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1.
Neurosciences (Riyadh) ; 26(2): 128-133, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33814365

RESUMO

The m.3243A >G mutation in the tRNA Leu (UUR) gene (MT-TL1) of the mitochondrial DNA is the most widely seen pathogenic mtDNA mutation which has major phenotypic variations. The clinical phenotype involves various organs such as the brain and nerves, skeletal muscles, heart, endocrine system, gastrointestinal tract, and skin. Some phenotypes conform to well established syndromes, while most of the symptoms appear individually or concomitant to other syndromes, making identification difficult. Furthermore, some progress has been made on cardiac manifestations as well as complications during pregnancy and perinatal period. This article provides a systematic review of the non-syndromic phenotypes and latest developments in m.3243A>G mutation.


Assuntos
DNA Mitocondrial/genética , Doenças Mitocondriais/diagnóstico , Mutação , Fenótipo , RNA de Transferência de Leucina/genética , Humanos , Doenças Mitocondriais/genética
2.
Am J Case Rep ; 22: e930175, 2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33867519

RESUMO

BACKGROUND The normalization of serum lactate levels in a patient with non-syndromic mitochondrial disorder due to the m.3243A>G mitochondrial DNA (mtDNA) variant has not been previously reported. CASE REPORT A 57-year-old woman was diagnosed with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) due to the m.3243A>G variant, with low heteroplasmy rates (31%), at age 50. The initial manifestations were short stature, migraine, and diabetes. With progression of the disease, multisystem involvement developed, affecting the brain (stroke-like episode, mild cognitive impairment), eyes (pigmentary retinopathy), ears and the vestibular system (impaired hearing, tinnitus, imbalance, drop attacks, vertigo), intestines (constipation, distended abdomen, gastro-esophageal reflux, gastroparesis), and the muscles (muscle weakness). The gastrointestinal involvement was most prominent and most significantly lowered the patient's quality of life. The diabetes was well controlled with an insulin pump. Recurrent, acute deteriorations responded favorably to L-arginine. Owing to lifestyle and diet changes 2 years after diagnosis (start of art classes, increase in spin biking to 22.5 km 3 times per week, travel to Hawaii, adherence to low-carbohydrate high-protein diet), the patient managed to lower elevated serum lactate levels to largely normal values. CONCLUSIONS Gastrointestinal compromise may be the prominent manifestation of the m.3243A>G variant, lifestyle and diet changes may lower serum lactate in m.3243A>G carriers, and low heteroplasmy rates of the m.3243A>G variant in scarcely affected tissues do not exclude pathogenicity.


Assuntos
DNA Mitocondrial/genética , Lactatos/sangue , Estilo de Vida , Síndrome MELAS/sangue , Síndrome MELAS/terapia , Doenças Mitocondriais/genética , Feminino , Humanos , Síndrome MELAS/diagnóstico , Pessoa de Meia-Idade , Doenças Mitocondriais/diagnóstico , Mutação , Qualidade de Vida
3.
Int J Mol Sci ; 22(4)2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670490

RESUMO

The mitochondrial respiratory chain is the main site of reactive oxygen species (ROS) production in the cell. Although mitochondria possess a powerful antioxidant system, an excess of ROS cannot be completely neutralized and cumulative oxidative damage may lead to decreasing mitochondrial efficiency in energy production, as well as an increasing ROS excess, which is known to cause a critical imbalance in antioxidant/oxidant mechanisms and a "vicious circle" in mitochondrial injury. Due to insufficient energy production, chronic exposure to ROS overproduction consequently leads to the oxidative damage of life-important biomolecules, including nucleic acids, proteins, lipids, and amino acids, among others. Different forms of mitochondrial dysfunction (mitochondriopathies) may affect the brain, heart, peripheral nervous and endocrine systems, eyes, ears, gut, and kidney, among other organs. Consequently, mitochondriopathies have been proposed as an attractive diagnostic target to be investigated in any patient with unexplained progressive multisystem disorder. This review article highlights the pathomechanisms of mitochondriopathies, details advanced analytical tools, and suggests predictive approaches, targeted prevention and personalization of medical services as instrumental for the overall management of mitochondriopathy-related cascading pathologies.


Assuntos
Metabolismo Energético , Mitocôndrias/patologia , Doenças Mitocondriais/patologia , Estresse Oxidativo , Animais , Carcinogênese/patologia , Humanos , Mitocôndrias/metabolismo , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/metabolismo , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Medicina de Precisão , Espécies Reativas de Oxigênio/metabolismo
4.
Medicine (Baltimore) ; 100(10): e25100, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33725905

RESUMO

BACKGROUND: Mitochondrial diabetes mellitus (MDM) is characterized by maternal inheritance, progressive neurosensory deafness, insulin secretory disorder, and progressive microvascular complications. Mitochondria are critical organelles that provide energy in the form of adenosine triphosphate (ATP). An impairment of ATP production in pancreatic ß cells is regarded as the main cause of the insulin secretory disorder in patients with MDM, and these patients require insulin replacement therapy early after the diagnosis. The amino acid 5-aminolevulinic acid (5-ALA), a precursor of heme metabolites, is a non-proteinogenic δ amino acid synthesized in mitochondria. An addition of ferrous iron to 5-ALA enhances heme biosynthesis and increases ATP production through an upregulation of the respiratory complex. Several studies have reported that the administration of 5-ALA and ferrous iron to existing treatment improved the glycemic control in both patients with prediabetes and those with type 2 diabetes mellitus. The additional administration of 5-ALA and ferrous iron to MDM patients on insulin therapy may improve their insulin secretory capacity and glycemic control by improving their mitochondrial function. The findings of this study are expected to provide new treatment options for MDM and improve the patients' glycemic control and prognosis. METHODS/DESIGN: This study is a single-arm, open-label pilot intervention study using clinical endpoints to investigate the effects of treatment with 5-ALA plus sodium ferrous citrate (SFC) to patients with MDM on their glucose tolerance. A total of 5 patients with MDM will be administered 5-ALA/SFC (200 mg/d) for 24 weeks. We will perform a 75-g oral glucose tolerance test before and at 24 weeks after the start of this 5-ALA/SFC treatment to evaluate glucose-dependent insulin responses. DISCUSSION: To the best of our knowledge, this study will be the first assessment of the effects of 5-ALA/SFC in patients with MDM. This study will obtain an evidence regarding the effectiveness and safety of 5-ALA/SFC for patients with MDM. TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Network (UMIN000040581) on July 1, 2020 and with the Japan Registry of Clinical Trials (jRCTs071200025) on August 3, 2020.


Assuntos
Surdez/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Compostos Ferrosos/administração & dosagem , Intolerância à Glucose/tratamento farmacológico , Insulina/administração & dosagem , Ácidos Levulínicos/administração & dosagem , Doenças Mitocondriais/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Adulto , Glicemia/análise , Surdez/sangue , Surdez/diagnóstico , Surdez/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/patologia , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Compostos Ferrosos/efeitos adversos , Intolerância à Glucose/sangue , Intolerância à Glucose/diagnóstico , Intolerância à Glucose/patologia , Teste de Tolerância a Glucose , Humanos , Japão , Ácidos Levulínicos/efeitos adversos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Doenças Mitocondriais/sangue , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/patologia , Projetos Piloto , Resultado do Tratamento
6.
Saudi Med J ; 41(7): 703-708, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32601637

RESUMO

OBJECTIVES: To determine the incidence of newborn screening (NBS) disorders and to study the key performance indicators of the program. METHODS: This retrospective single-center study enrolled all infants who underwent NBS from January 2012 to December 2017 at Prince Sultan Military Medical City, Riyadh, Saudi Arabia. We screened 17 NBS disorders. Blood samples were collected 24 hours after birth. If the initial result was positive, a second sample was collected. True positive cases were immediately referred for medical management. Data were extracted from laboratory computerized and non-computerized records using case report forms. RESULTS: During the study period, 56632 infants underwent NBS with a coverage rate of 100%. Thirty-eight cases were confirmed. The incidence of congenital hypothyroidism was 1:3775. The positive predictive value for the detection of congenital hypothyroidism was 11.8%. Propionic aciduria was the most common metabolic disorder, with an incidence of 1:14158. Very long-chain acyl CoA dehydrogenase deficiency and glutaric aciduria type 1 had an incidence of 1:18877 each. Phenylketonuria, biotinidase deficiency, maple syrup urine disease, and citrullinemia had an incidence of 1:28316 each. However, galactosemia and 3-methyl crotonyl carboxylase deficiency had the lowest incidence of 1:56632. CONCLUSION: The NBS coverage rate at our facility was 100%. Congenital hypothyroidism was the most frequently detected disorder with an incidence that matches worldwide figures. The incidence of other inherited disorders was consistent with regional figures.


Assuntos
Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/epidemiologia , Triagem Neonatal , Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/epidemiologia , Biomarcadores/sangue , Encefalopatias Metabólicas/diagnóstico , Encefalopatias Metabólicas/epidemiologia , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Síndrome Congênita de Insuficiência da Medula Óssea/epidemiologia , Glutaril-CoA Desidrogenase/deficiência , Humanos , Hipotireoidismo/diagnóstico , Hipotireoidismo/epidemiologia , Incidência , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/epidemiologia , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/epidemiologia , Doenças Musculares/diagnóstico , Doenças Musculares/epidemiologia , Valor Preditivo dos Testes , Acidemia Propiônica/diagnóstico , Acidemia Propiônica/epidemiologia , Estudos Retrospectivos , Arábia Saudita/epidemiologia , Fatores de Tempo
8.
Saudi Med J ; 41(6): 590-596, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32518924

RESUMO

OBJECTIVES: To describe the clinical and molecular characteristics of patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency.   Methods: A retrospective observational cross-sectional analysis was conducted on all patients with VLCAD deficiency at  (Genetic/Metabolic Section), Prince Sultan Military Medical City (PSMMC), Riyadh, Saudi Arabia from 2000 to 2019. Demographic, clinical, and laboratory data were abstracted from the electronic hospital records using a case report form. Results: A total of 14 children were analyzed. Six presented with hypoglycemia, 4 with cardiomyopathy, and 10 had rhabdomyolysis. Five patients had early onset severe phenotype, while 9 had mild form. The molecular study revealed homozygous mutations in ACADVL in all 14 patients. Three variants were not reported before. All patients were treated with medium-chain triglyceride and carnitine. Ten patients are alive and have normal development, while 4 died. Conclusion: Most of the patients in this cohort presented in the neonatal period either by newborn screening or clinically with hypoglycemia, cardiomyopathy, and rhabdomyolysis. The new molecular variants detected in this study broaden the genetic spectrum of VLCAD deficiency in Saudi Arabia.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Síndrome Congênita de Insuficiência da Medula Óssea , Erros Inatos do Metabolismo Lipídico , Doenças Mitocondriais , Doenças Musculares , Acil-CoA Desidrogenase de Cadeia Longa/genética , Cardiomiopatias/etiologia , Carnitina/uso terapêutico , Estudos de Coortes , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Síndrome Congênita de Insuficiência da Medula Óssea/tratamento farmacológico , Síndrome Congênita de Insuficiência da Medula Óssea/genética , Estudos Transversais , Homozigoto , Humanos , Hipoglicemia/etiologia , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/tratamento farmacológico , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/genética , Doenças Musculares/diagnóstico , Doenças Musculares/tratamento farmacológico , Doenças Musculares/genética , Mutação , Triagem Neonatal , Rabdomiólise/etiologia , Arábia Saudita , Triglicerídeos/uso terapêutico
9.
Am J Ophthalmol ; 218: 136-147, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32446735

RESUMO

PURPOSE: To investigate the development and progression of retinal pigment epithelial and outer retinal atrophy (RORA) secondary to maternally inherited diabetes and deafness (MIDD). DESIGN: Retrospective observational case series. METHODS: Thirty-six eyes of 18 patients (age range, 22.4-71.6 years) with genetically proven MIDD and serial optical coherence tomography (OCT) images were included. As proposed reference standard to diagnose and stage atrophy, OCT images were longitudinally evaluated and analyzed for presence and precursors of RORA. RORA was defined as an area of (1) hypertransmission, (2) disruption of the retinal pigment epithelium, (3) photoreceptor degeneration, and (4) absence of other signs of a retinal pigment epithelial tear. RESULTS: The majority of patients revealed areas of RORA in a circular area around the fovea of between 5° and 15° eccentricity. Over the observation time (range, 0.5-8.5 years), evidence for a consistent sequence of OCT features from earlier disease stages to the end stage of RORA could be found, starting with loss of ellipsoid zone and subretinal deposits, followed by loss of external limiting membrane and loss of retinal pigment epithelium with hypertransmission of OCT signal into the choroid, and leading to loss of the outer nuclear layer bordered by hyporeflective wedges. Outer retinal tabulations seemed to develop in regions of coalescent areas of RORA. CONCLUSIONS: The development and progression of RORA could be tracked in MIDD patients using OCT images, allowing potential definition of novel surrogate markers. Similarities to OCT features in age-related macular degeneration, where mitochondrial dysfunction has been implicated in the pathogenesis, support wide-ranging benefits from proof-of-concept studies in MIDD.


Assuntos
Surdez/complicações , Diabetes Mellitus Tipo 2/complicações , Doenças Mitocondriais/complicações , Distrofias Retinianas/diagnóstico , Epitélio Pigmentado da Retina/patologia , Adulto , Idoso , Atrofia , Surdez/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/diagnóstico , Distrofias Retinianas/etiologia , Epitélio Pigmentado da Retina/diagnóstico por imagem , Estudos Retrospectivos , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Adulto Jovem
11.
Am J Ophthalmol ; 213: 134-144, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31987901

RESUMO

PURPOSE: To investigate the prognostic value of demographic, functional, and imaging parameters on retinal pigment epithelium (RPE) atrophy progression secondary to maternally inherited diabetes and deafness (MIDD) and to evaluate the application of these factors in clinical trial design. DESIGN: Retrospective observational case series. METHODS: Thirty-five eyes of 20 patients (age range, 24.9-75.9 years) with genetically proven MIDD and demarcated RPE atrophy on serial fundus autofluorescence (AF) images were included. Lesion size and shape-descriptive parameters were longitudinally determined by 2 independent readers. A linear mixed-effect model was used to predict the lesion enlargement rate based on baseline variables. Sample size calculations were performed to model the power in a simulated interventional study. RESULTS: The mean follow-up time was 4.27 years. The mean progression rate of RPE atrophy was 2.33 mm2/year, revealing a dependence on baseline lesion size (+0.04 [0.02-0.07] mm2/year/mm2, P < .001), which was absent after square root transformation. The fovea was preserved in the majority of patients during the observation time. In the case of foveal involvement, the loss of visual acuity lagged behind central RPE atrophy in AF images. Sex, age, and number of atrophic foci predicted future progression rates with a cross-validated mean absolute error of 0.13 mm/year and to reduce the required sample size for simulated interventional trials. CONCLUSIONS: Progressive RPE atrophy could be traced in all eyes using AF imaging. Shape-descriptive factors and patients' baseline characteristics had significant prognostic value, guiding appropriate subject selection and sample size in future interventional trial design.


Assuntos
Surdez/complicações , Diabetes Mellitus Tipo 2/complicações , Doenças Mitocondriais/complicações , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/etiologia , Epitélio Pigmentado da Retina/patologia , Adulto , Idoso , Atrofia , Surdez/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/diagnóstico , Imagem Óptica , Prognóstico , Estudos Retrospectivos , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Adulto Jovem
12.
Curr Diabetes Rev ; 16(8): 807-819, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31886753

RESUMO

BACKGROUND: Diabetes mellitus (DM) is a complex disease with significant impression in today's world. Aside from the most common types recognized over the years, such as type 1 diabetes (T1DM) and type 2 diabetes (T2DM), recent studies have emphasized the crucial role of genetics in DM, allowing the distinction of monogenic diabetes. METHODS: Authors did a literature search with the purpose of highlighting and clarifying the subtypes of monogenic diabetes, as well as the accredited genetic entities responsible for such phenotypes. RESULTS: The following subtypes were included in this literature review: maturity-onset diabetes of the young (MODY), neonatal diabetes mellitus (NDM) and maternally inherited diabetes and deafness (MIDD). So far, 14 subtypes of MODY have been identified, while three subtypes have been identified in NDM - transient, permanent, and syndromic. DISCUSSION: Despite being estimated to affect approximately 2% of all the T2DM patients in Europe, the exact prevalence of MODY is still unknown, accentuating the need for research focused on biomarkers. Consequently, due to its impact in the course of treatment, follow-up of associated complications, and genetic implications for siblings and offspring of affected individuals, it is imperative to diagnose the monogenic forms of DM accurately. CONCLUSION: Currently, advances in the genetics field allowed the recognition of new DM subtypes, which until now, were considered slight variations of the typical forms. Thus, it is imperative to act in the close interaction between genetics and clinical manifestations, to facilitate diagnosis and individualize treatment.


Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/classificação , Diabetes Mellitus Tipo 2/genética , Surdez/classificação , Surdez/diagnóstico , Surdez/genética , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Testes Genéticos , Genótipo , Humanos , Lactente , Recém-Nascido , Doenças do Recém-Nascido/classificação , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/genética , Doenças Mitocondriais/classificação , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Mutação , Fenótipo , Medicina de Precisão , Síndrome
13.
J Hum Genet ; 65(2): 91-98, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31645654

RESUMO

Hereditary spastic paraplegias (HSPs) are characterized by lower extremity spasticity and weakness. HSP is often caused by mutations in SPG genes, but it may also be produced by inborn errors of metabolism. We performed next-generation sequencing of 4813 genes in one adult twin pair with HSP and severe muscular weakness occurring at the same age. We found two pathogenic compound heterozygous variants in MTHFR, including a variant not referenced in international databases, c.197C>T (p.Pro66Leu) and a known variant, c.470G>A (p.Arg157Gln), and two heterozygous pathogenic variants in POLG, c.1760C>T (p.Pro587Leu) and c.752C>T (p.Thr251Ile). MTHFR and POLG mutations were consistent with the severe muscle weakness and the metabolic changes, including hyperhomocysteinemia and decreased activity of both N(5,10)methylenetetrahydrofolate reductase (MTHFR) and complexes I and II of the mitochondrial respiratory chain. These data suggest the potential role of MTHFR and POLG mutations through consequences on mitochondrial dysfunction in the occurrence of spastic paraparesis phenotype with combined metabolic, muscular, and neurological components.


Assuntos
Polimerase do DNA Mitocondrial/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Doenças Mitocondriais/genética , Paraparesia Espástica/genética , Paraplegia Espástica Hereditária/genética , Feminino , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Doenças Mitocondriais/diagnóstico , Mutação , Paraparesia Espástica/diagnóstico , Análise de Sequência de DNA , Paraplegia Espástica Hereditária/diagnóstico , Gêmeos Monozigóticos
15.
Continuum (Minneap Minn) ; 25(6): 1732-1766, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31794469

RESUMO

PURPOSE OF REVIEW: This article provides an overview of mitochondrial and metabolic biology, the genetic mechanisms causing mitochondrial diseases, the clinical features of mitochondrial diseases, lipid myopathies, and glycogen storage diseases, all with a focus on those syndromes and diseases associated with myopathy. Over the past decade, advances in genetic testing have revolutionized patient evaluation. The main goal of this review is to give the clinician the basic understanding to recognize patients at risk of these diseases using the standard history and physical examination. RECENT FINDINGS: Primary mitochondrial disease is the current designation for the illnesses resulting from genetic mutations in genes whose protein products are necessary for mitochondrial structure or function. In most circumstances, more than one organ system is involved in mitochondrial disease, and the value of the classic clinical features as originally described early in the history of mitochondrial diseases has reemerged as being important to identifying patients who may have a primary mitochondrial disease. The use of the genetic laboratory has become the most powerful tool for confirming a diagnosis, and nuances of using genetic results will be discussed in this article. Treatment for mitochondrial disease is symptomatic, with less emphasis on vitamin and supplement therapy than in the past. Clinical trials using pharmacologic agents are in progress, with the field attempting to define proper goals of treatment. Several standard accepted therapies exist for many of the metabolic myopathies. SUMMARY: Mitochondrial, lipid, and glycogen diseases are not uncommon causes of multisystem organ dysfunction, with the neurologic features, especially myopathy, occurring as a predominant feature. Early recognition requires basic knowledge of the varied clinical phenotypes before moving forward with a screening evaluation and possibly a genetic evaluation. Aside from a few specific diseases for which there are recommended interventions, treatment for the majority of these disorders remains symptomatic, with clinical trials currently in progress that will hopefully result in standard treatments.


Assuntos
Doença de Depósito de Glicogênio , Transtornos do Metabolismo dos Lipídeos , Doenças Mitocondriais , Doenças Musculares , Adolescente , Idoso , Feminino , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/genética , Doença de Depósito de Glicogênio/fisiopatologia , Humanos , Transtornos do Metabolismo dos Lipídeos/diagnóstico , Transtornos do Metabolismo dos Lipídeos/genética , Transtornos do Metabolismo dos Lipídeos/fisiopatologia , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Doenças Mitocondriais/fisiopatologia , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Doenças Musculares/metabolismo , Doenças Musculares/fisiopatologia
16.
Sci Rep ; 9(1): 17411, 2019 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-31757988

RESUMO

Next-generation sequencing (NGS) is a revolutionary sequencing technology for analyzing genomes. However, preprocessing methods for mitochondrial DNA (mtDNA) sequencing remain complex, and it is required to develop an authenticated preprocessing method. Here, we developed a simple and easy preprocessing method based on isothermal rolling circle mtDNA amplification using commercially available reagents. Isothermal amplification of mtDNA was successfully performed using both nanoliter quantities of plasma directly and 25 ng of total DNA extracted from blood or tissue samples. Prior to mtDNA amplification, it was necessary to treat the extracted total DNA with Exonuclease V, but it was not required to treat plasma. The NGS libraries generated from the amplified mtDNA provided sequencing coverage of the entire human mitochondrial genome. Furthermore, the sequencing results successfully detected heteroplasmy in patient samples, with called mutations and variants matching those from previous, independent, Sanger sequencing analysis. Additionally, a novel single nucleotide variant was detected in a healthy volunteer. The successful analysis of mtDNA using very small samples from patients is likely to be valuable in clinical medicine, as it could reduce patient discomfort by reducing sampling-associated damage to tissues. Overall, the simple and convenient preprocessing method described herein may facilitate the future development of NGS-based clinical and forensic mtDNA tests.


Assuntos
Testes Genéticos , Genoma Mitocondrial , Genômica , Sequenciamento Completo do Genoma , Alelos , Mapeamento Cromossômico , Frequência do Gene , Testes Genéticos/métodos , Variação Genética , Genômica/métodos , Humanos , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Técnicas de Diagnóstico Molecular , Reação em Cadeia da Polimerase , Análise de Sequência de DNA
18.
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
19.
Semin Neurol ; 39(5): 620-639, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31639845

RESUMO

The inherited neuropathies are a common and heterogeneous group of slowly progressive disorders affecting motor, sensory, and autonomic nerves. These hereditary conditions can be confined to the peripheral nervous system, termed the primary hereditary neuropathies, or can occur as part of a multisystem disease. Identification of systemic involvement is necessary to distinguish the primary and secondary hereditary neuropathies to prevent the misdiagnosis of potentially treatable entities. Recent genetic and technological advances have dramatically improved our understanding of the underlying pathophysiology of these inherited neuropathies and hence provide the correct milieu for the future development of disease-modifying therapies. This review provides clinical, neurophysiological, genetic, pathophysiological, and treatment insights into the primary inherited neuropathies, and those associated with multisystem diseases, including porphyria and mitochondrial disorders.


Assuntos
Doenças Mitocondriais/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Porfirias/tratamento farmacológico , Erros de Diagnóstico/prevenção & controle , Humanos , Doenças Mitocondriais/diagnóstico , Doenças do Sistema Nervoso Periférico/diagnóstico , Porfirias/diagnóstico
20.
J Pediatr Ophthalmol Strabismus ; 56: e60-e64, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31622479

RESUMO

Retinopathy of prematurity (ROP) is a biphasic disease in which the first phase is characterized by high oxygen tension leading to vaso-obliteration in the retina. Pearson syndrome is a rare multisystem mitochondrial disease with a defect in cellular respiration. The authors describe a patient with Pearson syndrome and delayed onset of ROP at a postconceptual age of 42 weeks. The proposed mechanistic theory was the increased oxygen use associated with the metabolic impairments in Pearson syndrome counterbalancing the effects of supplemental oxygen during the vaso-obliterative stage of ROP. [J Pediatr Ophthalmol Strabismus. 2019;56:e60-e64.].


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Recém-Nascido de Baixo Peso , Erros Inatos do Metabolismo Lipídico/diagnóstico , Doenças Mitocondriais/diagnóstico , Doenças Musculares/diagnóstico , Oxigênio/metabolismo , Retinopatia da Prematuridade/diagnóstico , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Síndrome Congênita de Insuficiência da Medula Óssea/metabolismo , Progressão da Doença , Feminino , Angiofluoresceinografia/métodos , Seguimentos , Fundo de Olho , Idade Gestacional , Humanos , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Musculares/metabolismo , Retinopatia da Prematuridade/metabolismo , Fatores de Tempo
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