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1.
Zhonghua Er Ke Za Zhi ; 57(11): 844-851, 2019 Nov 02.
Artigo em Chinês | MEDLINE | ID: mdl-31665838

RESUMO

Objective: To summarize the clinical and genetic characteristics of children with mitochondrial epilepsy. Methods: Clinical data of 62 children who were clinically and genetically diagnosed with mitochondrial epilepsy by the Department of Neurology, Beijing Children's Hospital from October 2011 to December 2018 were analyzed retrospectively, and the control of epilepsy was followed up. T test or χ(2) test were used to analyze the related factors affecting the prognosis of epilepsy between the effective group and the ineffective group. Results: Of the 62 patients, 33 were male and 29 were female. The age of onset was 3.38 (0-12.00) years; for the type of seizures, 68% (42/62) of the patients had focal seizures, generalized or secondary generalized tonic-clonic seizures were seen in 32% (20/62), myoclonic seizures in 23% (14/62), spastic seizures in 7 cases, tonic seizures in 4 cases, absence seizure, atonic seizure and clonic seizure in 1 case each; 16 cases (26%) had status epilepticus, of whom 6 cases had epilepsia partialis continua; 52% (32/62) had 2 or more types of seizures. The clinical phenotypes were mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) in 29 cases, Leigh syndrome (LS) in 11 cases, combined oxidative phosphorylation deficiency in 6 cases, myoclonus epilepsy with ragged-red fibers in 5 cases, Alpers syndrome in 4 cases, pontocerebellar hypoplasia type 6 and mitochondrial DNA depletion syndrome 9 in 2 cases each, mitochondrial complex Ⅰ deficiency nuclear type 20, progressive cavitating leukoencephalopathy, and biotinidase deficiency in 1 case each. Of the 62 cases, 40 cases (65%) had mitochondrial DNA (mtDNA) variations, of which 26 cases had m.3243A>G variants, 6 cases had m.8344A>G variants, and 3 cases had m.8993T>G/C variants, m.3271T>C, m.3481G>A, m.3946G>A, m.13094T>C, m.14487T>C variant was in 1 case each; nuclear DNA (nDNA) variations were identified in 22 cases (35%), of which 7 cases carrying variations in mitochondrial ammonia acyl tRNA synthetase coding gene, mutations in POLG and the gene encoding complex Ⅰ were in 4 cases each, variations in SUCLG1 and SDHA genes were in 2 cases each, and variations in PDHA1, BTD and TRIT1 genes were in 1 case each. Forty-three patients were followed up, and the follow-up time was 20 (3-84) months. According to the follow-up results, the anti-epilepsy treatment was effective in 19 cases (44%) and ineffective in other 24 cases (56%). The onset age of the effective group was 3.42 (0-11.50) years and that of the ineffective group was 0.92 (0-9.50) years. The onset duration of the effective group was 0 (0-7.00) years and that of the ineffective group was 0 (0-4.83) years. There was no significant difference between the effective group and the ineffective group (t=1.662, 0.860; P=0.104, 0.395). In the effective group and the ineffective group, 12 cases and 9 cases used less than 2 kinds of antiepileptic drugs, 7 cases and 15 cases used more than or equal to 2 kinds of antiepileptic drugs, 13 and 15 cases had first epilepsy, 6 and 9 cases had non-first epilepsy, 14 and 11 cases had mtDNA variation, 5 and 13 cases had nDNA variation, respectively. There was no significant difference between the two groups (χ(2)=2.794, 0.164, 3.380; P=0.095, 0.686, 0.066). Conclusions: The types of seizures with mitochondrial epilepsy in children varied, with focal motor seizures being the most common, followed by generalized or secondary generalized tonic-clonic seizures. Most children have more than two types of seizures. MELAS is the most common clinical phenotype, followed by LS; mtDNA variation is the dominant gene variation, of which m.3243A>G variation is the most common hotspot variation, followed by gene variation encoding mitochondrial aminoacyl tRNA synthase.


Assuntos
Epilepsia/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Doenças Mitocondriais/diagnóstico por imagem , Anticonvulsivantes/uso terapêutico , Criança , Epilepsia/tratamento farmacológico , Epilepsia/genética , Feminino , Humanos , Masculino , Doenças Mitocondriais/genética , Fenótipo , Estudos Retrospectivos , Convulsões
2.
BMC Med Genet ; 20(1): 167, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664948

RESUMO

BACKGROUND: Mitochondrial DNA depletion syndromes (MDS) are clinically and phenotypically heterogeneous disorders resulting from nuclear gene mutations. The affected individuals represent a notable reduction in mitochondrial DNA (mtDNA) content, which leads to malfunction of the components of the respiratory chain. MDS is classified according to the type of affected tissue; the most common type is hepatocerebral form, which is attributed to mutations in nuclear genes such as DGUOK and MPV17. These two genes encode mitochondrial proteins and play major roles in mtDNA synthesis. CASE PRESENTATION: In this investigation patients in three families affected by hepatocerebral form of MDS who were initially diagnosed with tyrosinemia underwent full clinical evaluation. Furthermore, the causative mutations were identified using next generation sequencing and were subsequently validated using sanger sequencing. The effect of the mutations on the gene expression was also studied using real-time PCR. A pathogenic heterozygous frameshift deletion mutation in DGUOK gene was identified in parents of two affected patients (c.706-707 + 2 del: p.k236 fs) presenting with jaundice, impaired fetal growth, low-birth weight, and failure to thrive who died at the age of 3 and 6 months in family I. Moreover, a novel splice site mutation in MPV17 gene (c.461 + 1G > C) was identified in a patient with jaundice, muscle weakness, and failure to thrive who died due to hepatic failure at the age of 4 months. A 5-month-old infant presenting with jaundice, dark urine, poor sucking, and feeding problems was also identified to have another novel mutation in MPV17 gene leading to stop gain mutation (c.277C > T: p.(Gln93*)). CONCLUSIONS: These patients had overlapping clinical features with tyrosinemia. MDS should be considered a differential diagnosis in patients presenting with signs and symptoms of tyrosinemia.


Assuntos
DNA Mitocondrial/genética , Doenças Mitocondriais/genética , DNA Mitocondrial/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Lactente , Masculino , Mutação , Linhagem , Síndrome , Sequenciamento Completo do Exoma
3.
Enzymes ; 45: 311-341, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31627882

RESUMO

Mitochondria play a central role in bioenergetics, and fulfill a plethora of functions in cell signaling, programmed cell death, and biosynthesis of key protein cofactors. Mitochondria harbor their own genomic DNA, which encodes protein subunits of the electron transport chain and a full set of transfer and ribosomal RNAs. Mitochondrial DNA (mtDNA) is essential for cellular and organismal functions, and defects in mitochondrial genome maintenance have been implicated in common human diseases and mitochondrial disorders. mtDNA repair and degradation are known pathways to cope with mtDNA damage; however, molecular factors involved in this process have remained unclear. Such knowledge is fundamental to the understanding of mitochondrial genomic maintenance and pathology, because mtDNA degradation may contribute to the etiology of mtDNA depletion syndromes and to the activation of the innate immune response by fragmented mtDNA. This article reviews the current literature regarding the importance of mitochondrial DNA degradation in mtDNA maintenance and stress response, and the recent progress in uncovering molecular factors involved in mtDNA degradation. These factors include key components of the mtDNA replication machinery, such as DNA polymerase γ, helicase Twinkle, and exonuclease MGME1, as well as a major DNA-packaging protein, mitochondrial transcription factor A (TFAM).


Assuntos
DNA Mitocondrial/metabolismo , Genoma Mitocondrial/genética , Estresse Fisiológico , Replicação do DNA , Humanos , Doenças Mitocondriais/genética , Doenças Mitocondriais/patologia
4.
J Med Case Rep ; 13(1): 313, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31630688

RESUMO

BACKGROUND: Maternally inherited diabetes and deafness, and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes are examples of mitochondrial diseases that are relatively common in the adult population. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes are assumed to be associated with decreases in arginine and citrulline. Biomarkers, such as growth differentiation factor-15, were developed to assist in the diagnosis of mitochondrial diseases. CASE PRESENTATION: A 55-year-old Japanese man, an insulin user, presented after a loss of consciousness. A laboratory test showed diabetic ketoacidosis. He and his mother had severe hearing difficulty. Bilateral lesions on magnetic resonance imaging, the presence of seizure, and an elevated ratio of lactate to pyruvate, altogether suggested a diagnosis of mitochondrial disease. Mitochondrial DNA in our patient's peripheral blood was positive with a 3243A>G mutation, which is the most frequent cause of maternally inherited diabetes and deafness, and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. As a result, maternally inherited diabetes and deafness/mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes was diagnosed. We measured growth differentiation factor-15 and multiple amino acids in his blood, longitudinally during and after the stroke-like episode. Growth differentiation factor-15 was increased to an immeasurably high level on the day of the stroke-like episode. Although his diabetes improved with an increased dose of insulin, the growth differentiation factor-15 level gradually increased, suggesting that his mitochondrial insufficiency did not improve. Multiple amino acid species, including arginine, citrulline, and taurine, showed a decreased level on the day of the episode and a sharp increase the next day. In contrast, the level of aspartic acid increased to an extremely high level on the day of the episode, and decreased gradually thereafter. CONCLUSIONS: Growth differentiation factor-15 can be used not only for the diagnosis of mitochondrial disease, but as an indicator of its acute exacerbation. A stroke-like episode of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes reflects a drastic derangement of multiple amino acids. The involvement of aspartic acid in the episodes should be explored in future studies.


Assuntos
Surdez/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Síndrome MELAS/diagnóstico , Doenças Mitocondriais/diagnóstico , Arginina/sangue , Ácido Aspártico/sangue , Biomarcadores/sangue , DNA Mitocondrial/genética , Surdez/genética , Diabetes Mellitus Tipo 2/genética , Fator 15 de Diferenciação de Crescimento/sangue , Humanos , Síndrome MELAS/genética , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/genética , Mutação
5.
DNA Cell Biol ; 38(11): 1197-1206, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31618067

RESUMO

Researches establish an indispensable role of mitochondrial dysfunction in septic cardiomyopathy. We aimed to investigate the effects of long noncoding RNA (LncRNA) SOX2 overlapping transcript (SOX2OT) on mitochondrial dysfunction in septic cardiomyopathy. We observed an obvious overexpression of SOX2OT in septic hearts and cardiomyocytes. Knockdown of SOX2OT in mice recovered the reduced cardiac function, and improved the mitochondrial membrane potential impaired by lipopolysaccharide (LPS). SOX2OT overexpressed mice showed the opposite situation. In parallel, knockdown of SOX2OT in cardiomyocytes restored the mitochondrial membrane potential, along with reduced mitochondrial reactive oxygen species production induced by LPS, while overexpression of SOX2OT reversed these effects. Mechanistically, SOX2OT could regulate mitochondrial dysfunction in septic cardiomyopathy via SOX2. In general, SOX2OT contributed to mitochondrial dysfunction progression via inhibiting SOX2 expression in septic cardiomyopathy, which may provide a new insight for treatment of septic cardiomyopathy.


Assuntos
Cardiomiopatias , Mitocôndrias Cardíacas/fisiologia , Doenças Mitocondriais/genética , RNA Longo não Codificante/fisiologia , Sepse , Animais , Cardiomiopatias/genética , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/patologia , Doenças Mitocondriais/patologia , Ratos , Sepse/genética , Sepse/patologia , Sepse/fisiopatologia
8.
J Hum Genet ; 64(11): 1117-1125, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31451716

RESUMO

Whole exome sequencing (WES) is an effective tool for the genetic diagnosis of mitochondrial disorders due to various nuclear genetic defects. In this study, three patients affected by extremely rare mitochondrial disorders caused by nuclear genetic defects are described. The medical records of each patient were reviewed to obtain clinical symptoms, results of biochemical and imaging studies, and muscle biopsies. WES and massive parallel sequencing of whole mtDNA were performed for each patient. The oxygen consumption rate (OCR) and complex activity I and IV was measured. Patients 1 and 2 had exhibited global developmental delay and seizure since early infancy. Blood lactate, the lactate-to-pyruvate ratio, and urinary excretion of Krebs cycle intermediates were markedly elevated. Patient 1 also was noted for ophthalmoplegia. Patient 2 had left ventricular hypertrophy and ataxia. Patient 3 developed dysarthria, gait disturbance, and right-side weakness at age 29. Brain magnetic resonance imaging demonstrated abnormal signal intensity involving the bilateral thalami, midbrain, or pons. Based on WES, patient 1 had p.Glu415Gly and p.Arg484Trp variants in MTO1. In patient 2, p.Gln111ThrfsTer5 and RNA mis-splicing were identified in TSFM. Patient 3 carried p.Met151Thr and p.Met246Lys variants in AARS2. Skin fibroblasts of three patients exhibited decreased OCRs and complex 1 activity, and mitochondrial DNA was normal. These results demonstrate the utility of WES for identifying the genetic cause of extremely rare mitochondrial disorders, which has implications for genetic counseling.


Assuntos
Alanina-tRNA Ligase/genética , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Fatores de Alongamento de Peptídeos/genética , Proteínas de Ligação a RNA/genética , Doenças Raras/genética , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , DNA Mitocondrial/genética , Disartria/genética , Disartria/fisiopatologia , Exoma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Mitocôndrias/genética , Doenças Mitocondriais/diagnóstico por imagem , Doenças Mitocondriais/fisiopatologia , Mutação , Oftalmoplegia/genética , Oftalmoplegia/fisiopatologia , Linhagem , Doenças Raras/diagnóstico por imagem , Doenças Raras/fisiopatologia , Sequenciamento Completo do Exoma
9.
Adv Exp Med Biol ; 1158: 247-255, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31452144

RESUMO

The maternally inherited mitochondrial DNA (mtDNA) is located inside every mitochondrion, in variable number of copies, and it contains 37 crucial genes for cellular bioenergetics. This chapter will discuss the unique features of this circular genome including heteroplasmy, haplogroups, among others, along with the corresponding clinical relevance for each. The discussion also covers the nuclear-encoded mitochondrial genes (N > 1000) and the epistatic interactions between mtDNA and the nuclear genome. Examples of mitochondrial diseases related to specific mtDNA mutation sites of relevance for humans are provided. This chapter aims to provide an overview of mitochondrial genetics as an emerging hot topic for the future of medicine.


Assuntos
Metabolismo Energético , Mitocôndrias , DNA Mitocondrial/genética , Metabolismo Energético/genética , Epistasia Genética , Genes Mitocondriais/genética , Genoma/genética , Humanos , Mitocôndrias/genética , Doenças Mitocondriais/genética , Mutação
10.
Adv Exp Med Biol ; 1158: 269-277, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31452146

RESUMO

Mitochondria play a central role in maintaining normal cellular homeostasis as well as contributing to the pathogenesis of numerous disease states. The advent of CRISPR-Cas9 screening technologies has greatly accelerated the study of mitochondrial biology. In this chapter, we review the various CRISPR-Cas9 screening platforms that are currently available and prior studies that leveraged this technology to identify genes involved in mitochondrial biology in both healthy and disease states. In addition, we discuss the challenges associated with current CRISPR-Cas9 platforms and potential solutions to further enhance this promising technology.


Assuntos
Sistemas CRISPR-Cas , Mitocôndrias , Doenças Mitocondriais , Fenômenos Fisiológicos Celulares/genética , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/genética , Pesquisa/tendências
11.
Artigo em Chinês | MEDLINE | ID: mdl-31446694

RESUMO

Summary Mitochondrial DNA(mtDNA) deletion is a rare occurrence that results in defects to oxidative phosphorylation. The common clinical presentations of mtDNA deletion vary but include mitochondrial myopathy, Pearson syndrome, Kearns-Sayre syndrome, and progressive external ophthalmoplegia. However, in clinical practice, some cases cannot be classified as any typical syndrome due to the absence or overlap of phenotypes. Here, we report one case of a 5-year-old girl who presented with progressive deterioration of her clinical status, which included systemic electrolyte disturbance, Fanconi syndrome and sensorineural hearing loss. Through a combination of systematic examinations and molecular analyses, mitochondrial disease was confirmed. A novel 6991-base pair deletion(deletion of mtDNA nt 7808-14798) was identified which confirmed molecular pathogeny of patient. Following treatment, the patient was stabilized and her hearing loss improved by hearing aid. This paper provided an important reference for the diagnosis and treatment of similar patients in clinical practice.


Assuntos
DNA Mitocondrial/genética , Perda Auditiva Neurossensorial/genética , Doenças Mitocondriais/genética , Deleção de Sequência , Pré-Escolar , Síndrome de Fanconi/genética , Feminino , Auxiliares de Audição , Perda Auditiva Neurossensorial/terapia , Humanos
12.
Mol Cell ; 75(4): 835-848.e8, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31378462

RESUMO

Mitochondrial dysfunction and proteostasis failure frequently coexist as hallmarks of neurodegenerative disease. How these pathologies are related is not well understood. Here, we describe a phenomenon termed MISTERMINATE (mitochondrial-stress-induced translational termination impairment and protein carboxyl terminal extension), which mechanistically links mitochondrial dysfunction with proteostasis failure. We show that mitochondrial dysfunction impairs translational termination of nuclear-encoded mitochondrial mRNAs, including complex-I 30kD subunit (C-I30) mRNA, occurring on the mitochondrial surface in Drosophila and mammalian cells. Ribosomes stalled at the normal stop codon continue to add to the C terminus of C-I30 certain amino acids non-coded by mRNA template. C-terminally extended C-I30 is toxic when assembled into C-I and forms aggregates in the cytosol. Enhancing co-translational quality control prevents C-I30 C-terminal extension and rescues mitochondrial and neuromuscular degeneration in a Parkinson's disease model. These findings emphasize the importance of efficient translation termination and reveal unexpected link between mitochondrial health and proteome homeostasis mediated by MISTERMINATE.


Assuntos
Códon de Terminação , Proteínas de Drosophila/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Proteínas Mitocondriais/metabolismo , Deficiências na Proteostase/metabolismo , Animais , Proteínas de Drosophila/genética , Drosophila melanogaster , Células HeLa , Humanos , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/patologia , Proteínas Mitocondriais/genética , Deficiências na Proteostase/genética , Deficiências na Proteostase/patologia , RNA Mitocondrial/genética , RNA Mitocondrial/metabolismo
13.
Clin Chim Acta ; 497: 88-94, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31325447

RESUMO

BACKGROUND: Primary CoQ deficiency occurs because of the defective biosynthesis of coenzyme Q, one of the key components of the mitochondrial electron transport chain. Patients with this disease present with a myriad of non-specific symptoms and signs, posing a diagnostic challenge. Whole-exome sequencing is vital in the diagnosis of these cases. CASE: Three unrelated cases presenting as either encephalopathy or cardiomyopathy have been diagnosed to harbor a common pathogenic variant c.370G > A in COQ4. COQ4 encodes a key structural component for stabilizing the multienzymatic CoQ biosynthesis complex. This variant is detected only among East and South Asian populations. CONCLUSIONS: Based on the population data and our case series, COQ4-related mitochondriopathy is likely an underrecognized condition. We recommend including the COQ4 c.370G > A variant as a part of the screening process for mitochondriopathy in Chinese populations.


Assuntos
Ataxia/diagnóstico , Ataxia/genética , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Debilidade Muscular/diagnóstico , Debilidade Muscular/genética , Ubiquinona/deficiência , Sequenciamento Completo do Exoma , Ataxia/metabolismo , Ataxia/patologia , Feminino , Variação Genética/genética , Humanos , Lactente , Recém-Nascido , Masculino , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Debilidade Muscular/metabolismo , Debilidade Muscular/patologia , Mutação , Ubiquinona/genética , Ubiquinona/metabolismo
14.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340538

RESUMO

WW domain-containing oxidoreductase (Wwox) is a putative tumor suppressor. Several germline mutations of Wwox have been associated with infant neurological disorders characterized by epilepsy, growth retardation, and early death. Less is known, however, about the pathological link between Wwox mutations and these disorders or the physiological role of Wwox in brain development. In this study, we examined age-related expression and histological localization of Wwox in forebrains as well as the effects of loss of function mutations in the Wwox gene in the immature cortex of a rat model of lethal dwarfism with epilepsy (lde/lde). Immunostaining revealed that Wwox is expressed in neurons, astrocytes, and oligodendrocytes. lde/lde cortices were characterized by a reduction in neurite growth without a reduced number of neurons, severe reduction in myelination with a reduced number of mature oligodendrocytes, and a reduction in cell populations of astrocytes and microglia. These results indicate that Wwox is essential for normal development of neurons and glial cells in the cerebral cortex.


Assuntos
Sistemas de Transporte de Aminoácidos Acídicos/deficiência , Antiporters/deficiência , Córtex Cerebral/metabolismo , Nanismo/genética , Epilepsia/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Mitocondriais/genética , Neurogênese/genética , Transtornos Psicomotores/genética , Proteínas Supressoras de Tumor/genética , Oxidorredutase com Domínios WW/genética , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/genética , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/metabolismo , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Sistemas de Transporte de Aminoácidos Acídicos/genética , Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Animais , Antiporters/genética , Antiporters/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Contagem de Células , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/patologia , Modelos Animais de Doenças , Nanismo/metabolismo , Nanismo/patologia , Epilepsia/metabolismo , Epilepsia/patologia , Regulação da Expressão Gênica no Desenvolvimento , Mutação em Linhagem Germinativa , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/metabolismo , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Masculino , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Prosencéfalo/crescimento & desenvolvimento , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Transtornos Psicomotores/metabolismo , Transtornos Psicomotores/patologia , Ratos , Ratos Transgênicos , Transdução de Sinais , Proteínas Supressoras de Tumor/deficiência , Oxidorredutase com Domínios WW/deficiência
15.
BMC Neurol ; 19(1): 153, 2019 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-31279336

RESUMO

BACKGROUND: Multiple Mitochondrial Dysfunctions Syndrome 4 (MMDS4) is manifested as a result of ISCA2 mutations. ISCA2 is a vital component of 4Fe-4S clusters assembly machine. Therefore, in MMDS4 patients, deficient mitochondrial respiratory chain complexes I and II, Aconitase and Succinate dehydrogenase of Kerbs cycle and Lipoic Acid Synthetase in the biosynthesis of lipoic acid are expected. CASE PRESENTATIONS: A 7 months boy in an Iranian consanguineous family with progressive neurodegenerative problems was referred to us. Primarily, general laboratory tests, Abdomen ultrasonography and brain magnetic resonance imaging were performed. In order to find out the genetic problem in this case Whole Exome Sequencing (WES) following by Sanger sequencing was carried out. A novel variant (c.355G > A, p.Ala119Thr) in ISCA2 gene was identified by WES in the proband. Confirmation and segregation in the family for this variant was performed by Sanger sequencing. In-Silico prediction of the ISCA2 secondary structure showed that a helix motif in the Fe-S biosynthesis domain of ISCA2 protein will be eliminated as a result of this variant. CONCLUSIONS: We reported the first patient with ISCA2 variant in Iranian population and the third one in the world reported for ISCA2 gene, so far associated with early-onset mitochondrial neurodegeneration. However further functional studies on this variant or finding it in other patients with similar clinical problems are needed to confirm the pathogenicity of this variant.


Assuntos
Proteínas com Ferro-Enxofre/genética , Doenças Mitocondriais/genética , Complexo I de Transporte de Elétrons/genética , Humanos , Lactente , Irã (Geográfico) , Imagem por Ressonância Magnética , Masculino , Mitocôndrias , Doenças Mitocondriais/diagnóstico por imagem , Mutação , Doenças Neurodegenerativas/genética
16.
Clin Chim Acta ; 496: 93-99, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31271740

RESUMO

BACKGROUND: Mitochondrial DNA depletion syndrome is a group of heterogeneous diseases with non-specific presentation. The common feature is the quantitative depletion of mitochondrial DNA without qualitative defects. Diagnosis of these diseases poses a challenge and whole exome sequencing is often needed for their diagnoses. CASE: Two siblings of a quartet family, presenting with hypotonia, microcephaly and severe intellectual disability, have been diagnosed to harbor two heterozygous variants in trans in the DTYMK gene of the thymidine biosynthesis pathway. Mitochondrial DNA depletion has been demonstrated in silico in the more severe sibling. CONCLUSIONS: We suggest the consideration of incorporating DTYMK as one of the associated genes of mitochondrial DNA depletion syndrome (MDDS). DTYMK may be the missing link in the mitochondrial nucleotide salvage pathway but further characterization and additional evidence would be needed.


Assuntos
DNA Mitocondrial/metabolismo , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/genética , Núcleosídeo-Fosfato Quinase/genética , Criança , DNA Mitocondrial/genética , Humanos , Lactente , Masculino , Irmãos , Sequenciamento Completo do Exoma
19.
Nucleic Acids Res ; 47(14): 7430-7443, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31147703

RESUMO

Clonal expansion of mitochondrial DNA (mtDNA) deletions is an important pathological mechanism in adults with mtDNA maintenance disorders, leading to a mosaic mitochondrial respiratory chain deficiency in skeletal muscle. This study had two aims: (i) to determine if different Mendelian mtDNA maintenance disorders showed similar pattern of mtDNA deletions and respiratory chain deficiency and (ii) to investigate the correlation between the mitochondrial genetic defect and corresponding respiratory chain deficiency. We performed a quantitative analysis of respiratory chain deficiency, at a single cell level, in a cohort of patients with mutations in mtDNA maintenance genes. Using the same tissue section, we performed laser microdissection and single cell genetic analysis to investigate the relationship between mtDNA deletion characteristics and the respiratory chain deficiency. The pattern of respiratory chain deficiency is similar with different genetic defects. We demonstrate a clear correlation between the level of mtDNA deletion and extent of respiratory chain deficiency within a single cell. Long-range and single molecule PCR shows the presence of multiple mtDNA deletions in approximately one-third of all muscle fibres. We did not detect evidence of a replicative advantage for smaller mtDNA molecules in the majority of fibres, but further analysis is needed to provide conclusive evidence.


Assuntos
DNA Mitocondrial/genética , Genes Mitocondriais/genética , Mitocôndrias Musculares/genética , Doenças Mitocondriais/genética , Fibras Musculares Esqueléticas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Deleção de Sequência , Análise de Célula Única
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