Assuntos
Complexos de ATP Sintetase/genética , Acidose/genética , Cardiomegalia/genética , Retardo do Crescimento Fetal/genética , Glutaratos/metabolismo , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Complexos de ATP Sintetase/deficiência , Acidose/metabolismo , Acidose/patologia , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Criança , Consanguinidade , Análise Mutacional de DNA , Feminino , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/patologia , ATPase Trocadora de Hidrogênio-Potássio/deficiência , ATPase Trocadora de Hidrogênio-Potássio/genética , Heterozigoto , Humanos , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Proteínas de Membrana/deficiência , Proteínas Mitocondriais/deficiência , Proteínas/genética , Proteínas/metabolismo , Deleção de Sequência , Proteína Inibidora de ATPaseRESUMO
BACKGROUND: Neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) syndrome have been associated to m.8993T>G/C mutations in the subunit 6 of the ATP synthase (p.MT-ATP6). METHODS: We have performed a mutational screening of the mitochondrial DNA gene encoding for this protein in 62 patients with the disease, that do not carry any of the common mutations described to date. RESULTS: We report clinical and molecular data in one patient who harbours a de novo insertion in the MT-ATP6 gene that results in a truncated subunit. The mutation was heteroplasmic (85%) in muscle DNA and the BN-PAGE analysis showed a clear decrease in the amount of ATP synthase. CONCLUSION: Molecular analysis of NARP patients cannot be limited to the search of the m.8993T>G/C and either the ATP6 or the whole mtDNA should be sequenced.
Assuntos
Ataxia/genética , DNA Mitocondrial/genética , ATPases Mitocondriais Próton-Translocadoras/genética , Debilidade Muscular/genética , Retinose Pigmentar/genética , Adulto , Sequência de Aminoácidos , Sequência de Bases , Encéfalo/patologia , Humanos , Masculino , Dados de Sequência Molecular , Mutação Puntual , Análise de Sequência , SíndromeRESUMO
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by mutations in the thymidine phosphorylase gene (ECGF1). We present the first detailed report of a Brazilian MNGIE patient, harboring a novel ECGF1 homozygous mutation (C4202A, leading to a premature stop codon, S471X). Multiple deletions and the T5814C change were found in mitochondrial DNA. Together with gastrointestinal symptoms, endocrine involvement and memory dysfunction, not reported in MNGIE to date, were the most preeminent features.
Assuntos
Transtornos Cognitivos/genética , Gastroenteropatias/genética , Hipogonadismo/genética , Encefalomiopatias Mitocondriais/complicações , Encefalomiopatias Mitocondriais/genética , Mutação/genética , Timidina Fosforilase/genética , Adulto , Encéfalo/enzimologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Brasil , Códon sem Sentido/genética , Transtornos Cognitivos/enzimologia , Transtornos Cognitivos/fisiopatologia , Análise Mutacional de DNA , DNA Mitocondrial/genética , Gastroenteropatias/enzimologia , Gastroenteropatias/fisiopatologia , Deleção de Genes , Marcadores Genéticos/genética , Humanos , Hipogonadismo/enzimologia , Hipogonadismo/fisiopatologia , Masculino , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Encefalomiopatias Mitocondriais/psicologiaRESUMO
INTRODUCTION: Kearns-Sayre syndrome (KSS) is a mitochondrial disorder characterized by progressive external ophthalmoplegia, pigmentary retinopathy, onset before 20 years, and ragged-red fibers on muscle biopsy. KSS has been associated to mitochondrial DNA (mtDNA) mutations. We report neurological manifestations and mtDNA deletions in KSS. METHODS: Six KSS patients underwent neurological examination, biochemical analysis (muscle enzymes, lactate, cerebrospinal fluid analysis), electromicrography, muscle biopsy (Gomori stain, electronic microscopy), electrocardiogram, echocardiography, MRI/CT scan. MtDNA deletions were studied in blood and muscle samples using Southern blotting and long polymerase chain reaction. RESULTS: Four males and two females (mean age: 27.7 years; range: 17-42; mean age at onset: 8.2 years) were studied. Initial symptoms were ptosis and gaze restriction, fatigue, exercise intolerance and proximal limb weakness. Syncope and neurosensory hypoacusia were initial symptoms in two patients. All of them presented a unique deletion in the mitochondrial genome, in heteroplasmy, and their size was in the range of 4,420 and 9,437 basis pairs. Three of these deletions are reported for the first time in this article. Most of the deletions are flanked by small direct repeats elements. CONCLUSIONS: Proximal muscle weakness and fatigue appear frequently in KSS patients during follow up. The syndrome in these patients has been caused by mtDNA deletions.
Assuntos
DNA Mitocondrial/genética , Deleção de Genes , Síndrome de Kearns-Sayre/genética , Adolescente , Adulto , Sequência de Bases , Encéfalo/patologia , Análise Mutacional de DNA , Feminino , Humanos , Síndrome de Kearns-Sayre/patologia , Síndrome de Kearns-Sayre/fisiopatologia , Masculino , Dados de Sequência Molecular , Músculo Esquelético/patologiaRESUMO
AIM: The diseases of the oxidative phosphorylation system consist of a group of disorders originated by a deficient synthesis of adenosine triphosphate (ATP). These diseases are increasingly being diagnosed among patients with multisystemic disorders. Mitochondrial deoxyribonucleic acid (mtDNA) mutations are usually maternally inherited, but they also can be sporadic or secondary to nuclear mutations, that are inherited in a Mendelian mode, or due to environmental hazards. In this review we will update, from a genetic point of view, the knowledge on human mitochondrial diseases, remarking the difficulties to study these pathologies. DEVELOPMENT: To mirror these difficulties, we will use selected examples of mutations in the mitochondrial genome, and review recent advances on mitochondrial pathology due to mutations in the nuclear genes codifying for mitochondrial proteins that participate in a good performance of the oxidative phosphorylation system. CONCLUSIONS: Sequencing of the complete human mtDNA should be part of the basic profile in the study of mitochondrial diseases. Due to the increasing number of nuclear genes involved in the oxidative phosphorylation system performance, their analysis should be based on solid biochemical clues.
Assuntos
Doenças Mitocondriais/metabolismo , Fosforilação Oxidativa , DNA Mitocondrial/genética , Humanos , Doenças Mitocondriais/genética , MutaçãoRESUMO
INTRODUCTION: The syndrome of chronic progressive external ophthalmoplegia (CPEO) has been associated to the presence of large deletion, single or multiple, in the mitochondrial DNA of skeletal muscle. CASE REPORT: We report a sporadic case of chronic progressive external ophthalmoplegia that began at age 19 years and was associated with ragged red fibers in skeletal muscle. Genetic analysis of mitochondrial DNA revealed the presence of a single deletion of 4237 bp that encompasses the nucleotide positions 9486 to 13722, a location that has not been described before, and flanked by a direct repeat sequence. The deletion is flanked by a direct repeat. CONCLUSIONS: The amount of deleted mitochondrial DNA (55%) in this patient's muscle suggests that this deletion is the molecular cause of the phenotypic presentation of this patient.
Assuntos
Sequência de Bases , DNA Mitocondrial , Oftalmoplegia Externa Progressiva Crônica/genética , Deleção de Sequência , Adulto , Brasil , Mapeamento Cromossômico , Feminino , HumanosAssuntos
DNA Mitocondrial/genética , Síndrome de Kearns-Sayre/genética , Oftalmoplegia Externa Progressiva Crônica/genética , Sequências Repetitivas de Ácido Nucleico/genética , Deleção de Sequência , Sequência de Bases , Southern Blotting , Análise Mutacional de DNA , DNA Mitocondrial/química , Humanos , Reação em Cadeia da Polimerase/métodosRESUMO
Prescribing medication is a clinical procedure used quite often in Primary Care (PC). The quality of some prescriptions in the province of Albacete is studied, evaluating the characteristics of the PC physicians. The bottles of Cephalosporins, broad-spectrum Penicillins, Rawolfias, Diuretics, Beta-Blockers and Cerebral Blood Vessel Dilating Medications have been analyzed. Respectively, 38.4%, 30.8% and 28.5% of the physicians prescribed antibiotics, antihypertensives and blood vessel dilating medications acceptably. The logistic regression analysis only reveals a slight indication of: a better prescribing of antibiotics (p less than 0.02) at an older age, when employed in an urban environment and having a smaller number of patients to care for; and a better prescribing of cerebral blood vessel dilating medications (p less than 0.05) for specialists by way of MIR. The commercial information on medications could standardize behaviour with regard to writing prescriptions. To improve quality, it would be necessary to improve the scientific attitude of health care professionals.