RESUMEN
El objetivo de la presente investigación fue relacionar los estilos de aprendizaje, la habilidad emocional, las inteligencias múltiples y la detección emocional a través de la mirada en una selección de estudiantes de educación física de Chile. Para ello se utilizó una muestra de 116 estudiantes de educación física de una universidad privada de Santiago de Chile. Se aplicó el CHAEA-36, el cuestionario de inteligencia emocional de Rego y Fernandes, el Multiple Intelligences Developmental Assessment Scales (MIDAS) y el test de la mirada de Baron-Cohen. Los resultados muestran un mayor puntaje en el estilo de aprendizaje reflexivo, seguido del teórico, pragmático y activo. En la habilidad emocional la dimensión con mayor puntaje fue empatía y con menor valoración, la sensibilidad emocional. En las inteligencias múltiples la más desarrollada fue la interpersonal y con menor puntuación, la musical. La puntuación mínima lograda en el test de miradas fue de 11 puntos y la máxima 28, con una media de 21,3 ± 3,34. Se encontraron algunas relaciones bajas entre las variables estudiadas. Se sugieren nuevas investigaciones en muestras de mayor envergadura y en diferentes regiones del país para establecer resultados más representativos de esta población.
The aim of the present investigation was to relate learning styles, emotional ability, multiples intelligences and emotional detection through the look on a sample of physical education students from Chile. For it there was in use a sample of 116 physical education students from a private university in Santiago of Chile. The CHAEA-36, the Rego and Fernandes emotional intelligence questionnaire, the Multiple Intelligences Developmental Assessment Scales (MIDAS) and the test of the Baron-Cohen gaze test were applied. The results show a higher score in reflexive learning style, followed by theoretical, pragmaticand active. In emotional ability, the dimension with the highest score was empathy and with the lowest valuation was emotional sensitivity. In the multiple intelligences the most developed was the interpersonal and with lowest score was the musical. The minimum score obtained in the gaze test was 11 points and the maximum 28, with an average of 21,3±3,34. Some low relationships between the studied variables were found. Further investigations are suggested in larger samples and in different regions of the country to establish more representative results of this population.
Asunto(s)
Humanos , Masculino , Femenino , Adolescente , Adulto , Adulto Joven , Aptitud , Educación y Entrenamiento Físico , Estudiantes , Emociones , Aprendizaje , Chile , Encuestas y Cuestionarios , Inteligencia EmocionalAsunto(s)
GTP Fosfohidrolasas/genética , Proteínas Asociadas a Microtúbulos/genética , Proteínas Mitocondriales/genética , Mutación/genética , Trastornos Parkinsonianos/genética , Adulto , Dinaminas , Resultado Fatal , Femenino , Humanos , Mitocondrias/metabolismo , Trastornos Parkinsonianos/metabolismoRESUMEN
OBJECTIVE: To describe the clinical, biochemical, and genetic features of patients with congenital disorders of glycosylation (CDG) identified in Spain during the last 20 years. STUDY DESIGN: Patients were selected among those presenting with multisystem disease of unknown etiology. The isoforms of transferrin and of ApoC3 and dolichols were analyzed in serum; phosphomannomutase and mannosephosphate isomerase activities were measured in fibroblasts. Conventional or massive parallel sequencing (customized panel or Illumina Clinical-Exome Sequencing TruSight One Gene Panel) was used to identify genes and mutations. RESULTS: Ninety-seven patients were diagnosed with 18 different CDG. Eighty-nine patients had a type 1 transferrin profile; 8 patients had a type 2 transferrin profile, with 6 of them showing an alteration in the ApoC3 isoform profile. A total of 75% of the patients had PMM2-CDG presenting with a heterogeneous mutational spectrum. The remaining patients showed mutations in any of the following genes: MPI, PGM1, GFPT1, SRD5A3, DOLK, DPGAT1, ALG1, ALG6, RFT1, SSR4, B4GALT1, DPM1, COG6, COG7, COG8, ATP6V0A2, and CCDC115. CONCLUSION: Based on literature and on this population-based study of CDG, a comprehensive scheme including reported clinical signs of CDG is offered, which will hopefully reduce the timeframe from clinical suspicion to genetic confirmation. The different defects of CDG identified in Spain have contributed to expand the knowledge of CDG worldwide. A predominance of PMM2 deficiency was detected, with 5 novel PMM2 mutations being described.
Asunto(s)
Acetiltransferasas/metabolismo , Apolipoproteínas C/metabolismo , Trastornos Congénitos de Glicosilación/diagnóstico , Trastornos Congénitos de Glicosilación/epidemiología , Acetiltransferasas/genética , Apolipoproteínas C/genética , Estudios de Cohortes , Bases de Datos Factuales , Femenino , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Humanos , Incidencia , Recién Nacido , Masculino , Mutación , Estudios Retrospectivos , Medición de Riesgo , España/epidemiologíaRESUMEN
Congenital disorders of glycosylation (CDG) are a heterogeneous and rapidly growing group of diseases caused by abnormal glycosylation of proteins and/or lipids. Mutations in genes involved in the homeostasis of the endoplasmic reticulum (ER), the Golgi apparatus (GA), and the vesicular trafficking from the ER to the ER-Golgi intermediate compartment (ERGIC) have been found to be associated with CDG. Here, we report a patient with defects in both N- and O-glycosylation combined with a delayed vesicular transport in the GA due to mutations in TRAPPC11, a subunit of the TRAPPIII complex. TRAPPIII is implicated in the anterograde transport from the ER to the ERGIC as well as in the vesicle export from the GA. This report expands the spectrum of genetic alterations associated with CDG, providing new insights for the diagnosis and the understanding of the physiopathological mechanisms underlying glycosylation disorders.
Asunto(s)
Trastornos Congénitos de Glicosilación/diagnóstico , Trastornos Congénitos de Glicosilación/genética , Mutación , Proteínas de Transporte Vesicular/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Alelos , Sustitución de Aminoácidos , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Genotipo , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Fenotipo , Secuenciación Completa del GenomaRESUMEN
The genetic causes of Leigh syndrome are heterogeneous, with a poor correlation between the phenotype and genotype. Here, we present a patient with an NDUFS4 mutation to expand the clinical and biochemical spectrum of the disease. A combined defect in the CoQ, PDH and RCC activities in our patient was due to an inappropriate assembly of the RCC complex I (CI), which was confirmed using Blue-Native polyacrylamide gel electrophoresis (BN-PAGE) analysis. Targeted exome sequencing analysis allowed for the genetic diagnosis of this patient. We reviewed 198 patients with 24 different genetic defects causing RCC I deficiency and compared them to 22 NDUFS4 patients. We concluded that NDUFS4-related Leigh syndrome is invariably linked to an early onset severe phenotype that results in early death. Some data, including the clinical phenotype, neuroimaging and biochemical findings, can guide the genetic study in patients with RCC I deficiency.
Asunto(s)
Enfermedad de Leigh/diagnóstico , NADH Deshidrogenasa/deficiencia , Complejo I de Transporte de Electrón , Electroforesis en Gel de Poliacrilamida , Femenino , Humanos , Recién Nacido , Ubiquinona/deficienciaRESUMEN
Coenzyme Q10 (CoQ10) deficiency is associated to a variety of clinical phenotypes including neuromuscular and nephrotic disorders. We report two unrelated boys presenting encephalopathy, ataxia, and lactic acidosis, who died with necrotic lesions in different areas of brain. Levels of CoQ10 and complex II+III activity were increased in both skeletal muscle and fibroblasts, but it was a consequence of higher mitochondria mass measured as citrate synthase. In fibroblasts, oxygen consumption was also increased, whereas steady state ATP levels were decreased. Antioxidant enzymes such as NQO1 and MnSOD and mitochondrial marker VDAC were overexpressed. Mitochondria recycling markers Fis1 and mitofusin, and mtDNA regulatory Tfam were reduced. Exome sequencing showed mutations in PDHA1 in the first patient and in PDHB in the second. These genes encode subunits of pyruvate dehydrogenase complex (PDH) that could explain the compensatory increase of CoQ10 and a defect of mitochondrial homeostasis. These two cases describe, for the first time, a mitochondrial disease caused by PDH defects associated with unbalanced of both CoQ10 content and mitochondria homeostasis, which severely affects the brain. Both CoQ10 and mitochondria homeostasis appears as new markers for PDH associated mitochondrial disorders.
Asunto(s)
Encefalopatías/enzimología , Encefalopatías/genética , Mutación/genética , Complejo Piruvato Deshidrogenasa/genética , Ubiquinona/análogos & derivados , Secuencia de Bases , Niño , Preescolar , Resultado Fatal , Fibroblastos/patología , Humanos , Lactante , Masculino , Mitocondrias Musculares/metabolismo , Datos de Secuencia Molecular , Piel/patología , Ubiquinona/metabolismoRESUMEN
Mutations in NFU1 were recently identified in patients with fatal encephalopathy. NFU1 is an iron-sulfur cluster protein necessary for the activity of the mitochondrial respiratory chain complexes I-II and the synthesis of lipoic acid. We report two NFU1 compound heterozygous individuals with normal complex I and lipoic acid-dependent enzymatic activities and low, but detectable, levels of lipoylated proteins. We demonstrated a leaky splicing regulation due to a splice site mutation (c.545+5G>A) that produces small amounts of wild type NFU1 mRNA that might result in enough protein to partially lipoylate and restore the activity of lipoic acid-dependent enzymes and the assembly and activity of complex I. These results allowed us to gain insights into the molecular basis underlying this disease and should be considered for the diagnosis of NFU1 patients.
Asunto(s)
Encefalopatías Metabólicas/diagnóstico por imagen , Encefalopatías Metabólicas/genética , Proteínas Portadoras/genética , Mutación , Sitios de Empalme de ARN , Empalme del ARN , Encefalopatías Metabólicas/metabolismo , Proteínas Portadoras/metabolismo , Femenino , Humanos , Lactante , Lipoilación/genética , Masculino , RadiografíaRESUMEN
BACKGROUND: Phosphomannomutase deficiency (PMM2-CDG) is the most frequent congenital disorder of glycosylation. The cerebellum is nearly always affected in PMM2-CDG patients, a cerebellar atrophy progression is observed, and cerebellar dysfunction is their main daily functional limitation. Different therapeutic agents are under development, and clinical evaluation of drug candidates will require a standardized score of cerebellar dysfunction. We aim to assess the validity of the International Cooperative Ataxia Rating Scale (ICARS) in children and adolescents with genetically confirmed PMM2-CDG deficiency. We compare ICARS results with the Nijmegen Pediatric CDG Rating Scale (NPCRS), neuroimaging, intelligence quotient (IQ) and molecular data. METHODS: Our observational study included 13 PMM2-CDG patients and 21 control subjects. Ethical permissions and informed consents were obtained. Three independent child neurologists rated PMM2-CDG patients and control subjects using the ICARS. A single clinician administered the NPCRS. All patients underwent brain MRI, and the relative diameter of the midsagittal vermis was measured. Psychometric evaluations were available in six patients. The Mann-Whitney U test was used to compare ICARS between patients and controls. To evaluate inter-observer agreement in patients' ICARS ratings, intraclass correlation coefficients (ICC) were calculated. ICARS internal consistency was evaluated using Cronbach's alpha. Spearman's rank correlation coefficient test was used to correlate ICARS with NPCRS, midsagittal vermis relative diameter and IQ. RESULTS: ICARS and ICARS subscores differed between patients and controls (p < 0.001). Interobserver agreement of ICARS was "almost perfect" (ICC = 0.99), with a "good" internal reliability (Cronbach's alpha = 0.72). ICARS was significantly correlated with the total NPCRS score (rs 0.90, p < 0.001). However, there was no agreement regarding categories of severity. Regarding neuroimaging, inverse correlations between ICARS and midsagittal vermis relative diameter (rs -0.85, p = 0.003) and IQ (rs -0.94, p = 0.005) were found. Patients bearing p.E93A, p.C241S or p.R162W mutations presented a milder phenotype. CONCLUSIONS: ICARS is a reliable instrument for assessment of PMM2-CDG patients, without significant inter-rater variability. Despite our limited sample size, the results show a good correlation between functional cerebellar assessment, IQ and neuroimaging. For the first a correlation between ICARS, neuroimaging and IQ in PMM2-CDG patients has been demonstrated.
Asunto(s)
Ataxia Cerebelosa/diagnóstico , Cerebelo/patología , Trastornos Congénitos de Glicosilación/diagnóstico , Fosfotransferasas (Fosfomutasas)/deficiencia , Índice de Severidad de la Enfermedad , Adolescente , Ataxia Cerebelosa/enzimología , Ataxia Cerebelosa/genética , Niño , Preescolar , Trastornos Congénitos de Glicosilación/enzimología , Trastornos Congénitos de Glicosilación/genética , Femenino , Humanos , Masculino , Fosfotransferasas (Fosfomutasas)/genéticaRESUMEN
BACKGROUND: It has been demonstrated that glucose transporter (GLUT1) deficiency in a mouse model causes a diminished cerebral lipid synthesis. This deficient lipid biosynthesis could contribute to secondary CoQ deficiency. We report here, for the first time an association between GLUT1 and coenzyme Q10 deficiency in a pediatric patient. CASE PRESENTATION: We report a 15 year-old girl with truncal ataxia, nystagmus, dysarthria and myoclonic epilepsy as the main clinical features. Blood lactate and alanine values were increased, and coenzyme Q10 was deficient both in muscle and fibroblasts. Coenzyme Q10 supplementation was initiated, improving ataxia and nystagmus. Since dysarthria and myoclonic epilepsy persisted, a lumbar puncture was performed at 12 years of age disclosing diminished cerebrospinal glucose concentrations. Diagnosis of GLUT1 deficiency was confirmed by the presence of a de novo heterozygous variant (c.18+2T>G) in the SLC2A1 gene. No mutations were found in coenzyme Q10 biosynthesis related genes. A ketogenic diet was initiated with an excellent clinical outcome. Functional studies in fibroblasts supported the potential pathogenicity of coenzyme Q10 deficiency in GLUT1 mutant cells when compared with controls. CONCLUSION: Our results suggest that coenzyme Q10 deficiency might be a new factor in the pathogenesis of G1D, although this deficiency needs to be confirmed in a larger group of G1D patients as well as in animal models. Although ketogenic diet seems to correct the clinical consequences of CoQ deficiency, adjuvant treatment with CoQ could be trialled in this condition if our findings are confirmed in further G1D patients.
Asunto(s)
Ataxia/etiología , Transportador de Glucosa de Tipo 1/deficiencia , Enfermedades Mitocondriales/etiología , Debilidad Muscular/etiología , Ubiquinona/deficiencia , Adolescente , Ataxia/diagnóstico , Ataxia/dietoterapia , Proteínas de Transporte de Catión , Dieta Cetogénica , Suplementos Dietéticos , Femenino , Transportador de Glucosa de Tipo 1/genética , Humanos , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/dietoterapia , Debilidad Muscular/diagnóstico , Debilidad Muscular/dietoterapia , Mutación , Intercambiador 1 de Sodio-Hidrógeno , Intercambiadores de Sodio-Hidrógeno , Ubiquinona/análogos & derivados , Ubiquinona/uso terapéutico , Vitaminas/uso terapéuticoRESUMEN
Mitochondrial DNA mutations at MT-ATP6 gene are relatively common in individuals suffering from striatal necrosis syndromes. These patients usually do not show apparent histochemical and/or biochemical signs of oxidative phosphorylation dysfunction. Because of this, MT-ATP6 is not typically analyzed in many other mitochondrial disorders that have not been previously associated to mutations in this gene. To correct this bias, we have performed a screening of the MT-ATP6 gene in a large collection of patients suspected of suffering different mitochondrial DNA (mtDNA) disorders. In three cases, biochemical, molecular-genetics and other analyses in patient tissues and cybrids were also carried out. We found three new pathologic mutations. Two of them in patients showing phenotypes that have not been commonly associated to mutations in the MT-ATP6 gene. These results remark the importance of sequencing the MT-ATP6 gene in patients with striatal necrosis syndromes, but also within other mitochondrial pathologies. This gene should be sequenced at least in all those patients suspected of suffering an mtDNA disorder disclosing normal results for histochemical and biochemical analyses of respiratory chain.
Asunto(s)
ADN Mitocondrial/genética , ATPasas de Translocación de Protón Mitocondriales/genética , Femenino , Humanos , Enfermedad de Leigh/genética , Masculino , Enfermedades Mitocondriales/genética , Miopatías Mitocondriales/genética , Mutación , Fenotipo , Retinitis Pigmentosa/genéticaRESUMEN
Few therapeutic options are available to patients with oxidative phosphorylation disorders. Administering pharmacological agents that are able to stimulate mitochondrial biogenesis have been put forward as a possible treatment, yet the approach remains in need of thorough testing. We investigated the effect of resveratrol in an in vitro setting. Mitochondrial enzymatic activities were tested in cultured skin fibroblasts from patients harboring a nuclear defect in either complex II or complex IV (n = 11), and in fibroblasts from healthy controls (n = 11). In the latter, preincubation with resveratrol resulted in a significant increase of citrate synthase, complex II and complex IV enzyme activity. In patients with complex II or complex IV deficiency, however, activity of the deficient complex could not be substantially augmented, and response was dependent upon the residual activity. We conclude that resveratrol is not capable of normalizing oxidative phosphorylation activities in deficient cell lines.
Asunto(s)
Deficiencia de Citocromo-c Oxidasa/enzimología , Complejo II de Transporte de Electrones/deficiencia , Fibroblastos/efectos de los fármacos , Fosforilación Oxidativa/efectos de los fármacos , Estilbenos/farmacología , Células Cultivadas , Citrato (si)-Sintasa/metabolismo , Deficiencia de Citocromo-c Oxidasa/fisiopatología , Complejo II de Transporte de Electrones/metabolismo , Complejo IV de Transporte de Electrones/genética , Complejo IV de Transporte de Electrones/metabolismo , Fibroblastos/enzimología , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/enzimología , ResveratrolRESUMEN
Primary coenzyme Q10 (CoQ10) deficiencies are associated with mutations in genes encoding enzymes important for its biosynthesis and patients are responsive to CoQ10 supplementation. Early treatment allows better prognosis of the disease and therefore, early diagnosis is desirable. The complex phenotype and genotype and the frequent secondary CoQ10 deficiencies make it difficult to achieve a definitive diagnosis by direct quantification of CoQ10. We developed a non-radioactive methodology for the quantification of CoQ10 biosynthesis in fibroblasts that allows the identification of primary deficiencies. Fibroblasts were incubated 72 h with 28 µmol/L (2)H3-mevalonate or 1.65 mmol/L (13)C6-p-hydroxybenzoate. The newly synthesized (2)H3- and (13)C6- labelled CoQ10 were analysed by high performance liquid chromatography-tandem mass spectrometry. The mean and the reference range for (13)C6-CoQ10 and (2)H3-CoQ10 biosynthesis were 0.97 (0.83-1.1) and 0.13 (0.09-0.17) nmol/Unit of citrate synthase, respectively. We validated the methodology through the study of one patient with COQ2 mutations and six patients with CoQ10 deficiency secondary to other inborn errors of metabolism. Afterwards we investigated 16 patients' fibroblasts and nine showed decreased CoQ10 biosynthesis. Therefore, the next step is to study the COQ genes in order to reach a definitive diagnosis in these nine patients. In the patients with normal rates the deficiency is probably secondary. In conclusion, we have developed a non-invasive non-radioactive method suitable for the detection of defects in CoQ10 biosynthesis, which offers a good tool for the stratification of patients with these treatable mitochondrial diseases.
Asunto(s)
Ataxia/diagnóstico , Ataxia/metabolismo , Fibroblastos/metabolismo , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/metabolismo , Debilidad Muscular/diagnóstico , Debilidad Muscular/metabolismo , Mutación , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Línea Celular , Cromatografía Líquida de Alta Presión , Citrato (si)-Sintasa/metabolismo , Genotipo , Humanos , Técnicas de Diagnóstico Molecular , Fenotipo , Valores de Referencia , Reproducibilidad de los Resultados , Piel/metabolismo , Espectrometría de Masas en Tándem , Factores de Tiempo , Ubiquinona/biosíntesis , Ubiquinona/metabolismoRESUMEN
Cofactor disorders of mitochondrial energy metabolism are a heterogeneous group of diseases with a wide variety of clinical symptoms, particular metabolic profiles and variable enzymatic defects. Mutations in NFU1, BOLA3, LIAS and IBA57 have been identified in patients with deficient lipoic acid-dependent enzymatic activities and defects in the assembly and activity of the mitochondrial respiratory chain complexes. Here, we report a patient with an early onset fatal lactic acidosis presenting a biochemical phenotype compatible with a combined defect of pyruvate dehydrogenase (PDHC) and 2-ketoglutarate dehydrogenase (2-KGDH) activities, which suggested a deficiency in lipoic acid metabolism. Immunostaining analysis showed that lipoylated E2-PDH and E2-KGDH were extremely reduced in this patient. However, the absence of glycine elevation, the normal activity of the glycine cleavage system and the normal lipoylation of the H protein suggested a defect of lipoic acid transfer to particular proteins rather than a general impairment of lipoic acid biosynthesis as the potential cause of the disease. By analogy with yeast metabolism, we postulated LIPT1 as the altered candidate gene causing the disease. Sequence analysis of the human LIPT1 identified two heterozygous missense mutations (c.212C>T and c.292C>G), segregating in different alleles. Functional complementation experiments in patient's fibroblasts demonstrated that these mutations are disease-causing and that LIPT1 protein is required for lipoylation and activation of 2-ketoacid dehydrogenases in humans. These findings expand the spectrum of genetic defects associated with lipoic acid metabolism and provide the first evidence of a lipoic acid transfer defect in humans.
Asunto(s)
Aciltransferasas/genética , Lipoilación/genética , Oxo-Ácido-Liasas/genética , Acidosis Láctica/genética , Acidosis Láctica/mortalidad , Errores Innatos del Metabolismo de los Aminoácidos/genética , Animales , Células COS , Células Cultivadas , Chlorocebus aethiops , Metabolismo Energético/genética , Femenino , Humanos , Recién Nacido , Complejo Cetoglutarato Deshidrogenasa/deficiencia , Complejo Cetoglutarato Deshidrogenasa/genética , Ácidos Cetoglutáricos/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Mutación Missense , Complejo Piruvato Deshidrogenasa/genética , Ácido Tióctico/metabolismoRESUMEN
3-Methylglutaconic aciduria (3-MGA-uria) is a heterogeneous group of syndromes characterized by an increased excretion of 3-methylglutaconic and 3-methylglutaric acids. Five types of 3-MGA-uria (I to V) with different clinical presentations have been described. Causative mutations in TAZ, OPA3, DNAJC19, ATP12, ATP5E, and TMEM70 have been identified. After excluding the known genetic causes of 3-MGA-uria we used exome sequencing to investigate a patient with Leigh syndrome and 3-MGA-uria. We identified a homozygous variant in SERAC1 (c.202C>T; p.Arg68*), that generates a premature stop codon at position 68 of SERAC1 protein. Western blot analysis in patient's fibroblasts showed a complete absence of SERAC1 that was consistent with the prediction of a truncated protein and supports the pathogenic role of the mutation. During the course of this project a parallel study identified mutations in SERAC1 as the genetic cause of the disease in 15 patients with MEGDEL syndrome, which was compatible with the clinical and biochemical phenotypes of the patient described here. In addition, our patient developed microcephaly and optic atrophy, two features not previously reported in MEGDEL syndrome. We highlight the usefulness of exome sequencing to reveal the genetic bases of human rare diseases even if only one affected individual is available.
Asunto(s)
Hidrolasas de Éster Carboxílico/genética , Exoma/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Errores Innatos del Metabolismo/genética , Adolescente , Adulto , Niño , Femenino , Humanos , Lactante , Masculino , Errores Innatos del Metabolismo/patología , MutaciónRESUMEN
We evaluated coenzyme Q10 (CoQ) levels in patients studied under suspicion of mitochondrial DNA depletion syndromes (MDS) (n=39). CoQ levels were quantified by HPLC, and the percentage of mtDNA depletion by quantitative real-time PCR. A high percentage of MDS patients presented with CoQ deficiency as compared to other mitochondrial patients (Mann-Whitney-U test: p=0.001). Our findings suggest that MDS are frequently associated with CoQ deficiency, as a possible secondary consequence of disease pathophysiology. Assessment of muscle CoQ status seems advisable in MDS patients since the possibility of CoQ supplementation may then be considered as a candidate therapy.
Asunto(s)
Ataxia/epidemiología , Errores Innatos del Metabolismo/complicaciones , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/epidemiología , Miopatías Mitocondriales/complicaciones , Debilidad Muscular/epidemiología , Enfermedades Musculares/complicaciones , Ubiquinona/deficiencia , Adolescente , Ataxia/diagnóstico , Niño , Preescolar , Cromatografía Líquida de Alta Presión , ADN Mitocondrial/análisis , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Enfermedades Mitocondriales/diagnóstico , Debilidad Muscular/diagnóstico , Reacción en Cadena en Tiempo Real de la Polimerasa , Ubiquinona/análogos & derivados , Ubiquinona/análisis , Adulto JovenRESUMEN
OBJECTIVES: Coenzyme Q10 (CoQ10) deficiency syndrome is a rare condition that causes mitochondrial dysfunction and includes a variety of clinical presentations as encephalomyopathy, ataxia and renal failure. First, we sought to set up what all have in common, and then investigate why CoQ10 supplementation reverses the bioenergetics alterations in cultured cells but not all the cellular phenotypes. DESIGN MODELLING STUDY: This work models the transcriptome of human CoQ10 deficiency syndrome in primary fibroblast from patients and study the genetic response to CoQ10 treatment in these cells. SETTING: Four hospitals and medical centres from Spain, Italy and the USA, and two research laboratories from Spain and the USA. PARTICIPANTS: Primary cells were collected from patients in the above centres. MEASUREMENTS: We characterised by microarray analysis the expression profile of fibroblasts from seven CoQ10-deficient patients (three had primary deficiency and four had a secondary form) and aged-matched controls, before and after CoQ10 supplementation. Results were validated by Q-RT-PCR. The profile of DNA (CpG) methylation was evaluated for a subset of gene with displayed altered expression. RESULTS: CoQ10-deficient fibroblasts (independently from the aetiology) showed a common transcriptomic profile that promotes cell survival by activating cell cycle and growth, cell stress responses and inhibiting cell death and immune responses. Energy production was supported mainly by glycolysis while CoQ10 supplementation restored oxidative phosphorylation. Expression of genes involved in cell death pathways was partially restored by treatment, while genes involved in differentiation, cell cycle and growth were not affected. Stably demethylated genes were unaffected by treatment whereas we observed restored gene expression in either non-methylated genes or those with an unchanged methylation pattern. CONCLUSIONS: CoQ10 deficiency induces a specific transcriptomic profile that promotes cell survival, which is only partially rescued by CoQ10 supplementation.
RESUMEN
Recent investigations have suggested creatine (Cr) as an additional biomarker of mitochondrial diseases. With the aim of corroborating previous findings, we have studied plasma Cr in a cohort of 33 patients with different mitochondrial diseases. Cr was clearly increased in 9 out of 33 patients. Therefore, positive patients represent only 28% of the total number, suggesting that Cr is not a sensitive biomarker of mitochondrial diseases although it does present an acceptable specificity (83%). High plasma Cr, together with other biomarkers, might be useful to reinforce the diagnosis of mitochondrial diseases.
Asunto(s)
Creatina/sangre , Enfermedades Mitocondriales/sangre , Enfermedades Mitocondriales/diagnóstico , Adolescente , Adulto , Biomarcadores/sangre , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Ácido Láctico/sangre , Curva ROC , Adulto JovenRESUMEN
Cofactor disorders of mitochondrial energy metabolism are a heterogeneous group of diseases with a wide variety of clinical symptoms, particular metabolic profiles and variable enzymatic defects. Mutations in NFU1 were recently identified in patients with fatal encephalopathy displaying a biochemical phenotype consistent with defects in lipoic acid-dependent enzymatic activities and respiratory chain complexes. This discovery highlighted the molecular function of NFU1 as an iron-sulfur(Fe-S) cluster protein necessary for lipoic acid biosynthesis and respiratory chain complexes activities. To understand the pathophysiological mechanisms underlying this disease we have characterized the protein expression profiles of patients carrying NFU1 mutations. Fibroblasts from patients with the p.Gly208Cys mutation showed complete absence of protein-bound lipoic acid and decreased SDHA and SDHB subunits of complex II. In contrast, subunits of other respiratory chain complexes were normal. Protein lipoylation was also decreased in muscle and liver but not in other tissues available (brain, kidney, lung) from NFU1 patients. Although levels of the respiratory chain subunits were unaltered in tissues, BN-PAGE showed an assembly defect for complex II in muscle, consistent with the low enzymatic activity of this complex. This study provides new insights into the molecular bases of NFU1 disease as well as into the regulation of NFU1 protein in human tissues. We demonstrate a ubiquitous expression of NFU1 protein and further suggest that defects in lipoic acid biosynthesis and complex II are the main molecular signature of this disease, particularly in patients carrying the p.Gly208Cys mutation.
Asunto(s)
Proteínas Portadoras/genética , Enfermedades Mitocondriales/genética , Mutación Missense , Biosíntesis de Proteínas/genética , Proteínas/genética , Transcriptoma/genética , Transporte de Electrón/genética , Fibroblastos/metabolismo , Genotipo , Homocigoto , Humanos , Lactante , Mitocondrias/genética , Mitocondrias/metabolismo , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Proteínas/metabolismo , Ácido Tióctico/genética , Ácido Tióctico/metabolismoRESUMEN
Mitochondrial DNA depletion syndrome (MDS) is a clinically heterogeneous group of mitochondrial disorders characterised by a quantitative reduction of the mitochondrial DNA copy number. Three main clinical forms of MDS: myopathic, encephalomyopathic and hepatocerebral have been defined, although patients may present with other MDS associated clinical symptoms and signs that cover a wide spectrum of onset age and disease. We studied 52 paediatric individuals suspected to have MDS. These patients have been divided into three different groups, and the appropriate MDS genes have been screened according to their clinical and biochemical phenotypes. Mutational study of DGUOK, MPV17, SUCLA2, SUCLG1 and POLG allowed us to identify 3 novel mutations (c.1048G>A and c.1049G>T in SUCLA2 and c.531+4A>T in SUCLG1) and 7 already known mutations in 10 patients (8 families). Seventeen patients presented with mtDNA depletion in liver or muscle, but the cause of mtDNA depletion still remains unknown in 8 of them. When possible, we quantified mtDNA/nDNA and CS activity in the same tissue sample, providing an additional tool for the study of MDS. The ratio (mtDNA/nDNA)/CS has shed some light in the discrepant results between the mtDNA copy number and the enzymatic respiratory chain activities of some cases.
Asunto(s)
Errores Innatos del Metabolismo/genética , Enfermedades Mitocondriales/genética , Miopatías Mitocondriales/genética , Enfermedades Musculares/genética , Succinato-CoA Ligasas/genética , Adolescente , Niño , Citrato (si)-Sintasa/genética , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN , ADN Polimerasa gamma , ADN Mitocondrial/genética , ADN Polimerasa Dirigida por ADN/genética , Esclerosis Cerebral Difusa de Schilder/diagnóstico , Esclerosis Cerebral Difusa de Schilder/enzimología , Esclerosis Cerebral Difusa de Schilder/genética , Femenino , Humanos , Masculino , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/enzimología , Mitocondrias/enzimología , Mitocondrias/genética , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/enzimología , Miopatías Mitocondriales/diagnóstico , Miopatías Mitocondriales/enzimología , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/enzimología , Mutación , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Adulto JovenRESUMEN
The reported cases showed clinical, biochemical, histopathological, and molecular features lending support to the hypothesis of a pathogenic effect of the detected mutations. Case 1 was a neonatal presentation who showed multiple mitochondrial respiratory chain enzyme defects in muscle associated with a new homoplasmic m.5514A > G transition in the tRNA(Trp) gene. Case 2 was a late infantile presentation who also showed mitochondrial respiratory chain enzyme deficiencies in muscle together with a new m.1643A > G tRNA(Val) mutation in homoplasmy. Case 3 showed a MERRF phenotype presented in childhood associated with the once previously reported m.15923A > G mutation in heteroplasmy in all the tissues studied.