Myotonia Congenita (Thomsen's Disease)
The history of muscle stiffness, difficulty initiating movements after rest, and difficulty releasing grasp, is typical for myotonia (delayed relaxation of muscles). The neurological examination showed percussion and grip myotonia, but no weakness, atrophy, or muscle hypertrophy. Widespread myotonic discharges and myopathic motor units were documented on EMG. There was an increase in the myotonic discharges following cooling of the right EDC muscle. The patient's mother and aunt also had myotonic discharges and myopathic motor units on EMG. This indicated an autosomal dominant inheritance pattern.
Three groups of clinical disorders, each caused by a different genetic defect and transmitted by autosomal dominant inheritance, have myotonia as a prominent clinical feature. These include myotonic dystrophy, sodium channelopathies (paramyotonia congenita, hyperkalemic periodic paralysis, and potassium-aggravated myotonia), and chloride channelopathies (dominant and recessive myotonia congenita).
We initially considered myotonic dystrophy which is the most common myotonic disorder and the one most frequently associated with weakness. Although there was no atrophy or weakness of the distal muscles, which is frequently seen in myotonic dystrophy, the EMG showed both myotonia and myopathic features. Myopathy is more commonly associated with myotonic dystrophy than with the channelopathies. Myotonic dystrophy is a multi-system disease with highly variable clinical manifestations. The patient and his family members did not exhibit the typical features seen in myotonic dystrophy (ptosis, frontal baldness, wasting of the temporalis and facial muscles, cataracts, or testicular atrophy). However, the chest pain was suggestive of possible cardiac involvement. The cardiac conduction system is frequently affected resulting in sinus bradycardia, atrioventricular block, and bundle branch block. Also, the younger onset in the patient compared to his aunt and mother was suggestive of anticipation, a clinical phenomenon frequently observed in myotonic dystrophy where there is earlier onset of disease symptoms of greater severity in successive generations. The cardiac work up which consisted of an EKG, echocardiogram, holter monitor, and exercise stress test was completely normal. The DNA analysis did not demonstrate an expanded trinucleotide repeat sequence on chromosome 19 which is seen in myotonic dystrophy.
We then considered the nondystrophic causes of myotonia which include the sodium and chloride channelopathies. As the molecular defects in these diseases are elucidated, the categorization of these diseases is becoming less well defined. They have overlapping clinical phenotypes and there is considerable phenotypic variation even within families that have the same mutation. The diseases are clinically defined as follows:
The diagnosis was confirmed by gene mutation analysis. The patient, his mother, and aunt all had the same point mutation of the chloride channel gene. The mutation is a G to A transition at position 689, resulting in the substitution of a glutamic acid for a glycine residue at position 180. This particular base change was first described by George et al. (1993), whose findings established this substitution as a Thomsen's disease mutation. They hypothesized that substitution of a negatively charged residue for a neutral residue introduces an electrostatic force that affects conductance of chloride through the channel or may alter the conformation of the protein in the membrane affecting function.
The etiology of the chest pains which were associated with the most severe attacks in all three family members remain a mystery. Extensive cardiac work up in all three family members has failed to reveal an abnormality. Review of the literature does not show any cases of myotonia congenita associated with chest pain. However, there are reports of chest pain that have been associated with proximal myotonic myopathy and detailed evaluations have not revealed a cardiac cause. It is possible that myotonia of the chest wall is the etiology of the chest pains.
The patient was initially treated with phenytoin and his myotonia was markedly improved. However, he developed fever, adenopathy, and splenomegaly which resolved when the phenytoin was discontinued. He was also tried on acetazolamide and mexiletine which were not tolerated secondary to side effects. He is currently on carbamazepine and is no longer symptomatic from the myotonia and has had no further episodes of chest pain or weakness.
In 1876, the Danish physician Julius Thomsen reported the first well described myotonic syndrome, myotonia congenita, in himself and his family. The syndrome is characterized by muscle stiffness or myotonia (delayed relaxation) that occurs following voluntary contraction. Typical complaints are difficulty releasing the grip of a handshake or opening the eyelids after squinting in bright sunlight. Myotonia tends to be worse after prolonged rest and often improves with persistent activity. Symptoms typically begin during the first decade and the severity remains relatively constant into adulthood.
There is a dominantly inherited form referred to as Thomsen's disease and a recessive form known as Becker's generalized myotonia. In Becker's, myotonic symptoms are more severe and the excessive contractions often produce muscle hypertrophy. A recent review of four families with dominantly inherited myotonia congenita examined genotype-phenotype correlations. Three of these families displayed the same point mutation, a glutamic acid for a glycine at position 230, that was seen in the family of our patient. Of the mutation positive family members, 90% displayed mild symptoms and 10% showed no symptoms. The EMG was the clinical feature that most correlated with the mutation data. Approximately 55% of the mutation positive patients tested positive for percussion myotonia. Most of the clinically symptomatic individuals stated that cold temperature and stress substantially worsened their myotonia. One of the most striking features of their data was the considerable clinical heterogeneity exhibited by the 38 patients studied.
As early as 1962 studies from myotonic goats suggested that there was a decreased resting membrane conductance to chloride. Although the resting membrane potential in myotonic and normal goats is approximately the same (-80 mV), depolarizing pulses produced the following differences in the myotonic subject:
Identification of the molecular genetic defects in these disorders became possible after the cloning of the chloride channel from the electric organ of Torpedo marmorata. Both Thomsen's and Becker's disease have been linked to chromosome 7q35 in the region of the human skeletal muscle chloride channel gene (CLCN1). The functional channel is thought to be a homotetramer, with each subunit having 1000 amino acids. The coding sequence is interrupted by 22 introns and has 12 putative transmembrane domains (D1 to D12) and a conserved domain (D13) located intracellularly. To date, 19 point mutations, including 14 missense mutations, three nonsense mutations, and two deletions have been described in various exons of the chloride channel gene. Chloride channels account for 70-80% of skeletal muscle resting membrane conductance. Studies in the myotonic goat have shown a diminished chloride channel open probability at voltages near the resting membrane potential of skeletal muscles. The defect in the chloride channel is thought to reduce the rate of action potential repolarization. Jentsch (1993) suggested that this allows sufficient time for the sodium channels to recover from inactivation, although the membrane is still depolarized. This is particularly true in the transverse tubule where chloride currents have a stabilizing influence on the accumulation of potassium during the repolarization phase of an action potential. With loss of function of the chloride channel, potassium accumulation in the transverse tubule during repolarization can produce a depolarizing after-potential capable of inducing repetitive self-triggering activity in the muscle fiber. This results in the repetitive firing typical of myotonia.
Distinguishing paramyotonia congenita and other sodium channel myotonias from the chloride channel myotonia congenitas can be clinically difficult. DNA testing is becoming more readily available to accurately diagnose atypical clinical presentations. The relative efficacy of various treatments in chloride channel versus sodium channel myotonias has yet to be established. Since no agents are known to be effective at stimulating chloride conductance, the treatment has centered around agents that decrease sodium channel conductance. Quinine, which affects the kinetics of sodium channel activation, was one of the first agents used. Phenytoin and carbamazepine have also been effective. The oral lidocaine derivative mexiletine, which blocks the sodium channel under use-dependent conditions, has also been used successfully. Acetazolamide, which is thought to act by preventing lowering of potassium, is also used and has been more effective in treating sodium channel myotonia.
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