Disease relevance of Myotonia

• Paramyotonia congenita (PMC), a dominant disorder featuring cold-induced myotonia (muscle stiffness), has recently been genetically linked to a candidate gene, the skeletal muscle sodium channel gene SCN4A [1].
• The importance of chloride channels is illustrated by the phenotypes that can result from their malfunction: cystic fibrosis, in which transepithelial transport is impaired, and myotonia, in which ClC-1, the principal skeletal muscle Cl- channel, is defective [2].
• DM is an autosomal dominant, multisystemic disorder characterized primarily by myotonia and progressive muscle weakness [3].
• Autosomal dominant myotonia congenita (Thomsen's disease) is caused by mutations in the muscle chloride channel CIC-1 [4].
• DM is characterized by autosomal dominant inheritance, muscular dystrophy, myotonia, and multisystem involvement [5].

High impact information on Myotonia

• Hitherto, myotonia has been considered peculiar to homeotherms where it is associated with several hereditable diseases and can be induced by specific treatments, most of which seem to act by decreasing membrane chloride conductance [6].
• Frogs and toads treated with high doses of anthracene-9-carboxylic acid (A-9-C) develop prolonged muscular contractions and 'divebomber' electromyograms characteristic of myotonia [6].
• This suggests that different mutations in CLC-1 may cause dominant or recessive myotonia [7].
• Paradoxical effects of clofibrate on liver and muscle metabolism in rats. Induction of myotonia and alteration of fatty acid and glucose oxidation [8].
• Myotonia precipitated by propranolol therapy [9].

Chemical compound and disease context of Myotonia

• Effects of acetazolamide on myotonia [10].
• 20,25-diazacholesterol myotonia: an electrophysiological study [11].
• Successful treatment with tocainide of recessive generalized congenital myotonia [12].
• Myotonia induced by ACA is inhibited by concentrations of diphenylhydantoin that are clinically effective in controlling hereditary myotonia in humans [13].
• Severe myotonia relieved by nifedipine [14].

Biological context of Myotonia

• Mutations within CLCN1, the gene encoding the major skeletal muscle chloride channel, cause either dominant Thomsen disease or recessive Becker-type myotonia, which are sometimes difficult to discriminate, because of reduced penetrance or lower clinical expressivity in females [15].
• However, all heterozygous males, but none of the heterozygous females, exhibited myotonic discharges in the electromyogram suggesting (i) a gene dosage effect of the mutations on the chloride conductance and (ii) male predominance of subclinical myotonia [15].
• We have systematically screened the open reading frame of the CLCN1 gene for mutations by SSC analysis (SSCA) in a panel of 24 families and 17 single unrelated patients with human myotonia [16].
• This allowed us to predict via synteny the chromosomal location of human Thomsen's and Becker's myotonias as close to the TCRB gene on human chromosome 7q [17].
• Carbohydrate metabolism was studied in fourteen patients with myotonia dystrophica (MD) using oral glucose, fructose and galactose tolerance tests [18].

Anatomical context of Myotonia

• Certain forms of myotonia, a condition characterized by delayed relaxation of muscle secondary to sarcolemmal hyperexcitability, are caused by diminished chloride conductance in the muscle cell membrane [19].
• Electron spin resonance experiments have been performed on erythrocyte membranes from rats with myotonia induced by treatment with 20,25-diazacholesterol [20].
• Electromyographic (EMG) myotonia was seen only in the masseter muscle in one and in the masseter and flexor pollicis longus muscle in the other patient [21].
• The mechanism by which ritodrine unmasked the myotonia is unclear but may be related to changes in the cell membrane (chloride conductance, the sodium-potassium pump, or membrane polarization) [22].

Gene context of Myotonia

• Autosomal dominant myotonia congenita is an inherited disorder of skeletal muscle caused by mutations in a voltage-gated Cl- channel gene (CLCN1, 7q35) [23].
• PROMM: the expanding phenotype. A family with proximal myopathy, myotonia and deafness [24].
• Genomic organization of the human muscle chloride channel CIC-1 and analysis of novel mutations leading to Becker-type myotonia [25].
• The detection of the stop codon in the adrmto allele is further indication of the identity of the Clc-1 chloride channel with the adr myotonia gene in the mouse, because a chain termination close to the N terminus would necessarily destroy gene function [26].
• Functional characterization is most advanced with ClC-0, ClC-1 (mutations which cause myotonia) and ClC-2, a swelling-activated chloride channel [27].

Analytical, diagnostic and therapeutic context of Myotonia

• Standardized protocols comprising short and long exercise tests were applied on 41 unaffected control subjects and on 51 case patients with chloride, sodium, or calcium channel mutations known to cause myotonia or periodic paralysis [28].
• The major side effects were in the neuromuscular system and included severe muscle weakness, myopathy and/or myotonia by electromyography, and elevation of creatine phosphokinase and aldolase levels [29].
• Isotonic tetanic contractions of the muscles treated with 2,4-D after more than 10 days of denervation revealed prolonged relaxation times similar to those of the intact side and characteristic of clinical myotonia [30].
• Using intracellular microelectrodes, we studied the pathomechanism of myotonia experimentally induced in rabbits by HCR inhibitors, simvastatin, and pravastatin [31].
• Correlative ECG, electrophysiologic (EPS), and pathologic findings of the conduction system (CS) in dystrophica myotonia has not been documented to our knowledge in the English literature [32].

References