RESUMO
Camurati-Engelmann disease (CED) is a rare autosomal dominant disease with various phenotypic expressions. The hallmark of the disease is bilateral symmetric diaphyseal hyperostosis of the long bones with progressive involvement of the metaphysis. Ocular manifestations occur rarely and mainly result from bony overgrowth of the orbit and optic canal stenosis. We report a case of CED showing angioid streaks (ASs) in both fundi with no macular involvement and discuss the possible theories of the pathogenesis of AS in this disease.
Assuntos
Estrias Angioides/etiologia , Síndrome de Camurati-Engelmann/complicações , Retina/patologia , Adulto , Estrias Angioides/diagnóstico , Síndrome de Camurati-Engelmann/diagnóstico , Feminino , Angiofluoresceinografia , Fundo de Olho , Humanos , Tomografia de Coerência ÓpticaRESUMO
Catechol-O-methyl transferase (COMT) inhibition by entacapone enhances levodopa absorption and reduces 'off' time in Parkinson's disease (PD). We hypothesized that the administration of entacapone in a bimodal fashion (two doses 1 h apart) would enhance levodopa absorption and improve the motor symptoms of PD. Patients with PD (n = 17) were given immediate (IR)- or controlled (CR)-release levodopa each with either one or two doses of entacapone. Bimodal entacapone produced a significant increase in IR and CR levodopa half-life, 'area under the curve' (AUC), and C(max) with levodopa CR. For both IR and CR levodopa, bimodal entacapone resulted in a significant improvement in the Unified Parkinson's Disease Rating Scale part III (motor). Bimodal entacapone increased COMT inhibition, improved the pharmacokinetics of levodopa and improved motor scores for 6 to 8 h. Bimodal use of entacapone may be useful in selected patients to improve motor control and implies that controlled release COMT inhibition would be beneficial in PD patients.
Assuntos
Antiparkinsonianos/uso terapêutico , Catecóis/uso terapêutico , Transtornos dos Movimentos/tratamento farmacológico , Nitrilas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Área Sob a Curva , Catecol O-Metiltransferase , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/sangue , Transtornos dos Movimentos/etiologia , Doença de Parkinson/sangue , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Índice de Gravidade de DoençaRESUMO
Although genomic screening studies have identified several genes associated with Parkinson's disease (PD), there is evidence that environmental factors are also involved in the pathogenesis of the disease and that hydrocarbon-solvents may be one of them. The genetic component is less evident in late-onset PD. To assess whether age and PD may affect the catabolism of the hydrocarbon n-hexane, a two-part study was performed. In the first part the urinary levels of its main metabolites, 2,5-hexanedione and 2,5-dimethylpyrroles, were measured in 108 patients and 108 healthy controls, matched by age and sex. Metabolite urinary excretion was significantly reduced in PD patients as compared with controls and was inversely related to age in both groups. In the second part the same comparison was made between 24 non-smoking and 10 smoking patients, matched to controls, after smoking of a hydrocarbon-rich cigarette. In these subjects also n-hexane and 2,5-hexanedione blood levels were measured. There was no appreciable difference in n-hexane blood levels between patients and controls in non-smokers, whereas there was a significant increase in patients over controls in smokers (p < 0.01). 2,5-hexanedione blood levels were significantly lower in patients than in healthy controls, both in non-smokers and in smokers, but the reduction was more pronounced in smokers (-46.3 % versus -10.7 %). The same was true for 2,5-hexanedione and 2,5-dimethylpyrrole urinary levels. This study suggests that aging and PD may be associated with a reduction in the capacity to eliminate the hydrocarbon n-hexane. This metabolic alteration may play a role in the pathogenesis of PD.
Assuntos
Hexanos/sangue , Hexanos/urina , Doença de Parkinson/sangue , Doença de Parkinson/urina , Fatores Etários , Idoso , Análise de Variância , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Peripheral neuropathy has been described in a number of cases of mitochondrial diseases. In these patients the onset of neuropathy varies from childhood to adulthood, whereas late onset is quite rare. We report here three males, ranging from 71 to 75 years with onset of peripheral neuropathy between 64 and 74 years of age. They complain of ataxic gait, muscle aches, weakness and mild muscle atrophy, sensory impairment with predominant glove and stocking distribution, reduced or absent deep tendon reflexes. Neurophysiological examinations and sural nerve biopsy studies showed a sensorimotor neuropathy with axonal degeneration in two cases and demyelination in one. Peroneus brevis muscle biopsy revealed, apart from frank neurogenic changes, presence of ragged-red fibers and cytochrome c oxidase negative fibers. Electron microscopy confirmed an abnormally increased presence of subsarcolemmal and intermyofibrillar mitochondria in muscle samples. These morphological features suggested a mitochondrial disease that was confirmed by biochemical investigations on muscle homogenate showing that the mitochondrial respiratory chain (MRC) enzyme activities were all reduced when compared to citrate synthase activity. In addition the presence of a partially inactive cytochrome c oxidase protein by ELISA was demonstrated in two cases. According to a recent "mitochondrial theory of aging", we think that a progressive decline of MRC function has affected either skeletal muscle or peripheral nerves in our patients. Being energy-requiring processes, muscle metabolism as well as active axonal transport may become progressively defective with age resulting in a late-onset neuropathy.
RESUMO
A 16-year-old girl presented with early-onset cerebellar ataxia, myoclonus, elevated lactic acidosis and hypogonadotropic hypogonadism. Muscle biopsy specimens revealed fibres with a "ragged" appearance with increased mitochondria and lipid droplets. Biochemical investigation revealed a deficiency of complex bc1 (complex III) of the mitochondrial respiratory chain. Genetic analysis did not show either deletions or known mutations of mitochondrial DNA (mtDNA). Phosphorus magnetic resonance spectroscopy (31P-MRS) showed defective energy metabolism in brain and gastrocnemius muscle. A decreased phosphocreatine (PCr) content was found in the occipital lobes accompanied by normal inorganic phosphate (Pi) and cytosolic pH. These findings represented evidence of a high cytosolic adenosine diphosphate concentration and a relatively high rate of metabolism accompanied by a low phosphorylation potential. Muscle 31P-MRS showed a high Pi content at rest, abnormal exercise transfer pattern and a low rate of PCr post-exercise recovery. These findings suggested a deficit of mitochondrial function. Therapy with vitamins K3 and C normalized brain 31P-MRS indices, whereas it did not affect muscle bioenergetic metabolism. In this patient, the endocrinological disorder is putatively due to a mitochondrial cytopathy. Although an unknown mtDNA mutation cannot be ruled out, the genetic defect may lie in the nuclear genome.
Assuntos
Ácido Ascórbico/uso terapêutico , Complexo III da Cadeia de Transporte de Elétrons/deficiência , Mitocôndrias/enzimologia , Dissinergia Cerebelar Mioclônica/etiologia , Vitamina K/uso terapêutico , Adolescente , Idade de Início , Consanguinidade , DNA Mitocondrial/genética , Transporte de Elétrons/efeitos dos fármacos , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genéticaRESUMO
A woman with definite multiple sclerosis (MS) and mitochondrial myopathy is described. There were widespread white matter lesions on magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) abnormalities and evoked response changes. Muscle biopsy showed ragged red fibres (RRFs) and cytochrome c oxidase (CoX) deficiency. Southern blot analysis revealed a large deletion of mitochondrial DNA (mtDNA). The patient may be affected by two unrelated diseases, MS and mitochondrial myopathy, but this combination has never previously been reported.
Assuntos
Miopatias Mitocondriais/complicações , Esclerose Múltipla/complicações , Biópsia , Southern Blotting , DNA Mitocondrial/genética , Feminino , Deleção de Genes , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Miopatias Mitocondriais/diagnóstico , Esclerose Múltipla/diagnóstico , Músculo Esquelético/patologiaRESUMO
A 25-year-old woman had been complaining of episodes of muscle weakness, nausea and vomiting since the age of 10. Muscle biopsy showed free fatty acid accumulation and mitochondrial abnormalities. Mitochondrial DNA appeared to be normal at Southern analysis. Biochemical investigations demonstrated: glutaric aciduria type II, decreased levels of carnitine in liver and values at the lower level of normal in muscle, increased muscle carnitine palmitoyl transferase activity, partial cytochrome c oxidase and succinate cytochrome reductase deficiency in muscle homogenate. In isolated muscle mitochondria, cytochromes aa3, b and c were partially decreased, butyryl-CoA dehydrogenase and palmitoyl-CoA dehydrogenase activities were 10 and 54% of the normal, respectively. Muscle cell cultures did not show lipid storage. Low-lipid diet reduced critical episodes and lipid storage in muscle biopsy.
Assuntos
Acil-CoA Desidrogenases/deficiência , Creatina Quinase/sangue , Glutaratos/urina , Erros Inatos do Metabolismo Lipídico/diagnóstico , Doenças Neuromusculares/diagnóstico , Adulto , Biópsia , Feminino , Humanos , Metabolismo dos Lipídeos , Erros Inatos do Metabolismo Lipídico/enzimologia , Fígado/patologia , Microscopia Eletrônica , Mitocôndrias Musculares/ultraestrutura , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/enzimologia , Músculos/patologia , Exame Neurológico , Doenças Neuromusculares/enzimologiaRESUMO
A 34-year-old man affected by exercise intolerance, mild proximal weakness and severe lactic acidosis is described. Muscle biopsy revealed mitochondrial abnormalities and an increase of cytochrome c oxidase histochemical reaction. Biochemical investigations on isolated muscle mitochondria as well as polarographic studies revealed a mitochondrial NADH-CoQ reductase (complex I) deficiency. Mitochondrial dysfunction was confirmed by 31P nuclear magnetic resonance spectroscopy. Immunological investigation showed a generalized reduction of all complex I polypeptides. Genetic analysis did not reveal mitochondrial DNA deletions. The biochemical defect was not present in the patient's muscle tissue culture. Metabolic measurements and functional evaluation showed a reduced mechanical efficiency during exercise.
Assuntos
Acidose Láctica/etiologia , Mitocôndrias Musculares , Doenças Musculares/metabolismo , Quinona Redutases/deficiência , Trifosfato de Adenosina/metabolismo , Adulto , Células Cultivadas , DNA Mitocondrial/análise , Ensaio de Imunoadsorção Enzimática , Exercício Físico/fisiologia , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Mitocôndrias Musculares/ultraestrutura , Músculos/metabolismo , Músculos/ultraestrutura , Doenças Musculares/genética , Doenças Musculares/patologia , NAD(P)H Desidrogenase (Quinona) , Consumo de Oxigênio/fisiologia , Fosfocreatina/metabolismoRESUMO
A population of deleted mitochondrial DNA (mtDNA) was found in different amounts in autoptic muscle, heart, cortex, cerebellum, liver and kidney of a patient who died of Kearn-Sayre Syndrome (KSS). The widespread occurrence of the deletion correlates with the multisystem nature of KSS and supports the hypothesis that this is a genetic disease due to an alteration of mtDNA presumably arising in the oocyte or early embryo.
Assuntos
Encéfalo/patologia , DNA Mitocondrial/análise , Síndrome de Kearns-Sayre/genética , Músculos/patologia , Oftalmoplegia/genética , Humanos , Síndrome de Kearns-Sayre/patologiaRESUMO
Modern concepts regarding mitochondrial encephalomyopathies (ME) are summarized. Utilizing recent techniques of molecular biology we studied some cases of ME referred to the Institute of Clinical Neurology of Milan University. With these techniques we demonstrated different mitochondrial DNA deletions either in patients' muscle or in culture.
Assuntos
Encefalopatias/patologia , Deleção Cromossômica , DNA Mitocondrial/análise , Síndrome de Kearns-Sayre/enzimologia , Mitocôndrias Musculares/patologia , Doenças Musculares/patologia , Oftalmoplegia/enzimologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Encefalopatias/enzimologia , Encefalopatias/genética , DNA Mitocondrial/genética , Complexo IV da Cadeia de Transporte de Elétrons/análise , Saúde da Família , Humanos , Cariotipagem , Síndrome de Kearns-Sayre/genética , Microscopia Eletrônica , Pessoa de Meia-Idade , Mitocôndrias Musculares/enzimologia , Doenças Musculares/enzimologia , Doenças Musculares/genética , LinhagemAssuntos
Acidose Láctica/complicações , Encefalopatias/complicações , Síndrome de Kearns-Sayre/complicações , Mitocôndrias Musculares/patologia , Doenças Musculares/complicações , Oftalmoplegia/complicações , Acidose Láctica/metabolismo , Acidose Láctica/patologia , Adolescente , Adulto , Encefalopatias/metabolismo , Encefalopatias/patologia , Humanos , Síndrome de Kearns-Sayre/metabolismo , Síndrome de Kearns-Sayre/patologia , Masculino , Mitocôndrias Musculares/metabolismo , Doenças Musculares/metabolismo , Doenças Musculares/patologia , SíndromeRESUMO
Muscle glucose-6-phosphate dehydrogenase (G6PD) deficiency is described in four clinically heterogeneous patients: an athlete who developed myoglobinuria after physical exercise; a 7-year-old, mildly mentally retarded boy, who had episodes of dark urine and high creatine kinase; and two brothers of Sardinian origin, the elder showing moderate exercise intolerance. Histochemical and biochemical studies showed a lack of G6PD activity in muscle biopsy specimens as well as in erythrocytes. G6PD characterization in erythrocytes classified these mutant enzymes as Mediterranean variant in all the patients. The deficiency was confirmed in the patients' myotubes and skin fibroblasts, where residual activity was present. Electrophoretic studies in tissue culture extracts showed that the residual muscle enzyme migrated as a single electrophoretic band like normal human muscle G6PD.
Assuntos
Deficiência de Glucosefosfato Desidrogenase/metabolismo , Músculos/enzimologia , Adolescente , Adulto , Criança , Eritrócitos/enzimologia , Eritrócitos/metabolismo , Feminino , Humanos , Masculino , Microscopia Eletrônica , Músculos/ultraestrutura , Fatores de TempoRESUMO
A 19-year-old man born with thyroprivic hypothyroidism, due to congenital development defect, manifested hypogonadism, stunted growth, chronic progressive external ophthalmoplegia (CPEO), diffuse muscle weakness and wasting, right bundle branch block, cerebral atrophy. Muscle biopsy showed mitochondrial abnormalities. Biochemical investigations on muscle disclosed partial (50%) cytochrome c oxidase deficiency, 58% decrease of cytochrome aa3 and 41% decrease of cytochrome b. Enzyme-linked immunosorbent assay showed decrease of the immunologically active enzyme protein.
Assuntos
Encefalopatias/patologia , Deficiência de Citocromo-c Oxidase , Hipogonadismo/patologia , Hipotireoidismo/patologia , Mitocôndrias Musculares/ultraestrutura , Oftalmoplegia/patologia , Adulto , Biópsia , Humanos , Masculino , Microscopia Eletrônica , Músculos/patologia , Atrofia Muscular/patologiaRESUMO
Histochemical, biochemical and immunologic analysis of cytochrome c oxidase (COX) in skeletal muscle, heart and kidney during human fetal development was performed. COX histochemical activity was present only in few muscle fibres from the 11th to the 20th week of gestation. At the same developmental stage intrafusal muscle fibres, heart and kidney already showed strong activity. At the 28th week of gestation muscular COX activity was present in about 90% of the fibres. Tissue biochemical analysis confirmed these histochemical findings. Histochemical and biochemical findings compared to the immunocytochemical results and ELISA indicate that COX activity parallels the progressive synthesis of the enzyme in each tissue.
Assuntos
Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feto/enzimologia , Rim/enzimologia , Músculos/enzimologia , Miocárdio/enzimologia , Idade Gestacional , Coração/embriologia , Humanos , Rim/metabolismo , Músculos/embriologiaRESUMO
We tested the efficacy of coenzyme Q10 (ubidecarenone, CoQ10) therapy in patients with Kearns-Sayre syndrome and other mitochondrial myopathies with chronic progressive external ophthalmoplegia (CPEO). We treated seven patients for 1 year with daily oral administration of 120 mg of CoQ10. Throughout the treatment most of our patients showed a progressive reduction of serum lactate and pyruvate levels following standard muscle exercise and generally improved neurologic functions. The ECG and echocardiogram showed no significant changes in our patients. None of our patients showed any improvement in ptosis and CPEO.
Assuntos
Síndrome de Kearns-Sayre/tratamento farmacológico , Mitocôndrias Musculares , Doenças Musculares/tratamento farmacológico , Oftalmoplegia/tratamento farmacológico , Ubiquinona/análogos & derivados , Adolescente , Adulto , Coenzimas , Feminino , Humanos , Síndrome de Kearns-Sayre/patologia , Masculino , Mitocôndrias Musculares/ultraestrutura , Doenças Musculares/patologia , Ubiquinona/uso terapêuticoRESUMO
A multicenter, double-blind, between-patient trial comparing two doses of ketazolam (15 and 30 mg) with placebo, each given once daily, in the evening, to 92 outpatients affected by generalized anxiety disorders for at least 1 month, was carried out. After 1-week washout period 47 patients were randomized to ketazolam 15 mg, and 45 to placebo for 15 days (first period). At the end of this period, if the patient experienced a decrease on the total Hamilton Anxiety Rating Scale (HAM-A) of at least 25% of basal value, the treatment was kept unchanged for a further 15 days, otherwise 15 mg of ketazolam were added to the previous treatment (second period). Anxiety was rated after 2 and 4 weeks with the Italian HAM-A scale and with a 4-point scale (patient's assessment). Seventy-eight patients completed the first period and 75 the whole study. During the first period the percentage of responders was almost identical in both treatment groups, but during the second period a further slight improvement was observed in the early placebo responders, while the HAM-A score of patients on ketazolam continued to improve significantly (p less than 0.01) throughout the study. Likewise a significant (p less than 0.001) difference between treatments was observed, on the 4-point scale, in the population as a whole (end of first period) as well as in responder patients (end second period). Tolerability was good, except in 1 patient on placebo, who was withdrawn from the study because of severe headache.
Assuntos
Ansiolíticos/administração & dosagem , Transtornos de Ansiedade/tratamento farmacológico , Benzodiazepinas , Benzodiazepinonas/administração & dosagem , Adolescente , Adulto , Idoso , Transtornos de Ansiedade/psicologia , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes PsicológicosAssuntos
Síndrome de Kearns-Sayre/tratamento farmacológico , Oftalmoplegia/tratamento farmacológico , Ubiquinona/análogos & derivados , Coenzimas , Avaliação de Medicamentos , Transporte de Elétrons , Coração/fisiopatologia , Humanos , Síndrome de Kearns-Sayre/sangue , Síndrome de Kearns-Sayre/imunologia , Síndrome de Kearns-Sayre/patologia , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Músculos/fisiopatologia , Projetos Piloto , Ubiquinona/uso terapêuticoRESUMO
Mitochondria and myosin were isolated from a muscle biopsy of a 9-year-old boy with an unusual congenital myopathy characterized by type I fiber uniformity, jagged Z-line, and transverse network hypertrophy of mitochondria. Biochemical examination of isolated mitochondria showed that only citrate synthase activity was significantly reduced. Electrophoresis of myosin heavy chains and immunoenzymatic analysis of myosin heavy and light chains with antibodies specific to either fast or slow myosins showed that only the slow-type isoform of myosin was detectable. Indirect immunofluorescence of muscle biopsy showed that all muscle fibers homogeneously expressed only the slow type of myosin.