Fine structural alterations of muscle fibers in diseases accompanied by myotonia.

The authors have reported the results of examination by electron microscopy of two muscle biopsy specimens from cases of myotonia congenita and three cases of myotonia dystrophica. They have stated that "peripheral annular formation" was a frequently observed alteration in the myotonia congenita cases. In the myotonia dystrophica cases there were additionally disorganized myofibrils in the subsarcolemmal region and inclusion body vacuoles morphologically connected with the sarcolemma. The term "peripheral annular formation" refers to the situation in which the peripheral myofibrils of the muscle fiber fracture and the fragments retract and form a helical sheath around the central myofibrils of the same muscle fiber.     

Myotonia congenita. A histochemical and ultrastructural study in the goat: comparison with abnormalities found in human myotonia dystrophica.

Muscle biopsy specimens from the myotonic goat, an animal model of heritable myotonia, were examined histochemically and by electron microscopy. After Periodic acid-Schiff (PAS) staining with diastase digestion, there was increased PAS-positive material within myotonic goat fibers, as compared with those of normal goats. Myotonic muscle stained with alizarin red S, a histochemical stain for calcium, also had an increased staining reaction when compared with muscle from normal goats. Several ultrastructural abnormalities were found in myotonic goat muscle using routine osmium and uranyl acetate staining. These included increased density of the t-tubules, electron-dense material within t-tubules, proliferation and dilatation of sarcotubular elements, and abnormal mitochondria in the myotonic biopsy specimens. To further study muscle ultrastructure, ruthenium red and lanthanum were used as electron microscopic stains with specificity for membranes. There was increased density of the sarcolemma and t-tubules in myotonic muscle stained with ruthenium red as compared to normal, and lanthanum produced a darker staining reaction of the myotonic goat sarcolemma. The histochemical and ultrastructural differences between normal and myotonic goat muscle were interpreted to be consistent with a morphologic basis for the abnormal contraction-relaxation properties characteristic of myotonia.     

Effects of acute and chronic denervation on human myotonia

A 32-year-old man with myotonia congenita (Becker type) sustained multiple gunshot wounds. These produced a partial thoracic spinal cord injury and a severe sciatic nerve injury. Six days following the incident, clinical (percussion) and electrophysiologic (EMG) myotonia could be elicited in paretic leg muscles resulting both from the myelopathy and peripheral nerve disruption. Eight months later, the myotonia was no longer present in denervated muscles from the sciatic nerve injury, but was still noted in muscles with upper-motor neuron weakness from the myelopathy. Although myotonia is related principally to abnormalities in the muscle fiber itself, it appears that it is also dependent upon the structural integrity of the peripheral nerve supply to the muscle for myotonia to continue to occur. The findings in this patient suggest that myotonia may well have diminished and disappeared in muscles shortly after the nerves had undergone Wallerian degeneration. Myotonia does not recur if there is no significant reinnervation.     

Identification of five new mutations and three novel polymorphisms in the muscle chloride channel gene (CLCN1) in 20 Italian patients with dominant and recessive myotonia congenita. Mutations in brief no. 118. Online

Autosomal dominant myotonia congenita or Thomsen's disease and autosomal recessive myotonia congenita or Becker's are rare nondystrophic disorders due to allelic mutations of the muscle chloride channel gene, CLCN1. We have analysed all 24 exons of the CLCN1 gene, in a panel of 20 unrelated patients (9 with dominant and 11 with recessive mytotonia congenita). We have found five novel mutations including two missense (V5631, F708L), one nonsense (C481X), one splicing (IVS19+2T->A), and one frameshift (2264delC), and also detected the recurrent R894X mutation. These account for 10 of the 22 recessive alleles examined, while no mutations were found in the dominant form. We report three novel polymorphisms (-134T/G, 898C/A and 2154T/C). Our results support high molecular heterogeneity of these myotonias in Italian population and provide new insight for the diagnosis and genetic counselling of these diseases.     

Myotonia congenita in northern Finland: an epidemiological and genetic study.

An epidemiological and genetic investigation of myotonia congenita was carried out in northern Finland. Altogether 58 patients were identified (of whom 54 lived in the study area) in 23 families, with a prevalence of 7.3 per 100000. The majority of the families originated from a sparsely populated area in western Lapland. The mean age at onset of the disease was 11 years with a range of 2 to 45 years. The mean time that had passed before verification of the clinical disease was 18 (SD 14) years. The sex ratio M/F was 2.2/1.0. Forty-seven cases were familial and 11 were sporadic. In six families/pedigrees the inheritance was compatible with autosomal recessive and in two families with autosomal dominant inheritance. In five additional families, in which autosomal recessive inheritance seemed most plausible, vertical transmission was also noticed. This could be explained either by consanguinity of the parents or by variant expression of the mutation(s) involved. Our results suggest that myotonia congenita is unusually frequent in northern Finland, most probably as a consequence of an enrichment of the gene mutation(s) in the population.     

A CLCN1 mutation in dominant myotonia congenita impairs the increment of chloride conductance during repetitive depolarization

Myotonia congenita is caused by mutation of the CLCN1 gene, which encodes the human skeletal muscle chloride channel (ClC-1). The ClC-1 protein is a dimer comprised of two identical subunits each incorporating its own separate pore. However, the precise pathophysiological mechanism underlying the abnormal ClC-1 channel gating in some mutants is not fully understood. We characterized a ClC-1 mutation, Pro-480-Thr (P480T) identified in dominant myotonia congenita, by using whole-cell recording. P480T ClC-1 revealed significantly slowed activation kinetics and a slight depolarizing shift in the voltage-dependence of the channel gating. Wild-type/mutant heterodimers exhibited similar kinetic properties and voltage-dependency to mutant homodimers. Simulating myotonic discharge with the voltage clamp protocol of a 50 Hz train pulse, the increment of chloride conductance was impaired in both wild-type/mutant heterodimers and mutant homodimers, clearly indicating a dominant-negative effect. Our data showed that slow activation gating of P480T ClC-1 impaired the increment of chloride conductance during repetitive depolarization, thereby accentuating the chloride conductance reduction caused by a slight depolarizing shift in the voltage-dependence of the channel gating. This pathophysiology may explain the clinical features of myotonia congenita.     

Anomalien des T-Systems und des sarkoplasmatischen Reticulums bei der Myotonie,Paramyotinie und Adynamie

Zusammenfassung Die vergleichende licht- und elektronenmikroskopische Untersuchung von Muskelbiopsien bei dominant und recessiv erblicher Myotonie, Paramyotonia congenita, Adynamia episodica hereditaria mit Myotonie und myotonischer Dystrophie ergab bestimmte Unterschiede, aber auch einzelne, nicht bei allen untersuchten Fällen nachweisbare Gemeinsamkeiten.Nach ihrer Feinstruktur ließen sich 6 verschiedene Formen intrasarkoplasmatischer Tubulus- und Zisternensysteme differenzieren: Proliferierte Komponenten des sarkoplasmatischen Reticulums (s.R.) mit drei Sonderformen: (Ia) proliferierte Terminalzisternen; (Ib) tubuläre Aggregate mit oder (Ic) ohne innere Tubuli; (IIa und b) sehr seltene, aber wesentlich größere Tubuli von unbekannter Herkunft, die mit ca. 100 Å dicken Filamenten Komplexe bilden; und (III) flache Zisternensysteme, deren Einzelkomponenten nach Art septierter Verbindungen miteinander in engem Kontakt stehen.Die Proliferationserscheinungen am s.R. (Typ I) ließen sich nur bei der dominant erblichen myotonischen Dystrophie, Myotonia congenita und Paramyotonia congenita nachweisen, während bei der recessiv erblichen Myotonie in Übereinstimmung mit den bisherigen elektronenmikroskopischen Untersuchungen keine derartigen strukturellen Veränderungen nachweisbar waren. Mit Filamenten kombinierte Tubuli vom kleineren Typ (IIa) fanden sich lediglich bei einem Fall mit dominant erblicher Myotonia congenita; Riesentubuli (Typ IIb) nur bei einem Fall von Adynamia episodica hereditaria.Außer dem Fehlen von tubulären Aggregaten fiel bei der recessiv erblichen Myotonie das häufigere Vorkommen von ausgeprägten Faserhypertrophien auf, während die Häufigkeitsgipfel der Kaliberspektren bei den dominant erblichen Myotonia congenita-Fällen im Bereich kleinerer Faserkaliber lagen.Bei einigen Fällen fanden sich an zahlreichen Muskelfasern winzige elektronendichte Präcipitate (Inkrustationen), die selektiv an der Oberfläche des Sarkolemms, auf der Sarkoplasmaseite des T-Systems und an Pinocytosevesikeln, nicht aber an den übrigen membranösen Bestandteilen der Muskelfasern oder an Fibroblasten oder Endothelzellen zu beobachten waren. Offensichtlich handelt es sich um ein unspezifisches, vermutlich artifizielles Präcipitationsphänomen, das wegen seiner geradezu cytochemischen Selektivität hinsichtlich der Lokalisation Beachtung verdient.

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Alterations of the T-system and the sarcoplasmic reticulum in myotonia, paramyotonia and adynamia

Summary By comparing biopsies of autosomal dominant, autosomal recessive myotonia congenita, paramyotonia congenita, paramyotonia congenita, adynamia episodica hereditaria with myotonia, and myotonic dystrophy by light and electron microscopy, various alterations were observed, most of which however were non-specific.Six types of intrasarcoplasmic tubular aggregates or cisternae were identified: three types of proliferated derivatives of the sarcoplasmic reticulum (s.r.): proliferated terminal cisternae; tubular aggregates (presumably proliferated longitudinal components of the s.r.) with (Ib), or without internal tubules (Ic). Also, there wre two types of tubules of much larger diameter surrounded by 100 Å filaments (IIa and IIb), and closely packed cisternae with dentate junctions connecting adjacent membranes (III).Proliferated components of the s.r. were only seen in autosomal dominant myotonic dystrophy, myotonia congenita, and paramyotonia congenita, whereas in autosomal recessive myotonia no such changes were observed. Tubules forming complexes with filaments were seen in autosomal dominant myotonia congenita (type IIa), and in adynamia episodica hereditaria (type IIb, giant tubules).Tubular aggregates were not seen in autosomal recessive generalized myotonia. There were more hypertrophic fibers in autosomal recessive than in autosomal dominant myotonia.In some cases, numerous muscle fibers showed minute electron dense precipitates (incrustations) which were selectively located on the outer surface of the sarcolemma, on the sarcoplasmic side of the T-system and on micro-pinocytotic vesicles, but not on other membranous constituents of the muscle fiber, or fibroblasts or endothelial cells. Although the incrustations were considered artificial precipitates, that appeared to be rather non-specific, their distinctive location apparently reflected some kind of a cytochemical reaction of considerable selectivity but of unknown origin.

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Auszugsweise vorgetragen bei der II. Konferenz über Myopathien in Janské Lázne, CSSR, 18.–19. 3. 1971.     

Difference in allelic expression of the CLCN1 gene and the possible influence on the myotonia congenita phenotype

Mutations in the CLCN1 gene, encoding a muscle-specific chloride channel, can cause either recessive or dominant myotonia congenita (MC). The recessive form, Becker's myotonia, is believed to be caused by two loss-of-function mutations, whereas the dominant form, Thomsen's myotonia, is assumed to be a consequence of a dominant-negative effect. However, a subset of CLCN1 mutations can cause both recessive and dominant MC. We have identified two recessive and two dominant MC families segregating the common R894X mutation. Real-time quantitative RT-PCR did not reveal any obvious association between the total CLCN1 mRNA level in muscle and the mode of inheritance, but the dominant family with the most severe phenotype expressed twice the expected amount of the R894X mRNA allele. Variation in allelic expression has not previously been described for CLCN1, and our finding suggests that allelic variation may be an important modifier of disease progression in myotonia congenita.     

Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia

Myotonia congenita is a non-dystrophic muscle disorder affecting the excitability of the skeletal muscle membrane. It can be inherited either as an autosomal dominant (Thomsen's myotonia) or an autosomal recessive (Becker's myotonia) trait. Both types are characterised by myotonia (muscle stiffness) and muscular hypertrophy, and are caused by mutations in the muscle chloride channel gene, CLCN1. At least 50 different CLCN1 mutations have been described worldwide, but in many studies only about half of the patients showed mutations in CLCN1. Limitations in the mutation detection methods and genetic heterogeneity might be explanations. In the current study, we sequenced the entire CLCN1 gene in 15 Northern Norwegian and three Northern Swedish MC families. Our data show a high prevalence of myotonia congenita in Northern Norway similar to Northern Finland, but with a much higher degree of mutation heterogeneity. In total, eight different mutations and three polymorphisms (T87T, D718D, and P727L) were detected. Three mutations (F287S, A331T, and 2284+5C>T) were novel while the others (IVS1+3A>T, 979G>A, F413C, A531V, and R894X) have been reported previously. The mutations F413C, A531V, and R894X predominated in our patient material. Compound heterozygosity for A531V/R894X was the predominant genotype. In two probands, three mutations cosegregated with myotonia. No CLCN1 mutations were identified in two families. Our data support the presence of genetic heterogeneity and additional modifying factors in myotonia congenita.     

Genetic variation in LINGO-1 (rs9652490) and risk of Parkinson's disease: twelve studies and a meta-analysis

Mutations of the voltage gated sodium channel gene (SCN4A) are responsible for non-dystrophic myotonia including hyperkalemic periodic paralysis, paramyotonia congenita, and sodium channel myotonia, as well as congenital myasthenic syndrome. In vitro functional analyses have demonstrated the non-dystrophic mutants to show a gain-of-function defect of the channel; a disruption of fast inactivation, an enhancement of activation, or both, while the myasthenic mutation presents a loss-of function defect. This report presents a case of non-dystrophic myotonia that is incidentally accompanied with acquired myasthenia. The patient presented a marked warm-up phenomenon of myotonia but the repeated short exercise test suggested mutations of the sodium channel. The genetic analysis identified a novel mutation, G1292D, of SCN4A. A functional study of the mutant channel revealed marked enhancement of activation and slight impairment of fast inactivation, which should induce muscle hyperexcitability. The effects of the alteration of channel function to the myasthenic symptoms were explored by using stimulation of repetitive depolarization pulses. A use-dependent channel inactivation was reduced in the mutant in comparison to normal channel, thus suggesting an opposing effect to myasthenia.     

Genetic CLC-1 chloride channel deficiency modifies diaphragm muscle isometric contractile properties

Genetic deficiency of the muscle chloride channel CLC-1 leads to myotonia congenita in humans as well as myotonia in mice and goats. The hallmark of myotonia is delayed muscle relaxation due to persistent electrical discharges in the muscle. The present study tested the hypothesis that performance of CLC-1 deficient diaphragm muscle is also altered during the contractile phase of the contraction-relaxation cycle. Diaphragm of CLC-1 deficient and wild type mice underwent in vitro isometric contractility testing. Myotonia was easily demonstrable during contractions elicited by train stimulation, but was not seen during twitch stimulation or during train stimulation preceded by a series of twitch stimulations. Twitch force was reduced from 16.7+/-2.5 N/cm(2) in normal muscle to 7.2+/-1.9 N/cm(2) in CLC-1 deficient muscle (P<0.002). Isometric twitch contraction time was shortened from 19.6+/-0.9 to 15.7+/-1.0 ms (P<0.002). During repetitive 25 Hz stimulation, force/area was lower for diseased than normal muscle, whereas force as a percent of initial values declined at a faster rate for normal than diseased muscle. The latter could be accounted for by a rightward shift in the force-frequency relationship of CLC-1 deficient relative to normal muscle, as use of stimulation frequencies which elicited comparable force levels as a percentage of maximum 100 Hz tetanic force led to similar rates of fatigue. These findings indicate that genetic CLC-1 deficiency not only affects muscle relaxation (myotonia) but also modulates diaphragm performance during the contractile phase of the contraction-relaxation cycle.     

A novel alteration of muscle chloride channel gating in myotonia levior

Mutations in the voltage-dependent skeletal muscle chloride channel, ClC-1, result in dominant or recessive myotonia congenita. The Q552R mutation causes a variant of dominant myotonia with a milder phenotype, myotonia levior. To characterise the functional properties of this mutation, homodimeric mutant and heterodimeric wild-type (WT) mutant channels were expressed in tsA201 cells and studied using the whole-cell recording technique. Q552R ClC-1 mutants formed functional channels with normal ion conduction but altered gating properties. Mutant channels were activated by membrane depolarisation, with a voltage dependence of activation that was shifted by more than +90 mV compared to WT channels. Q552R channels were also activated by hyperpolarisation, and this process was dependent upon the intracellular chloride concentration ([  Cl⁻  ]_i). Together, these alterations resulted in a substantial reduction in the open probability at −85 mV at a physiological [  Cl⁻  ]_i. Heterodimeric WT-Q552R channels did not exhibit hyperpolarisation-activated gating transitions. As was the case for WT channels, activation occurred upon depolarisation, but the activation curve was shifted by 28 mV to more positive potentials. The functional properties of heterodimeric channels suggest a weakly dominant effect, a finding that correlates with the inheritance pattern and symptom profile of myotonia levior.     

Proof of a non-functional muscle chloride channel in recessive myotonia congenita (Becker) by detection of a 4 base pair deletion

Recessive myotonia congenlta (Becker) is genetically linkedto HUMCLC, the gene encoding the muscular chloride channel,localized on chromosome 7q35. Three point mutations have sofar been reported In HUMCLC, one causing recessive Becker-typemyotonia, the others causing the clinically similar Thomsen-typemyotonia, which is Inherited as a dominant trait. We reporta homozygous patient having a 4 base pair deletion in HUMCLCthat shifts the reading frame and causes early stop codons,thus destroying the gene's coding potential for several membrane-spanningdomains. In addition, we report a patient homozygous for a novelpoint mutation located at the extracellular side of the firstmembrane-spanning domain that causes removal of a negative charge(aspartic acid-136-glyclne). Both mutations lead to the recessivetype of myotonia congenita. Since the patient having the deletionpresents less severe clinical myotonia than the patient carryingthe missense mutation, it seems that the absence or truncationof the channel protein may disturb muscle fibre function lessthan the substitution of a single amino acid.     

Chloride conductance in normal and myotonic muscle fibres and the action of monocarboxylic aromatic acids

1. Cable parameters, component conductances, excitability and membrane potentials in isolated external intercostal fibre bundles at 38 degrees C from normal and myotonic goats were measured in normal and low-chloride Ringer, and in the presence of monocarboxylic aromatic acids that produce myotonic responses in mammalian muscle.2. The mean resting chloride conductance in mumho/cm(2) of myotonic fibres (range 0-147) was significantly less than that of normal fibres (range 376-951). The mean resting potassium conductance was higher in myotonic fibres (range 123-285) than in normal fibres (range 44-132). Potassium conductance increased about 10 mumho/cm(2) per mV increase in absolute resting potential.3. In normal fibres in normal Ringer 3-chloro-2,5,6-trimethylbenzoic acid; 5,6-dihydro-5,5-dimethyl-7-carboxybenz[c]acridine; phenanthrene-9-carboxylic acid; and anthracene-9-carboxylic acid at 10(-5)-10(-4)M decreased membrane conductance without consistently changing diameter or capacitance. In low-chloride Ringer 3-chloro-2,5,6-trimethylbenzoic acid (5 x 10(-5)M) increased potassium conductance in myotonic and normal fibres. It is concluded that these compounds block chloride conductance.4. The carboxylic acids produced myotonia in normal fibres similar to that in untreated myotonic fibres.5. Anthracene-9-carboxylic acid intravenously (8 mg/kg) in normal goats produced acutely a condition resembling myotonia congenita. The carboxylic acids produced no myotonic effects in frog muscle.     

Mechanisms of cold sensitivity of paramyotonia congenita mutation R1448H and overlap syndrome mutation M1360V

Missense mutations of the human skeletal muscle voltage-gated Na⁺ channel (hSkM1) cause a variety of neuromuscular disorders. The mutation R1448H results in paramyotonia congenita and causes cold-induced myotonia with subsequent paralysis. The mutation M1360V causes an overlapping syndrome with both K⁺-induced muscle weakness and cold-induced myotonia. The molecular mechanisms of the temperature dependence of these disorders are not well understood. Therefore we investigated physiological parameters of these Na⁺ channel mutations at different temperatures. Channel proteins were recombinantly expressed in human embryonic kidney cells and studied electrophysiologically, using the whole-cell patch-clamp technique. We compared the wild-type (WT) channel with both mutants at different temperatures. Both mutations had slower inactivation and faster recovery from inactivation compared to WT channels. This effect was more pronounced at the R1448H mutation, leading to a larger depolarization of the cell membrane causing myotonia and paralysis. The voltage dependence of activation of R1448H was shifted to more negative membrane potentials at lower temperature but not at the M1360V mutation or in the WT. The window current by mutation R1448H was increased at lower temperatures. The results of this study may explain the stronger cold-induced clinical symptoms resulting from the R1448H mutation in contrast to the M1360V mutation.     

Severe neonatal non-dystrophic myotonia secondary to a novel mutation of the voltage-gated sodium channel (SCN4A) gene

We report on a patient with a severe, rare neonatal form of non-dystrophic myotonia. The patient presented with facial dysmorphism, muscle hypertrophy, severe constipation, psychomotor delay, and frequent cold-induced episodes of myotonia and muscle weakness leading to severe hypoxia and loss of consciousness. Muscle biopsy was non-specific and electromyography revealed intense generalized myotonia. The myotonic episodes improved after introducing oral mexiletine and maintaining room temperature at 28 degrees C. The patient died at 20 months of age following a bronchopulmonary infection. A previously undescribed de novo heterozygous c.3891C > A change, which predicts p.N1297K in the SCN4A gene. Mutations within the voltage-gated sodium channel alpha-subunit gene (SCN4A) have been described in association with several phenotypes including paramyotonia congenita, hyperkalemic or hypokalemic periodic paralysis, and potassium-aggravated myotonias. The cold-sensitive episodes of stiffness followed by weakness suggested the diagnosis of channelopathy in our patient. However, her neonatal onset, the triggering of severe episodes by exposure to modest decreases in temperature, involvement of respiratory muscles with prolonged apnea, early-onset muscle hypertrophy, psychomotor retardation, and fatal outcome are evocative of a distinct clinical subtype. Our observation expands the phenotypic spectrum of sodium channelopathies.     

Novel CLCN1 Mutations and Clinical Features of Korean Patients with Myotonia Congenita

Myotonia congenita (MC) is a form of nondystrophic myotonia caused by a mutation of CLCN1, which encodes human skeletal muscle chloride channel (CLC-1). We performed sequence analysis of all coding regions of CLCN1 in patients clinically diagnosed with MC, and identified 10 unrelated Korean patients harboring mutations. Detailed clinical analysis was performed in these patients to identify their clinical characteristics in relation to their genotypes. The CLCN1 mutational analyses revealed nine different point mutations. Of these, six (p.M128I, p.S189C, p.M373L, p.P480S, p.G523D, and p.M609K) were novel and could be unique among Koreans. While some features including predominant lower extremity involvement and normal to slightly elevated creatine kinase levels were consistently observed, general clinical features were highly variable in terms of age of onset, clinical severity, aggravating factors, and response to treatment. Our study is the first systematic study of MC in Korea, and shows its expanding clinical and genetic spectrums.     

SCN4A variants and Brugada syndrome: phenotypic and genotypic overlap between cardiac and skeletal muscle sodium channelopathies

SCN5A mutations involving the α-subunit of the cardiac voltage-gated muscle sodium channel (NaV1.5) result in different cardiac channelopathies with an autosomal-dominant inheritance such as Brugada syndrome. On the other hand, mutations in SCN4A encoding the α-subunit of the skeletal voltage-gated sodium channel (NaV1.4) cause non-dystrophic myotonia and/or periodic paralysis. In this study, we investigated whether cardiac arrhythmias or channelopathies such as Brugada syndrome can be part of the clinical phenotype associated with SCN4A variants and whether patients with Brugada syndrome present with non-dystrophic myotonia or periodic paralysis and related gene mutations. We therefore screened seven families with different SCN4A variants and non-dystrophic myotonia phenotypes for Brugada syndrome and performed a neurological, neurophysiological and genetic work-up in 107 Brugada families. In the families with an SCN4A-associated non-dystrophic myotonia, three patients had a clinical diagnosis of Brugada syndrome, whereas we found a remarkably high prevalence of myotonic features involving different genes in the families with Brugada syndrome. One Brugada family carried an SCN4A variant that is predicted to probably affect function, one family suffered from a not genetically confirmed non-dystrophic myotonia, one family was diagnosed with myotonic dystrophy (DMPK gene) and one family had a Thomsen disease myotonia congenita (CLCN1 variant that affects function). Our findings and data suggest a possible involvement of SCN4A variants in the pathophysiological mechanism underlying the development of a spontaneous or drug-induced type 1 electrocardiographic pattern and the occurrence of malignant arrhythmias in some patients with Brugada syndrome.     

Myotonic dystrophy: limited electromyographic abnormalities in 2 definite cases

Two women, aged 37 and 38 , with definite myotonic dystrophy are presented. Neither patient had clinical myotonia although both experienced intermittent jaw tightness. 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. The detection rate of EMG-myotonia in clinically normal heterozygotes increases if distal, proximal and cranial nerve innervated muscles are examined.     

Macrophagic myofasciitis in childhood: the role of scanning electron microscopy/energy-dispersive spectroscopy for diagnosis

Macrophagic myofasciitis (MMF) is an inflammatory myopathy related to aluminum-containing vaccines. Described in 1998, most cases were reported in adults, with only 22 cases being reported in children. Three children aged between 13 months and 3(1/2) years were investigated in our institution for neuromuscular symptoms. They underwent thorough clinical, familial, and laboratory investigations, electroneuromyography, muscle biopsy with transmission electron microscopy, scanning electron microscopy/energy dispersive spectroscopy (SEM/EDS), and, in one case, brain magnetic resonance imaging. They had received regular immunizations. Two patients were hypotonic and one presented with myotonia. Muscle biopsy of all patients presented macrophagic infiltrates with intracytoplasmic aluminum content as revealed by SEM/EDS analysis. Their diverse clinical picture does not support a direct relationship between local morphologic findings and systemic symptoms. The atypical clinical presentation of these children may not result from the superposition of MMF upon a background systemic neuromyopathy, suggesting instead that they are two coincident and independent conditions. Although the finding of macrophage infiltrates in muscle tissue is not new, the identification of aluminum content is recent. The use of tissue sections for aluminum detection and mapping by SEM/EDS is conclusive for, diagnosis; it has not been reported previously in a pathology journal, to the authors' knowledge.