RESUMO
In daily hospital activity a frequent observation is that of patients in conditions of acute global suffering of the central nervous system due to a primary cause or symptomatic of other diseases. This condition shows an alteration of the state of consciousness, which involves three possible semeiologic manifestations: delirium (acute confusional state), acute confusional state associated with psychomotor underactivity and coma. The possible causes of an acute encephalopathy (AE) are: metabolic, iatrogenic and toxic, infective, primary neurologic, surgery-related and others. Diagnostic-therapeutic routes to be followed by emergency room doctors and neurologists dealing with AE are defined.
Assuntos
Encefalopatias/complicações , Encefalopatias/etiologia , Doença Aguda , HumanosAssuntos
Cardiopatias/genética , Lamina Tipo A/genética , Laminas/genética , Distrofias Musculares/genética , Mutação , Adolescente , Adulto , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/genética , Criança , Análise Mutacional de DNA , Humanos , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Distrofias Musculares/diagnóstico , Distrofia Muscular de Emery-Dreifuss/diagnóstico , Distrofia Muscular de Emery-Dreifuss/genética , Proteínas Nucleares , Fenótipo , Timopoietinas/genéticaRESUMO
Limb girdle muscular dystrophy (LGMD) type 2B and distal Miyoshi myopathy (MM) are caused by mutations in a recently discovered mammalian gene coding for a skeletal muscle protein called dysferlin. The protein is normally expressed at the skeletal muscle level and absent or reduced in affected patients. We selected a clinically heterogeneous population of Italian myopathic patients with clinical evidence of myopathy and/or hyperCKemia, EMG myopathic pattern, and no alterations of the dystrophin-sarcoglycan complex. Calpain, merosin, emerin and caveolin were also tested and found normal in all patients. Dysferlin immunohistochemical and Western blot analyses allowed us to identify six patients with dysferlin deficiency: one with distal myopathy, four with limb girdle myopathy and one with hyperCKemia. No apoptosis was found in any of the six muscle specimens, although expression of the pro-apoptotic Fas antigen was mildly increased in two cases. Inflammatory reactions were present in two of the six cases, but we found no evidence of immune-mediated processes.
Assuntos
Proteínas de Membrana , Proteínas Musculares/deficiência , Proteínas Musculares/metabolismo , Distrofias Musculares/metabolismo , Adolescente , Adulto , Western Blotting/métodos , Criança , Disferlina , Distrofina/metabolismo , Estudos de Avaliação como Assunto , Feminino , Humanos , Imuno-Histoquímica/métodos , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/genética , Músculo Esquelético/patologia , Distrofias Musculares/classificação , Distrofias Musculares/diagnóstico , Distrofias Musculares/genética , Receptor fas/metabolismoRESUMO
Mitochondrial disorders are human genetic diseases with extremely variable clinical and genetic features. To better define them, we made a genotype-phenotype correlation in a series of 207 affected patients, and we examined most of them with six laboratory examinations (serum CK and basal lactate levels, EMG, cardiac and EEG studies, neuroradiology). We found that, depending on the genetic abnormality, hyperckemia occurs most often with either chronic progressive external ophthalmoplegia (CPEO) and ptosis or with limb weakness. Myopathic EMGs are more common than limb weakness, except in patients with A8344G mutations. Peripheral neuropathy, when present, is always axonal. About 80% of patients with A3243G and A8344G mutations have high basal lactate levels, whereas pure CPEO is never associated with increased lactate levels. Cardiac abnormalities mostly consist of conduction defects. Abnormalities on CT or MRI of the brain are relatively common in A3243G mutations independently of the clinical phenotype. Patients with multiple mtDNA deletions are somehow "protected" against the development of abnormalities with any of the tests. We conclude that, despite the phenotypic heterogeneity of mitochondrial disorders, correlation of clinical features and laboratory findings may give the clinician important clues to the genetic defect, allowing earlier diagnosis and counselling.
Assuntos
DNA Mitocondrial/genética , Deleção de Genes , Doenças Mitocondriais/genética , Doenças Mitocondriais/fisiopatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Pré-Escolar , Creatina Quinase/sangue , Eletroencefalografia , Eletromiografia , Feminino , Coração/fisiopatologia , Humanos , Lactente , Ácido Láctico/sangue , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/diagnóstico , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Fenótipo , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
Overexpression of mutated superoxide dismutase (SOD1) in transgenic mice causes a progressive motor neuron degeneration in the spinal cord similar to that in human amyotrophic lateral sclerosis (ALS). Ultrastructural analysis of motor neurons at different stages of the disease in transgenic C57BL/6 mice carrying the G93A mutation of SOD1 showed, at about 2 weeks of age, much earlier than the initial symptoms of the disease, microvacuoles in the cytoplasm, with marked swelling of the mitochondria. Nuclei with an apoptotic morphology were never observed in these motor neurons. Swollen mitochondria were also seen in the distal part of motor axons of phrenic nerves and in the large axons of sciatic nerves before the onset of the disease, but no mitochondrial alterations were seen in skeletal muscles or in the small sciatic nerve axons. Moreover, we found no apparent changes in the histochemical reactivity of cytochrome oxidase in motor neurons of transgenic mice even at the advanced stage of the disease, suggesting that partial neuronal activity in these cells may be maintained despite the altered mitochondria. Immunoreactivity for human SOD1 was high around vacuoles in the motor neurons of transgenic mice but no cytoplasmic intracellular SOD1 aggregates were observed. Our data indicate that mitochondrial swelling may be an important factor triggering the cascade leading to progressive motor neuron death. Activation of the mitochondrial permeability transition pore may be involved in this process, through excitotoxicity or other neurotoxic stimuli.
Assuntos
Esclerose Lateral Amiotrófica/enzimologia , Apoptose , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Mitocôndrias/patologia , Neurônios Motores/enzimologia , Vacúolos/patologia , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Humanos , Imuno-Histoquímica , Região Lombossacral , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/enzimologia , Neurônios Motores/patologia , Músculo Esquelético/ultraestrutura , Nervo Frênico/patologia , Nervo Frênico/ultraestrutura , Medula Espinal/patologia , Medula Espinal/ultraestrutura , Succinato Desidrogenase/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1 , Vacúolos/ultraestruturaRESUMO
A severe muscle enolase deficiency, with 5% of residual activity, was detected in a 47-year-old man affected with exercise intolerance and myalgias. No rise of serum lactate was observed with the ischemic forearm exercise. Ultrastructural analysis showed focal sarcoplasmic accumulation of glycogen beta particles. The enzyme enolase catalyzes the interconversion of 2-phosphoglycerate and phosphoenolpyruvate. In adult human muscle, over 90% of enolase activity is accounted for by the beta-enolase subunit, the protein product of the ENO3 gene. The beta-enolase protein was dramatically reduced in the muscle of our patient, by both immunohistochemistry and immunoblotting, while alpha-enolase was normally represented. The ENO3 gene of our patient carries two heterozygous missense mutations affecting highly conserved amino acid residues; a G467A transition changing a glycine residue at position 156 to aspartate, in close proximity to the catalytic site, and a G1121A transition changing a glycine to glutamate at position 374. These mutations were probably inherited as autosomal recessive traits since the mother was heterozygous for the G467A and a sister was heterozygous for the G1121A transition. Our data suggest that ENO3 mutations result in decreased stability of mutant beta-enolase. Muscle beta-enolase deficiency should be considered in the differential diagnosis of metabolic myopathies due to inherited defects of distal glycolysis.
Assuntos
Músculos/metabolismo , Músculos/patologia , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Fosfopiruvato Hidratase/deficiência , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND/OBJECTIVE: Apoptosis, or programmed cell death, is an evolutionary conserved mechanism essential for morphogenesis and tissue homeostasis, but it plays an important role also in pathologic conditions, including neurologic disorders. Its execution pathway is critically regulated at the mitochondrial level. Evidence of apoptosis in muscle specimens was investigated in patients with genetically defined mitochondrial encephalomyopathies. METHODS: Thirty-three muscle biopsies from patients with genotypically different mitochondrial diseases (single and multiple deletions, A3243G/A8344G point mutations of the mitochondrial DNA) were studied. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) reaction was used as a marker of nuclear DNA fragmentation, as well as antibodies against pro- (Fas) or anti- (Bcl-2) apoptotic factors. Also, because one hallmark of apoptosis is morphologic, ultrastructural studies were performed on skeletal muscle from 18 of 33 patients, examining both phenotypically normal and ragged red fibers. RESULTS: In all muscle biopsies, no significant expression of either pro (Fas) and inhibiting (Bcl-2) apoptosis-related proteins was found, nor TUNEL positivity. This latter finding is confirmed by lack of morphologic evidence of apoptosis in all the fibers examined at the ultrastructural level. CONCLUSION: The authors' findings suggest that genetically determined defects of oxidative phosphorylation do not induce the apoptotic process and that apoptosis is not involved in the pathogenesis of mitochondrial disorders.