RESUMO
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare, autosomal recessive disorder associated with mutations in the thymidine phosphorylase (TYMP) gene. The main objective of this study was to characterize the genetic profiles of the deceased proband's family members (N = 4) using DNA sequencing and to determine miRNA deregulation in MNGIE using miRNA microarray profiling and bioinformatic analysis. We found that the genetic profile of the younger sister showed similar TYMP gene mutations as that of the proband with the exception of a heterozygous mutation in exon 10. The miRNA microarray revealed 55 significantly up-regulated and 65 significantly down-regulated miRNAs. These miRNAs have been implicated in various mitochondrial dynamics such as energy metabolism, Krebs cycle, mitochondria-associated apoptosis, and mitophagy. In conclusion, we demonstrate that blood miRNAs are deregulated in the pathogenesis of MNGIE and these changes may have therapeutic implications. Further experimental studies will be required to elucidate the functional miRNA-mRNA interactions in MNGIE.
Assuntos
MicroRNAs/genética , Encefalomiopatias Mitocondriais/genética , Transcriptoma , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Malásia , Masculino , Pessoa de Meia-Idade , Encefalomiopatias Mitocondriais/diagnóstico , Mutação , Linhagem , Timidina Fosforilase/genética , Adulto JovemRESUMO
OBJECTIVES: To review all patients with SCO2 mutations and to describe a Brazilian patient with cardioencephalomyopathy carrying compound heterozygous mutations in SCO2, one being the known pathogenic p.E140K mutation and the other a novel 12-base pair (bp) deletion at nucleotides 1519 through 1530 (c.1519_1530del). DESIGN: Case report and literature review. SETTING: University hospital. PATIENT: Infant girl presenting with an encephalomyopathy, inspiratory stridor, ventilator failure, progressive hypotonia, and weakness, leading to death. MAIN OUTCOME MEASURES: Clinical features, neuroimaging findings, muscle biopsy with histochemical analysis, and genetic studies. RESULTS: This infant girl was the first child of healthy, nonconsanguineous parents. She developed progressive muscular hypotonia and ventilatory failure. At the end of the first month of life, she developed cardiomegaly and signs of cardiac failure. Routine blood tests showed lactic acidosis and mild elevation of the creatine kinase level. Brain magnetic resonance imaging showed increased T2 and fluid-attenuated inversion recovery signals in the putamen bilaterally. Nerve conduction studies showed severe axonal sensorimotor neuropathy. Muscle biopsy revealed a neurogenic pattern with mitochondrial proliferation and total absence of cytochrome- c oxidase histochemical stain. Sequencing of SCO2 showed that the patient had compound heterozygote SCO2 mutations: the previously described c.1541G>A (p.E140K) mutation and a novel 12-bp deletion at nucleotides 1519 through 1530 (c.1519_1530del). The patient died at age 45 days. CONCLUSIONS: Our findings and the literature review indicate that it is important to consider the diagnosis of mitochondrial disease in newborns with hypotonia and cardiomyopathy. In our case, the accurate diagnosis of SCO2 mutations is particularly important for genetic counseling.
Assuntos
Cardiomiopatias/genética , Proteínas de Transporte/genética , Encefalomiopatias Mitocondriais/genética , Proteínas Mitocondriais/genética , Mutação/genética , Sequência de Bases , Brasil , Cardiomiopatias/diagnóstico , Evolução Fatal , Feminino , Humanos , Lactente , Encefalomiopatias Mitocondriais/diagnóstico , Chaperonas Moleculares , Dados de Sequência MolecularRESUMO
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by mutations in the thymidine phosphorylase gene located on chromosome 22q13.32-ter, causing defective functioning of the enzyme. At present 87 sporadic or familial cases have been reported and 52 different mutations identified. We present herein the clinical, neuromuscular and molecular findings of two affected brothers from an indigenous Mexican family living in a very small village not far from Mexico City, both brothers being homozygous for a novel mutation (Leu133Pro) in exon 3 of the ECGF1 gene.
Assuntos
Encefalomiopatias Mitocondriais/genética , Mutação , Timidina Fosforilase/genética , Adulto , Feminino , Humanos , Masculino , México , Encefalomiopatias Mitocondriais/enzimologia , LinhagemRESUMO
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
Understanding muscle cell in disease and health is an unfinished process. Following the lead of Jaime Alvarez, I have had the opportunity of working on two complementary approaches to this field. One is the study of muscle cell surface molecules. Both synaptic muscle molecules, such as the asymmetric form of acetylcholinesterase, and extrasynaptic molecules, such as the extracellular matrix proteoglycans, are regulated by the motor nerve activity. This illustrates one of Jaime's teachings: cell phenotypes are a dynamic process that reflects the influence of other cells (Alvarez, 2001). Proteoglycans have many functions, including growth factor receptors. Studying them in muscular dystrophy will contribute to the comprehension of the muscle regeneration failure, characteristic of this disease. Muscle cells are highly dependent upon energy production, and the mitochondriae produce most of it. These organelles are unique in having their own genome. Mutations in these genes have recently been recognized as the cause of human disease and originally in muscle pathology. The physiopathology of these diseases is summarized here.
Assuntos
Doenças Mitocondriais/fisiopatologia , Músculos/citologia , Acetilcolinesterase/química , Comunicação Celular , DNA Mitocondrial/genética , Humanos , Doenças Mitocondriais/genética , Encefalomiopatias Mitocondriais/genética , Encefalomiopatias Mitocondriais/fisiopatologiaRESUMO
Mitochondrial diseases are a group of disorders produced by defects in the oxidative phosphorylation system (Oxphos system), the final pathway of the mitochondrial energetic metabolism, resulting in a deficiency of the biosynthesis of ATP. Part of the polypeptide subunits involved in the Oxphos system are codified by the mitochondrial DNA. In the last years, mutations in this genetic system have been described and associated to well defined clinical syndromes. The clinical features of these disorders are very heterogeneous affecting, in most cases, to different organs and tissues and their correct diagnosis require precise clinical, morphological, biochemical and genetic data. The peculiar genetic characteristics of the mitochondrial DNA (maternal inheritance, polyplasmia and mitotic segregation) give to these disorders very distinctive properties. The English version of this paper is available at: http://www.insp.mx/salud/index.html.
Assuntos
DNA Mitocondrial , Miopatias Mitocondriais , Trifosfato de Adenosina/biossíntese , Adulto , Fatores Etários , Criança , DNA Mitocondrial/genética , Feminino , Humanos , Recém-Nascido , Encefalomiopatias Mitocondriais/diagnóstico , Encefalomiopatias Mitocondriais/genética , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/epidemiologia , Miopatias Mitocondriais/genética , Miopatias Mitocondriais/metabolismo , Mutação , Oftalmoplegia Externa Progressiva Crônica/genética , Atrofias Ópticas Hereditárias/diagnóstico , Atrofias Ópticas Hereditárias/genética , Prevalência , Pesquisa , EspanhaRESUMO
Several mitochondrial diseases are known to occasionally involve the cerebral white matter, namely Leigh syndrome, Kearns-Sayre syndrome, and MELAS syndrome, but in these cases the major finding is alteration in the basal ganglia and brainstem. Here we report on severe diffuse white matter involvement and respiratory chain enzyme deficiency or mitochondrial DNA rearrangement in 5 unrelated families. It is interesting that white matter lesions were the only abnormal neuroradiologic feature in 3 of the 5 families, and multiple small cyst-like white matter lesions were found in 2 of 5 probands. Respiratory chain deficiency should be considered in the diagnosis of severe white matter involvement in childhood.