducing clinical myotonia in DM1; originally developed as a cardiac antiarrhythmic (class IB sodium channel blocker)
• Symptomatic treatment is indicated only when myotonia is bothersome or interferes with daily activities—many patients do not require treatment
• Cardiac clearance is mandatory before starting mexiletine—ECG at baseline and periodically during treatment; avoid in patients with cardiac conduction abnormalities
• A randomized controlled trial showed no benefit of mexiletine on 6-minute walk time, though it remained effective for myotonia symptoms

CNS and Sleep Management

• Modafinil: For central hypersomnia and excessive daytime sleepiness when sleep apnea has been adequately treated
• CPAP/BiPAP: For obstructive and/or central sleep apnea; perform overnight oximetry or polysomnography
• Neuropsychologic evaluation for executive dysfunction, apathy, and behavioral issues
• Low threshold for brain imaging (temporal pole FLAIR hyperintensities described in DM1)

Multidisciplinary Surveillance

Pregnancy Considerations

Pregnancy in women with DM carries significant maternal and fetal risks that require multidisciplinary management:

• Maternal complications: Miscarriage rate ~32.5%; preterm labor (~28%); peripartum hemorrhage (~14%); pre-eclampsia (~10%); polyhydramnios; increased respiratory insufficiency and cardiac strain from physiologic changes of pregnancy
• Myotonia and weakness may worsen during pregnancy and may not fully return to baseline postpartum
• Congenital DM1: Exclusively maternal transmission; affected neonates require NICU admission for respiratory and feeding support; a mother with mild or undiagnosed DM1 (premutation carrier) can have a severely affected infant due to anticipation
• DM2 and pregnancy: 21% of women with DM2 had their first symptom during pregnancy; more frequent urinary tract infections and preterm labor; no congenital DM2 form
• Pre-conception counseling: Essential for all women with DM; discuss anticipation risk (DM1), anesthesia precautions, and the need for high-risk obstetric care
• Delivery should be planned at a center with neonatal ICU capabilities

Epidemiology and Prognosis

DM1 is the most common muscular dystrophy in adults, with a worldwide estimated prevalence of 9.27 per 100,000 (highest in European populations at 12.25 per 100,000). Population-based newborn screening studies suggest the true prevalence may be substantially higher (~1 in 2,100), with over half of identified cases carrying expansions in the 50–150 repeat range (late-onset phenotype). DM2 prevalence is estimated at 2.29 per 100,000 worldwide but may be as high as 1 in 1,830 in Finland. Both forms are significantly underdiagnosed, particularly in patients without prominent skeletal muscle involvement.

Life expectancy is reduced in DM1: median survival is approximately 60 years, with an inverse correlation between survival and CTG expansion length. Respiratory complications are the leading cause of death, followed by cardiac complications. Whether survival is also reduced in DM2 is not yet established.

Emerging Therapies

The recognition of RNA toxicity as the common pathogenic mechanism in DM1 and DM2 has opened the door to disease-modifying strategies targeting expanded DNA or RNA. Several therapeutic approaches are in development:

• DYNE-101 (Dyne Therapeutics): An antisense oligonucleotide (ASO) conjugated to a transferrin receptor 1 (TfR1)-binding antibody fragment to enhance muscle delivery. The phase 1/2 ACHIEVE trial has shown compelling results: correction of alternative splicing (19–27% improvement in composite splicing index), ~20% improvement in muscle strength at 12 months, and improved functional endpoints including video hand opening time and quantitative muscle testing. FDA Fast Track designation was granted in January 2025, with a registrational expansion cohort planned for potential accelerated approval submission in H1 2026
• PGN-EDODM1 (PepGen): A peptide-conjugated ASO evaluated in the phase 1 FREEDOM-DM1 trial; received FDA Fast Track designation; designed for enhanced tissue delivery using PepGen’s Enhanced Delivery Oligonucleotide (EDO) platform
• Tideglusib: A small molecule glycogen synthase kinase 3-beta (GSK-3β) inhibitor with demonstrated safety in congenital and childhood-onset DM1 (phase 2); an open-label study in the pediatric DM1 population is ongoing
• CRISPR/Cas9 approaches: Aimed at removing the pathogenic DNA expansion using recombinant adeno-associated virus delivery; currently in preclinical development
• Biomarker development: Splicing biomarkers in biofluids (urine, blood, CSF) are under investigation as noninvasive measures of disease progression and treatment response, though no single biomarker is likely to capture all disease manifestations

Because DM1 and DM2 share a common RNA-mediated mechanism, therapeutic success in one form may accelerate development for the other.

Differential Diagnosis: DM vs. Nondystrophic Myotonic Disorders

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