RESUMO
BACKGROUND: Mitochondrial disease is a rare, hereditary disease with a heterogeneous clinical presentation. However, fatigue is a common and burdensome complaint in children and adolescents with mitochondrial disease. No psychological intervention targeting fatigue exists for paediatric patients with a mitochondrial disease. We designed the PowerMe intervention, a blended cognitive behaviour therapy targeting fatigue in children and adolescents with mitochondrial disease. The aim of the intervention is to reduce perceived fatigue by targeting fatigue-related cognitions and behaviours. METHODS: A multiple baseline single case experiment will be conducted in five children (8-12 years old) and 5 adolescents (12-18 years old) with mitochondrial disease and severe fatigue. Patients will be included in the study for 33 weeks, answering weekly questions about the fatigue. Patients will be randomly assigned a baseline period of 5 to 9 weeks before starting the PowerMe intervention. The intervention consists of face-to-face and online sessions with a therapist and a website with information and assignments. The treatment will be tailored to the individual. Each patient will work on their personalized treatment plan focusing on personally relevant goals. The primary outcome is perceived fatigue. Secondary outcomes are quality of life, school presence and physical functioning. DISCUSSION: The results of the PowerMe study will provide information on the efficacy of a blended cognitive behaviour therapy on reducing perceived fatigue and its impact on daily life in children and adolescents with mitochondrial disease. Strengths and limitations of the study design are discussed. TRIAL REGISTRATION: Dutch Trial Register NTR 7675. Registered on 17 December 2018. Identifier https://www.trialregister.nl/trial/7433.
Assuntos
Terapia Cognitivo-Comportamental , Doenças Mitocondriais , Adolescente , Criança , Fadiga/diagnóstico , Fadiga/terapia , Humanos , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/terapia , Qualidade de Vida , Projetos de PesquisaRESUMO
Mitochondrial respiratory chain complex I consists of 44 different subunits and contains 3 functional modules: the Q-, the N- and the P-module. NDUFA9 is a Q-module subunit required for complex I assembly or stability. However, its role in complex I biogenesis has not been studied in patient fibroblasts. So far, a single patient carrying an NDUFA9 variant with a severe neonatally fatal phenotype has been reported. Via exome sequencing, we identified a novel homozygous NDUFA9 missense variant in another patient with a milder phenotype including childhood-onset progressive generalized dystonia and axonal peripheral neuropathy. We performed complex I assembly analysis using primary skin fibroblasts of both patients. Reduced complex I abundance and an accumulation of Q-module subassemblies were present in both patients but more pronounced in the severe clinical phenotype patient. The latter displayed additional accumulation of P-module subassemblies, which was not present in the milder-phenotype patient. Lentiviral complementation of both patient fibroblast cell lines with wild-type NDUFA9 rescued complex I deficiency and the assembly defects. Our report further characterizes the phenotypic spectrum of NDUFA9 deficiency and demonstrates that the severity of the clinical phenotype correlates with the severity of the effects of the different NDUFA9 variants on complex I assembly.
Assuntos
Complexo I de Transporte de Elétrons/genética , Proteínas Mitocondriais/genética , Mutação Puntual , Células Cultivadas , Complexo I de Transporte de Elétrons/metabolismo , Evolução Fatal , Células HEK293 , Humanos , Recém-Nascido , Masculino , Proteínas Mitocondriais/metabolismo , Sequenciamento do Exoma/métodosRESUMO
OBJECTIVES: Cardiomyopathy is a common complication of mitochondrial disorders, associated with increased mortality. Two dimensional speckle tracking echocardiography (2DSTE) can be used to quantify myocardial deformation. Here, we aimed to determine the usefulness of 2DSTE in detecting and monitoring subtle changes in myocardial dysfunction in carriers of the 3243A>G mutation in mitochondrial DNA. METHODS: In this retrospective pilot study, 30 symptomatic and asymptomatic carriers of the mitochondrial 3243A>G mutation of whom two subsequent echocardiograms were available were included. We measured longitudinal, circumferential and radial strain using 2DSTE. Results were compared to published reference values. RESULTS: Speckle tracking was feasible in 90 % of the patients for longitudinal strain. Circumferential and radial strain showed low face validity (low number of images with sufficient quality; suboptimal tracking) and were therefore rejected for further analysis. Global longitudinal strain showed good face validity, and was abnormal in 56-70 % (depending on reference values used) of the carriers (n = 27). Reproducibility was good (mean difference of 0.83 for inter- and 0.40 for intra-rater reproducibility; ICC 0.78 and 0.89, respectively). The difference between the first and the second measurement exceeded the measurement variance in 39 % of the cases (n = 23; feasibility of follow-up 77 %). DISCUSSION: Even in data collected as part of clinical care, two-dimensional strain echocardiography seems a feasible method to detect and monitor subtle changes in longitudinal myocardial deformation in adult carriers of the mitochondrial 3243A>G mutation. Based on our data and the reported accuracy of global longitudinal strain in other studies, we suggest the use of global longitudinal strain in a prospective follow-up or intervention study.
Assuntos
Cardiomiopatias/genética , Cardiomiopatias/patologia , Miocárdio/patologia , Adolescente , Adulto , DNA Mitocondrial/genética , Ecocardiografia/métodos , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mutação/genética , Projetos Piloto , Reprodutibilidade dos Testes , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Previous research has shown that dysphagia and gastrointestinal problems occur frequently in carriers of the m.3243A>G mutation; however, the exact frequency and severity have not been determined. We hypothesise that adult carriers have an increased risk for malnutrition. METHODS: In this observational study we evaluated the presence of gastrointestinal problems and dysphagia in 92 carriers of the m.3243A>G mutation. The severity of the general disease involvement was classified using the Newcastle Mitochondrial Disease Adult Scale (NMDAS). Gastrointestinal involvement, dysphagia and the risk for malnutrition were scored using the Gastrointestinal Symptoms Questionnaire and the Malnutrition Universal Screening Tool. Gastrointestinal symptoms and anthropometrics were compared with healthy controls. RESULTS: Our results show that the height, weight and body mass index (BMI) of these carriers were lower than the national average (p < 0.05). Seventy-nine carriers (86%) suffered from at least one gastrointestinal symptom, mainly flatulence or hard stools. Both frequency and severity of symptoms were significantly increased compared with reference data of healthy Dutch adults. Of the carriers, 45% reported (mostly mild) dysphagia. Solid foods cause more problems than liquids. A negative correlation between BMI and heteroplasmy levels in urinary epithelial cells (UEC) was present (Spearman correlation coefficient = - 0.319, p = 0.003). CONCLUSION: Dysphagia and gastrointestinal problems, especially constipation, are common symptoms in the total m.3243A>G carriers cohort and are not related to heteroplasmy levels in UEC or disease severity. The severity of gastrointestinal problems as well as overall disease severity is associated with an increased risk for malnutrition.
Assuntos
Constipação Intestinal/genética , DNA Mitocondrial/genética , Transtornos de Deglutição/genética , Síndrome MELAS/genética , Desnutrição/genética , Mutação , Adulto , Constipação Intestinal/etiologia , Análise Mutacional de DNA , Transtornos de Deglutição/etiologia , Feminino , Seguimentos , Heterozigoto , Humanos , Síndrome MELAS/complicações , Masculino , Desnutrição/etiologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Inquéritos e QuestionáriosRESUMO
The development of neurologic disease is a complex and multi-faceted process. Several factors, such as physiology, environment and genetics may play key roles in the manifestation of the associated illnesses. During the past decades, it has become clear that, at the cellular level, mitochondria function as more than "just" an energy source for our cells and plays a significant role in such aspects as neuronal development, maintenance and degeneration. Malfunctions in mitochondrial respiration and ATP production may prove disastrous for our cells and neurons, ultimately resulting in apoptosis, neurodegeneration and consequently, neurodegenerative diseases.
Assuntos
Mitocôndrias/metabolismo , Doenças Neurodegenerativas/metabolismo , Fosforilação Oxidativa , Animais , Metabolismo Energético/fisiologia , Humanos , Mitocôndrias/patologia , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologiaRESUMO
Mitochondrial complex I is the largest multi-protein enzyme complex of the oxidative phosphorylation system. Seven subunits of this complex are encoded by the mitochondrial and the remainder by the nuclear genome. We review the natural disease course and signs and symptoms of 130 patients (four new cases and 126 from literature) with mutations in nuclear genes encoding structural complex I proteins or those involved in its assembly. Complex I deficiency caused by a nuclear gene defect is usually a non-dysmorphic syndrome, characterized by severe multi-system organ involvement and a poor prognosis. Age at presentation may vary, but is generally within the first year of life. The most prevalent symptoms include hypotonia, nystagmus, respiratory abnormalities, pyramidal signs, dystonia, psychomotor retardation or regression, failure to thrive, and feeding problems. Characteristic symptoms include brainstem involvement, optic atrophy and Leigh syndrome on MRI, either or not in combination with internal organ involvement and lactic acidemia. Virtually all children ultimately develop Leigh syndrome or leukoencephalopathy. Twenty-five percent of the patients died before the age of six months, more than half before the age of two and 75 % before the age of ten years. Some patients showed recovery of certain skills or are still alive in their thirties . No clinical, biochemical, or genetic parameters indicating longer survival were found. No clear genotype-phenotype correlations were observed, however defects in some genes seem to be associated with a better or poorer prognosis, cardiomyopathy, Leigh syndrome or brainstem lesions.
Assuntos
Núcleo Celular/genética , Doenças Mitocondriais/genética , Mutação , Complexo I de Transporte de Elétrons/deficiência , Complexo I de Transporte de Elétrons/genética , Estudos de Associação Genética , Humanos , Mitocôndrias/genéticaRESUMO
Defective complex I (CI) is the most common type of oxidative phosphorylation disease, with an incidence of 1 in 5000 live births. Here, whole genome expression profiling of fibroblasts from CI deficient patients was performed to gain insight into the cell pathological mechanism. Our results suggest that patient fibroblasts responded to oxidative stress by Nrf2-mediated induction of the glutathione antioxidant system and Gadd45-mediated activation of the DNA damage response pathway. Furthermore, the observed reduced expression of selenoproteins, might explain the disturbed calcium homeostasis previously described for the patient fibroblasts and might be linked to endoplasmic reticulum stress. These results suggest that both glutathione and selenium metabolism are potentially therapeutic targets in CI deficiency.
Assuntos
Cálcio/metabolismo , Complexo I de Transporte de Elétrons/deficiência , Complexo I de Transporte de Elétrons/genética , Redes e Vias Metabólicas/genética , Doenças Mitocondriais/genética , Fator 2 Relacionado a NF-E2/metabolismo , Antioxidantes/metabolismo , Proteínas de Ciclo Celular/metabolismo , Pré-Escolar , Dano ao DNA , Estresse do Retículo Endoplasmático , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Glutationa/metabolismo , Homeostase/genética , Humanos , Lactente , Recém-Nascido , Masculino , Doenças Mitocondriais/metabolismo , Proteínas Nucleares/metabolismo , Fosforilação Oxidativa , Estresse Oxidativo , Selenoproteínas/metabolismoRESUMO
The oxidative phosphorylation (OXPHOS) system, comprising five enzyme complexes, is located in the inner membrane of mitochondria and is the final biochemical pathway in oxidative ATP production. Defects in this energy-generating system can cause a wide range of clinical symptoms; these diseases are often progressive and multisystemic. Numerous genes have been implicated in OXPHOS deficiencies and many mutations have been described. However, in a substantial number of patients with decreased enzyme activities of two or more OXPHOS complexes, no mutations in the mitochondrial DNA or in nuclear genes known to be involved in these disorders have been found. In this study, four nuclear candidate genes--NIPSNAP1, GBAS, CHCHD1 and METT11D1--were screened for mutations in 22 patients with a combined enzymatic deficiency of primarily the OXPHOS complexes I, III and IV to determine whether a mutation in one of these genes could explain the mitochondrial disorder. For each variant not yet reported as a polymorphism, 100 control samples were screened for the presence of the variant. This way we identified 14 new polymorphisms and 2 presumably non-pathogenic mutations. No mutations were found that could explain the mitochondrial disorder in the patients investigated in this study. Therefore, the genetic defect in these patients must be located in other nuclear genes involved in mtDNA maintenance, transcription or translation, in import, processing or degradation of nuclear encoded mitochondrial proteins, or in assembly of the OXPHOS system.
Assuntos
Metabolismo Energético/genética , Proteínas de Membrana/genética , Erros Inatos do Metabolismo/genética , Metiltransferases/genética , Doenças Mitocondriais/genética , Mutação , Proteínas Nucleares/genética , Fosfoproteínas/genética , Polimorfismo Genético , Proteínas/genética , Estudos de Casos e Controles , Células Cultivadas , Análise Mutacional de DNA , Fibroblastos/enzimologia , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos/métodos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana/metabolismo , Erros Inatos do Metabolismo/enzimologia , Doenças Mitocondriais/enzimologia , Dados de Sequência Molecular , Músculo Esquelético/enzimologia , Proteínas Nucleares/metabolismo , Fosforilação Oxidativa , Fenótipo , Fosfoproteínas/metabolismo , Proteínas/metabolismoRESUMO
A higher incidence of major depression has been described in adults with a primary oxidative phosphorylation disease. Intriguingly however, not all patients carrying the same mutation develop symptoms of major depression, pointing out the significance of the interplay of genetic and non-genetic factors in the etiology. In a series of paediatric patients evaluated for mitochondrial dysfunction, out of 35 children with a biochemically and genetically confirmed mitochondrial disorder, we identified five cases presenting with major depression prior to the diagnosis. The patients were diagnosed respectively with mutations in MTTK, MTND1, POLG1, PDHA1 and the common 4977 bp mtDNA deletion. Besides cerebral lactic acidemia protein and glucose concentrations, immunoglobins, anti-gangliosides and neurotransmitters were normal. No significant difference could be confirmed in the disease progression or the quality of life, compared to the other, genetically confirmed mitochondrial patients. In three out of our five patients a significant stress life event was confirmed. We propose the abnormal central nervous system energy metabolism as the underlying cause of the mood disorder in our paediatric patients. Exploring the genetic etiology in children with mitochondrial dysfunction and depression is essential both for safe medication and adequate counselling.
Assuntos
DNA Mitocondrial/genética , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/epidemiologia , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/epidemiologia , Deleção de Sequência , Adolescente , Criança , Pré-Escolar , Comorbidade , Transtorno Depressivo Maior/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Imageamento por Ressonância Magnética , Masculino , Doenças Mitocondriais/genética , Países Baixos , Fenótipo , Escalas de Graduação PsiquiátricaRESUMO
Mitochondrial disorders are caused by a defect in intracellular energy production. In general, these are multi-system disorders, predominantly affecting organs with high energy requirements. Due to the fact that mitochondrial disorders are not as rare as is generally assumed, and due to the diversity of symptoms, many different medical specialists will at some time be confronted with these patients. Early recognition ofa mitochondrial disorder reduces patient anxiety and avoids unnecessary ancillary investigations and potentially hazardous treatments. A mitochondrial disease should be considered in the event of dysfunction of more than 2 organ systems or processes with high energy requirements, certainly if there is a positive maternal family history. If fatigue includes exercise-induced muscle pain or muscle weakness, and if muscle pain predominantly occurs during exertion, a mitochondrial disease should be considered. The combination ofdiabetes mellitus and deafness is also a strong indicator of mitochondrial disease. An extensive family history should always be taken. In adults, the most frequently occurring mitochondrial syndromes are chronic progressive external ophthalmoplegia (CPEO), maternally inherited diabetes and deafness syndrome (MIDDS) and Leber's hereditary optic neuropathy. Since much research effort is currently being invested in the development of causal medical treatments, the importance of an early diagnosis is likely to become of increasing importance in the future.
Assuntos
DNA Mitocondrial/genética , Metabolismo Energético/genética , Doenças Metabólicas/diagnóstico , Doenças Mitocondriais/diagnóstico , Metabolismo Energético/fisiologia , Predisposição Genética para Doença , Humanos , Doenças Metabólicas/etiologia , Doenças Metabólicas/genética , Doenças Mitocondriais/complicações , Doenças Mitocondriais/genética , Miopatias Mitocondriais/complicações , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/genéticaRESUMO
We report a 5-year-old child carrying polymerase gamma (POLG1) mutations, but strikingly normal oxidative phosphorylation analysis in muscle, fibroblasts and liver. Mutations in POLG1 have so far been described in children with severe combined oxidative phosphorylation (OXPHOS) deficiencies and with the classical Alpers-Huttenlocher syndrome. The patient presented with a delayed psychomotor development and ataxia during the first two years of life. From the third year of life he developed epilepsy and regression in development, together with symptoms of visual impairment and sensorineuronal deafness. Cerebrospinal fluid showed elevated lactic acid and protein concentrations. An elder brother had died due to combined OXPHOS deficiencies. Despite the clinical similarity with the elder brother, except for liver involvement, the OXPHOS system analysis in a frozen muscle biopsy was normal. For this reason a fresh muscle biopsy was performed, which has the advantage of the possibility of measuring the substrate oxidation rates and ATP production, part of the mitochondrial energy-generating system (MEGS). During the same session, biopsies of liver and fibroblasts were taken. These three tissues showed normal measurements of the MEGS capacity. Based on the phenotype of Alpers-Huttenlocher syndrome in the elder brother, we decided to screen the POLG1 gene. Mutation analysis showed compound heterozygosity with two known mutations, A467T and G848S. The normal MEGS capacity in this patient expands the already existing complexity and heterogeneity of the childhood POLG1 patients and, on the basis of the high frequency of POLG1 mutations in childhood, warrants a liberal strategy with respect to mutation analysis.
Assuntos
DNA Polimerase Dirigida por DNA/genética , Esclerose Cerebral Difusa de Schilder/diagnóstico , Fibroblastos/enzimologia , Fígado/enzimologia , Músculo Esquelético/enzimologia , Mutação , Fosforilação Oxidativa , Biomarcadores/sangue , Biomarcadores/urina , Biópsia , Pré-Escolar , Análise Mutacional de DNA , DNA Polimerase gama , Esclerose Cerebral Difusa de Schilder/complicações , Esclerose Cerebral Difusa de Schilder/enzimologia , Esclerose Cerebral Difusa de Schilder/genética , Progressão da Doença , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Linhagem , FenótipoRESUMO
PURPOSE: To identify the biochemical and molecular genetic defect in a 16-year-old patient presenting with apical hypertrophic cardiomyopathy and neuropathy suspected for a mitochondrial disorder. METHODS: Measurement of the mitochondrial energy-generating system (MEGS) capacity in muscle and enzyme analysis in muscle and fibroblasts were performed. Relevant parts of the mitochondrial DNA were analysed by sequencing. Transmitochondrial cybrids were obtained by fusion of 143B206 TK(-) rho zero cells with patient-derived enucleated fibroblasts. Immunoblotting techniques were applied to study the complex V assembly. RESULTS: A homoplasmic nonsense mutation m.8529G-->A (p.Trp55X) was found in the mitochondrial ATP8 gene in the patient's fibroblasts and muscle tissue. Reduced complex V activity was measured in the patient's fibroblasts and muscle tissue, and was confirmed in cybrid clones containing patient-derived mitochondrial DNA. Immunoblotting after blue native polyacrylamide gel electrophoresis showed a lack of holocomplex V and increased amounts of mitochondrial ATP synthase subcomplexes. An in-gel activity assay of ATP hydrolysis showed activity of free F(1)-ATPase in the patient's muscle tissue and in the cybrid clones. CONCLUSION: We describe the first pathogenic mutation in the mitochondrial ATP8 gene, resulting in an improper assembly and reduced activity of the complex V holoenzyme.
Assuntos
Cardiomiopatia Hipertrófica/enzimologia , Cardiomiopatia Hipertrófica/genética , Códon sem Sentido , Genes Mitocondriais , ATPases Mitocondriais Próton-Translocadoras/deficiência , ATPases Mitocondriais Próton-Translocadoras/genética , Doenças do Sistema Nervoso/enzimologia , Doenças do Sistema Nervoso/genética , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Primers do DNA/genética , Humanos , Células Híbridas , Masculino , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/genética , ATPases Mitocondriais Próton-Translocadoras/química , Dados de Sequência Molecular , Homologia de Sequência de AminoácidosRESUMO
We report on a patient with congenital distal limb contractures, characteristic face, prominent metopic sutures, narrow forehead, severe psychomotor and growth retardation, white matter lesions and failure to thrive. The child has many overlapping features with those reported previously by Chitayat. We suggest that the central nervous anomalies are responsible for the congenital contractures in Chitayat syndrome.
Assuntos
Anormalidades Múltiplas , Deficiências do Desenvolvimento , Deficiência Intelectual , Deformidades Congênitas dos Membros , Sistema Nervoso Central/anormalidades , Contratura/congênito , Fácies , Humanos , Recém-Nascido , Masculino , Músculos/anormalidades , SíndromeRESUMO
Two girls aged 4 and 3 years, respectively, experienced acute liver failure due to accidental ingestion of supratherapeutic doses of paracetamol (90 mg/kg/day or more). Recognition of chronic paracetamol intoxication as a cause of acute hepatic failure is often delayed. It is important to consider the possibility of paracetamol-induced hepatotoxicity because many patients will recover if treated with N-acetylcysteine, as did both of these children. Patients with acute liver failure due to chronic paracetamol intoxication present with very high transaminase levels (> 4000 U/l), disproportionately low total bilirubin levels (< 200 micromol/l) and often hypoglycaemia.
Assuntos
Acetaminofen/intoxicação , Acetilcisteína/uso terapêutico , Analgésicos não Narcóticos/intoxicação , Sequestradores de Radicais Livres/uso terapêutico , Falência Hepática Aguda/induzido quimicamente , Pré-Escolar , Overdose de Drogas , Feminino , Humanos , Fígado/metabolismo , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/tratamento farmacológico , Prognóstico , Transaminases/sangueRESUMO
UNLABELLED: The phenotypic spectrum of the mitochondrial A3243G DKA mutation is highly variable, particularly when occuring in childhood. In contrast to the classical presentation in adulthood (MELAS syndrome; mitochondria! myopathy, encephalopathy, lactic acidosis and stroke-like episodes) children show a different pattern of symptoms, often without the typical encephalopathy or psychomotor regression. We present six children carrying the A3243G mtDNA mutation with a heteroplasmy above 50 % in muscle tissue. The age of diagnosis ranged from 2 weeks up to 14.5 years. The clinical presentation was rather non-specific including muscle weakness, developmental delay and epilepsy. In this small pediatric group we detected presymptomatic cardiac involvement in five out of six children already at an early stage of disease. The cardiac pathology included cardiomyopathy and biventricular hypertrophy with rhythm disturbances (for example long QT-syndrome). The observed cardiac changes do not always increase the risk of cardiac deterioration; however, two of our patients died early on. CONCLUSION: We hypothesize that the A3243G mutation might be underdiagnosed, as patients could suffer from an unexplained cardiac death before the diagnosis is made. We advise performing regular repeated ECGs and echocardiography in all children carrying a A3243G mtDNA mutation independently from the presence of cardiac symptoms.
Assuntos
Arritmias Cardíacas/etiologia , Cardiomiopatias/etiologia , Mitocôndrias Musculares/genética , Miopatias Mitocondriais/complicações , Miopatias Mitocondriais/genética , Adolescente , Arritmias Cardíacas/genética , Cardiomiopatias/genética , Criança , Análise Mutacional de DNA , Eletrocardiografia , Feminino , Humanos , Lactente , Recém-Nascido , MasculinoRESUMO
BACKGROUND: Based on a previous prospective clinical and biochemical study, a consensus mitochondrial disease scoring system was established to facilitate the diagnosis in patients with a suspected mitochondrial disorder. OBJECTIVE: To evaluate the specificity of the diagnostic system, we applied the mitochondrial disease score in 61 children with a multisystem disease and a suspected oxidative phosphorylation disorder who underwent a muscle biopsy and were consecutively diagnosed with a genetic mutation. METHODS: We evaluated data of 44 children diagnosed with a disorder in oxidative phosphorylation, carrying a mutation in the mitochondrial or nuclear DNA. We compared them with 17 children who, based on the clinical and metabolic features, also had a muscle biopsy but were finally diagnosed with a nonmitochondrial multisystem disorder by further genetic analysis. RESULTS: All children with a genetically established diagnosis of a primary oxidative phosphorylation disorder had a mitochondrial disease score above 6 (probable mitochondrial disorder), and 73% of the children had a score above 8 (definite mitochondrial disorder) at evaluation of the muscle biopsy. In the nonmitochondrial multisystem disorder group, the score was significantly lower, and no patients reached a score comparable with a definite respiratory chain disorder. CONCLUSIONS: The mitochondrial disease criteria system has a high specificity to distinguish between mitochondrial and other multisystem disorders. The method could also be applied in children with a suspected mitochondrial disorder, prior to performing a muscle biopsy.
Assuntos
DNA Mitocondrial/genética , Predisposição Genética para Doença/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Biópsia/normas , Criança , Análise Mutacional de DNA/métodos , Análise Mutacional de DNA/normas , DNA Mitocondrial/análise , Diagnóstico Diferencial , Feminino , Testes Genéticos/métodos , Testes Genéticos/normas , Humanos , Masculino , Mitocôndrias/genética , Doenças Mitocondriais/fisiopatologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Doenças Musculares/fisiopatologia , Mutação/genética , Valor Preditivo dos TestesRESUMO
BACKGROUND: Enzyme deficiencies of the oxidative phosphorylation (OXPHOS) system may be caused by mutations in the mitochondrial DNA (mtDNA) or in the nuclear DNA. OBJECTIVE: To analyse the sequences of the mtDNA coding region in 25 patients with OXPHOS system deficiency to identify the underlying genetic defect. RESULTS: Three novel non-synonymous substitutions in protein-coding genes, 4681T-->C in MT-ND2, 9891T-->C in MT-CO3 and 14122A-->G in MT-ND5, and one novel substitution in the 12S rRNA gene, 686A-->G, were found. The definitely pathogenic mutation 3460G-->A was identified in an 18-year-old woman who had severe isolated complex I deficiency and progressive myopathy. CONCLUSIONS: Bioinformatic analyses suggest a pathogenic role for the novel 4681T-->C substitution found in a boy with Leigh's disease. These results show that the clinical phenotype caused by the primary Leber's hereditary optic neuropathy mutation 3460G-->A is more variable than has been thought. In the remaining 23 patients, the role of mtDNA mutations as a cause of the OXPHOS system deficiency could be excluded. The deficiency in these children probably originates from mutations in the nuclear genes coding for respiratory enzyme subunits or assembly factors.
Assuntos
DNA Mitocondrial/química , Doenças Mitocondriais/genética , Adolescente , Criança , Pré-Escolar , Biologia Computacional , Análise Mutacional de DNA , Testes Genéticos/métodos , Humanos , Lactente , Recém-Nascido , Doenças Mitocondriais/diagnóstico , FilogeniaRESUMO
Mutations in SURF1, an assembly gene for cytochrome c oxidase (COX), the fourth complex of the oxidative phosphorylation system, are most frequently encountered in patients with COX deficiency. We describe a patient with Leigh syndrome harbouring a mutation in SURF1 who was reported decades ago with a tissue-specific cytochrome c oxidase deficiency.
Assuntos
Deficiência de Citocromo-c Oxidase/diagnóstico , Deficiência de Citocromo-c Oxidase/genética , Deficiência de Citocromo-c Oxidase/terapia , Doença de Leigh/diagnóstico , Doença de Leigh/genética , Mutação , Adulto , Análise Mutacional de DNA , Eletroforese em Gel Bidimensional , Feminino , Seguimentos , Humanos , Fígado/enzimologia , FosforilaçãoRESUMO
In this paper, we describe a distinct clinical subtype of 3-methylglutaconic aciduria. 3-Methylglutaconic aciduria is a group of different metabolic disorders biochemically characterized by increased urinary excretion of 3-methylglutaconic acid. We performed biochemical and genetic investigations, including urine organic acid analysis, NMR spectroscopy, measurement of 3-methylglutaconyl-CoA hydratase activity, cardiolipin levels, OPA3 gene analysis and measurement of the oxidative phosphorylation in four female patients with 3-methylglutaconic aciduria. 3-Methylglutaconic aciduria type I, Barth syndrome, and Costeff syndrome were excluded as the activity of 3-methylglutaconyl-CoA hydratase, the cardiolipin levels, and molecular analysis of the OPA3 gene, respectively, showed no abnormalities. The children presented with characteristic association of hearing loss and the neuro-radiological evidence of Leigh disease. They also had neonatal hypotonia, recurrent lactic acidemia, episodes with hypoglycemia and severe recurrent infections, feeding difficulties, failure to thrive, developmental delay, and progressive spasticity with extrapyramidal symptoms. Our patients were further biochemically characterized by a mitochondrial dysfunction and persistent urinary excretion of 3-methylglutaconic acid.
Assuntos
Encefalopatias Metabólicas/fisiopatologia , Glutaratos/urina , Perda Auditiva Neurossensorial/fisiopatologia , Doença de Leigh/fisiopatologia , Doenças Mitocondriais/fisiopatologia , Adolescente , Criança , Pré-Escolar , Consanguinidade , Evolução Fatal , Feminino , Humanos , Recém-Nascido , Masculino , Fosforilação Oxidativa , Síndrome , Valeratos/urinaRESUMO
Essential fatty acids (EFAs), and their longer-chain more-unsaturated derivatives (LCPUFAs) in particular, are essential for normal growth and cognitive development during childhood. Children with inborn errors of amino acid metabolism represent a risk population for a reduced LCPUFA status because their diet is low in EFAs and LCPUFAs. We have investigated the EFA and LCPUFA status of children with various amino acid metabolism disorders (not PKU) under treatment. Fatty acid profiles of plasma and erythrocyte phospholipids of 33 patients (aged 0-18 years) and 38 matched controls were determined by gas-liquid chromatography. Food-frequency questionnaires were used to assess the mean fatty acid intake. The dietary intake of the EFAs linoleic acid (LA) and alpha-linolenic acid (ALA) was comparable in both groups, while the LCPUFA intake was much lower in patients. This was associated with lower relative concentrations (% of total fatty acids) of n-3 docosahexaenoic acid (DHA) in plasma and erythrocyte phospholipids. Concentrations of arachidonic acid (AA) did not differ. The same was observed for the two EFAs LA and ALA. Thus, as compared to healthy controls, children with amino acid metabolism disorders have a lower intake of LCPUFAs and have lower concentrations of DHA but not of AA in plasma and erythrocyte phospholipids. This suggests that endogenous AA synthesis might guarantee an adequate AA status. The lower DHA status, however, warrants further investigations regarding the impact of DHA supplementation on growth and development of these children.