Myotonia Congenita
AD (Thomsen) and AR (Becker's) forms
Autosomal recessive myotonia congenita (Becker dystrophy): usually caused by loss of functional channel proteins due to several different mutations, including deletions and missense mutations. Seen in 1st or 2nd decade.
Autosomal dominant myotonia congenita (Thomsen's disease): usually caused by loss of function (dominant negative effect) or gain of abnormal function (such as increasing sodium conductance). Present since birth.
Becker's form is clinically worse and more common.
Mutations in the gene on 7q35 that encodes a muscle chloride channel (CLCN1)
Low chloride conductance interferes with fast depolarization of the muscle membrane, specifically the T tubule channels, resulting in repeated firing of the muscle membrane.
Chloride channels act as buffer and cause large chloride current flow when there is any deviation from the resting muscle membrane potential; this avoids any spontaneous discharges that could be produced by increased muscle excitability from accumulation of potassium ions in T tubules; this duration of depolarization of T tubules is limited by resting chloride current.
Dysfunction of chloride channel as a result of genetic mutation, causes partial depolarization of the membrane and allows a hyperexcitable state to exist, resulting in myotonia. Because chloride are responsible for 70% of the skeletal muscle resting membrane potential, reduced chloride conductance leads to a decrease in rate of muscle membrane repolarization. The sodium channel is able to recover from inactivation faster. As a result of the muscle membrane being in a state of depolarization, recurrent firings of action potential or myotonic discharges occur. It is postulated that permanent excitability gives rise to constant mild muscle activity, resulting in muscle hypertrophy.
Myotonia causes muscle stiffness and decreased speed. It improves after exercise.
Patients experience a warm-up phenomenon. They complain of stiffness and weakness in muscles (transient paresis) following a period of rest, which improves with increasing strength following exercise.
Transient paresis of biceps test: Have the patient resist you at the biceps for 5 seconds. Almost all patient start out with MRC 5/5 strength. If within the 5 seconds when patients are resisting you detect the MRC score falls below 5/5, then you follow that with a warm-up exercise with 10 successive 10 seconds contraction with you as the examiner exerting counterforce. If the MRC score increases by at least 1 point after the warm-up exercise then the transient paresis test is considered positive and indicative of a chloride channelopathy.
Patients reports that their hands stiffen up after turning a doorknob or after shaking somebody’s hand. Their legs seem to "lock up’’ when they start to jog or run, but after a few minutes of running, the symptoms seem to abate.
If they perform the same task repeatedly, it becomes easier.
Patients are usually quite muscular for their age, demonstrates percussion myotonia at the thenar eminence, and have full muscle strength throughout.
Muscle hypertrophy may be seen
Grip and percussion myotonia can be seen
EDX: SET decrement.
Tx: Mexiletene.
Mexiletine is a type 1B antiarrhythmic agent with high affinity for muscle sodium channels.
Muscle stiffness responds well to drugs that reduce the associated hyperexcitability of the sarcolemma by interfering with sodium channels located on it. These drugs theoretically reduce spontaneous discharges of electrical myotonia by decreasing the number of available sodium channels, but they have no known effects on chloride channels. One such drug is mexiletine, which is able to reduce myotonia with doses of 200 mg 2 or 3 times a day. Phenytoin 200 mg/d to 300 mg/d can also be used to treat myotonia.
Treatment of manifestations: Muscle stiffness may respond to sodium channel blockers such as mexiletine (currently the medication with best documented effect), lamotrigine carbamazepine, or phenytoin. Beneficial effects have also been reported with quinine, dantrolene, and acetazolamide.
Agents/circumstances to avoid: Depolarizing muscle relaxants (e.g., suxamethonium), adrenaline, beta-adrenergic agonists, and propranolol may aggravate myotonia.
Daube JR, Cascino GD, Dotson RM, Silber MH, Westmoreland BF. Electromyography and nerve conduction studies. Continuum Lifelong Learning Neurol 1998;4(5):101-102.
and
Saperstein DS. Muscle channelopathies. Continuum Lifelong Learning Neurol 2006;12(3): 121-125.
1. General Information
Myotonia congenita is a channelopathy due to a point mutation in the muscle chloride channel gene CLCN1 on chromosome 7. Over 50 mutations have been described. Abnormal chloride ion conductance in the muscle membrane is thought to be responsible for the spontaneous prolonged and repetitive firing of muscle fibers, which may be seen at rest or after voluntary activity. The spontaneous activity manifests as myotonic discharges, muscle fiber action potentials that wax and wane in amplitude and frequency due to the muscle membrane abnormality. The variable discharge frequency of 40 to 100 per second accounts for the characteristic sound during EMG needle testing, likened to a bomber aircraft diving toward its target.
2. Symptoms and Signs
Myotonia is the consequence of impaired muscle relaxation and may cause nonspecific cramping or muscle pain, particularly after activation. Muscles may tighten or “lock-up” on attempting sudden activity and falls may occur on first trying to walk or sprint. Eye closure myotonia may be seen as delayed eyelid opening after forceful eye closure, for example in infants after a crying spell. In severe cases myotonia may impair chewing and swallowing. Difficulty releasing a grip (grip myotonia) is commonly experienced such as after turning a doorknob, grasping a handle or after a handshake. A warm-up phenomenon is seen with improvement in myotonia upon continued repetitive activity. Reduction in myotonia after several repetitions is consistent with the warm-up phenomenon. Percussion myotonia is commonly tested by tapping the thenar eminence with a reflex hammer. This generally results in thumb elevation/abduction and slow relaxation over a few seconds. Percussion of the extensor digitorum communis muscle while the forearm is extended and the wrist is hanging down may elicit sustained reflex extension of the wrist and fingers for a second or more. The severity of myotonia may fluctuate within an individual and vary among affected family members.
There are two forms of myotonia congenita, an autosomal dominant (Thomsen disease) and an autosomal recessive (Becker disease which should not to be confused with the dystrophinopathy). Age of onset is earlier in the dominant form, usually within the first 2 years of life, as compared to between 4 to 12 years in the recessive form. The recessive form tends to be associated with more severe symptoms and gradually progresses in the first two decades of life. Limb stiffness tends to be worse in the legs and to a greater degree proximal than distal. After a severe bout of myotonia, transient muscle weakness may occur, especially in the hands. Some individuals develop mild fixed weakness with a distal predominance. Muscle weakness is unusual in Thomsen disease as opposed to myotonic dystrophy.
3. Diagnosis
The diagnosis of myotonia congenita is based on the clinical history, the findings of myotonia without prominent weakness, and supportive electrodiagnostic evidence of myotonic discharges both at rest and with volitional activity. Serum CK levels are usually normal or slightly elevated. Electrical myotonia is not unique to myotonia congenita and can be seen in other conditions including myotonic dystrophy, paramyotonia, hyperkalemic periodic paralysis, polymyositis, acid maltase deficiency and toxic myopathies. Serum creatine kinase levels may be mildly elevated but are usually normal. Chloride channel gene testing is commercially available to confirm the diagnosis and to help guide genetic counseling.
4. Treatment
Most patients with myotonia congenita do not require symptomatic treatment with medication. When myotonia is severe, antiarrhythmic or antiepileptic medications that interfere with sodium channel function may be beneficial, but these have not been well-studied in prospective trials. Mexiletine is often used as it reduces myotonia and may prevent the transient weakness that can occur in Becker form of the disease. An electrocardiogram should be obtained prior to use of mexiletine and periodically after to ensure there are no cardiac conduction abnormalities. A cardiologist should be consulted if the latter are found. Dantrolene may also be helpful in reducing muscle stiffness by acting to block the release of calcium from the sarcoplasmic reticulum.
5. Remember
Clinical and electrical myotonia is not specific to myotonic dystrophy
Weakness is generally not a feature of myotonia congenita
Myotonia congenita is due to a mutation in the muscle chloride channel gene CLCN1
A warm-up phenomenon is seen with lessening myotonia during persistent activity
Myotonia congenita may be mild and may not require pharamacologic treatment.
Increased risk of malignant hyperthermia with anesthetic agents.
Neurophysiology in MC:
Routine NCS are normal. Needle EMG shows myotonic discharges at rest and during volitional activity. It may be difficult to appreciate MUAPs as myotonic discharges may obscure the voluntary MUAPs, but morphology and recruitment is usually normal. Short duration, small amplitude MUAPs may be occasionally seen in weak muscles. SFEMG reveals normal fiber density but slightly increased jitter. On RNS, a decrement is appreciated when a prolonged train of stimuli are delivered at 10 Hz or more. The CMAP amplitude may decrease to 65% of normal and even to more percentage of decrement if stimulation is given at higher rates. The SET is associated with a decrease in CMAP amplitude immediately after exercise and return to baseline after 20-40 seconds, in 48-80% of individuals with MC. The reduction in CMAP amplitudes is lesser with repeated trials of SET corresponding to the clinical warm-up phenomena. This is called Fournier pattern II. A greater than 40% decrement of SET is specific for MC. It is seen in AR forms (Becker's) MC, while the AD (Thomsen) MC is not associated with significant change. However, performing the SET in a cooled limb in these patients (AD form) may result in drop of CMAP amplitude that later improves with repeated SET (normal converted to type II with cold). In AR form of MC, there is no difference in results when SET is performed in a warm or cool limb (remains type II). PEMPs (post-exercise repetitive discharges) are seen in 1/3 of MC after short exercise but disappear within 10-30 seconds after exercise. LET is usually normal.