Throughout this issue the point has been made repeatedly that "normal" human muscle is mutable and that consequently physical therapists should consider the muscular component in the evaluation and treatment of almost every patient. Other articles in this issue have described the changes that take place in normal muscle in response to a number of stimuli. The following article deals with muscle from a different orientation: what is found when diseases primarily affect muscle. The structural changes are examined that occur in response to many neuromuscular diseases. Frequently, the diagnosis of different diseases and the clinical management of the conditions by stages are based on the types of alterations described. This review provides the therapist with the background knowledge to better understand the diagnoses of neuromuscular diseases and with a concise resource when reading the literature concerning muscle pathology and when evaluating or treating patients with pathological conditions of muscle. (+info)
Late infantile autosomal recessive myotonia, mental retardation, and skeletal abnormalities: a new autosomal recessive syndrome.
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Four sibs of non-consanguineous parents who had myotonia from late infancy are described. Mild to moderate mental retardation, severe bone abnormalities of the vertebral column (mainly in the thoracolumbar region), and short stature were also observed. Autosomal recessive inheritance is demonstrated. These cases are compared with reported cases of the Schwartz-Jampel syndrome. (+info)
Hypothyroidism with true myotonia.
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A patient with subclinical hypothyroidism who presented with true myotonia is described. There was no evidence that either he or members of his family had dystrophia myotonica or myotonia congenita. Treatment with thyroxine resolved his symptoms completely. (+info)
Myotonia as a side effect of diuretic action.
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1. Commonly used loop diuretics produce side effects in man which are similar to chemically induced myotonia. These diuretics have structural affinity with known myotonic agents. 2. We have observed EMG myotonia in vivo in leg muscles of rats treated with intravenous frusemide. 3. In the presence of several different diuretics, rat isolated diaphragm, soleus and extensor digitorum longus muscles as well as frog sartorius muscles produce typically myotonic contractions with relaxation times up to several seconds. 4. Intracellular recording of action potentials from diuretic-treated muscles reveals long lasting after-discharges following a brief electrical stimulus, again typical of chemically induced myotonia. 5. Having demonstrated a myotonic action of several diuretics we suggest a need for caution in using these drugs in persons with hereditary myotonia and a need to be aware of possible provocation of myotonia in subclinical cases. Myopathies and neuropathies which are known to result from chronic exposure to myotonic agents also need to be considered. 6. In our study, the diuretic, acetazolamide, unmasked subthreshold myotonia. This seems to be at variance with reports of its usefulness in the treatment of myotonia. 7. Diuretics should probably not be employed in the treatment of herbicide intoxication where their myotonic activity would be expected to add to the known myotonic activity of the herbicide. (+info)
Different effects on gating of three myotonia-causing mutations in the inactivation gate of the human muscle sodium channel.
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1. Three mutations at the same site in the inactivation gate of the alpha-subunit of the human muscle Na+ channel, G1306E, G1306V and G1306A, cause three phenotypes of K(+)-aggravated myotonia: G1306E as the most severe and G1306A as the most benign form. 2. Recombinant wildtype (WT) and mutant (G1306E, G1306V and G1306A) human Na+ channels were expressed in human embryonic kidney cells (HEK293). G1306E and G1306V channels showed a distinct increase in the time constants of inactivation (tau h1 and tau h2) and in the ratios of steady-state to peak currents (Iss/Ipeak) (e.g. at 0 mV, G1306E vs. WT; tau h1, 1.29 +/- 0.10 vs. 0.52 +/- 0.01 ms; Iss/Ipeak, 2.90 +/- 0.40 vs. 0.93 +/- 0.19%). G1306A channels showed only an increase in tau h1 (0.74 +/- 0.07 ms). For G1306E and G1306V channels, the steady-state inactivation curves, as well as the voltage dependence of the rate of recovery from inactivation, were shifted by +15 mV. For G1306A the h infinity curve was shifted by only +5 mV. 3. G1306E and G1306V channels showed prolonged current rise times and later first openings suggesting slowing of activation. For G1306E channels only, the steady-state activation curve was shifted by -7 mV. For all mutants the deactivation time constants were increased. 4. We conclude that (i) the combination of alterations in inactivation and activation produces the slowing of the current decay, (ii) the slowed inactivation is most responsible for myotonia, and (iii) the shift of the steady-state activation curve, seen only with G1306E channels, may explain the severity of this phenotype. 5. The results suggest that two of the mutations in the Na+ channel inactivation gate also alter channel activation and deactivation. (+info)
Modifications of gene expression in myotonic murine skeletal muscle are associated with abnormal expression of myogenic regulatory factors.
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The mouse mutants ADR ("arrested development of righting") and the allelic CRP ("cramp") are characterized by a myotonic phenotype resulting from a dysfunction of the skeletal muscle chloride channel which leads to myotonic trains of actions potentials in response to stimuli. Compared to normal mouse muscle, numerous biochemical modifications have been found in the ADR muscle, and changes are observed in the expression of certain isoforms of contractile proteins. We have therefore measured the levels of the mRNA transcripts encoding the myosin heavy chain isoforms (MyHC) in both mutants. Transcripts for the myogenic regulatory factors were also studied since they are known to play a role in the induction of muscle-specific gene transcription, and their own expression is modified by different electrical activity patterns. In both mutants, the mRNA encoding the IIB MyHC was considerably decreased. In contrast, the mRNAs for the IIA, IIX, and beta/slow MyHCs were increased. The mRNA for the neonatal MyHC mRNA was not detectable, and therefore fiber regeneration does not appear to play a role in these phenomena. Among the myogenic regulatory factors, herculin is the most abundant in adult muscle; however, herculin mRNA undergoes a large decrease in myotonic muscle which does not seem to be related to the changing fiber type. The levels of MyoD and myogenin mRNAs are also modified with the former decreasing and the latter increasing. Qualitatively similar changes are seen in the ADR and CRP mutants; however, they are generally less pronounced in CRP. These observations suggest that specific myogenic factors may be linked to the expression of individual MyHC genes and that abnormal expression of some of the factors may be associated with myotonic muscle pathology. (+info)
Absence of the skeletal muscle sarcolemma chloride channel ClC-1 in myotonic mice.
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The voltage-dependent chloride channel ClC-1 stabilizes resting membrane potential in skeletal muscle. Mutations in the ClC-1 gene are responsible for both human autosomal recessive generalized myotonia and autosomal dominant myotonia congenita. To understand the tissue distribution and subcellular localization of ClC-1 and to evaluate its role in an animal model of myotonia, antibodies were raised against the carboxyl terminus of this protein. Expression of the 130-kDa ClC-1 protein is unique to skeletal muscle, consistent with its mRNA tissue distribution. Immunolocalization shows prominent ClC-1 antigen in the sarcolemma of both type I and II muscle fibers. Sarcolemma localization is confirmed by Western analysis of skeletal muscle subcellular fractions. The ADR myotonic mouse (phenotype ADR, genotype adr/adr), in which defective ClC-1 mRNA has been identified, is shown here to be absent in ClC-1 protein expression, whereas other skeletal muscle sarcolemma protein expression appears normal. Immunohistochemistry of skeletal muscle from ADR and other mouse models of human muscle disease demonstrate that the absence of ClC-1 chloride channel is a defect specific to ADR mice. (+info)
Sodium channel mutations in paramyotonia congenita exhibit similar biophysical phenotypes in vitro.
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Mutations in the skeletal muscle voltage-gated Na+ channel alpha-subunit have been found in patients with two distinct hereditary disorders of sarcolemmal excitation: hyperkalemic periodic paralysis (HYPP) and paramyotonia congenita (PC). Six of these mutations have been functionally expressed in a heterologous cell line (tsA201 cells) using the recombinant human skeletal muscle Na+ channel alpha-subunit cDNA hSkM1. PC mutants from diverse locations in this subunit (T1313M, L1433R, R1448H, R1448C, A1156T) all exhibit a similar disturbance in channel inactivation characterized by reduced macroscopic rate, accelerated recovery, and altered voltage dependence. PC mutants had no significant abnormality in activation. In contrast, one HYPP mutation studied (T704M) has a normal inactivation rate but exhibits shifts in the midpoints of steady-state activation and inactivation along the voltage axis. These findings help to explain the phenotypic differences between HYPP and PC at the molecular and biophysical level and contribute to our understanding of Na+ channel structure and function. (+info)