Myotonic disorders are a group of genetic disorders, the hallmark of which is the presence of myotonia. They may or may not be clinically evident to the patient or examiner. Clinically, myotonia can be described as the inability to relax a muscle following activation. 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 with other disorders such as hypothyroidism or with the administration of certain drugs. This review will describe the clinical presentation and pathophysiology of some 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.
Myotonic disorders are classified as either dystrophic or non-dystrophic. Both dystrophic and non-dystrophic forms can be inherited or acquired. Autosomal dominant inheritance is most common, with Becker Dystrophy the most common autosomal recessive outlier. Both type one (DM1) and type two (DM2) are caused by DNA tandem repeats.
Epidemiology including risk factors and primary prevention
DM1 is the most common form of muscular dystrophy in adult has an estimated incidence of 1:8000 or 13.5 per 100,000 live births and a prevalence of 3-15 per 100,000, with rates nearly 20 times higher in certain areas such as Sweden and the Basque region of Spain. It can present at any age, and frequently demonstrates an anticipation phenomenon, in which the disease will present at a younger age in subsequently later generations. Longer DNA tandem repeats are associated with earlier disease onset, as well as more severe disease. Most commonly, DM1 presents in the second through fourth decades of life, with d the most severe cases presenting in infancy.
DM2, or proximal myotonic myopathy (PROMM), also occurs predominantly in the second through sixth decades of life and may be even more common in certain parts of the world, such as Finland. There is no clear correlation between length of tandem repeats and severity of disease.
Of note, myotonic dystrophy is a systemic, rather than an isolated muscle, disorder.
Ion conductance abnormalities result in delayed relaxation of muscle. Blockade of nerve or of the neuromuscular junction does not alter myotonia. Volitional contraction or mechanical stimulation, such as needle insertion or muscle percussion, will trigger both clinical and electrical myotonia. Muscle membrane repolarization results from Na+ channel inactivation and increased K+ channel permeability. Changes in K+ permeability and concentration result in equal and opposite Cl- ion changes. Decreased chloride conductance results in a prolonged after-potential. Ingestion of carboxylic acids and sterol inhibitors are thought to cause a steric block of chloride channels. DM1 results from a mutation that alters expression of myotonin protein kinase and nuclear retention of mutant mRNA, due to a cytosine-thymine-guanine (CTG) trinucleotide repeat on the DMPK gene on chromosome 19q13.2 (Table 1).
TABLE 1: MYOTONIC DISORDERS OF MUSCLE
|Myotonic Dystrophy (DM1)||Myotonic Dystrophy (DM2)||Myotonia Congenita||Paramyotonia Congenita||Hypokalemic Periodic Paralysis||Hyperkalemic Periodic Paralysis|
|Inheritance||AD||AD||AD (Thomsen) AR (Becker)||AD||AD||AD|
|Ion Channel Affected||Cl-+ Na+||Cl-+ Na+||Cl-||Na+||Ca++ Na||Na+|
|Gene||DMPK||CNBP (ZNF9)||CLCN1||SCNA4||CACNL1A3or SCNA4||SCNA4|
|Triggers||Exercise||Exercise||Sudden movement, cold||Cold, rest after exercise||Rest after exercise, high carb Na+||Cold, rest after exercise|
|Therapy (avoid triggers)||Mexiletine Exercise||Mexiletine||K+ Acetazolamide (Diamox)||Thiazides Tocainide|
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 eg, single finger weakness, problems 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
|Onset||Later onset||2nd decade||Childhood||1/4 of offspring of DM1 mothers||3th – 4th decade|
|Weak||Rare||Distal||Distal, Mild||Floppy infant||Proximal, may have no or remarkable atrophy|
|Myotonia||EMG only||Mild clinical||Mild clinical||EMG only||Variable|
|Other Signs||Premature balding, cataracts||Cataracts, balding, fatigue, gastrointestinal symptoms, cardiac conduction defects||Like classical with cognitive and behavioral issues||Polyhydramnios, poor fetal movements, facial & jaw muscles affected, decreased feeding, club feet, contractures, mental retardation, developmental delay, high mortality||Pain, Cataracts|
Specific secondary or associated conditions and complications
The gene’s penetrance and degree of complications are variable. These include cardiac conduction defects (often asymptomatic), mild cognitive dysfunction, hypoventilation, aspiration due to dysphagia, hypersomnia, smooth muscle changes resulting in esophageal, stomach and intestinal motility dysfunction, cataracts, retinal degeneration, ocular weakness, cranial and spinal skeletal deformity, hormone changes (pituitary, growth, pancreatic), complications in pregnancy including prolonged labor, weakness, increased neonatal mortality; and intolerance to anesthetics.
2. ESSENTIALS OF ASSESSMENT
Unlike in the congenital form of DM, if a patient presents as an adult, the onset may have been slow and progressive, with the vast majority of patients remaining ambulatory nearly twenty years after the onset. Typically, a patient with DM1 will present with facial weakness, possibly characterized by ptosis, and weakness in neck flexion and extension. Additionally, patients are predisposed to distal extremity weakness, noted particularly with finger flexor and extensor weakness, as well as difficulty with dorsiflexion. Superficially, they may also be noted to have temporal atrophy and frontal balding, as well as typical “myotonic facies”, which may present as a pleasant, apathetic facial expression. In conjunction with this facial expression, patient’s with DM1 have also been noted to have mild cognitive impairments, with a marked impassivity toward their symptoms, which may contribute to the advanced stated in which they can sometimes present. In addition to their cognitive deficits, they may also present with visual deficits, as early cataracts (before age 50) with bilateral iridescent cortical lens opacities being pathognomonic for DM1. Patients may also struggle with dysphagia and dysarthria, further contributing to their functional impairments. Due to smooth muscle dysfunction, patients may also experience gastrointestinal dysmotility resulting in GERD, diarrhea, or constipation. For unknown reasons, there is also a higher incidence of endocrine dysfunction in this population. Reports have also been given of an increased risk of malignancy in patients with DM, though this continues to be a topic of research.
DM2 typically presents in a more mild form than DM1. While proximal weakness and early cataracts are often presenting symptoms, 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.
Congenital DM, the disease’s most severe form, may present initially not as myotonia, but rather as a typically “floppy baby,” which may result in a search for DM1 in the baby’s parents. They may also be noted to have issues with ventilation, gastric hypomotility, and facial diplegia. If the child survives past birth, they may develop significant intellectual disability. However, muscle strength can improve over time with rehabilitation intervention.
The most obvious first sign upon first seeing the patient may be the appearance of facial atrophy and weakness, including ptsosis, along with the flat affect and frontal balding. As the exam progresses, weakness may be noted, particularly distally in the finger flexors and extensors as well as in the ankle dorsiflexors. Tone may be normal to decreased. Unlike in other proximal myopathies, patient may have sternocleidomastoid weakness with relative sparing of shoulder girdle muscles. 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.
Due to their predilection for dorsiflexor weakness, patients may be noted to have a steppage gait pattern. Since it is a peripheral process, balance is usually preserved, but the decreased foot clearance may lead to an increased incidence of falls. 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. With the slow progression and years of compensating, independence is maintained until late in the course. Dysphagia and constipation, coupled with nutritional concerns from cognitive/behavioral changes and difficulty with self-feeding, may occur, while speech is less often affected. Affect is influenced by the bizarre facial appearance but is often indifferent and pleasant.
While DM2 in particular may present with asymptomatically elevated CK, muscle enzymes often are normal or only mildly elevated. Genetic testing is commercially available for both type 1 and 2. Muscle biopsy may be done to demonstrate type 1 fiber atrophy and centralized nuclei, which is present in both types, but may be milder in type
Not required for diagnosis, though there have been reports of dilated Virchow-Robbin spaces, hyperintensities in the periventricular areas and deep white matter, and asymmetrical involvement of the subcortical white matter The full significance of these findings has not yet been determined.
While myotonic discharges on EMG are nonspecific and may be seen inflammatory myopathies, hypothyroidism, and drug induced myopathies, myotonic discharges will be present in 100% of DM1 cases and 90-100% of all DM2 cases. Nerve conduction studies are typically normal.
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 a 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. The initiation of accessibility modifications in the home or for transportation services have an effect on the patient’s family as well. Additionally,
Consider genetic counseling and testing of family members, particularly given asymptomatic cardiac conduction defects in those yet undiagnosed.
3. REHABILITATION MANAGEMENT AND TREATMENTS
Available or current treatment guidelines
No treatment guidelines exist. Currently, treatment is primarily focused on symptomatic management, however research into promising genetic treatments is currently underway.
At different disease stages
Stretching, submaximal strengthening, NSAIDs, and modalities are useful for myalgias and stiffness. Compensate for home and work accessibility and provide patient education as appropriate. Link to resources such as Myotonic Dystrophy Foundation or a local clinic for support and information.
Manage blood glucose as needed. Provide mexiletine for function-limiting myotonia and NSAIDs for muscle pain. Coordinate thorough screening and treatment for cardiac, cancer, GI, and respiratory complications. Address nutritional concerns if dysphagia, difficulty with self-feeding, or jaw dislocation are present. 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. 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 the care of DM requires a multi-disciplinary approach. Management typically involves, at the very least, primary care, neurology, physiatry, and physical and occupational therapy. Depending on the severity of the disease, speech therapy, nutrition, cardiology, pulmonology, endocrinology, or oncology may also be involved. A focus should also be placed on the prevention of common comorbidities.t. 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. Surgical intervention is rare (eyelid procedures, contracture release) and requires careful communication of surgical risks. Geneticists and counselors are also vital members of the team. Obstetricians also need education about this special needs population, given that labor may be difficult due to poor uterine contractions.
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
Cutting edge concepts and practice
Antisense oligonucleotides (ASOs) are short nucleic acid sequences designed for use as small-molecule drugs in the treatment of neuromuscular diseases. This area of research is progressing rapidly in myotonic dystrophy, with a growing number of AONs entering preclinical and clinical development. Recent studies have shown evidence that treatment with gene therapy using ASO shows clinical improvement in strength, weight, and histological findings in mice with the same DNA tandem repeats as seen in DM1.
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.
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
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. The exact mechanism of myotonia production in myotonic dystrophy is not as well understood as in the other myotonic disorders.
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Original Version of the Topic
Kathryn Stolp, MD. Myotonic Disorders of Muscle. 12/27/2012.
Kaile Eison, MD
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Heakyung Kim, MD
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