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BACKGROUND: The impact of the coronavirus disease 2019 (COVID-19) pandemic on mental health is still being unravelled. It is important to identify which individuals are at greatest risk of worsening symptoms. This study aimed to examine changes in depression, anxiety and post-traumatic stress disorder (PTSD) symptoms using prospective and retrospective symptom change assessments, and to find and examine the effect of key risk factors. METHOD: Online questionnaires were administered to 34 465 individuals (aged 16 years or above) in April/May 2020 in the UK, recruited from existing cohorts or via social media. Around one-third (n = 12 718) of included participants had prior diagnoses of depression or anxiety and had completed pre-pandemic mental health assessments (between September 2018 and February 2020), allowing prospective investigation of symptom change. RESULTS: Prospective symptom analyses showed small decreases in depression (PHQ-9: -0.43 points) and anxiety [generalised anxiety disorder scale - 7 items (GAD)-7: -0.33 points] and increases in PTSD (PCL-6: 0.22 points). Conversely, retrospective symptom analyses demonstrated significant large increases (PHQ-9: 2.40; GAD-7 = 1.97), with 55% reported worsening mental health since the beginning of the pandemic on a global change rating. Across both prospective and retrospective measures of symptom change, worsening depression, anxiety and PTSD symptoms were associated with prior mental health diagnoses, female gender, young age and unemployed/student status. CONCLUSIONS: We highlight the effect of prior mental health diagnoses on worsening mental health during the pandemic and confirm previously reported sociodemographic risk factors. Discrepancies between prospective and retrospective measures of changes in mental health may be related to recall bias-related underestimation of prior symptom severity.
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COVID-19 , Trastornos por Estrés Postraumático , Femenino , Humanos , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/psicología , COVID-19/epidemiología , Pandemias , Depresión/psicología , Estudios Retrospectivos , Estudios Prospectivos , SARS-CoV-2 , Ansiedad/psicología , Reino Unido/epidemiologíaRESUMEN
AIMS: Neuroferritinopathy (NF) or hereditary ferritinopathy (HF) is an autosomal dominant movement disorder due to mutation in the light chain of the iron storage protein ferritin (FTL). HF is the only late-onset neurodegeneration with brain iron accumulation disorder and study of HF offers a unique opportunity to understand the role of iron in more common neurodegenerative syndromes. METHODS: We carried out pathological and biochemical studies of six individuals with the same pathogenic FTL mutation. RESULTS: CNS pathological changes were most prominent in the basal ganglia and cerebellar dentate, echoing the normal pattern of brain iron accumulation. Accumulation of ferritin and iron was conspicuous in cells with a phenotype suggesting oligodendrocytes, with accompanying neuronal pathology and neuronal loss. Neurons still survived, however, despite extensive adjacent glial iron deposition, suggesting neuronal loss is a downstream event. Typical age-related neurodegenerative pathology was not normally present. Uniquely, the extensive aggregates of ubiquitinated ferritin identified indicate that abnormal FTL can aggregate, reflecting the intrinsic ability of FTL to self-assemble. Ferritin aggregates were seen in neuronal and glial nuclei showing parallels with Huntington's disease. There was neither evidence of oxidative stress activation nor any significant mitochondrial pathology in the affected basal ganglia. CONCLUSIONS: HF shows hallmarks of a protein aggregation disorder, in addition to iron accumulation. Degeneration in HF is not accompanied by age-related neurodegenerative pathology and the lack of evidence of oxidative stress and mitochondrial damage suggests that these are not key mediators of neurodegeneration in HF, casting light on other neurodegenerative diseases characterized by iron deposition.
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Apoferritinas/metabolismo , Encéfalo/efectos de los fármacos , Trastornos del Metabolismo del Hierro/metabolismo , Hierro/metabolismo , Distrofias Neuroaxonales/metabolismo , Animales , Apoferritinas/química , Apoferritinas/genética , Encéfalo/patología , Modelos Animales de Enfermedad , Ferritinas/química , Ferritinas/genética , Ferritinas/metabolismo , Humanos , Trastornos del Metabolismo del Hierro/patología , Persona de Mediana Edad , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mutación/genética , Distrofias Neuroaxonales/patología , Enfermedades Neurodegenerativas/patología , Estrés Oxidativo/efectos de los fármacos , Agregado de Proteínas/fisiologíaRESUMEN
The first draft human mitochondrial DNA (mtDNA) sequence was published in 1981, paving the way for two decades of discovery linking mtDNA variation with human disease. Severe pathogenic mutations cause sporadic and inherited rare disorders that often involve the nervous system. However, some mutations cause mild organ-specific phenotypes that have a reduced clinical penetrance, and polymorphic variation of mtDNA is associated with an altered risk of developing several late-onset common human diseases including Parkinson's disease. mtDNA mutations also accumulate during human life and are enriched in affected organs in a number of age-related diseases. Thus, mtDNA contributes to a wide range of human pathologies. For many decades, it has generally been accepted that mtDNA is inherited exclusively down the maternal line in humans. Although recent evidence has challenged this dogma, whole-genome sequencing has identified nuclear-encoded mitochondrial sequences (NUMTs) that can give the false impression of paternally inherited mtDNA. This provides a more likely explanation for recent reports of 'bi-parental inheritance', where the paternal alleles are actually transmitted through the nuclear genome. The presence of both mutated and wild-type variant alleles within the same individual (heteroplasmy) and rapid shifts in allele frequency can lead to offspring with variable severity of disease. In addition, there is emerging evidence that selection can act for and against specific mtDNA variants within the developing germ line, and possibly within developing tissues. Thus, understanding how mtDNA is inherited has far-reaching implications across medicine. There is emerging evidence that this highly dynamic system is amenable to therapeutic manipulation, raising the possibility that we can harness new understanding to prevent and treat rare and common human diseases where mtDNA mutations play a key role.
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ADN Mitocondrial/genética , Enfermedades Mitocondriales/genética , Enfermedades Raras/genética , Genoma Mitocondrial/genética , Humanos , Mutación/genética , Enfermedades Raras/diagnósticoRESUMEN
This Article was originally published under Nature Research's License to Publish, but has now been made available under a [CC BY 4.0] license. The PDF and HTML versions of the Article have been modified accordingly.
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Having excluded common structural, inflammatory and vascular causes of a spastic paraparesis, the diagnostic yield of further clinical investigations is low. Here, we show that testing for rare metabolic and genetic causes can have important implications for both the patient and their family.
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Transportadoras de Casetes de Unión a ATP/genética , Paraparesia Espástica/genética , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , LinajeRESUMEN
Mitochondrila DNA (mtDNA) is the only extrachromosomal DNA in humans. It is a small (16.5 kb) genome which encodes 13 essential peptides of the respiratory chain, two rRNAs and 22 tRNAs. Defects of this genome are now recognized as important causes of disease and may take the form of point mutations or rearrangements. There is no effective treatment for patients with mtDNA mutations. In the majority of patients with mtDNA defects, both mutant and wild-type molecules are present in the same cell-a phenomenon known as intracellular heteroplasmy. In addition, in the presence of heteroplasmy there is a threshold whereby a certain level of mutant mtDNA is necessary before the disease becomes biochemically and clinically apparent. Based on the presence of heteroplasmy and the recessive nature of these mutations, we believe it will be possible to treat patients by selectively inhibiting the replication of the mutant mtDNA, thereby allowing propagation of only the wild-type molecule. To confirm the validity of such an approach we synthesised peptide nucleic acids (PNAs) complementary to human mtDNA templates containing a deletion breakpoint or single base mutation, both mutations well documented to cause disease. Using an in vitro replication run-off assay under physiological conditions, the antigenomic PNAs specifically inhibited replication of mutant but not wild-type mtDNA templates. Furthermore, we have shown uptake of these PNAs into cultured human myoblasts. We believe that we have therefore established the potential value of antigenomic PNA therapy for patients with heteroplasmic mtDNA disorders.
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Replicación del ADN/efectos de los fármacos , ADN Mitocondrial/efectos de los fármacos , Oligodesoxirribonucleótidos/farmacología , Péptidos/farmacología , Línea Celular , ADN Mitocondrial/biosíntesis , ADN de Cadena Simple/biosíntesis , ADN de Cadena Simple/efectos de los fármacos , Depresión Química , Diseño de Fármacos , Humanos , Síndrome MERRF/genética , Síndrome MERRF/patología , Mitocondrias Musculares/química , Moldes GenéticosRESUMEN
We describe here a previously unknown, dominantly inherited, late-onset basal ganglia disease, variably presenting with extrapyramidal features similar to those of Huntington's disease (HD) or parkinsonism. We mapped the disorder, by linkage analysis, to 19q13.3, which contains the gene for ferritin light polypeptide (FTL). We found an adenine insertion at position 460-461 that is predicted to alter carboxy-terminal residues of the gene product. Brain histochemistry disclosed abnormal aggregates of ferritin and iron. Low serum ferritin levels also characterized patients. Ferritin, the main iron storage protein, is composed of 24 subunits of two types (heavy, H and light, L) which form a soluble, hollow sphere. Brain iron deposition increases normally with age, especially in the basal ganglia, and is a suspected causative factor in several neurodegenerative diseases in which it correlates with visible pathology, possibly by its involvement in toxic free-radical reactions. We found the same mutation in five apparently unrelated subjects with similar extrapyramidal symptoms. An abnormality in ferritin strongly indicates a primary function for iron in the pathogenesis of this new disease, for which we propose the name 'neuroferritinopathy'.
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Enfermedades de los Ganglios Basales/genética , Ferritinas/genética , Genes Dominantes/genética , Mutación , Subunidades de Proteína , Adulto , Edad de Inicio , Enfermedades de los Ganglios Basales/diagnóstico , Enfermedades de los Ganglios Basales/epidemiología , Secuencia de Bases , Encéfalo/patología , Cromosomas Humanos Par 19/genética , Análisis Mutacional de ADN , Femenino , Ferritinas/metabolismo , Efecto Fundador , Ligamiento Genético , Globo Pálido/metabolismo , Globo Pálido/patología , Humanos , Hierro/metabolismo , Escala de Lod , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Linaje , Homología de Secuencia de Aminoácido , Terminología como AsuntoRESUMEN
Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal 'dominant optic atrophy plus' variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44-6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08-4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment.
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Enfermedades del Sistema Nervioso Central/complicaciones , GTP Fosfohidrolasas/genética , Atrofia Óptica Autosómica Dominante/complicaciones , Adolescente , Adulto , Anciano , Enfermedades del Sistema Nervioso Central/genética , Enfermedades del Sistema Nervioso Central/metabolismo , Enfermedades del Sistema Nervioso Central/patología , Niño , Estudios de Cohortes , ADN Mitocondrial/análisis , ADN Mitocondrial/genética , Familia , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Mutación , Atrofia Óptica Autosómica Dominante/genética , Atrofia Óptica Autosómica Dominante/metabolismo , Atrofia Óptica Autosómica Dominante/patología , Fenotipo , Adulto JovenRESUMEN
BACKGROUND: Primary open angle glaucoma is a progressive optic neuropathy characterised by the selective loss of retinal ganglion cells, pathological optic disc cupping and visual field defects. The OPA1 gene encodes an inner mitochondrial membrane protein crucial for normal mitochondrial function, and pathogenic mutations cause autosomal dominant optic atrophy by specifically targeting retinal ganglion cells. This raises the distinct possibility that more subtle genetic variations in OPA1 could alter the risk of developing glaucoma. METHODS: 137 patients with primary open angle glaucoma (67 patients with high-tension glaucoma (HTG), 70 patients with normal-tension glaucoma (NTG)) and 75 controls from the North East of England were studied. Three single-nucleotide polymorphisms in intron 8 (IVS8+4c-->t and IVS8+32t-->c) and exon 4 (c.473A-->G) of the OPA1 gene were genotyped in the study group. In addition, the entire OPA1 coding region was sequenced in 24 individuals with the CT/TT compound genotype using standard BigDye chemistries. RESULTS: There was no difference in either allele or genotype frequency for the IVS8+32t-->c single-nucleotide polymorphisms between patients and controls, but there was a significant association between the T allele at IVS8+4c-->t and the risk of developing NTG (OR=2.04, 95% CI=1.10 to 3.81, p=0.004), but not HTG. Logistic regression analysis also confirmed a strong association between the CT/TT compound genotype at IVS8+4 and IVS8+32 with NTG (OR=29.75, 95% CI=3.83 to 231.21, p=0.001). CONCLUSIONS: The CT/TT compound genotype at IVS8+4 and IVS8+32 is a strong genetic risk determinant for NTG but not HTG.
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GTP Fosfohidrolasas/genética , Glaucoma de Ángulo Abierto/genética , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Intrones , Modelos Logísticos , Datos de Secuencia Molecular , Polimorfismo de Nucleótido Simple , Alineación de SecuenciaRESUMEN
BACKGROUND: Genomic copy number variants have been shown to be responsible for multiple genetic diseases. Recently, a duplication in septin 9 (SEPT9) was shown to be causal for hereditary neuralgic amyotrophy (HNA), an episodic peripheral neuropathy with autosomal dominant inheritance. This duplication was identified in 12 pedigrees that all shared a common founder haplotype. METHODS AND RESULTS: Based on array comparative genomic hybridisation, we identified six additional heterogeneous tandem SEPT9 duplications in patients with HNA that did not possess the founder haplotype. Five of these novel duplications are intragenic and result in larger transcript and protein products, as demonstrated through reverse transcription-PCR and western blotting. One duplication spans the entire SEPT9 gene and does not generate aberrant transcripts and proteins. The breakpoints of all the duplications are unique and contain regions of microhomology ranging from 2 to 9 bp in size. The duplicated regions contain a conserved 645 bp exon within SEPT9 in which HNA-linked missense mutations have been previously identified, suggesting that the region encoded by this exon is important to the pathogenesis of HNA. CONCLUSIONS: Together with the previously identified founder duplication, a total of seven heterogeneous SEPT9 duplications have been identified in this study as a causative factor of HNA. These duplications account for one third of the patients in our cohort, suggesting that duplications of various sizes within the SEPT9 gene are a common cause of HNA.
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Neuritis del Plexo Braquial/enzimología , Neuritis del Plexo Braquial/genética , Duplicación Cromosómica/genética , Septinas/genética , Emparejamiento Base/genética , Secuencia de Bases , Análisis Mutacional de ADN , Exones/genética , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , RecurrenciaRESUMEN
A 39-year-old woman presented to the neurology clinic with an abnormal gait. Subsequent investigations confirmed a rare neurodegenerative disease. This case highlights the key clinical features and diagnostic approach to neuroferritinopathy, and describes the discovery of the disease in a family from Cumbria in the north west of England.
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Enfermedades de los Ganglios Basales/diagnóstico , Distonía/etiología , Trastornos Neurológicos de la Marcha/etiología , Trastornos del Metabolismo del Hierro/diagnóstico , Adulto , Enfermedades de los Ganglios Basales/complicaciones , Enfermedades de los Ganglios Basales/genética , Enfermedades de los Ganglios Basales/patología , Distonía/genética , Distonía/patología , Femenino , Trastornos Neurológicos de la Marcha/genética , Trastornos Neurológicos de la Marcha/patología , Humanos , Trastornos del Metabolismo del Hierro/complicaciones , Trastornos del Metabolismo del Hierro/genética , Trastornos del Metabolismo del Hierro/patología , Distrofias Neuroaxonales/complicaciones , Distrofias Neuroaxonales/diagnóstico , Distrofias Neuroaxonales/genética , Distrofias Neuroaxonales/patologíaRESUMEN
Mitochondrial DNA mutations cause disease in >1 in 5000 of the population, and approximately 1 in 200 of the population are asymptomatic carriers of a pathogenic mtDNA mutation. Many patients with these pathogenic mtDNA mutations present with a progressive, disabling neurological syndrome that leads to major disability and premature death. There is currently no effective treatment for mitochondrial disorders, placing great emphasis on preventing the transmission of these diseases. An empiric approach can be used to guide genetic counseling for common mtDNA mutations, but many families transmit rare or unique molecular defects. There is therefore a pressing need to develop techniques to prevent transmission based on a solid understanding of the biological mechanisms. Several recent studies have cast new light on the genetics and cell biology of mtDNA inheritance, but these studies have also raised new controversies. Here we compare and contrast these findings and discuss their relevance for the transmission of human mtDNA diseases.
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ADN Mitocondrial/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Mitocondriales/genética , Mutación/genética , Animales , HumanosRESUMEN
Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA) are the two most common inherited optic neuropathies and they result in significant visual morbidity among young adults. Both disorders are the result of mitochondrial dysfunction: LHON from primary mitochondrial DNA (mtDNA) mutations affecting the respiratory chain complexes; and the majority of DOA families have mutations in the OPA1 gene, which codes for an inner mitochondrial membrane protein critical for mtDNA maintenance and oxidative phosphorylation. Additional genetic and environmental factors modulate the penetrance of LHON, and the same is likely to be the case for DOA which has a markedly variable clinical phenotype. The selective vulnerability of retinal ganglion cells (RGCs) is a key pathological feature and understanding the fundamental mechanisms that underlie RGC loss in these disorders is a prerequisite for the development of effective therapeutic strategies which are currently limited.
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Atrofia Óptica Autosómica Dominante , Atrofia Óptica Hereditaria de Leber , ADN Mitocondrial , Femenino , GTP Fosfohidrolasas/genética , Humanos , Masculino , Atrofia Óptica Autosómica Dominante/diagnóstico , Atrofia Óptica Autosómica Dominante/epidemiología , Atrofia Óptica Autosómica Dominante/genética , Atrofia Óptica Autosómica Dominante/patología , Atrofia Óptica Hereditaria de Leber/diagnóstico , Atrofia Óptica Hereditaria de Leber/epidemiología , Atrofia Óptica Hereditaria de Leber/genética , Atrofia Óptica Hereditaria de Leber/patología , Mutación PuntualRESUMEN
BACKGROUND: Insulin resistance and hyperglycaemia are common in severe sepsis. Mitochondrial uncoupling protein 2 (UCP2) plays a role in insulin release and sensitivity. OBJECTIVES: To determine if a common, functional polymorphism in the UCP2 gene promoter region (the -866 G/A polymorphism) contributes to the risk of hyperglycaemia in severe sepsis. RESULTS: In the prospective group 120 non-diabetic patients who were carriers of the G allele had significantly higher maximum blood glucose recordings than non-carriers (mean (SD) AA 8.5 (2.2) mmol/l; GA 8.5 (2.4) mmol/l; GG 10.1 (3.1) mmol/l; p = 0.0042) and required significantly more insulin to maintain target blood glucose (p = 0.0007). In the retrospective study 103 non-diabetic patients showed a similar relationship between maximum glucose and UCP genotype (AA 6.8 (2.3) mmol/l; GA 7.8 (2.2) mmol/l; GG 9.2 (2.9) mmol/l; p = 0.0078). CONCLUSIONS: A common, functional polymorphism in the promoter region of the UCP2 gene is associated with hyperglycaemia and insulin resistance in severe sepsis. This has implications for our understanding of the genetic pathophysiology of sepsis and is of use in the stratification of patients for more intensive management.
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Hiperglucemia/genética , Canales Iónicos/genética , Proteínas Mitocondriales/genética , Sepsis/genética , Estrés Fisiológico/genética , Adulto , Anciano , Glucemia/genética , Femenino , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Hiperglucemia/complicaciones , Hiperglucemia/epidemiología , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Regiones Promotoras Genéticas , Estudios Prospectivos , Estudios Retrospectivos , Sepsis/complicaciones , Proteína Desacopladora 2RESUMEN
BACKGROUND: The POLG1 gene encodes the catalytic subunit of DNA polymerase gamma, essential for mitochondrial DNA replication and repair. Mutations in POLG1 have been linked to a spectrum of clinical phenotypes, and may account for up to 25% of all adult presentations of mitochondrial disease. METHODS AND RESULTS: We present 14 patients, with characteristic features of mitochondrial disease including progressive external ophthalmoplegia (PEO) and Alpers-Huttenlocher syndrome and laboratory findings indicative of mitochondrial dysfunction, including cytochrome c oxidase (COX) deficiency and multiple deletions or depletion of the mitochondrial DNA. Four novel POLG1 missense substitutions (p.R597W, p.L605R, p.G746S, p.A862T), are described, together with the first adult patient with a recently described polymerase domain mutation (p.R1047W). All novel changes were rare in a control population and affected highly conserved amino acids. CONCLUSION: The addition of these substitutions-including the first report of a dinucleotide mutation (c.1814_1815TT>GC)-to the growing list of defects further confirms the importance of POLG1 mutations as the underlying abnormality in a range of neurological presentations.
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ADN Polimerasa Dirigida por ADN/genética , Enfermedades Mitocondriales/genética , Adolescente , Adulto , Niño , Deficiencia de Citocromo-c Oxidasa/genética , Deficiencia de Citocromo-c Oxidasa/patología , ADN Polimerasa gamma , Esclerosis Cerebral Difusa de Schilder/genética , Esclerosis Cerebral Difusa de Schilder/patología , Femenino , Humanos , Lactante , Hígado/ultraestructura , Masculino , Persona de Mediana Edad , Enfermedades Mitocondriales/patología , Músculo Esquelético/ultraestructura , Mutación Missense , Oftalmoplejía Externa Progresiva Crónica/genética , Oftalmoplejía Externa Progresiva Crónica/patología , Alineación de SecuenciaAsunto(s)
Atrofia Óptica Hereditaria de Leber/tratamiento farmacológico , Ubiquinona/análogos & derivados , Adolescente , Adulto , Anciano , Estudios de Cohortes , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Atrofia Óptica Hereditaria de Leber/epidemiología , Atrofia Óptica Hereditaria de Leber/fisiopatología , Factores de Tiempo , Resultado del Tratamiento , Ubiquinona/farmacología , Ubiquinona/uso terapéutico , Agudeza Visual/efectos de los fármacos , Agudeza Visual/fisiología , Adulto JovenRESUMEN
The m.8993T-->C MTATP6 mutation of mitochondrial DNA (mtDNA) usually causes mitochondrial disease in childhood, but was recently described in a family with adult onset ataxia and polyneuropathy. Cytochrome c oxidase muscle histochemistry, which is the standard clinical investigation for mitochondrial disease in adults, is usually normal in patients with MTATP6 mutations. This raises the possibility that these cases have been missed in the past. We therefore studied 308 patients with unexplained ataxia and 96 patients with suspected Charcot-Marie-Tooth disease to determine whether the m.8993T-->C MTATP6 mutation is common in unexplained inherited ataxia and/or polyneuropathy. We identified a three-generation family with the m.8993T-->C mutation of mtDNA. One subject had episodic ataxia (EA) and transient hemipareses, broadening the phenotype. However, no further cases were identified in an additional cohort of 191 patients with suspected EA. In conclusion, m.8993T-->C MTATP6 should be considered in patients with unexplained ataxia, CMT or EA, but cases are uncommon.
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Neuropatía Hereditaria Motora y Sensorial/genética , Enfermedades Mitocondriales/genética , ATPasas de Translocación de Protón Mitocondriales/genética , Mutación Missense , Paresia/genética , Mutación Puntual , Degeneraciones Espinocerebelosas/genética , Adulto , Anciano , Enfermedad de Charcot-Marie-Tooth/genética , Estudios de Cohortes , ADN Mitocondrial/genética , Disartria/genética , Femenino , Heterogeneidad Genética , Neuropatía Hereditaria Motora y Sensorial/diagnóstico , Humanos , Persona de Mediana Edad , ATPasas de Translocación de Protón Mitocondriales/deficiencia , Trastornos de la Motilidad Ocular/genética , Linaje , PeriodicidadRESUMEN
Mitochondria play a central role in the secretion of insulin by pancreatic beta-cells, and pathogenic mutations of mitochondrial DNA (mtDNA) can cause diabetes. The aetiology of type 2 diabetes has a strong genetic component, raising the possibility that genetic variants of mtDNA alter the risk of developing the disorder. Recent studies have produced conflicting results. By studying 897 UK cases of type 2 diabetes and 1010 population-matched controls, it is shown that European mtDNA haplogroups are unlikely to play a major role in the risk of developing the disorder.
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ADN Mitocondrial/genética , Diabetes Mellitus Tipo 2/genética , Haplotipos , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Persona de Mediana Edad , Reino Unido , Población Blanca/genéticaRESUMEN
PURPOSE: Leber hereditary optic neuropathy (LHON) is recognized as the most common cause of isolated blindness in young men. The current study was designed to test whether LHON as a mitochondrial disease is associated with vascular functional alterations characterized by aortic elastic properties during echocardiography. METHODS: A total of 19 patients with typical features of LHON aged 42+/-13 years (10 males) were included. Their results were compared to 19 age- and gender-matched healthy controls. Aortic stiffness index was calculated from the echocardiographically derived aortic diameters and the clinical blood pressure data. RESULTS: In this patient population, the point mutation was present in 3460G>A position in five cases, in 11778G>A position in five cases, and in 14484T>C position in nine patients. Diastolic aortic diameter (26.0+/-2.5 mm vs 28.4+/-4.1 mm, p<0.05) and aortic stiffness index (5.1+/-2.6 vs 12.0+/-7.9, p<0.05) were significantly increased in LHON patients compared to controls. CONCLUSIONS: Aortic stiffness can be increased in LHON disease, but further studies are warranted to confirm these findings in a larger LHON patient population with a more reliable method focusing on the pathophysiologic background.