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1.
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
2.
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 , 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 , 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
3.
Rom J Morphol Embryol ; 60(1): 273-279, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31263856

RESUMO

Mitochondriopathies are a heterogeneous group of genetic diseases of all ages, with a very diverse clinical presentation related to genetic heteroplasmy. The clinical symptoms display a large variability and generally, the more severe phenotypes have an early onset, even from the neonatal period, while milder ones are manifested later in the adulthood. Most publications have already demonstrated deletions or point mutations in mitochondrial deoxyribonucleic acid (DNA), but in recent years, the field of investigation has expanded to syndromes caused by mutations in the nuclear DNA (nDNA), with a Mendelian inheritance. We present the case of a male patient with a mitochondriopathy with phenotype of chronic progressive external ophthalmoplegia (PEO), due to an autosomal dominant mutation in nDNA, in the DNA polymerase subunit gamma (POLG) gene, the pathogenic variant c.2864A>G (p.Tyr955Cys), morphologically investigated and diagnosed using a skeletal muscle biopsy. The aim of this presentation is to emphasize the diagnostic value of the muscle biopsy both in cases of clinical suspicion and in more challenging cases of mitochondrial diseases with atypical or unusual features. Although genetic testing may be the initial test of choice in cases with suggestive clinical presentation, muscle biopsy is an alternative diagnostic aid with high value even in our molecular era. We present pathological and ultrastructural data to confirm the diagnosis.


Assuntos
Biópsia/métodos , Doenças Mitocondriais/diagnóstico , Músculo Esquelético/cirurgia , Oftalmoplegia Externa Progressiva Crônica/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/patologia , Oftalmoplegia Externa Progressiva Crônica/patologia
4.
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
5.
Int J Med Sci ; 16(7): 931-938, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341406

RESUMO

The diagnosis of mitochondrial diseases is a real challenge because of the vast clinical and genetic heterogeneity. Classically, the clinical examination and genetic analysis must be completed by several biochemical assays to confirm the diagnosis of mitochondrial disease. Here, we tested the validity of microscale XF technology in measuring oxygen consumption in human skin fibroblasts isolated from 5 pediatric patients with heterogeneous mitochondrial disorders. We first set up the protocol conditions to allow the determination of respiratory parameters including respiration associated with ATP production, proton leak, maximal respiration, and spare respiratory capacity with reproducibility and repeatability. Maximum respiration and spare capacity were the only parameters decreased in patients irrespective of the type of OXPHOS deficiency. These results were confirmed by high-resolution oxygraphy, the reference method to measure cellular respiration. Given the fact that microscale XF technology allows fast, automated and standardized measurements, we propose to use microscale oxygraphy among the first-line methods to screen OXPHOS deficiencies.


Assuntos
Fibroblastos/patologia , Mitocôndrias/patologia , Doenças Mitocondriais/diagnóstico , Fosforilação Oxidativa , Oxigênio/análise , Adolescente , Biópsia , Técnicas de Cultura de Células , Linhagem Celular , Estudos de Viabilidade , Feminino , Fibroblastos/citologia , Humanos , Lactente , Recém-Nascido , Masculino , Doenças Mitocondriais/patologia , Oxigênio/metabolismo , Consumo de Oxigênio , Reprodutibilidade dos Testes , Estudos Retrospectivos , Pele/citologia , Pele/patologia
6.
Pediatrics ; 144(1)2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31227563

RESUMO

A 2-day old term male infant was found to be hypotonic and minimally reactive during routine nursing care in the newborn nursery. At 40 hours of life, he was hypoglycemic and had intermittent desaturations to 70%. His mother had an unremarkable pregnancy and spontaneous vaginal delivery. The mother's prenatal serology results were negative for infectious risk factors. Apgar scores were 9 at 1 and 5 minutes of life. On day 1 of life, he fed, stooled, and voided well. Our expert panel discusses the differential diagnosis of hypotonia in a neonate, offers diagnostic and management recommendations, and discusses the final diagnosis.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Letargia/etiologia , Erros Inatos do Metabolismo Lipídico/diagnóstico , Doenças Mitocondriais/diagnóstico , Hipotonia Muscular/etiologia , Doenças Musculares/diagnóstico , /terapia , Diagnóstico Diferencial , Humanos , Hipotermia/etiologia , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/terapia , Masculino , Doenças Mitocondriais/terapia , Doenças Musculares/terapia
8.
Mol Genet Metab ; 127(1): 64-73, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31031081

RESUMO

BACKGROUND: Very-Long-Chain Acyl-CoA Dehydrogenase (VLCAD) deficiency is a disorder of fatty acid oxidation included in the recommended uniform newborn screening (NBS) panel in the USA. It can have variable clinical severity and there is limited information on the natural history of this condition, clinical presentation according to genotype and effectiveness of newborn screening. METHODS: Retrospective data (growth parameters, morbidity, biochemical and genetic testing results) were collected from patients with VLCAD deficiency, to evaluate biochemical and clinical outcomes. Descriptive statistics was used for qualitative variables, while linear regression analysis was used to correlate continuous variables. RESULTS: VLCAD deficiency (screened by measuring elevated levels of C14:1-carnitine in blood spots) was more frequent in Utah than the national average (1:27,617 versus 1:63,481) in the first ten years of screening. Twenty-six patients had a confirmed diagnosis of VLCAD deficiency using DNA testing or functional studies. The c.848T>C (p.V283A) variant in the ACADVL gene was the most frequent in our population. Novel variants (c.623-21A>G (IVS7-21A>G); c.1052C>T (p.T351I); c.1183-7A>G (IVS11-7A>G); c.1281G>C (p.W427C); c.1923G>C (p.L641F); c.1924G>A (p.V642M)) were identified in this study, with their pathogenicity remaining unclear in most cases. C14:1-carnitine levels decreased with age and significantly correlated with CK levels as index of muscle involvement. There were no cases of HELLP syndrome nor liver disease during pregnancies in the mothers of VLCAD patients. None of our patients developed cardiac involvement after birth and all patients had normal growth parameters while on treatment. Clinical manifestations were related to concomitant infections and altered biochemical parameters. DISCUSSION: VLCAD deficiency can be identified by neonatal screening. Most patients compliant with therapy normalized biochemical parameters and had no major clinical manifestations. Complications were completely prevented with a relatively low number of pre-emptive ER visits or hospital admissions. It remains unclear whether neonatal screening is now identifying less severely affected patient or if complications will arise as subjects become older. Observation beyond puberty is necessary to fully understand the impact of VLCAD deficiency on morbidity in patients with VLCAD deficiency.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Variação Genética , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Triagem Neonatal , Acil-CoA Desidrogenase de Cadeia Longa/genética , Adolescente , Carnitina/sangue , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/terapia , Masculino , Doenças Mitocondriais/terapia , Morbidade , Doenças Musculares/terapia , Estudos Retrospectivos , Resultado do Tratamento , Utah , Adulto Jovem
9.
Clin Biochem ; 72: 71-80, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30954436

RESUMO

OBJECTIVES: Altered amyloid metabolism and mitochondrial dysfunction play key roles in the development of Alzheimer's disease (AD). We asked whether an association exists between disturbed platelet mitochondrial respiration and the plasma concentrations of Aß40 and Aß42 in patients with AD. DESIGN AND METHODS: Plasma Aß40 and Aß42 concentrations and mitochondrial respiration in intact and permeabilized platelets were measured in 50 patients with AD, 15 patients with vascular dementia and 25 control subjects. A pilot longitudinal study was performed to monitor the progression of AD in a subgroup 11 patients with AD. RESULTS: The mean Aß40, Aß42 and Aß42/Aß40 levels were not significantly altered in patients with AD compared with controls. The mitochondrial respiratory rate in intact platelets was significantly reduced in patients with AD compared to controls, particularly the basal respiratory rate, maximum respiratory capacity, and respiratory reserve; however, the flux control ratio for basal respiration was increased. A correlation between the plasma Aß42 concentration and mitochondrial respiration in both intact and permeabilized platelets differs in controls and patients with AD. CONCLUSIONS: Based on our data, (1) mitochondrial respiration in intact platelets, but not the Aß level itself, may be included in a panel of biomarkers for AD; (2) dysfunctional mitochondrial respiration in platelets is not explained by changes in plasma Aß concentrations; and (3) the association between mitochondrial respiration in platelets and plasma Aß levels differs in patients with AD and controls. The results supported the hypothesis that mitochondrial dysfunction is the primary factor contributing to the development of AD.


Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/sangue , Mitocôndrias/metabolismo , Doenças Mitocondriais/diagnóstico , Fragmentos de Peptídeos/sangue , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/complicações , Biomarcadores/sangue , Respiração Celular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/sangue , Doenças Mitocondriais/complicações , Consumo de Oxigênio
10.
Hum Genet ; 138(6): 613-624, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30968252

RESUMO

Variations in mitochondrial DNA (mtDNA) have been fundamental for understanding human evolution and are causative for a plethora of inherited mitochondrial diseases, but the mutation signatures of germline mtDNA and their value in understanding mitochondrial pathogenicity remain unknown. Here, we carried out a systematic analysis of mutation patterns in germline mtDNA based on 97,566 mtDNA variants from 45,494 full-length sequences and revealed a highly non-stochastic and replication-coupled mutation signature characterized by nucleotide-specific mutation pressure (G > T>A > C) and position-specific selection pressure, suggesting the existence of an intensive mutation-selection interplay in germline mtDNA. We provide evidence that this mutation-selection interplay has strongly shaped the mtDNA sequence during evolution, which not only manifests as an oriented alteration of amino acid compositions of mitochondrial encoded proteins, but also explains the long-lasting mystery of CpG depletion in mitochondrial genome. Finally, we demonstrated that these insights may be integrated to better understand the pathogenicity of disease-implicated mitochondrial variants.


Assuntos
DNA Mitocondrial/genética , Evolução Molecular , Genoma Mitocondrial/genética , Mutação em Linhagem Germinativa , Doenças Mitocondriais/genética , Sequência de Bases , Mapeamento Cromossômico/métodos , Análise Mutacional de DNA/métodos , Humanos , Doenças Mitocondriais/diagnóstico , Proteínas Mitocondriais/genética
11.
BMJ Case Rep ; 12(3)2019 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-30936349

RESUMO

Mutations in the nuclear POLG1 gene compromise the integrity of mitochondrial DNA and show great allelic and clinical heterogeneity. Among adult POLG1-associated mitochondrial disease, the main clinical feature is chronic progressive external ophthalmoplegia. Other related clinical manifestations are sensory or cerebellar ataxia, peripheral neuropathy, myopathy or extrapyramidal symptoms. We report the case of a 72-year-old man who presented with a late onset sensory neuronopathy, chronic progressive external ophthalmoplegia, gait ataxia and parkinsonism. Genetic studies showed a compound heterozygosity of known pathogenic mutations in the POLG1 gene (variant T252I/P587 L in cis configuration in allele 1 and variant R807C in allele 2). Late life presentation highlights that mitochondrial disorders should be considered regardless of age of onset of symptoms.


Assuntos
Antiparkinsonianos/uso terapêutico , Polimerase do DNA Mitocondrial/genética , Levodopa/uso terapêutico , Doenças Mitocondriais/diagnóstico , Oftalmoplegia Externa Progressiva Crônica/diagnóstico , Transtornos Parkinsonianos/fisiopatologia , Idade de Início , Idoso , Blefaroptose , Progressão da Doença , Humanos , Masculino , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/genética , Doenças Mitocondriais/fisiopatologia , Oftalmoplegia Externa Progressiva Crônica/tratamento farmacológico , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/etiologia , Transtornos Parkinsonianos/genética , Mutação Puntual/genética , Resultado do Tratamento
12.
Analyst ; 144(8): 2531-2540, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30839952

RESUMO

Mitochondrial activity is a widely used criterion to judge the metabolic condition of a living specimen. Numerous methods have been developed for related analyses, including the detection of O2 consumption, trans-membrane potential, and ATP production. In this study, we demonstrate that the redox state of cytochromes can serve as a sensitive mitochondrial activity indicator in glutamate-stressed neuronal cells. Mitochondrial dysfunction was detected by Raman imaging as early as 30 min after glutamate-stress induction. By comparing this result with other commonly used mitochondrial function assays, we found Raman imaging has a similar sensitivity to ATP production and trans-membrane potential assays. Other viability tests, such as MTT assay and ROS production tests, showed a slower response than our method. A thorough understanding of cytochrome dynamics with our new method will help establish Raman spectroscopy as a competitive clinical diagnosis tool for neurodegenerative diseases involving mitochondrial dysfunction.


Assuntos
Citocromos/química , Citocromos/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/diagnóstico , Animais , Linhagem Celular , Ácido Glutâmico , Camundongos , Doenças Mitocondriais/induzido quimicamente , Oxirredução , Análise Espectral Raman/métodos
13.
EBioMedicine ; 42: 511-523, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30898651

RESUMO

BACKGROUND: The vast majority of mitochondrial disorders have limited the clinical management to palliative care. Rapamycin has emerged as a potential therapeutic drug for mitochondrial diseases since it has shown therapeutic benefits in a few mouse models of mitochondrial disorders. However, the underlying therapeutic mechanism is unclear, the minimal effective dose needs to be defined and whether this therapy can be generally used is unknown. METHODS: We have evaluated whether low and high doses of rapamycin administration may result in therapeutic effects in a mouse model (Coq9R239X) of mitochondrial encephalopathy due to CoQ deficiency. The evaluation involved phenotypic, molecular, image (histopathology and MRI), metabolomics, transcriptomics and bioenergetics analyses. FINDINGS: Low dose of rapamycin induces metabolic changes in liver and transcriptomics modifications in midbrain. The high dose of rapamycin induces further changes in the transcriptomics profile in midbrain due to the general inhibition of mTORC1. However, neither low nor high dose of rapamycin were able to improve the mitochondrial bioenergetics, the brain injuries and the phenotypic characteristics of Coq9R239X mice, resulting in the lack of efficacy for increasing the survival. INTERPRETATION: These results may be due to the lack of microgliosis-derived neuroinflammation, the limitation to induce autophagy, or the need of a functional CoQ-junction. Therefore, the translation of rapamycin therapy into the clinic for patients with mitochondrial disorders requires, at least, the consideration of the particularities of each mitochondrial disease. FUND: Supported by the grants from "Fundación Isabel Gemio - Federación Española de Enfermedades Neuromusculares - Federación FEDER" (TSR-1), the NIH (P01HD080642) and the ERC (Stg-337327).


Assuntos
Doenças Mitocondriais/tratamento farmacológico , Sirolimo/uso terapêutico , Animais , Autofagia , Respiração Celular/efeitos dos fármacos , Respiração Celular/genética , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Metabolômica/métodos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/etiologia , Encefalomiopatias Mitocondriais/tratamento farmacológico , Encefalomiopatias Mitocondriais/genética , Encefalomiopatias Mitocondriais/metabolismo , Fenótipo , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Sirolimo/farmacocinética , Resultado do Tratamento , Ubiquinona/análogos & derivados , Ubiquinona/genética , Ubiquinona/metabolismo
15.
Int J Pediatr Otorhinolaryngol ; 121: 143-149, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30909120

RESUMO

OBJECTIVES: Although hearing loss is a well-known symptom of mitochondria-related disorders, it is not clear how often it is a congenital and cochlear impairment. The Newborn Hearing Screening Program (NHSP) enables to distinguish congenital cochlear deafness from an acquired hearing deficit. The initial aim of the study was to research the frequency of the congenital cochlear hearing loss among patients with various gene defects resulting in mitochondrial disorders. The research process brought on an additional gain: basing on our preliminary study group of 80 patients, in 12 patients altogether we identified two defected genes responsible for mitochondrial disorders, whose carriers did not pass the NHSP. Finally, these patients were diagnosed with the congenital cochlear deafness. MATERIAL AND METHODS: The results of the NHSP in the patients with mitochondrial disorders diagnosed in our tertiary reference center were analyzed. Only the cases with confirmed mutations were qualified for the study group. The NHSP database included 80 patients with mutations in 31 different genes: 25 nuclear-encoded and 6 mtDNA-encoded. We searched the literature for the presence of a congenital hearing impairment (CHI) in mitochondrial disorders caused by changes in 278 already known genes. RESULTS: For 68 patients from the study group the NHSP test indicated a proper cochlear function and thus suggested normal hearing. For 12 mitochondrial patients, the NHSP test indicated the requirement for the further audiological diagnosis, and finally CHI was confirmed in 8 of them. This latter subset included patients with pathogenic variants in RRM2B and SERAC1, known as "deafness-causing genes". Contrary to our initial expectations, the patients carrying mutations in other "deafness-causing genes": MPV17, POLG, COX10, as well as other mitochondria-related genes, all reported in literature, did not indicate any CHI following the NHSP test. CONCLUSION: Our study indicates that the cochlear CHI is a phenotypic feature of the RRM2B and SERAC1 related defects. The diagnosis of the CHI following the NHSP allows to early distinguish those defects from other mitochondria-related disorders in which the NHSP test result is correct. Wider studies are needed to assess the significance of this observation.


Assuntos
Hidrolases de Éster Carboxílico/genética , Proteínas de Ciclo Celular/genética , Surdez/genética , Perda Auditiva Neurossensorial/genética , Doenças Mitocondriais/genética , Ribonucleotídeo Redutases/genética , Adolescente , Criança , Pré-Escolar , DNA Mitocondrial , Surdez/congênito , Feminino , Perda Auditiva Neurossensorial/congênito , Testes Auditivos , Heterozigoto , Hospitais , Humanos , Lactente , Recém-Nascido , Masculino , Doenças Mitocondriais/complicações , Doenças Mitocondriais/diagnóstico , Mutação , Triagem Neonatal , Polônia
16.
Can J Cardiol ; 35(2): 221-224, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30760430

RESUMO

Mitochondrial diseases are a heterogeneous group of rare hereditary disorders that may manifest with single organ involvement or as multisystemic disease. The pathophysiology of mitochondrial disease is complex and related to mutations of genes encoding mitochondrial proteins that are crucial to the cellular respiratory chain. Given its almost exclusive aerobic metabolism, the heart is particularly susceptible to mitochondrial dysfunction and commonly involved in mitochondrial disorders. Various clinical presentations are described, making clinical recognition challenging. Some patients may evolve towards the early need for heart transplantation, which emphasizes the importance of appropriate diagnosis and referral to a specialized centre.


Assuntos
Cardiologistas/normas , Cardiomiopatias/genética , DNA/genética , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Mutação , Miocárdio/patologia , Adulto , Biópsia , Cardiomiopatias/diagnóstico , Análise Mutacional de DNA , Ecocardiografia , Eletrocardiografia , Humanos , Masculino , Doenças Mitocondriais/diagnóstico , Proteínas Mitocondriais/metabolismo
19.
Eur J Pediatr ; 178(3): 387-394, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30617651

RESUMO

Fatty acid ß-oxidation (FAO) disorders have a wide variety of symptoms, not usually evident between episodes of acute decompensations. Cardiac involvement is frequent, and severe ventricular arrhythmias are suspected of causing sudden death. Expanded newborn screening (ENS) for these disorders, hopefully, contribute to prevent potentially acute life-threatening events. In order to characterize acute decompensations observed in FAO-deficient cases identified by ENS, a retrospective analysis was performed, covering a period of 9 years. Demographic data, number/type of acute decompensations, treatment, and follow-up were considered. Eighty-three clinical charts, including 66 medium-chain acyl-CoA dehydrogenase deficiency (MCADD), 5 carnitine-uptake deficiency (CUD), 3 carnitine palmitoyltransferase I and II (CPT I/II) deficiency, 5 very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), and 4 multiple acyl-CoA dehydrogenase deficiency (MADD) cases were reviewed. Nineteen patients had acute decompensations (1 CPT I, 1 CPT II, 3 MADD, 14 MCADD). Six patients developed symptoms previously to ENS diagnosis. Severe clinical manifestations included multiple organ failure, liver failure, heart failure, and sudden death. Long-chain FAO disorders had the highest number of decompensations per patient.Conclusion: Despite earlier diagnosis by ENS, sudden deaths were not avoided and acute decompensations with severe clinical manifestations still occur as well. What is Known: • Severe ventricular arrhythmias are suspected to cause unexpected death in FAO disorders. • Neonatal screening intends to reduce the incidence of severe metabolic crisis and death. What is New: • Acute severe decompensations occurred in FAO disorders diagnosed through neonatal screening. • Sudden deaths were not avoided by starting treatment precociously.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo Lipídico/diagnóstico , Triagem Neonatal/métodos , Acil-CoA Desidrogenase/deficiência , Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/mortalidade , Cardiomiopatias/complicações , Cardiomiopatias/diagnóstico , Cardiomiopatias/mortalidade , Carnitina/deficiência , Carnitina O-Palmitoiltransferase/deficiência , Criança , Pré-Escolar , Diagnóstico Precoce , Feminino , Seguimentos , Humanos , Hiperamonemia/complicações , Hiperamonemia/diagnóstico , Hiperamonemia/mortalidade , Hipoglicemia/complicações , Hipoglicemia/diagnóstico , Hipoglicemia/mortalidade , Lactente , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/complicações , Erros Inatos do Metabolismo Lipídico/mortalidade , Masculino , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/mortalidade , Doenças Mitocondriais/complicações , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/mortalidade , Deficiência Múltipla de Acil Coenzima A Desidrogenase/complicações , Deficiência Múltipla de Acil Coenzima A Desidrogenase/diagnóstico , Deficiência Múltipla de Acil Coenzima A Desidrogenase/mortalidade , Doenças Musculares/complicações , Doenças Musculares/diagnóstico , Doenças Musculares/mortalidade , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença
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