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Background: Non-dystrophic myotonias (NDMs) are skeletal muscle disorders involving myotonia distinct from myotonic dystrophy. It has been reported that the muscle pathology is usually normal or comprises mild myopathic changes in NDMs. We describe various pathological findings mimicking those of myotonic dystrophy (DM) in biopsied muscle specimens from a patient with NDMs with a long disease duration., Case Presentation: A 66-year-old Japanease man presented eye closure myotonia, percussion myotonia and grip myotonia together with the warm-up phenomenon and cold aggravation from early childhood. On genetic analysis, a heterozygous mutation of the SCN4A gene (c.2065 C > T, p.L689F), with no mutation of the CLCN1, DMPK, or ZNF9/CNBP gene, was detected. He was diagnosed as having NDMs. A biopsy of the biceps brachii muscle showed increasing fiber size variation, internal nuclei, chained nuclei, necrotic fibers, fiber splitting, endomysial fibrosis, pyknotic nuclear clumps and disorganized intermyofibrillar networks. Sarcoplasmic masses, tubular aggregates and ragged-red fibers were absent., Conclusion: It is noteworthy that the present study revealed various pathological findings resembling those seen in DM, although the pathology is usually normal or mild in NDMs. The pathological similarities may be due to muscular modification with long-standing myotonia or excessive muscle contraction based on abnormal channel activity.

Recessive mutations in the gene encoding the histidine triad nucleotide binding protein 1 (HINT1) were recently shown to cause a motor-predominant Charcot-Marie-Tooth neuropathy. About 80% of the patients exhibit neuromyotonia, a striking clinical and electrophysiological hallmark that can help to distinguish this disease and to guide diagnostic screening. HINT1 neuropathy has worldwide distribution and is particularly prevalent in populations inhabiting central and south-eastern Europe. With 12 different mutations identified in more than 60 families, it ranks among the most common subtypes of axonal Charcot-Marie-Tooth neuropathy. This article provides an overview of the present knowledge on HINT1 neuropathy with the aim to increase awareness and spur interest among clinicians and researchers in the field. We propose diagnostic guidelines to recognize and differentiate this entity and suggest treatment strategies to manage common symptoms. As a recent player in the field of hereditary neuropathies, the role of HINT1 in peripheral nerves is unknown and the underlying disease mechanisms are unexplored. We provide a comprehensive overview of the structural and functional characteristics of the HINT1 protein that may guide further studies into the molecular aetiology and treatment strategies of this peculiar Charcot-Marie-Tooth subtype., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: To compare the clinical and electrophysiological findings in hereditary inclusion body myopathy (hIBM) and sporadic inclusion body myositis (sIBM) patients., Methods: We retrospectively identified 8 genetically proven hIBM patients and 1 DNAJB6 myopathy with pathological features of hIBM, and compared their clinical, electromyographic, and serological data with a group of 51 pathologically proven sIBM patients., Results: hIBM patients had a younger mean age of onset (36 vs. 60 years, P = 0.0001). Diagnostic delay was shorter in sIBM (6 vs. 15 years, P = 0.0003). Wrist flexors (P = 0.02), digit flexors (P = 0.01), digit extensors (P = 0.02), and quadriceps (P = 0.008) muscles were more frequently affected in sIBM. Fibrillation potentials were more common in sIBM patients (P = 0.03). Electrical myotonia was found in 4 hIBM patients, not significantly different from sIBM patients (P = 0.45). Creatinine kinase was higher in sIBM patients (799 vs 232, P = 0.03)., Conclusions: sIBM and hIBM seem to have similar electromyographic changes. The combination of clinical, serological, and histopathological findings can guide genetic testing to the final diagnosis.

We describe the case of a 33-year-old man with a 4-year history of worsening muscle stiffness and weakness in his right hand. He showed elevated serum creatine kinase levels at the onset of muscle stiffness that was characterized by delayed muscle relaxation after voluntary contraction. This symptom often occurred during cold exposure, and was partially attenuated by sodium channel blockade. Electrodiagnostic findings in repetitive nerve stimulation, short-exercise, and cooling tests were normal. Electromyography showed chronic denervation potentials in his cranial, cervical, thoracic, and lumbosacral myotomes without myotonic discharge. He exhibited facial and tongue fasciculations, hypernasality, gynecomastia, neurogenic changes in muscle biopsy, and increased serum testosterone levels. Spinal and bulbar muscular atrophy (SBMA) was diagnosed on the basis of the CAG trinucleotide expansion in the gene coding androgen receptor. A myotonia-like symptom without myotonic discharge may present as an early neurological sign of SBMA, which possibly reflects a sodium channel dysfunction in skeletal muscles., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Centronuclear myopathy (CNM) is a rare hereditary myopathy characterized by centrally located muscle fiber nuclei. Mutations in the dynamin 2 (DNM2) gene are estimated to account for about 50 % of CNM cases. Electromyographic recordings in CNM may show myopathic motor unit potentials without spontaneous activity at rest. Myotonic discharges, a distinctive electrical activity caused by membrane hyperexcitability, are characteristic of certain neuromuscular disorders. Such activity has been reported in only one CNM case without a known genetic cause. We sequenced the DNM2 gene and the genes associated with myotonia (CLCN1, SCN4A, DMPK and ZNF9) in a sporadic adult patient with CNM and myotonic discharges. Sequencing the entire coding region and exon-intron boundaries revealed a heterozygous c.1106g-a substitution in exon 8, resulting in a R369Q change in the DNM2. Sequencing the CLCN1, SCN4A, DMPK and ZNF9 genes ruled out mutations in these genes. This is the first report of DNM2-related CNM presenting with myotonia. The diagnosis of CNM should be considered in patients with myotonic discharges of an unknown cause.

Mutations in the cytoplasmic tail (CT) of voltage gated sodium channels cause a spectrum of inherited diseases of cellular excitability, yet to date only one mutation in the CT of the human skeletal muscle voltage gated sodium channel (hNaV1.4F1705I) has been linked to cold aggravated myotonia. The functional effects of altered regulation of hNaV1.4F1705I are incompletely understood. The location of the hNaV1.4F1705I in the CT prompted us to examine the role of Ca(2+) and calmodulin (CaM) regulation in the manifestations of myotonia. To study Na channel related mechanisms of myotonia we exploited the differences in rat and human NaV1.4 channel regulation by Ca(2+) and CaM. hNaV1.4F1705I inactivation gating is Ca(2+)-sensitive compared to wild type hNaV1.4 which is Ca(2+) insensitive and the mutant channel exhibits a depolarizing shift of the V1/2 of inactivation with CaM over expression. In contrast the same mutation in the rNaV1.4 channel background (rNaV1.4F1698I) eliminates Ca(2+) sensitivity of gating without affecting the CaM over expression induced hyperpolarizing shift in steady-state inactivation. The differences in the Ca(2+) sensitivity of gating between wild type and mutant human and rat NaV1.4 channels are in part mediated by a divergence in the amino acid sequence in the EF hand like (EFL) region of the CT. Thus the composition of the EFL region contributes to the species differences in Ca(2+)/CaM regulation of the mutant channels that produce myotonia. The myotonia mutation F1705I slows INa decay in a Ca(2+)-sensitive fashion. The combination of the altered voltage dependence and kinetics of INa decay contribute to the myotonic phenotype and may involve the Ca(2+)-sensing apparatus in the CT of NaV1.4.

We report an unusual case involving a patient with myotonia. A 57-year-old man had multisystemic symptoms including skeletal muscle weakness, atrophy and percussion myotonia, cataract, heart involved, gastrointestinal tract symptoms, and urinary incontinence. The electromyography revealed myotonic discharges. Muscle biopsy showed myopathic features and a striking number of ring fibers. It was genetically proven that the case was not myotonic dystrophy type 1 (DM1) or 2 (DM2). The case might be DM3 or an unusual case of unclassified myopathy with multisystemic damage., (Copyright © 2013. Published by Elsevier B.V.)

Introduction: The pathogenesis of muscle involvement in patients with myotonic dystrophy type 1 (DM1) is not well understood. In this study, we characterized the muscle phenotype in patients with confirmed DM1., Methods: In 38 patients, muscle strength was tested by hand-held dynamometry. Myotonia was evaluated by a handgrip test and by analyzing the decrement of the compound muscle action potential. Muscle biopsies were assessed for morphological changes and Na(+)-K(+) pump content., Results: Muscle strength correlated with a decline in Na(+)-K(+) pump content (r = 0.60, P < 0.001) and with CTG expansion. CTG expansion did not correlate with severity of myotonia, proximal histopathological changes, or Na(+)-K(+) pump content. Histopathologically, we found few centrally placed nuclei (range 0.2-6.9%)., Conclusions: The main findings of this study are that muscle weakness correlated inversely with CTG expansion and that central nuclei are not a prominent feature of proximal muscles in DM1., (Copyright © 2012 Wiley Periodicals, Inc., a Wiley company.)

Disease-specific biomarkers play a central diagnostic and therapeutic role in muscle pathology. Serum levels of a variety of muscle-derived enzymes are routinely used for the detection of muscle damage in diagnostic procedures, as well as for the monitoring of physical training status in sports medicine. Over the last few years, the systematic application of mass spectrometry-based proteomics for studying skeletal muscle degeneration has greatly expanded the range of muscle biomarkers, including new fiber-associated proteins involved in muscle transformation, muscular atrophy, muscular dystrophy, motor neuron disease, inclusion body myositis, myotonia, hypoxia, diabetes, obesity and sarcopenia of old age. These mass spectrometric studies have clearly established skeletal muscle proteomics as a reliable method for the identification of novel indicators of neuromuscular diseases.

We describe a large Brazilian consanguineous kindred with 3 clinically affected patients with a Thomsen myotonia phenotype. They carry a novel homozygous nonsense mutation in the CLCN1 gene (K248X). None of the 6 heterozygote carriers show any sign of myotonia on clinical evaluation or electromyography. These findings confirm the autosomal recessive inheritance of the novel mutation in this family, as well as the occurrence of phenotypic variability in the autosomal recessive forms of myotonia., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Myotonic dystrophy type 2 (DM2) is an autosomal dominant, multisystem disorder caused by a CCTG tetranucleotide repeat expansion located in intron 1 of the zinc finger protein 9 gene (ZNF9 gene) on chromosome 3q 21.3., Objectives: To describe the clinical, electrophysiologic and pathologic findings in patients with myotonic dystrophy 2., Methods: We evaluated 10 patients genetically, clinically and electrophysiologically during the years 2007 to 2008., Results: All patients were of Jewish European ancestry. Among affected individuals, eight patients had symptoms of proximal muscle weakness, two had muscle pain, and two exhibited myotonia. On physical examination six patients had severe weakness of hip flexor muscles. Seven individuals underwent cataract surgery, and cardiac involvement was seen in one case. On the initial electromyographic (EMG) examination five patients demonstrated myotonic discharges; repeated studies showed these discharges in nine cases. Six muscle biopsies showed non-specific pathological changes. Seven patients had an affected first-degree relative with either a diagnosed or an undiagnosed muscular disorder consistent with an autosomal dominant trait., Conclusions: DM2 may often present with proximal muscle weakness without myotonia. EMG may initially fail to show myotonic discharges, but these discharges may eventually show in most cases on repeated EMG. Thus, DM2 may be underdiagnosed and should be included in the differential diagnosis of adult patients of Jewish European ancestry presenting with proximal lower limb weakness.

Many mutations in the skeletal-muscle sodium-channel gene SCN4A have been associated with myotonia and/or periodic paralysis, but so far all of these mutations are located in exons. We found a patient with myotonia caused by a deletion/insertion located in intron 21 of SCN4A, which is an AT-AC type II intron. This is a rare class of introns that, despite having AT-AC boundaries, are spliced by the major or U2-type spliceosome. The patient's skeletal muscle expressed aberrantly spliced SCN4A mRNA isoforms generated by activation of cryptic splice sites. In addition, genetic suppression experiments using an SCN4A minigene showed that the mutant 5' splice site has impaired binding to the U1 and U6 snRNPs, which are the cognate factors for recognition of U2-type 5' splice sites. One of the aberrantly spliced isoforms encodes a channel with a 35-amino acid insertion in the cytoplasmic loop between domains III and IV of Nav1.4. The mutant channel exhibited a marked disruption of fast inactivation, and a simulation in silico showed that the channel defect is consistent with the patient's myotonic symptoms. This is the first report of a disease-associated mutation in an AT-AC type II intron, and also the first intronic mutation in a voltage-gated ion channel gene showing a gain-of-function defect., (© 2011 Wiley-Liss, Inc.)

Introduction: Non-dystrophic myotonia (NDM) is caused by mutations in muscle chloride and sodium channels. Currently, there is no standardized instrument for documenting symptom frequency and severity in NDM., Methods: Subjects used an automated, interactive, telephone-based voice response diary (IVR) to record frequency and severity of stiffness, weakness, pain, and tiredness once a week for 8 weeks, after their baseline visits., Results: We describe the IVR and report data on 76 subjects for a total of 385 person-weeks. Overall there were 5.1 calls per subject. Forty-eight subjects called in 5 or more times, and 14 called in 8 times. Stiffness was both the most frequent and severe symptom. Warm-up and handgrip myotonia were associated with higher severity scores for stiffness., Conclusions: IVR is a convenient technology to allow patient reporting of repeated and real-time symptom frequency and severity, and it is presently being used in a trial of mexiletine in NDM., (Copyright © 2011 Wiley Periodicals, Inc.)

Purpose of Review: The aim is to review the recent findings in relation to the genetics, pathophysiology, clinical phenotypes, investigation and treatment of the nondystrophic myotonias (NDMs) and periodic paralyses., Recent Findings: The number of pathogenic mutations causing NDMs and periodic paralyses in known genes continues to expand. In addition, a mutation has been identified in the ryanodine receptor gene manifesting as an atypical periodic paralysis phenotype. Another recent study indicated that thyrotoxic hypokalaemic periodic paralysis is determined by mutations in a novel gene encoding an inwardly rectifying potassium channel, Kir2.6. Work studying molecular mechanisms indicates that 90% of the known mutations causing hypokalaemic periodic paralysis (HypoPP) result in loss of positively charged arginine residues in the S4 segments of either SCN4A or CACNA1S, possibly creating a gating-pore current that may be important in the pathogenesis of HypoPP. Recent studies evaluating clinical features and health status in NDM patients have provided more detailed insights into the significant morbidity associated with these diseases. Ultrasound has been successfully used to demonstrate muscle abnormalities in NDM patients and magnetic resonance spectroscopy studies applied to HypoPP patients suggest that this technique can demonstrate both disease-related and treatment-related changes., Summary: Recent discoveries in the skeletal muscle channelopathies have increased our understanding of the genetics and pathophysiology of these diseases. Studies reporting imaging techniques raise the possibility of improved disease monitoring and better outcome measures for clinical trials. Randomized controlled trials to establish an evidence base upon which to recommend standard treatments are required.

Although the diagnostic work-up for myopathies can be difficult, it should be carried out for medical and financial reasons if the suspicion is supported by evidence. The diagnosis is based on the history, neurological investigation, blood chemical investigations at rest and under stress, electromyography, muscle MRI, biopsy, the in-vitro coffeine-halothan contracture test, and molecular genetic studies. There is some role for muscle enzyme determinations in the diagnostic work-up, although these values are frequently multifactorial. However, if muscle enzymes are repeatedly increased without explanation but in the presence of muscular symptoms, the diagnostic work-up should be initiated. Stress tests can be of some additional help. Needle electromyography may be normal, myogenic, neurogenic or non-specifically abnormal. Muscle MRI may show trophic disturbances, and may guide one to the muscle most adequate for biopsy. A muscle biopsy may be taken for a number of further investigations and may lead to the correct diagnosis. Only if there is a profound suspicion for a certain genetic defect, molecular genetic investigations should be initiated. In the case that a pathogenic mutation is found, genetic counselling, and assessment of the prognosis, and therapy can be initiated. For diagnostic, therapeutic and prognostic implications, diagnostic work-up should be carried out as soon as possible if myopathy is suspected., ((c) Georg Thieme Verlag KG Stuttgart-New York)

Background: Mutations in SCN4A may lead to myotonia., Methods: Presentation of a large family with myotonia, including molecular studies and patch clamp experiments using human embryonic kidney 293 cells expressing wild-type and mutated channels., Results: In a large family with historic data on seven generations and a clear phenotype, including myotonia at movement onset, with worsening by cold temperature, pregnancy, mental stress, and especially after rest after intense physical activity, but without weakness, the phenotype was linked with the muscle sodium channel gene (SCN4A) locus, in which a novel p.I141V mutation was found. This modification is located within the first transmembrane segment of domain I of the Na(v)1.4 alpha subunit, a region where no mutation has been reported so far. Patch clamp experiments revealed a mutation-induced hyperpolarizing shift (-12.9 mV) of the voltage dependence of activation, leading to a significant increase (approximately twofold) of the window current amplitude. In addition, the mutation shifted the voltage dependence of slow inactivation by -8.7 mV and accelerated the entry to this state., Conclusions: We propose that the gain-of-function alteration in activation leads to the observed myotonic phenotype, whereas the enhanced slow inactivation may prevent depolarization-induced paralysis.

We describe two Chinese families with a mild form of the myotonia congenita due to novel chloride channel (ClCN1) mutations. In one case, heterozygous I553F and H555N mutations were found. The patient shared the I553F mutation with his healthy father, and his mother had a history of mild myotonia when she was younger. In another family, autosomal dominant myotonia congenita was due to a L844F change. The physiological effects of the mutations were examined by using the two-electrode voltage-clamp technique after expression of the channels in Xenopus oocytes. All mutations drastically shifted the voltage required for half-maximal activation, more under conditions mimicking the homozygous situation, than under conditions mimicking the heterozygous situation. The larger effect was seen in the compound heterozygous situation combining the I553F and the H555N mutations. Our data suggest that myotonia congenita caused by CLCN1 mutations in Chinese have similar variable features to those found in the West.

Hyperkalemic periodic paralysis (HyperKPP) produces myotonia and attacks of muscle weakness triggered by rest after exercise or by K+ ingestion. We introduced a missense substitution corresponding to a human familial HyperKPP mutation (Met1592Val) into the mouse gene encoding the skeletal muscle voltage-gated Na+ channel NaV1.4. Mice heterozygous for this mutation exhibited prominent myotonia at rest and muscle fiber-type switching to a more oxidative phenotype compared with controls. Isolated mutant extensor digitorum longus muscles were abnormally sensitive to the Na+/K+ pump inhibitor ouabain and exhibited age-dependent changes, including delayed relaxation and altered generation of tetanic force. Moreover, rapid and sustained weakness of isolated mutant muscles was induced when the extracellular K+ concentration was increased from 4 mM to 10 mM, a level observed in the muscle interstitium of humans during exercise. Mutant muscle recovered from stimulation-induced fatigue more slowly than did control muscle, and the extent of recovery was decreased in the presence of high extracellular K+ levels. These findings demonstrate that expression of the Met1592ValNa+ channel in mouse muscle is sufficient to produce important features of HyperKPP, including myotonia, K+-sensitive paralysis, and susceptibility to delayed weakness during recovery from fatigue.

Myotonia permanens is associated with a G1306E mutation in the SCN4A gene. Two sporadic patients have been reported, but the clinical phenotype has not been fully characterized. The authors report a family in which the disease is autosomal dominantly inherited. The patients have severe myotonia, but the clinical picture is not qualitatively different from that seen in other nondystrophic myotonias.

A 6-year-old boy with Schwartz-Jampel syndrome and severe myotonia-induced blepharospasm and ptosis did not respond to botulinum toxin A injections in the orbicularis muscle. The clinical diagnosis was further supported by electromyography. Surgical management using a combination of techniques in one operation produced a satisfactory result for both function and appearance. Muscle biopsy was also done during surgery.

Objective: In order to find some appropriate medicine to suppress myotonia without decreasing muscle strength experiments were performed on myotonic (mto) mice whose Cl channel does not develop due to stop codon and serves as an animal model of myotonia. In myotonic dystrophy dehydroepiandrosterone is low in the serum and it has been reported that intravenous injections of DHEAS to human cases improves myotonia and activities of daily living., Materials and Methods: Three pairs of heterozygote mto mice, SWR/J-Clcn1(adr-mto/+) and ten Wistar rats were used. We performed intracellular recordings of myotonia from mto mice and the drug effects on insertion myotonia were recorded from the hemidiaphragm preparations of mto mice with different concentrations of DHEAS. Isometric twitch tension was recorded from rat hemidiaphragm preparations in Tyrode's solution and the effect of DHEAS on the muscle twitch tension was measured at different concentrations of DHEAS from 100 mg/l to 300 mg/l. The effect of mexiletine on ITT was also measured., Results: In mto mice insertion myotonia was recorded as soon as the microelectrode was inserted in the muscle cells. When DHEAS was added to Tyrode's solution, insertion myotonia was suppressed. DHEAS decreased ITT up to 70% of the original value, though mexiletine decreased ITT to 30% of the original value. Therefore, the decrement of the muscle strength in DHEAS solution is much smaller than that of mexiletine., Conclusion: Since myotonic dystrophy shows progressive muscle weakness in addition to myotonia, medications like DHEAS are more favorable than the typical Na channel blocker.

Background: Myotonia and weakness are the most important components of dysarthric speech in myotonic dystrophy., Objective: To specify and quantify possible defects in speech execution in patients with adult onset myotonic dystrophy., Methods: Studies on speech production were done on 30 mildly affected patients with myotonic dystrophy. Special attention was paid to myotonia. Because muscle activity can result in a decrease of myotonia, speech characteristics were measured before and after warm up. The possibility that warming up causes increased weakness was also assessed., Results: As with other motor skills, a warm up effect was found in speech production, resulting in an increase in repetition rate and a decrease in variability of repetition rate. Signs of fatigue did not occur., Conclusions: Warming up is valuable for patients with myotonic dystrophy in reducing the influence of myotonia on speech production.

We describe a patient with chronic progressive external ophthalmoplegia (CPEO) due to a deletion of mitochondrial DNA (mtDNA) who had electromyographic evidence of myotonic discharges. Myotonia has not previously been described in association with mitochondrial disease and this report extends the known phenotypic expression of these disorders.

In Duchenne muscular dystrophy (DMD) and its murine model, the dystrophic mouse (MDX), the skeletal musculature lacks dystrophin. The presumed function of this cytoskeletal protein is to protect the sarcolemma against mechanical stress during muscle activity. To test this hypothesis in vivo, we bred a double mutant mouse that combines two genetic defects: the dystrophin-deficiency of the MDX mouse and the Cl- channel myotonia of the arrested development of righting response (ADR) mouse. We hypothesized that high mechanical muscle activity would aggravate muscular dystrophy in double mutant ADR-MDX mice. On the contrary, ADR-MDX mice showed fewer signs of muscle fiber necrosis and fibrosis than MDX mice at all ages. Plasma creatine kinase levels were slightly increased in ADR-MDX, but significantly lower when compared to MDX mice. Sections of ADR-MDX muscle showed a uniform pattern of oxidative muscle fibers. Similar findings have been obtained in dystrophin-positive ADR mice, they result from a complete fiber-type IIB to IIA transformation in myotonic muscle. Our results suggest that small, oxidative fibers of myotonic mice are less sensitive to dystrophin deficiency. Therefore, ADR-MDX mice develop less severe muscular dystrophy than MDX mice do, although their muscles are continually stressed. The new ADR-MDX double mutant mouse is the first animal model combining both a dystrophinopathy and a channelopathy. The results presented here give new insights into the pathomechanism of muscular dystrophy and may be helpful for the therapeutic management of DMD.

We describe a family with a proximal myopathy, subclinical EMG myotonia, cataracts and deafness. Transmission through two generations and down the male line confirms autosomal dominant inheritance. There was no abnormal expansion of the CTG triplet repeat in the last exon of the dystrophia myotonica protein kinase (DMPK) gene associated with myotonic dystrophy. Heteroduplex analysis of all but the promoter region of the DMPK gene has excluded point mutations in this gene as an underlying cause for this myotonic disorder. The family was not sufficiently informative to exclude linkage to the sodium channel gene SCN4A or the chloride channel gene CLC1. This family clearly fulfils the recently established diagnostic criteria for PROMM (proximal myotonic myopathy) and in addition shows consistent severe deafness as a hitherto undescribed feature of PROMM. We discuss the diagnostic criteria of PROMM in relation to this family and other recent papers, all of which would now fulfil the aforementioned diagnostic criteria for PROMM.

A combination of electrophysiological, pathological, and biochemical studies were performed in myopathy induced by 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. Simvastatin (a lipophilic inhibitor) or pravastatin (a hydrophilic inhibitor) were administered by gavage to rabbits. In Group I (simvastatin-treated group, 50 mg/kg/day for 4 weeks), four rabbits showed muscle necrosis and high serum creatine kinase (CK) levels, and all six rabbits showed electrical myotonia. In Group II (pravastatin-treated group, 100 mg/kg/day for 4 weeks), no rabbit showed either condition. In Group III (pravastatin-treated group, 200 mg/kg/day for 3 weeks plus 300 mg/kg/day for 3 weeks), one rabbit showed muscle necrosis and high serum CK level and two rabbits showed electrical myotonia. The pathological findings were muscle fiber necrosis and degeneration with increased acid phosphatase activity by light microscopy, autophagic vacuoles and mitochondrial swelling, and disruption and hypercontraction of myofibrils by electron microscopy. Ubiquinone content decreased in skeletal muscle by 22 to 36% in Group I, by 18 to 52% in Group II, and by 49 to 72% in Group III. However, mitochondrial enzyme activities of respiratory chain were normal in all groups. These results indicate that myopathy was not induced by a secondary dysfunction of mitochondrial respiration due to low ubiquinone levels., (Copyright 1998 Academic Press.)

Proximal myotonic myopathy (PROMM) is a recently described autosomal dominantly inherited disorder resulting in proximal muscles weakness, myotonia, and cataracts. A few patients with cardiac involvement (sinus bradycardia, supraventricular bigeminy, conduction abnormalities) have been reported. The cases of three relatives with PROMM (weakness of neck flexors and proximal extremity muscles, calf hypertrophy, myotonia, cataracts) are reported: a 54 year old man, his 73 year old mother, and 66 year old aunt. All three presented with conduction abnormalities and one had repeated, life threatening, sustained monomorphic ventricular tachycardia. This illustrates that severe cardiac involvement may occur in PROMM.

Colchicine may induce a myoneuropathy in patients with renal insufficiency. To date, myotonia has not been described in this disorder. We recently studied 4 patients treated with routine doses of colchicine who, in the setting of renal insufficiency, developed a severe myoneuropathy characterized by prominent myotonic discharges on electromyography. In addition, 1 of the 4 patients had profound clinical myotonia. In the 3 patients in whom biopsies were performed, marked myopathic change with intracytoplasmic vacuolization was identified. All 4 patients improved rapidly with discontinuation of the medication. The patient in whom electrophysiologic studies were repeated had a complete resolution of the myotonic discharges. Colchicine myoneuropathy can present with prominent clinical and electrophysiologic myotonia that resolves completely with discontinuation of the medication.

The expression of neutral glycosphingolipids (GSLs) and gangliosides was investigated in cryosections of normal mouse skeletal muscle and in muscle of mice with neuromuscular diseases using indirect immunofluorescence microscopy. Transversal and longitudinal sections were immunostained with specific polyclonal antibodies against lactosylceramide, lacto-N-neotetraosylceramide, globoside, GM3(Neu5Ac), GM3(Neu5Gc) and Gm1(Neu5Ac) as well as monoclonal anti-Forssman GSL antibody. In normal CBA/J mouse muscle (control) the main immunohistochemically detected ganglioside was GM3(Neu5Ac) followed by moderately expressed GM3(Neu5Gc) and GM1. The neutral GSLs lactosylceramide and globoside were stained with almost identical, high fluorescence intensity. Low amounts of lacto-N-neotetraosylceramide and trace quantities of Forssman GSL were immunostained. All GSLs were detected in the sarcolemma, but also in considerable amounts at the intracellular level. Mice with neuromuscular diseases were the A2G-adr mouse mutant (a model for human recessive myotonia of Becker type), the BL6-wr mutant (a model for motor neuron disease) and the BL10-mdx mouse mutant (a model for human Duchenne muscular dystrophy). No changes in GSL expression were found in the A2G-adr mouse, while muscle of the BL6-wr mouse showed increased intensity of immunofluorescence in stainings with anti-lactosylceramide and anti-GM3(Neu5Ac) antibodies. Muscle of BL10-mdx mice showed the most prominent changes in GSL expression with reduced fluorescence intensity for all antibodies. Major differences were not observed in the intensities of GSLs, but there were significant differences in the patterns of distribution on plasma membrane and at the subcellular level. The exact nature and pathogenesis of these changes should be elucidated since such investigations could furnish advances in understanding the functional role of neutral GSLs and gangliosides in normal as well as in diseased muscle.

The progression of the pathological changes that occur in the skeletal muscle was examined in 19 Japanese quail of the LWC strain, affected with an autosomal dominant inherited muscular disorder producing electrical myotonia. The muscle samples were obtained every 10 days from 20 to 70 days of age. Muscle samples from 18 age-matched commercial quail were used as normal controls. Characteristic histological lesions found in the skeletal muscles included sarcoplasmic masses, ringed fibres, internal migration of nuclei and fibre size variation. These lesions, which mainly occurred in the proximal muscles, appeared first in the pectoral region and later in the muscles of the thoracic and pelvic limbs. The most predominant lesion observed at all ages consisted of sarcoplasmic masses. The presence of histological changes did not affect muscle fibre typing by two staining methods, for myosin ATPase at pH 4.5, and by NADH-TR stain. The histological changes were observed in type 2A and less commonly in 2B fibres, but not in type 1. The pectoralis thoracicus muscle, in which lesions were particularly common, showed abnormally large type 2B muscle fibres at 20 days of age. These fibres began to decrease in size at 30 days of age, and at 70 days had become strikingly atrophic, their diameter being only about half that observed at 20 days. The atrophic type 2B muscle fibres were eventually replaced by lipocytes. Chronological staging of the histopathological changes in muscle was impossible since no inter-relationship was observed between the age of the quail, the severity of clinical signs and the extent of muscle lesions. This variability in the severity and age of onset may have been due to the variable expression or incomplete penetrance of the defective gene. Because the disorder is hereditary and progressive in nature, it can be classified as a type of progressive muscular dystrophy.

To investigate the etiological factors responsible for intellectual impairment and mood changes in patients with myotonic dystrophy (DM), we evaluated 14 patients with DM by means of neuropsychological evaluation and magnetic resonance images (MRI). There were significant differences between patients and controls in regard to the Barthel index, Zung's depression scale, attention, verbal fluency and digit span. All patients had ventricular enlargement and white matter abnormalities on MRI. However, the severity was variable and there was no difference in neuropsychological testing between patients with mild ventricular dilatation and those with severe dilatation. On the other hand, significant differences were present between patients with mild white matter lesions and those with severe white matter abnormalities in regard to verbal fluency and attention. Neuropathologic examination of an autopsied brain showed an increase in the interfascicular space of the white matter which produced pallor on myelin staining. The present findings suggested that the white matter abnormalities were the cause of cognitive impairment among patients with DM.

Objectives: To define a new type of dominant myotonic muscle disorder and to identify the gene lesion., Design: Case series, clinical examination and electromyography, measurements of grip force and relaxation time, and DNA analysis to probe for mutation in the gene for the skeletal muscle sodium channel., Setting: Outpatient clinic and home., Patients: Three families studied; all together, 17 affected and nine unaffected individuals., Results: The findings in these three families confirm the existence of myotonia fluctuans as we described it previously in another family. Myotonia (prolongation of relaxation time) developed 20 to 40 minutes after exercise. Potassium caused generalized myotonia. Cooling had no major effect on muscle function. Three families had a common mutation in exon 22 and one family had a mutation in exon 14 of the gene for the sodium channel alpha subunit., Conclusions: Myotonia fluctuans is a disorder of the muscle sodium channel. There are at present two other distinct clinical muscle disorders associated with mutations in the sodium channel: hyperkalemic periodic paralysis and paramyotonia congenita. The findings in the present report indicate that myotonia fluctuans belongs to a third type of sodium channel disorder. Further work is needed to understand the complex genotype-phenotype correlations in sodium channel disorders.

Background: Over the past 3 years, the genetics of the myotonic diseases have been substantially elaborated. Three genetically different groups of myotonic disease can be discerned: (1) the chloride channel myotonias, (2) the adynamia-paramyotonia complex, and (3) myotonic dystrophy., Methods and Results: Electrophysiology has suggested and molecular biology has proven that the diseases belonging to the adynamia-paramyotonia complex, ie, paramyotonia congenita, hyperkalemic and normokalemic periodic paralysis, and some rare forms of myotonic disease, are caused by point mutations in the gene encoding the alpha subunit of the sodium channel in adult human skeletal muscle, located on chromosome 17q23. Thirteen different mutations have been described by various groups in the United States and Germany. The various mutations causing a particular form of the complex are not located in the gene in a predictable or easily understandable regular manner., Conclusions: Further study of the genotype-phenotype correlations should not only increase our understanding of the variability of signs in this group of diseases, it could also provide us with a deeper insight in the function of the various regions of the sodium channel protein.

In a new, typical case of Schwartz-Jampel syndrome (SJS) the origin of the disorder was found to be purely myogenic. Concentric needle EMG showed abundant and persistent spontaneous activity, maximal at insertion, and uninfluenced by local curarization. Single-fiber EMG showed rather stable, sometimes intermittent, discharge series with occasional amplitude and/or frequency fluctuations. It could be demonstrated that this activity did not consist of complex repetitive discharges, but of independent activity of individual muscle fibers. This contrasts with findings by other investigators that have been published in this journal. Light microscopic studies of quadriceps and intercostal muscles showed no abnormalities, whereas electron-microscopic findings were in accordance with earlier studies in SJS. Endplate analysis revealed no specific changes; the postsynaptic structures gave the impression of an accelerated-maturation.

We studied two patients with abnormal spontaneous muscular activity. The first had widespread fasciculations, painful spasms, delayed muscular relaxation, and hyperhidrosis. Improvement occurred after several years. The second case had generalized paresthesia, mild stiffness, a positive result from Trusseau's test, and was relieved by administration of carbamazepine. Both patients had abnormal conduction velocity. Examination of muscle biopsy specimens disclosed fiber type grouping and increased collateral ramification of motor axons. These observations exemplify symptoms and signs that resemble those of myotonia and tetany and occasionally occur in partial denervation. they provide additional evidence of the neurogenic nature of Isaacs-Mertens syndrome.

The authors begin this general review with the pseudohypertrophies due either to an underlying extramuscular process, or to a focal lesion within the muscle, or else to miscellaneous interstitial infiltrates such as those found in cysticercosis, sarcoidosis, amylosis. True hypertrophy is most often observed in the course of muscular dystrophy. It is an usual finding in myopathies, and the prominent symptom of Thomsen disease ; it is the only symptom of hypertrophia musculorum vera and masseters hypertrophy ; it is associated with a peculiar deficit in the "Hereditary Distal Myopathy with Onset in Infancy"; it is a classical symptom of some endocrine myopathies (hypothyroidism and acromegaly). Paradoxically, true hypertrophy may, though very rarely, be encountered in the course of nervous system diseases, most often of the neuritic type : sciatica, hypertrophic neuritis, progressive spinal muscular atrophy. The mechanism of this very unusual muscular reaction remains unknown.

The pathology of two cases of canine myopathy associated with myotonia are presented. The changes were interpreted as dystrophic. The most obvious features were a rounding on cross section and variation in fibre size with numerous internal nuclei, many of which formed chains. Degeneration and regeneration were seen and there was a slight increase in perimysial and endomysial connective tissue. Only one ringed fibre was seen, but no sarcoplasmic masses. Enzyme histochemistry failed to demonstrate any selective Type I fibre atrophy. The peripheral and central nervous systems were normal in both cases.

The gastrocnemius muscles of 3 groups of 10 rats, sacrified 5, 7, and 12 days respectively, following tenotomy, were submitted to different types of fixation, fixative and embedding. The occurrence of target fibres is shown not to be an artefact due to the histological procedures. Further examination demonstrates that the target phenomenon occurs in the shortest fibres on the medial side of both heads of the gastrocnemius muscle and that it consists mainly of a disarrangement of the contractile elements of the muscle fibres. This study argues that this phenomenon represents some kind of myotonic state of a pathological muscle.

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.

Available experimental and clinical evidence strongly suggests that deficiency in type 2B muscle fibres in generalized myotonia and paramyotonia congenita will develop consequent to lasting myotonic activity as its adequate stimulus. Type 2B fibre deficiency need not be regarded as the product of a hypothetical genetic factor.