RESUMO
Hereditary rippling muscle disease (RMD) is an autosomal dominant human disorder characterized by mechanically triggered contractions of skeletal muscle. Genome-wide linkage analysis has identified an RMD locus on chromosome 3p25. We found missense mutations in positional candidate CAV3 (encoding caveolin 3; ref. 5) in all five families analyzed. Mutations in CAV3 have also been described in limb-girdle muscular dystrophy type 1C (LGMD1C; refs. 6,7), demonstrating the allelism of dystrophic and non-dystrophic muscle diseases.
Assuntos
Caveolinas/genética , Contração Muscular , Músculo Esquelético , Doenças Musculares/genética , Mutação de Sentido Incorreto , Caveolina 3 , Creatina Quinase/sangue , Proteínas do Citoesqueleto/genética , Humanos , Glicoproteínas de Membrana/genética , Distrofias Musculares/genética , Estimulação FísicaRESUMO
Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, can be caused by a mutation on either chromosome 19q13 (DM1) or 3q21 (DM2/PROMM). DM1 is caused by a CTG expansion in the 3' untranslated region of the dystrophia myotonica-protein kinase gene (DMPK). Several mechanisms have been invoked to explain how this mutation, which does not alter the protein-coding portion of a gene, causes the specific constellation of clinical features characteristic of DM. We now report that DM2 is caused by a CCTG expansion (mean approximately 5000 repeats) located in intron 1 of the zinc finger protein 9 (ZNF9) gene. Parallels between these mutations indicate that microsatellite expansions in RNA can be pathogenic and cause the multisystemic features of DM1 and DM2.
Assuntos
Proteínas de Ligação a DNA/genética , Íntrons , Repetições de Microssatélites , Distrofia Miotônica/genética , Proteínas de Ligação a RNA/genética , Dedos de Zinco , Alelos , Southern Blotting , Mapeamento Cromossômico , Cromossomos Humanos Par 3/genética , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Doenças em Gêmeos/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Desequilíbrio de Ligação , Escore Lod , Masculino , Músculos/metabolismo , Mutação , Distrofia Miotônica/metabolismo , Fenótipo , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Gêmeos Monozigóticos , Dedos de Zinco/genéticaRESUMO
Autosomal recessive generalized myotonia (Becker's disease) (GM) and autosomal dominant myotonia congenita (Thomsen's disease) (MC) are characterized by skeletal muscle stiffness that is a result of muscle membrane hyperexcitability. For both diseases, alterations in muscle chloride or sodium currents or both have been observed. A complementary DNA for a human skeletal muscle chloride channel (CLC-1) was cloned, physically localized on chromosome 7, and linked to the T cell receptor beta (TCRB) locus. Tight linkage of these two loci to GM and MC was found in German families. An unusual restriction site in the CLC-1 locus in two GM families identified a mutation associated with that disease, a phenylalanine-to-cysteine substitution in putative transmembrane domain D8. This suggests that different mutations in CLC-1 may cause dominant or recessive myotonia.
Assuntos
Cromossomos Humanos Par 7 , Genes Dominantes , Genes Recessivos , Canais Iônicos/genética , Proteínas de Membrana/genética , Distrofias Musculares/genética , Miotonia Congênita/genética , Sequência de Aminoácidos , Animais , Southern Blotting , Canais de Cloreto , Clonagem Molecular , DNA/genética , Feminino , Ligação Genética , Humanos , Escore Lod , Masculino , Dados de Sequência Molecular , Linhagem , Polimorfismo de Fragmento de Restrição , Receptores de Antígenos de Linfócitos T/genética , Recombinação Genética , Homologia de Sequência do Ácido NucleicoRESUMO
Acute porphyrias are inherited disorders caused by partial deficiency of specific heme biosynthesis enzymes. Clinically, porphyrias are manifested by a neuropsychiatric syndrome that includes peripheral neuropathy. Although much is known about the porphyrias' enzyme defects and their biochemical consequences, the cause of the neurological manifestations remains unresolved. We have studied porphyric neuropathy in mice with a partial deficiency of porphobilinogen deaminase (PBGD). PBGD-deficient mice (PBGD-/-) imitate acute porphyria through massive induction of hepatic delta-aminolevulinic acid synthase by drugs such as phenobarbital. Here we show that PBGD-/- mice develop impairment of motor coordination and muscle weakness. Histologically femoral nerves of PBGD-/- mice exhibit a marked decrease in large-caliber (>8 microm) axons and ultrastructural changes consistent with primary motor axon degeneration, secondary Schwann cell reactions, and axonal regeneration. These findings resemble those found in studies of affected nerves of patients with acute porphyria and thus provide strong evidence that PBGD deficiency causes degeneration of motor axons without signs of primary demyelination, thereby resolving a long-standing controversy. Interestingly, the neuropathy in PBGD-/- mice developed chronically and progressively and in the presence of normal or only slightly (twofold) increased plasma and urinary levels of the putative neurotoxic heme precursor delta-aminolevulinic acid. These data suggest that heme deficiency and consequent dysfunction of hemeproteins can cause porphyric neuropathy.
Assuntos
Hidroximetilbilano Sintase/fisiologia , Neurônios Motores/patologia , Nervos Periféricos/fisiopatologia , Porfirias/fisiopatologia , Doença Aguda , Ácido Aminolevulínico/sangue , Ácido Aminolevulínico/urina , Animais , Modelos Animais de Doenças , Eletrofisiologia , Nervo Femoral/patologia , Nervo Femoral/fisiopatologia , Nervo Femoral/ultraestrutura , Humanos , Hidroximetilbilano Sintase/genética , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora , Neurônios Motores/ultraestrutura , Nervos Periféricos/patologia , Nervos Periféricos/ultraestrutura , Porfirias/patologiaRESUMO
Inhibitory G protein activity (Gi) and nitric oxide (NO) modulate muscarinic-cholinergic (MC) inhibition of cardiac beta-adrenergic inotropic responses. We hypothesized that Gi mediates MC-NO synthase (NOS) signal transduction. Isoproterenol (0.2-0.8 microg/min) and acetylcholine (1 microM) were administered to isolated perfused rat hearts pretreated with saline (controls; n = 8) or pertussis toxin (PT; 30 microg/kg intraperitoneally 3 d before study; n = 20). PT abrogated in vitro ADP-ribosylation of Gi protein alpha subunit(s) indicating near-total decrease in Gi protein function. Isoproterenol increased peak +dP/dt in both control (peak isoproterenol effect: +2, 589+/-293 mmHg/s, P < 0.0001) and PT hearts (+3,879+/-474 mmHg/s, P < 0.0001). Acetylcholine reversed isoproterenol inotropy in controls (108+/-21% reduction of +dP/dt response, P = 0.001), but had no effect in PT hearts. In controls, NG-monomethyl-L-arginine (100 microM) reduced basal +dP/dt, augmented isoproterenol +dP/dt (peak effect: +4,634+/-690 mmHg/s, P < 0.0001), and reduced the MC inhibitory effect to 69+/-8% (P < 0.03 vs. baseline). L-arginine (100 M) had no effect in controls but in PT hearts decreased basal +dP/dt by 1, 426+/-456 mmHg/s (P < 0.005), downward-shifted the isoproterenol concentration-effect curve, and produced a small MC inhibitory effect (27+/-4% reduction, P < 0.05). This enhanced response to NO substrate was associated with increased NOS III protein abundance, and a three- to fivefold increase in in vitro calcium-dependent NOS activity. Neomycin (1 microM) inhibition of phospholipase C did not reverse L-arginine enhancement of MC inhibitory effects. These data support a primary role for Gi in MC receptor signal transduction with NOS in rat heart, and demonstrate regulatory linkage between Gi and NOS III protein levels.
Assuntos
Proteínas de Ligação ao GTP/metabolismo , Coração/efeitos dos fármacos , Miocárdio/metabolismo , Óxido Nítrico Sintase/metabolismo , Toxina Pertussis , Proteínas/metabolismo , Fatores de Virulência de Bordetella/farmacologia , Acetilcolina/metabolismo , Acetilcolina/farmacologia , Difosfato de Adenosina/metabolismo , Agonistas Adrenérgicos beta/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Animais , Arginina/farmacologia , Cálcio/metabolismo , Inibidores Enzimáticos/farmacologia , Proteínas de Ligação ao GTP/fisiologia , Técnicas In Vitro , Isoproterenol/metabolismo , Isoproterenol/farmacologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Neomicina/farmacologia , Óxido Nítrico/metabolismo , Inibidores da Síntese de Proteínas/farmacologia , Ratos , Ratos Wistar , Receptores Adrenérgicos beta/metabolismo , Receptores Muscarínicos/metabolismo , Transdução de Sinais , Fosfolipases Tipo C/antagonistas & inibidoresRESUMO
Cardiovascular aging is associated with decreased endothelial vasoreactivity and prolonged diastolic relaxation. As diminished NO signaling contributes to age-associated endothelial dysfunction, we tested the hypothesis that impaired NO signaling or bioactivity also contributes to slowed ventricular relaxation with age. Accordingly, we measured myocardial NO synthase (NOS) enzyme activity, protein abundance, and cGMP production in old (22 to 25 months) and young adult (4 to 7 months) male Wistar rats. Both NOS3 protein abundance and calcium-dependent NOS activity were elevated in old compared with young adult hearts (7.2+/-1.1 versus 4.2+/-0.6 pmol/mg protein, respectively, P=0.03). However, NOS activity and protein abundance were similar in isolated myocytes, indicating that endothelial NOS likely explains the age difference. Cardiac effluent cGMP (enzyme immunoassay) was 4.8-fold higher (1794+/-373 fmol/min per mg heart tissue) in older versus younger hearts (P=0.003). To assess NO pathway responsiveness, we administered the NOS substrate l-arginine (100 micrometer) to isolated perfused rat hearts. Baseline isovolumic relaxation (tau) was prolonged in old (42.9+/-2.5 ms, n=16) versus young hearts (36.0+/-1.9 ms, n=11, P=0.03). l-Arginine decreased tau (P<0.001) and left ventricular end-diastolic pressure in both old and young hearts. Supporting an NO/cGMP-mediating mechanism, the NO donor sodium nitroprusside reduced tau (maximal effect, -14+/-2%, n=5, P<0.001), and this lusitropic effect was attenuated by the soluble guanylyl cyclase inhibitor 1H:-[1,2,4]oxadiazolo-[4,3,-a]quinoxalin-1-one (n=7, P<0.001). Thus, the NO-cGMP pathway is upregulated in the endothelial cells of aged hearts. l-Arginine, the NOS precursor, enhances ventricular relaxation in old and young hearts, indicating that the NOS pathway may be exploited to modulate diastolic function in aged myocardium.
Assuntos
Envelhecimento/fisiologia , GMP Cíclico/metabolismo , Miocárdio/metabolismo , Óxido Nítrico/metabolismo , Animais , Arginina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Coração/efeitos dos fármacos , Coração/fisiologia , Técnicas In Vitro , Masculino , Contração Miocárdica/efeitos dos fármacos , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo III , Nitroprussiato/farmacologia , Oxidiazóis/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Transdução de Sinais , Regulação para CimaRESUMO
Myocardial NO signaling appears elevated in heart failure (HF). Whether this results from increased NO production, induction of the high-output NO synthase (NOS)2 isoform, or changes in NOS regulatory pathways (such as caveolae) remains controversial. We tested the hypothesis that increased abundance of caveolin-3 and/or sarcolemmal caveolae contribute to increased NO signaling in pacing-induced HF. Abundance of caveolin-3 (0.59+/-0.08 versus 0.29+/-0.08 arbitrary units, P = 0.01) but not caveolin-1 was increased in HF compared with control conditions, assessed by Western blot. Additionally, transmission electron microscopy revealed increased caveolae (2. 7+/-0.4 versus 1.3+/-0.3 per micrometer myocyte membrane, P<0.005). The association between caveolin-3 and NOS3 at the sarcolemma and T tubules was unchanged in HF compared with control myocytes. The impact of NOS inhibition with L-N(G)-methylarginine hydrochloride (L-NMMA) on beta-adrenergic inotropy was assessed in conscious dogs before and after HF. In control dogs, dobutamine (5 microg. kg(-1) x min(-1)) increased +dP/dt by 36+/-7%, and this was augmented to 66+/-24% by 20 mg/kg L-NMMA (P = 0.04 versus without L-NMMA, n = 8) but not affected by 10 mg/kg L-NMMA (34+/-10%, P = NS; n = 8). In HF, dobutamine +dP/dt response was depressed (P<0.001 versus control), and increased concentrations were required to match control inotropic responses (10 to 15 microg. kg(-1) x min(-1), 48+/-7%). L-NMMA enhanced +dP/dt responses similarly at 10 mg/kg (61+/-17%, P = 0.02; n = 4) and 20 mg/kg (54+/-7%, P = 0.04; n = 7). Caveolin-3 abundance positively correlated with L-NMMA augmentation of dobutamine inotropic responses in HF (r = 0.9, P = 0.03; n = 4). Thus, in canine pacing-induced HF, expression of caveolin-3 and of sarcolemmal caveolae is increased. This increase is associated with augmented agonist-stimulated NO signaling, likely via a compartmentation effect.
Assuntos
Baixo Débito Cardíaco/fisiopatologia , Caveolinas , Proteínas de Membrana/metabolismo , Miocárdio/metabolismo , Óxido Nítrico/fisiologia , Transdução de Sinais , Animais , Baixo Débito Cardíaco/etiologia , Baixo Débito Cardíaco/patologia , Estimulação Cardíaca Artificial , Caveolina 1 , Caveolina 3 , Cães , Inibidores Enzimáticos/farmacologia , Feminino , Hemodinâmica , Masculino , Miocárdio/ultraestrutura , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , ômega-N-Metilarginina/farmacologiaRESUMO
A family was studied in which four generations (16 of 41 members) suffered from painful recurrent muscle cramping. A clear pattern of autosomal dominant inheritance was noted. The cramping first developed during adolescence or early adulthood. Electromyographic analysis indicated a neurogenic origin. The cramps seemed to be due to dysfunction of the motor neurons. The mechanisms underlying this alteration are unclear and require further investigation.
Assuntos
Cãibra Muscular/genética , Adolescente , Adulto , Idoso , Eletromiografia , Feminino , Humanos , Perna (Membro) , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
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.
Assuntos
Miotonia/genética , Canais de Sódio , Eletrofisiologia , Genótipo , Humanos , Hipopotassemia/genética , Hipopotassemia/metabolismo , Hipopotassemia/patologia , Hipopotassemia/fisiopatologia , Músculos/fisiopatologia , Mutação , Miotonia/metabolismo , Miotonia/patologia , Miotonia/fisiopatologia , Miotonia Congênita/genética , Miotonia Congênita/metabolismo , Miotonia Congênita/patologia , Miotonia Congênita/fisiopatologia , Distrofia Miotônica/genética , Distrofia Miotônica/metabolismo , Distrofia Miotônica/patologia , Distrofia Miotônica/fisiopatologia , Paralisias Periódicas Familiares/genética , Paralisias Periódicas Familiares/metabolismo , Paralisias Periódicas Familiares/patologia , Paralisias Periódicas Familiares/fisiopatologia , Fenótipo , Canais de Sódio/genética , Canais de Sódio/metabolismoRESUMO
Autosomal-dominantly inherited nondystrophic myotonic disorders are an interesting group of muscle diseases that provide considerable opportunity for future molecular genetic studies to identify the genes responsible for specific membrane functions. A family with such a myotonic disorder is described with features that are distinctly different from myotonia congenita and paramyotonia congenita. Five members were affected in three generations. The myotonia fluctuated to an unusual degree. It did not worsen with cold but increased markedly with potassium loading. Muscle weakness never occurred. Analysis of the contraction force of the flexor digitorum muscle showed a unique type of myotonia, namely, exercise-induced delayed-onset myotonia. Microelectrode studies done on one muscle biopsy specimen revealed a normal chloride conductance of the muscle fiber membrane.
Assuntos
Miotonia/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Temperatura Baixa , Eletromiografia , Feminino , Humanos , Masculino , Potenciais da Membrana , Pessoa de Meia-Idade , Músculos/efeitos dos fármacos , Músculos/fisiopatologia , Miotonia/fisiopatologia , Miotonia Congênita/fisiopatologia , Linhagem , Potássio/farmacologiaRESUMO
Six patients from two families with an autosomal dominantly inherited disease, apparently a myopathy, are described. Their major complaint was muscle stiffness, primarily in the legs. The muscles displayed an unusual sensitivity to stretch, manifested by rippling waves of muscle contraction. These rippling contractions were not accompanied by muscle fiber action potentials. Nonspecific, mild abnormalities were seen on muscle biopsy. These findings raise the possibility that there is an intracellular derangement in the muscle fiber responsible for the muscle rippling; further studies are necessary to establish the underlying pathophysiologic condition.
Assuntos
Doenças Musculares/genética , Adulto , Creatina Quinase/sangue , Eletromiografia , Testes de Função Cardíaca , Testes Hematológicos , Humanos , Contração Isométrica , Masculino , Pessoa de Meia-Idade , Músculos/patologia , Doenças Musculares/diagnóstico , Doenças Musculares/tratamento farmacológico , Testes de Função TireóideaRESUMO
Occasionally, chronic denervation is associated with enlargement rather than atrophy of muscle tissue. We studied seven patients with S-1 radiculopathy who developed ipsilateral enlargement of the calf. On the basis of results of calf muscle biopsies, it seems likely that the enlargement was due to muscle fiber hypertrophy and atrophy combined with an increase in connective tissue. Computed tomograms of the legs revealed no evidence of tumor. Surgical decompression of the involved S-1 nerve root had no obviously beneficial effect in reducing the calf enlargement. More information is needed to define the natural course of the calf enlargement and to clarify the pathophysiologic processes involved.
Assuntos
Perna (Membro)/patologia , Músculos/patologia , Doenças do Sistema Nervoso Periférico/patologia , Raízes Nervosas Espinhais , Adulto , Humanos , Hipertrofia , Perna (Membro)/inervação , Masculino , Pessoa de Meia-Idade , Músculos/inervaçãoRESUMO
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.
Assuntos
Miotonia/patologia , Sequência de Bases , Teste de Esforço , Feminino , Antebraço , Humanos , Masculino , Mexiletina/uso terapêutico , Dados de Sequência Molecular , Miotonia/tratamento farmacológico , Miotonia/etiologia , Miotonia/genética , Miotonia/fisiopatologia , Potássio/efeitos adversos , Análise de Sequência de DNA , Canais de Sódio/metabolismo , TemperaturaRESUMO
BACKGROUND: Previous investigations in three families have shown that proximal myotonic myopathy (PROMM) is not linked to the gene loci for myotonic dystrophy (DM) or to the loci of the genes of the muscle sodium and chloride channels associated with other myotonic disorders. It is important to extend our clinical knowledge of this interesting new disorder by studying other families. PATIENTS: Thirty-five patients in 14 new families; 27 patients were examined. METHODS: Clinical examination, electromyography, muscle biopsy, DNA analysis. RESULTS: The following findings were noted: proximal without distal weakness of the legs (n = 21); myotonia on electromyograms (n = 23); intermittent clinical myotonia (n = 17); cataracts (n = 24) and a number of the cataracts were identical to the type in DM (n = 11); and peculiar muscle pain (n = 14). A few patients had cardiac arrhythmias, and others had elevations in the concentrations of serum gamma-glutamyltransferase. None of the patients had significant muscle atrophy. Muscle biopsy specimens showed mild myopathic changes. All patients had normal trinucleotide (cytosine, thymine, and guanine) repeat size of the DM gene in leukocyte DNA. Muscle DNA probes from three patients showed findings identical to those of their leukocyte DNA probes. CONCLUSIONS: Proximal myotonic myopathy is a new genetic disorder similar to, but distinct from, DM. Patients suspected of having DM but with negative DNA studies may have PROMM. The gene defect for PROMM awaits discovery. Because of the similarities between PROMM and DM, this discovery will not only shed light on the pathomechanism of PROMM, but it may also increase our understanding of DM.
Assuntos
Distrofia Miotônica/complicações , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/sangue , Doenças Musculares/complicações , Doenças Musculares/genética , Doenças Musculares/patologia , Distrofia Miotônica/sangue , Distrofia Miotônica/genética , Distrofia Miotônica/patologia , Análise de Sequência de DNARESUMO
We studied hyperkalemic attacks in one family with adynamia episodica (AE) and one family with paralysis periodica paramyotonica (PPP). Under exercise, serum potassium increased as in healthy subjects. Thiazide did not affect this increase. Thirty minutes after exercise, a second potassium increase occurred, but could be prevented by thiazide and not by mexiletine. After cooling, muscle relaxation time was normal in AE but increased up to 100 times in PPP; this cooling effect was prevented by mexiletine. Although hyperkalemic attacks are similar in AE and in PPP, the membrane defect in PPP seems more complex.
Assuntos
Hiperpotassemia/sangue , Doenças Musculares/sangue , Miotonia/sangue , Adulto , Feminino , Humanos , Hiperpotassemia/complicações , Hiperpotassemia/fisiopatologia , Masculino , Doenças Musculares/complicações , Doenças Musculares/fisiopatologia , Miotonia/complicações , Miotonia/fisiopatologia , Paralisia/sangue , Paralisia/complicações , Paralisia/fisiopatologia , Esforço FísicoRESUMO
We investigated the effectiveness of tocainide and hydrochlorothiazide on muscular symptoms in a patient with paramyotonia congenita and episodic attacks of hyperkalemic paralysis. Generalized weakness was evoked by exercise and potassium loading. Myotonia and weakness were evoked by local muscle cooling. Tocainide prevented myotonia and weakness induced by cooling, but failed to prevent hyperkalemic weakness. Hydrochlorothiazide prevented hyperkalemic weakness, but did not influence symptoms evoked by cooling. These results suggest that, in this disorder, two different mechanisms cause muscular weakness.
Assuntos
Hidroclorotiazida/uso terapêutico , Hiperpotassemia/tratamento farmacológico , Lidocaína/análogos & derivados , Miotonia Congênita/tratamento farmacológico , Paralisia/tratamento farmacológico , Adulto , Humanos , Hiperpotassemia/complicações , Hipotermia Induzida , Lidocaína/uso terapêutico , Masculino , Miotonia Congênita/etiologia , Paralisia/complicações , Esforço Físico , Potássio , TocainideRESUMO
We studied a family in which seven individuals in three generations had slowly progressive weakness without atrophy, myalgia, cramps, or episodic weakness. Creatine kinase was normal, and EMG showed only slight "myopathic" changes. Neuromuscular transmission was undisturbed. Muscle biopsies were performed in three patients. About 60 to 90% of all fibers contained tubular aggregates. There was a marked variation in fiber size and a marked type II fiber atrophy. Biopsy of an asymptomatic family member was normal. The nature of the underlying disease was obscure.
Assuntos
Músculos/ultraestrutura , Doenças Musculares/patologia , Adulto , Feminino , Doenças Genéticas Inatas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/genéticaRESUMO
Previous studies have suggested that an abnormal release of potassium from muscle may accompany attacks of paramyotonic weakness. We investigated 3 patients with paramyotonia congenita before and after the induction of forearm muscle weakness by exercise in cold water. Two of these patients had paralysis periodica paramyotonica and the 3rd had paramyotonia congenita. At the time of paramyotonic weakness there was a marked increase in the arterialized-venous concentration difference of potassium across forearm muscle. This indicated a significant uptake of potassium by forearm muscle in all 3 patients. Normal controls showed a slight release of potassium both at rest and after exercise in cold water. These results suggest that (1) the sodium-potassium pump of the muscle fiber is operating efficiently during paramyotonic weakness; and (2) there is a different mechanism responsible for the generalized weakness that occurs in hyperkalemic periodic paralysis.
Assuntos
Músculos/metabolismo , Miotonia/metabolismo , Potássio/metabolismo , Adulto , Artérias , Temperatura Baixa , Exercício Físico , Antebraço , Humanos , Hiperpotassemia/complicações , Lactente , Lidocaína/análogos & derivados , Lidocaína/farmacologia , Masculino , Músculos/fisiopatologia , Miotonia/etiologia , Miotonia/fisiopatologia , Paralisia/sangue , Paralisia/etiologia , Paralisia/metabolismo , Periodicidade , Potássio/sangue , Tocainide , VeiasRESUMO
Rippling muscle disease (RMD) is an inherited disorder of skeletal muscle in which mechanical stimuli provoke electrically silent contractions. Patient symptoms are muscle cramps, pain, and stiffness, particularly during or following exercise. Clinical signs are balling of muscle following percussion and a characteristic lateral rolling movement of muscle occurring after contraction followed by stretching. We report a new 44-member pedigree segregating RMD as an autosomal dominant trait. A genetic linkage study in this family, using a novel approach of testing closely spaced highly polymorphic markers in affected individuals, localized the responsible gene to the distal end of the long arm of chromosome 1 with a maximum multipoint lod score of 3.56 (theta = 0). In this family, RMD is localized to a 12-cM region near D1S235. We studied two previously reported German families for linkage to the same locus, and this same area did not cosegregate with the disease, a finding that shows that different genetic defects can cause a similar clinical phenotype (genetic heterogeneity). An understanding of the defect in contraction control within the muscle fibers in this disease may lead to a better understanding of muscle force transduction, intracellular calcium homeostasis, or both.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 1 , Contração Muscular/fisiologia , Doenças Musculares/genética , Adolescente , Adulto , Criança , Feminino , Ligação Genética/genética , Marcadores Genéticos , Humanos , Masculino , Músculo Esquelético/fisiopatologia , Doenças Musculares/fisiopatologia , Linhagem , Reação em Cadeia da PolimeraseRESUMO
Evaluation of thyroid function in 104 patients with myasthenia gravis by T3, T4, TBG, and TSH radioimmunoassays and the TRH-stimulation test in 47 patients disclosed thyrotoxicosis in 5.7%, preclinical hyperthyroidism probably due to autonomously functioning thyroid tissue in about 10% of patients stimulated with TRH, hypothyroidism in 1.9%, and preclinical hypothyroidism in 3.4%. Eighty-four percent were euthyroid. Antithyroid antibody activity was detected by hemagglutination tests. Twelve patients had antithyroglobulin antibodies (Tab), and 28 had antimicrosomal antibodies (Mab). Among the euthyroid myasthenic patients, 7 were Tab-positive and 20 were Mab-positive. Euthyroid antibody-positive patients had a significantly higher TSH response in the TRH stimulation test and may be at high risk for hypothyroidism.