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1.
J Neurol ; 269(12): 6555-6565, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35980466

RESUMO

OBJECTIVES: To assess natural history and 12-month change of a series of scales and functional outcome measures in a cohort of 117 patients with primary mitochondrial myopathy (PMM). METHODS: Twelve months follow-up data of 117 patients with PMM were collected. We analysed the 6-min walk test (6MWT), timed up-and-go test (× 3) (3TUG), five-times sit-to-stand test (5XSST), timed water swallow test (TWST), and test of masticating and swallowing solids (TOMASS) as functional outcome measures; the Fatigue Severity Scale and West Haven-Yale Multidimensional pain inventory as patient-reported outcome measures. PMM patients were divided into three phenotypic categories: mitochondrial myopathy (MiMy) without extraocular muscles involvement, pure chronic progressive external ophthalmoplegia (PEO) and PEO&MiMy. As 6MWT is recognized to have significant test-retest variability, we calculated MCID (minimal clinically important difference) as one third of baseline 6 min walking distance (6MWD) standard deviation. RESULTS: At 12-month follow-up, 3TUG, 5XSST and FSS were stable, while TWST and the perceived pain severity (WHYMPI) worsened. 6MWD significantly increased in the entire cohort, especially in the higher percentiles and in PEO patients, while was substantially stable in the lower percentile (< 408 m) and MiMy patients. This increase in 6MWD was considered not significant, as inferior to MCID (33.3 m). NMDAS total score showed a slight but significant decline at 12 months (0.9 point). The perceived pain severity significantly worsened. Patients with PEO performed better in functional measures than patients with PEO&MiMy or MiMy, and had lower values of NMDAS. CONCLUSIONS: PMM patients showed a slow global decline valued by NMDAS at 12 months; 6MWT was a more reliable measurement below 408 m, substantially stable at 12 months. PEO patients had better motor performance and lower NMDAS than PEO&MiMy and MiMy also at 12 months of follow-up.


Assuntos
Miopatias Mitocondriais , Oftalmoplegia Externa Progressiva Crônica , Humanos , Seguimentos , Teste de Caminhada/métodos , Miopatias Mitocondriais/complicações , Miopatias Mitocondriais/diagnóstico , Fatores de Tempo , Caminhada
2.
J Neurol ; 269(3): 1413-1421, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34259909

RESUMO

INTRODUCTION: Both prevalence and clinical features of the various movement disorders in adults with primary mitochondrial diseases are unknown. METHODS: Based on the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases", we reviewed the clinical, genetic, neuroimaging and neurophysiological data of adult patients with primary mitochondrial diseases (n = 764) where ataxia, myoclonus or other movement disorders were part of the clinical phenotype. RESULTS: Ataxia, myoclonus and movement disorders were present in 105/764 adults (13.7%), with the onset coinciding or preceding the diagnosis of the mitochondrial disease in 49/105 (46.7%). Ataxia and parkinsonism were the most represented, with an overall prevalence at last follow-up of 59.1% and 30.5%, respectively. Hyperkinetic movement disorders were reported in 15.3% at last follow-up, being the less common reported movement disorders. The pathogenic m.8344A > G and POLG variants were always associated with a movement disorder, while LHON variants and mtDNA single deletions were more commonly found in the subjects who did not present a movement disorder. The most common neuroimaging features were cortical and/or cerebellar atrophy, white matter hyperintensities, basal ganglia abnormalities and nigro-striatal degeneration. Almost 70% of patients with parkinsonism responded to dopaminergic therapy, mainly levodopa, and 50% with myoclonus were successfully treated with levetiracetam. CONCLUSION: Movement disorders, mainly ataxia and parkinsonism, are important findings in adult primary mitochondrial diseases. This study underlies the importance of looking for a mitochondrial etiology in the diagnostic flowchart of a movement disorder and may help direct genetic screening in daily practice.


Assuntos
Doenças Mitocondriais , Transtornos dos Movimentos , Mioclonia , Transtornos Parkinsonianos , Humanos , Doenças Mitocondriais/complicações , Doenças Mitocondriais/epidemiologia , Doenças Mitocondriais/genética , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/epidemiologia , Transtornos dos Movimentos/genética , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/epidemiologia , Transtornos Parkinsonianos/genética , Fenótipo
3.
Radiat Prot Dosimetry ; 191(2): 125-128, 2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33125499

RESUMO

The estimation of the indoor radon exposure of the population of a country is generally carried out by the means of surveys designed in order to have sample representativeness as a target (population-based survey). However, the estimates of radon concentration distributions could be affected by biases if sampling was not random or in case of differences between sample and target population characteristics. In this work, we performed a preliminary check of the representativeness of the sample used for the second Italian national survey aimed to evaluate radon concentration distribution in each Province. We found that sampled dwellings are mostly located in the main administrative centres, where average radon concentration is generally lower, as compared with the other towns of the Province. The potential source of bias identified in this work suggests to carefully control the occurrence of a sampling imbalance between 'main' cities and other cities of Province and to take it into account in data analysis.


Assuntos
Poluentes Radioativos do Ar , Poluição do Ar em Ambientes Fechados , Monitoramento de Radiação , Radônio , Poluentes Radioativos do Ar/análise , Poluição do Ar em Ambientes Fechados/análise , Cidades , Habitação , Radônio/análise
4.
J Intern Med ; 287(6): 592-608, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32463135

RESUMO

Mitochondrial medicine is a field that expanded exponentially in the last 30 years. Individually rare, mitochondrial diseases as a whole are probably the most frequent genetic disorder in adults. The complexity of their genotype-phenotype correlation, in terms of penetrance and clinical expressivity, natural history and diagnostic algorithm derives from the dual genetic determination. In fact, in addition to the about 1.500 genes encoding mitochondrial proteins that reside in the nuclear genome (nDNA), we have the 13 proteins encoded by the mitochondrial genome (mtDNA), for which 22 specific tRNAs and 2 rRNAs are also needed. Thus, besides Mendelian genetics, we need to consider all peculiarities of how mtDNA is inherited, maintained and expressed to fully understand the pathogenic mechanisms of these disorders. Yet, from the initial restriction to the narrow field of oxidative phosphorylation dysfunction, the landscape of mitochondrial functions impinging on cellular homeostasis, driving life and death, is impressively enlarged. Finally, from the clinical standpoint, starting from the neuromuscular field, where brain and skeletal muscle were the primary targets of mitochondrial dysfunction as energy-dependent tissues, after three decades virtually any subspecialty of medicine is now involved. We will summarize the key clinical pictures and pathogenic mechanisms of mitochondrial diseases in adults.


Assuntos
Doenças Mitocondriais/genética , Adulto , Reparo do DNA/genética , DNA Mitocondrial/genética , Genoma Mitocondrial/genética , Humanos , Síndrome MELAS/diagnóstico , Síndrome MELAS/genética , Mitocôndrias/genética , Mitocôndrias/metabolismo , Doenças Mitocondriais/diagnóstico , Mutação/genética
5.
BMC Neurol ; 19(1): 350, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31888524

RESUMO

INTRODUCTION: Charles Bonnet syndrome is characterized by simple or complex visual hallucinations (VH) due to damage along the visual pathways. We report a functional MRI study of brain correlates of VH in the context of a severe optic atrophy in a patient with Leber's Hereditary Optic Neuropathy (LHON). CASE REPORT: A 62-year-old man was diagnosed with LHON (11778/ND4 mtDNA mutation) after subacute visual loss in left eye (right eye was amblyopic). One month later, he experienced VH of a few seconds consisting in "moving red and blue miniature cartoons". One year later VH content changed in colored mosaic (10-15 s duration), usually stress-related, and blue and white flashes (2-5 s), triggered by unexpected auditory stimuli. Audiometry revealed mild sensorineural hearing loss. Three block design functional MRI paradigms were administrated: 1) random "clap", 2) "checkerboard" and 3) non-random "beep". After random "claps" simple flashes were evoked with bilateral activation of primary and secondary visual cortex, cuneus, precuneus and insula. Neither hallucinations nor cortex activation were registered after "checkerboard" stimulation, due to the severe visual impairment. Primary and secondary auditory cortices were "beep"-activated, without eliciting VH by non-random "beep". CONCLUSIONS: The peculiarity of our case is that VH were triggered by random auditory stimuli, possibly due to a cross-modal plasticity between visual and auditory networks, likely influenced by the sensorineural deafness. Functional alterations of both networks in resting conditions have been demonstrated in LHON patients, even without an auditory deficit. Finally, the absence of VH triggered by expected stimuli is consistent with the "expectation suppression theory", based on increased neural activations after unexpected but not by predicted events.


Assuntos
Córtex Cerebral/fisiopatologia , Síndrome de Charles Bonnet/complicações , Síndrome de Charles Bonnet/fisiopatologia , Atrofia Óptica Hereditária de Leber/complicações , Estimulação Acústica , Adulto , DNA Mitocondrial/genética , Neuroimagem Funcional , Alucinações/complicações , Alucinações/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , NADH Desidrogenase/genética , Atrofia Óptica Hereditária de Leber/genética , Transtornos da Visão/complicações
6.
AJNR Am J Neuroradiol ; 39(3): 427-434, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29348134

RESUMO

BACKGROUND AND PURPOSE: Mitochondrial neurogastrointestinal encephalopathy is a rare disorder due to recessive mutations in the thymidine phosphorylase gene, encoding thymidine phosphorylase protein required for mitochondrial DNA replication. Clinical manifestations include gastrointestinal dysmotility and diffuse asymptomatic leukoencephalopathy. This study aimed to elucidate the mechanisms underlying brain leukoencephalopathy in patients with mitochondrial neurogastrointestinal encephalopathy by correlating multimodal neuroradiologic features to postmortem pathology. MATERIALS AND METHODS: Seven patients underwent brain MR imaging, including single-voxel proton MR spectroscopy and diffusion imaging. Absolute concentrations of metabolites calculated by acquiring unsuppressed water spectra at multiple TEs, along with diffusion metrics based on the tensor model, were compared with those of healthy controls using unpaired t tests in multiple white matters regions. Brain postmortem histologic, immunohistochemical, and molecular analyses were performed in 1 patient. RESULTS: All patients showed bilateral and nearly symmetric cerebral white matter hyperintensities on T2-weighted images, extending to the cerebellar white matter and brain stem in 4. White matter, N-acetylaspartate, creatine, and choline concentrations were significantly reduced compared with those in controls, with a prominent increase in the radial water diffusivity component. At postmortem examination, severe fibrosis of brain vessel smooth muscle was evident, along with mitochondrial DNA replication depletion in brain and vascular smooth-muscle and endothelial cells, without neuronal loss, myelin damage, or gliosis. Prominent periependymal cytochrome C oxidase deficiency was also observed. CONCLUSIONS: Vascular functional and histologic alterations account for leukoencephalopathy in mitochondrial neurogastrointestinal encephalopathy. Thymidine toxicity and mitochondrial DNA replication depletion may induce microangiopathy and blood-brain-barrier dysfunction, leading to increased water content in the white matter. Periependymal cytochrome C oxidase deficiency could explain prominent periventricular impairment.


Assuntos
Doenças de Pequenos Vasos Cerebrais/patologia , Leucoencefalopatias/patologia , Mitocôndrias/patologia , Encefalomiopatias Mitocondriais/patologia , Adulto , Encéfalo/metabolismo , Encéfalo/patologia , Doenças de Pequenos Vasos Cerebrais/etiologia , Doenças de Pequenos Vasos Cerebrais/metabolismo , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Leucoencefalopatias/etiologia , Leucoencefalopatias/metabolismo , Masculino , Mitocôndrias/metabolismo , Encefalomiopatias Mitocondriais/complicações , Encefalomiopatias Mitocondriais/metabolismo
7.
J Neurol ; 264(8): 1777-1784, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28695364

RESUMO

Ocular myopathy, typically manifesting as progressive external ophthalmoplegia (PEO), is among the most common mitochondrial phenotypes. The purpose of this study is to better define the clinical phenotypes associated with ocular myopathy. This is a retrospective study on a large cohort from the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases". We distinguished patients with ocular myopathy as part of a multisystem mitochondrial encephalomyopathy (PEO-encephalomyopathy), and then PEO with isolated ocular myopathy from PEO-plus when PEO was associated with additional features of multisystemic involvement. Ocular myopathy was the most common feature in our cohort of mitochondrial patients. Among the 722 patients with a definite genetic diagnosis, ocular myopathy was observed in 399 subjects (55.3%) and was positively associated with mtDNA single deletions and POLG mutations. Ocular myopathy as manifestation of a multisystem mitochondrial encephalomyopathy (PEO-encephalomyopathy, n = 131) was linked to the m.3243A>G mutation, whereas the other "PEO" patients (n = 268) were associated with mtDNA single deletion and Twinkle mutations. Increased lactate was associated with central neurological involvement. We then defined, among the PEO group, as "pure PEO" the patients with isolated ocular myopathy and "PEO-plus" those with ocular myopathy and other features of neuromuscular and multisystem involvement, excluding central nervous system. The male proportion was significantly lower in pure PEO than PEO-plus. This study reinforces the need for research on the role of gender in mitochondrial diseases. The phenotype definitions here revisited may contribute to a more homogeneous patient categorization, useful in future studies and clinical trials.


Assuntos
Oftalmoplegia Externa Progressiva Crônica/genética , Oftalmoplegia Externa Progressiva Crônica/fisiopatologia , Adulto , Idade de Início , DNA Polimerase gama/genética , DNA Mitocondrial , Feminino , GTP Fosfo-Hidrolases/genética , Estudos de Associação Genética , Humanos , Itália , Masculino , Mutação , Oftalmoplegia Externa Progressiva Crônica/diagnóstico , Oftalmoplegia Externa Progressiva Crônica/epidemiologia , Fenótipo , Estudos Retrospectivos , Adulto Jovem
8.
Cell Death Dis ; 6: e2021, 2015 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-26673666

RESUMO

Leber's hereditary optic neuropathy (LHON), the most frequent mitochondrial disease, is associated with mitochondrial DNA (mtDNA) point mutations affecting Complex I subunits, usually homoplasmic. This blinding disorder is characterized by incomplete penetrance, possibly related to several genetic modifying factors. We recently reported that increased mitochondrial biogenesis in unaffected mutation carriers is a compensatory mechanism, which reduces penetrance. Also, environmental factors such as cigarette smoking have been implicated as disease triggers. To investigate this issue further, we first assessed the relationship between cigarette smoke and mtDNA copy number in blood cells from large cohorts of LHON families, finding that smoking was significantly associated with the lowest mtDNA content in affected individuals. To unwrap the mechanism of tobacco toxicity in LHON, we exposed fibroblasts from affected individuals, unaffected mutation carriers and controls to cigarette smoke condensate (CSC). CSC decreased mtDNA copy number in all cells; moreover, it caused significant reduction of ATP level only in mutated cells including carriers. This implies that the bioenergetic compensation in carriers is hampered by exposure to smoke derivatives. We also observed that in untreated cells the level of carbonylated proteins was highest in affected individuals, whereas the level of several detoxifying enzymes was highest in carriers. Thus, carriers are particularly successful in reactive oxygen species (ROS) scavenging capacity. After CSC exposure, the amount of detoxifying enzymes increased in all cells, but carbonylated proteins increased only in LHON mutant cells, mostly from affected individuals. All considered, it appears that exposure to smoke derivatives has a more deleterious effect in affected individuals, whereas carriers are the most efficient in mitigating ROS rather than recovering bioenergetics. Therefore, the identification of genetic modifiers that modulate LHON penetrance must take into account also the exposure to environmental triggers such as tobacco smoke.


Assuntos
DNA Mitocondrial/genética , Atrofia Óptica Hereditária de Leber/etiologia , Espécies Reativas de Oxigênio/metabolismo , Fumar/efeitos adversos , Fumar/genética , DNA Mitocondrial/metabolismo , Feminino , Humanos , Masculino , Atrofia Óptica Hereditária de Leber/genética , Atrofia Óptica Hereditária de Leber/metabolismo , Atrofia Óptica Hereditária de Leber/patologia , Fosforilação Oxidativa , Fumar/metabolismo , Fumar/patologia
9.
AJNR Am J Neuroradiol ; 36(7): 1259-65, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25792533

RESUMO

BACKGROUND AND PURPOSE: Brain white matter is frequently affected in mitochondrial diseases; optic atrophy gene 1-autosomal dominant optic atrophy and Leber hereditary optic neuropathy are the most frequent mitochondrial monosymptomatic optic neuropathies. In this observational study, brain white matter microstructure was characterized by DTI in patients with optic atrophy gene 1-autosomal dominant optic atrophy and Leber hereditary optic neuropathy, in relation to clinical and genetic features. MATERIALS AND METHODS: Nineteen patients with optic atrophy gene 1-autosomal dominant optic atrophy and 17 with Leber hereditary optic neuropathy older than 18 years of age, all genetically diagnosed, and 19 healthy volunteers underwent DTI by using a 1.5T MR imaging scanner and neurologic and ophthalmologic assessments. Brain white matter DTI metrics were calculated for all participants, and, in patients, their correlations with genetics and clinical findings were calculated. RESULTS: Compared with controls, patients with optic atrophy gene 1-autosomal dominant optic atrophy had an increased mean diffusivity in 29.2% of voxels analyzed within major white matter tracts distributed throughout the brain, while fractional anisotropy was reduced in 30.3% of voxels. For patients with Leber hereditary optic neuropathy, the proportion of altered voxels was only 0.5% and 5.5%, respectively, of which half was found within the optic radiation and 3.5%, in the smaller acoustic radiation. In almost all regions, fractional anisotropy diminished with age in patients with optic atrophy gene 1-autosomal dominant optic atrophy and correlated with average retinal nerve fiber layer thickness in several areas. Mean diffusivity increased in those with a missense mutation. Patients with Leber hereditary optic neuropathy taking idebenone had slightly milder changes. CONCLUSIONS: Patients with Leber hereditary optic neuropathy had preferential involvement of the optic and acoustic radiations, consistent with trans-synaptic degeneration, whereas patients with optic atrophy gene 1-autosomal dominant optic atrophy presented with widespread involvement suggestive of a multisystemic, possibly a congenital/developmental, disorder. White matter changes in Leber hereditary optic neuropathy and optic atrophy gene 1-autosomal dominant optic atrophy may be exploitable as biomarkers.


Assuntos
Imagem de Tensor de Difusão , Atrofia Óptica Autossômica Dominante/patologia , Atrofia Óptica Hereditária de Leber/patologia , Substância Branca/patologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
10.
Curr Mol Med ; 14(8): 985-992, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25323873

RESUMO

Over two decades have elapsed since the first mtDNA point mutation was associated with Leber's hereditary optic neuropathy (LHON) in 1988. We have subsequently witnessed a substantial understanding of the molecular basis of hereditary optic neuropathies, as well as of their clinical features and pathogenic mechanisms. It became clear that the large majority of genetic optic neuropathies have a primary or an indirect involvement of mitochondrial functions, justifying the definition of "mitochondrial optic neuropathies". Despite this progress many unsolved features remain to be understood, such as incomplete penetrance and variable clinical expressivity in LHON and dominant optic atrophy (DOA), gender prevalence in LHON, and complex gene/environment interactions in both LHON and DOA. The most recent advancement in our understanding of the molecular basis of mitochondrial optic neuropathies is the topic of this review. In particular, we analyze the role that mitochondrial biogenesis may play in the compensatory mechanisms that underlie incomplete penetrance and clinical expressivity, a scenario relevant for the possible design of future therapeutic approaches.

11.
Indoor Air ; 24(3): 315-26, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24118252

RESUMO

UNLABELLED: In order to optimize the design of a national survey aimed to evaluate radon exposure of children in schools in Serbia, a pilot study was carried out in all the 334 primary schools of 13 municipalities of Southern Serbia. Based on data from passive measurements, rooms with annual radon concentration >300 Bq/m(3) were found in 5% of schools. The mean annual radon concentration weighted with the number of pupils is 73 Bq/m(3), 39% lower than the unweighted 119 Bq/m(3) average concentration. The actual average concentration when children are in classrooms could be substantially lower. Variability between schools (CV = 65%), between floors (CV = 24%) and between rooms at the same floor (CV = 21%) was analyzed. The impact of school location, floor, and room usage on radon concentration was also assessed (with similar results) by univariate and multivariate analyses. On average, radon concentration in schools within towns is a factor of 0.60 lower than in villages and at higher floors is a factor of 0.68 lower than ground floor. Results can be useful for other countries with similar soil and building characteristics. PRACTICAL IMPLICATIONS: On average, radon concentrations are substantially higher in schools in villages than in schools located in towns (double,on average). Annual radon concentrations exceeding 300 Bq/m3 were found in 5% of primary schools (generally on ground floors of schools in villages). The considerable variability of radon concentration observed between and within floors indicates a need to monitor concentrations in several rooms for each floor. A single radon detector for each room can be used provided that the measurement error is considerable lower than variability of radon concentration between rooms.


Assuntos
Poluentes Radioativos do Ar/análise , Radônio/análise , Criança , Humanos , Análise Multivariada , Projetos Piloto , Monitoramento de Radiação/métodos , Análise de Regressão , População Rural , Instituições Acadêmicas , Sérvia , População Urbana
12.
Cell Death Dis ; 4: e663, 2013 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-23764844

RESUMO

Mitochondrial biogenesis is an orchestrated process that presides to the regulation of the organelles homeostasis within a cell. We show that γ-rays, at doses commonly used in the radiation therapy for cancer treatment, induce an increase in mitochondrial mass and function, in response to a genotoxic stress that pushes cells into senescence, in the presence of a functional p53. Although the main effector of the response to γ-rays is the p53-p21 axis, we demonstrated that mitochondrial biogenesis is only indirectly regulated by p53, whose activation triggers a murine double minute 2 (MDM2)-mediated hypoxia-inducible factor 1α (HIF1α) degradation, leading to the release of peroxisome-proliferator activated receptor gamma co-activator 1ß inhibition by HIF1α, thus promoting mitochondrial biogenesis. Mimicking hypoxia by HIF1α stabilization, in fact, blunts the mitochondrial response to γ-rays as well as the induction of p21-mediated cell senescence, indicating prevalence of the hypoxic over the genotoxic response. Finally, we also show in vivo that post-radiotherapy mitochondrial DNA copy number increase well correlates with lack of HIF1α increase in the tissue, concluding this may be a useful molecular tool to infer the trigger of a hypoxic response during radiotherapy, which may lead to failure of activation of cell senescence.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Mitocôndrias/efeitos da radiação , Renovação Mitocondrial , Proteína Supressora de Tumor p53/metabolismo , Sequência de Bases , Sítios de Ligação , Proteínas de Transporte/metabolismo , Forma Celular , Senescência Celular , Variações do Número de Cópias de DNA , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Regulação da Expressão Gênica , Genoma Mitocondrial , Células HCT116 , Humanos , Mitocôndrias/metabolismo , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Regiões Promotoras Genéticas , Estabilidade Proteica , Proteólise , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteínas de Ligação a RNA , Elementos de Resposta , Proteína Supressora de Tumor p53/genética
13.
Eur J Neurol ; 20(1): 198-201, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22436028

RESUMO

BACKGROUND AND PURPOSE: Optic nerve involvement is frequent in mitochondrial disease, and retinal abnormalities are described in Parkinson's disease (PD). METHODS: We evaluated retinal nerve fiber layer (RNFL) thickness by optical coherence tomography in 43 patients with PD and in 86 age-matched controls. We considered separately the eyes ipsilateral and contralateral to the most affected body side in patients with PD. ancova analysis, Pearson test, and multiple regression analysis were used (P < 0.05). RESULTS: Patients with PD showed significantly thinner temporal RNFL thickness compared to controls (P = 0.004), more evident in the eye contralateral to the most affected body side. Average RNFL thickness significantly correlated with age in both controls and patients with PD (P-values ranging from 0.001 to 0.019), whereas in patients with PD RNFL thickness did not correlate with clinical variables. CONCLUSIONS: Our study reveals a loss of retinal nerve fibers in the temporal quadrant in PD, which is typically susceptible in mitochondrial optic neuropathies.


Assuntos
Fibras Nervosas/patologia , Doenças do Nervo Óptico/etiologia , Nervo Óptico/patologia , Doença de Parkinson/complicações , Retina/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteínas Serina-Treonina Quinases/genética , Tomografia de Coerência Óptica
14.
Neuromuscul Disord ; 22 Suppl 3: S226-9, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23182644

RESUMO

Fatigue and exercise intolerance are common symptoms of mitochondrial diseases, but difficult to be clinically assessed. New methods to quantify these rather common complaints are strongly needed in the clinical practice. Coenzyme Q10 administration and aerobic exercise may improve exercise intolerance, but more definite studies are still pending. Herein, we have revised "how to measure" and "how to treat" these symptoms of mitochondrial patients. Subsequently, we reviewed the clinical data of the 1164 confirmed mitochondrial patients present in the Italian nation-wide database of mitochondrial disease, with special regard to exercise intolerance. We observed that more of 20% of mitochondrial patients complain of exercise intolerance. This symptom seems to be frequently associated with specific patient groups and/or genotypes. Ragged red fibers and COX-negative fibers are more often present in subjects with exercise intolerance, whereas lactate levels could not predict this symptom. Multicenter efforts are strongly needed for rare disorders such as mitochondrial diseases, and may represent the basis for more rigorous longitudinal studies.


Assuntos
Exercício Físico/fisiologia , Fadiga , Doenças Mitocondriais , Fadiga/diagnóstico , Fadiga/genética , Humanos , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Mutação/genética , Ubiquinona/análogos & derivados , Ubiquinona/metabolismo
15.
Cell Death Dis ; 2: e222, 2011 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-22030538

RESUMO

Mitochondrial dysfunction often leads to cell death and disease. We can now draw correlations between the dysfunction of one of the most important mitochondrial enzymes, NADH:ubiquinone reductase or complex I, and its structural organization thanks to the recent advances in the X-ray structure of its bacterial homologs. The new structural information on bacterial complex I provide essential clues to finally understand how complex I may work. However, the same information remains difficult to interpret for many scientists working on mitochondrial complex I from different angles, especially in the field of cell death. Here, we present a novel way of interpreting the bacterial structural information in accessible terms. On the basis of the analogy to semi-automatic shotguns, we propose a novel functional model that incorporates recent structural information with previous evidence derived from studies on mitochondrial diseases, as well as functional bioenergetics.


Assuntos
Complexo I de Transporte de Elétrons/metabolismo , Doenças Mitocondriais/patologia , Morte Celular/fisiologia , Complexo I de Transporte de Elétrons/genética , Humanos , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo
16.
Radiat Prot Dosimetry ; 145(2-3): 305-11, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21586545

RESUMO

In an international collaboration, a long-term radon concentration survey was carried out in schools of Southern Serbia with radon detectors prepared, etched and read-out in Italy. In such surveys it is necessary to evaluate measurement precision in field conditions, and to check whether quality assurance protocols were effective in keeping uncertainties under control, despite the complex organisation of measurements. In the first stage of the survey, which involves only some of the total number of municipalities, paired detectors were exposed in each monitored room in order to experimentally assess measurement precision. Paired passive devices (containing CR-39 detectors) were exposed for two consecutive 6-month periods. Two different measurement systems were used to read out CR-39s of the first and second period, respectively. The median of the coefficient of variation (CV) of the measured exposures was 8 % for 232 paired devices of the first 6-month period and 4 % for 242 paired devices of the second 6-month period, respectively. This difference was mainly due to a different track count repeatability of the two read-out systems, which was 4 and 1 %, respectively, as the median value of CV of repeated countings. The in-field measured precision results are very similar to the precision assessed in calibration conditions and are much lower than the room-to-room variation of radon concentration in the monitored schools. Moreover, a quality assurance protocol was followed to reduce extra-exposures during detector transport from Rome to schools measured and back.


Assuntos
Poluentes Radioativos do Ar/análise , Monitoramento de Radiação/normas , Radônio/análise , Humanos , Cooperação Internacional , Instituições Acadêmicas , Sérvia
18.
Neurol Sci ; 31 Suppl 1: S81-2, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20464590

RESUMO

Headache is one of the most common health complaints in children and adolescents. The initial assessment of acute headache aims to recognize whether there is a secondary cause for headache. According to the literature, the secondary headaches due to non-life-threatening diseases are the most frequent ones in pediatrics. In particular, respiratory tract infections and minor head trauma represent the majority. In a small minority of patients, headache is secondary to serious life-threatening intracranial disorders. Meningitis is the most common cause of headache due to serious neurological condition. These patients do not constitute a diagnostic problem, as they usually have clear systemic and neurological signs of intracranial hypertension. Recent onset of headache attacks, occipital location of pain, patient's inability to describe headache characteristics seem frequently recur, together with neurological signs, in intracranial life-threatening conditions.


Assuntos
Transtornos da Cefaleia Secundários/diagnóstico , Transtornos da Cefaleia Secundários/epidemiologia , Adolescente , Fatores Etários , Criança , Diagnóstico Diferencial , Humanos , Exame Neurológico , Prevalência , Inquéritos e Questionários
19.
Brain ; 133(Pt 3): 771-86, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20157015

RESUMO

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.


Assuntos
Doenças do Sistema Nervoso Central/complicações , GTP Fosfo-Hidrolases/genética , Atrofia Óptica Autossômica Dominante/complicações , Adolescente , Adulto , Idoso , Doenças do Sistema Nervoso Central/genética , Doenças do Sistema Nervoso Central/metabolismo , Doenças do Sistema Nervoso Central/patologia , Criança , Estudos de Coortes , DNA Mitocondrial/análise , DNA Mitocondrial/genética , Família , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Mutação , Atrofia Óptica Autossômica Dominante/genética , Atrofia Óptica Autossômica Dominante/metabolismo , Atrofia Óptica Autossômica Dominante/patologia , Fenótipo , Adulto Jovem
20.
Vis Neurosci ; 25(3): 469-74, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18598420

RESUMO

We examined achromatic contrast discrimination in asymptomatic carriers of 11778 Leber's hereditary optic neuropathy (LHON 18 controls) and 18 age-match were also tested. To evaluate magnocellular (MC) and Parvocellular (PC) contrast discrimination, we used a version of Pokorny and Smith's (1997) pulsed/steady-pedestal paradigms (PPP/SPP) thought to be detected via PC and MC pathways, respectively. A luminance pedestal (four 1 degree x 1 degree squares) was presented on a 12 cd/m2 surround. The luminance of one of the squares (trial square, TS) was randomly incremented for either 17 or 133 ms. Observers had to detect the TS, in a forced-choice task, at each duration, for three pedestal levels: 7, 12, 19 cd/m2. In the SPP, the pedestal was fixed, and the TS was modulated. For the PPP, all four pedestal squares pulsed for 17 or 133 ms, and the TS was simultaneously incremented or decremented. We found that contrast discrimination thresholds of LHON carriers were significantly higher than controls' in the condition with the highest luminance of both paradigms, implying impaired contrast processing with no evidence of differential sensitivity losses between the two systems. Carriers' thresholds manifested significantly longer temporal integration than controls in the SPP, consistent with slowed MC responses. The SPP and PPP paradigms can identify contrast and temporal processing deficits in asymptomatic LHON carriers, and thus provide an additional tool for early detection and characterization of the disease.


Assuntos
Sensibilidades de Contraste , Triagem de Portadores Genéticos , Atrofia Óptica Hereditária de Leber/genética , Adolescente , Adulto , Discriminação Psicológica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Testes Visuais , Acuidade Visual , Vias Visuais
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