RESUMO
The present study investigates the spectrum and analysis of mitochondrial DNA (mtDNA) variants associated with Leber hereditary optic neuropathy (LHON) in an Argentinean cohort, analyzing 3 LHON-associated mitochondrial genes. In 32% of the cases, molecular confirmation of the diagnosis could be established, due to the identification of disease-causing variants. A total of 54 variants were observed in a cohort of 100 patients tested with direct sequencing analysis. The frequent causative mutations m.11778G>A in MT-ND4, m.3460G>A in MT-ND1, and m.14484T>C in MT-ND6 were identified in 28% of the cases of our cohort. Secondary mutations in this Argentinean LHON cohort were m.11253T>C p.Ile165Thr in MT-ND4, identified in three patients (3/100, 3%) and m.3395A>G p.Tyr30Cys in MT-ND1, in one of the patients studied (1%). This study shows, for the first time, the analysis of mtDNA variants in patients with a probable diagnosis of LHON in Argentina. Standard molecular methods are an effective first approach in order to achieve genetic diagnosis of the disease, leaving NGS tests for those patients with negative results.
Assuntos
DNA Mitocondrial , Atrofia Óptica Hereditária de Leber , Humanos , DNA Mitocondrial/genética , Atrofia Óptica Hereditária de Leber/diagnóstico , Atrofia Óptica Hereditária de Leber/genética , Argentina , Mitocôndrias/genética , MutaçãoRESUMO
PURPOSE: Leber hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by bilateral vision loss. More than 95% of LHON cases are associated with one of the three main mtDNA mutations: G11778A, T14484C, and G3460A. The other 5% of cases are due to other rare mutations related to the disease. The aim of this study was to identify the prevalence and spectrum of LHON mtDNA mutations, including the haplogroup, in a cohort of Brazilian patients with optic neuropathy and to evaluate the usefulness of iPLEX Gold/matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) technology in detecting LHON mutations. METHODS: We analyzed a total of 101 patients; 67 had a clinical diagnosis of LHON and 34 had optic neuropathy of unknown etiology. Direct sequencing and iPLEX Gold/MALDI-TOF MS were used to screen for the most common pathogenic point mutations in LHON, together with the rare mutations G3733A, C4171A, T10663C, G14459A, C14482G, A14495G, C14568T, and C14482A. RESULTS: We identified mutations in 36 patients, of whom 83.3% carried the G11778A mutation and 16.7% carried the T14484C mutation. In individuals with mutations, the haplogroups found were L1/L2, L3, C, R, U, D, and H. Rare mutations were not detected in any of the patients analyzed. CONCLUSIONS: The frequencies of the main LHON mutations were similar to those previously reported for Latin America. A different frequency was found only for the A3460G mutation. The most frequent haplogroups identified were of African origin. The iPLEX Gold/MALDI-TOF MS technology proved to be highly accurate and efficient for screening mutations and identifying the haplogroups related to LHON. The MassArray platform, combined with other techniques, enabled definitive diagnosis of LHON in 36% (36/101) of the cases studied.
Assuntos
DNA Mitocondrial/genética , Mitocôndrias/genética , Doenças Mitocondriais/diagnóstico , Atrofia Óptica Hereditária de Leber/diagnóstico , Polimorfismo de Nucleotídeo Único , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Adolescente , Adulto , Brasil , Criança , Análise Mutacional de DNA , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/genética , Atrofia Óptica Hereditária de Leber/genéticaRESUMO
INTRODUCTION: Functional impairment of the optic nerve is characterized by visual loss, dyschromatopsia, visual field defects, relative afferent pupillary defect, and swelling or atrophy of the optic nerve. AIM: To describe the spectrum of acute optic neuropathies, focusing on clinical features, diagnosis and treatment with an emphasis on pediatric entities. DEVELOPMENT: Optic neuritis may be monophasic, recurrent, or part of a polysymptomatic demyelinating process. The aim of the treatment is to reduce number and severity of attacks and prevent future disability. Infectious neuritis is secondary to different microorganisms (bacteria, virus, fungi, or protozoa). Treatment is related to etiology. Nonarteritic ischemic optic neuropathy or idiopathic optic neuropathy is the most frequent form and is secondary to a disorder of small retinal vessels. Leber hereditary optic neuropathy is an important cause of chronic visual impairment and is characterized by selective involvement of the retinal ganglion cells. Until now, no curative treatment is available. Visual acuity is frequently conserved in papilledema associated with intracranial hypertension. The aim of treatment is to reduce intracranial hypertension and risk factors in case it is secondary. CONCLUSIONS: Acute optic neuropathies are broad group of entities, of different etiologies, and with a variable visual prognosis. Findings of neurological examination, fundoscopy, and neuroimaging guide diagnosis and prompt treatment.
TITLE: Neuropatia optica aguda: diagnosticos diferenciales.Introduccion. La alteracion funcional del nervio optico se caracteriza por un deficit en la agudeza visual, en la vision cromatica y en el campo visual, defecto pupilar aferente y, en algunos casos, edema del nervio o atrofia y palidez. Objetivo. Describir el espectro de neuropatias opticas agudas, su clinica, diagnostico y tratamiento, con mayor interes en aquellas de presentacion en la edad pediatrica. Desarrollo. La neuritis optica puede ser monofasica, recurrente o el componente de un cuadro desmielinizante polisintomatico. El objetivo del tratamiento es reducir el numero y la gravedad de los ataques y prevenir discapacidad. La infecciosa es secundaria a diferentes microorganismos (bacterias, virus, hongos y protozoos). El tratamiento depende de la etiologia. La isquemica anterior no arteritica o idiopatica es la forma mas frecuente y es secundaria a enfermedad de pequeños vasos (ciliares posteriores). La neuropatia optica hereditaria o de Leber representa una causa importante de afectacion visual cronica y se caracteriza por la afectacion selectiva de las celulas ganglionares de la retina. Hasta el momento, la terapia solo es de apoyo. En el papiledema asociado a hipertension endocraneal, la agudeza visual generalmente se conserva pero existe aumento de la mancha ciega. El tratamiento se basa en disminuir la hipertension y el factor etiologico si existe. Conclusiones. Las neuropatias opticas agudas constituyen un amplio grupo de entidades, de etiologia diversa y con un pronostico visual variable. La presencia de signos del examen neurologico, fondo de ojo y neuroimagenes pueden orientar hacia el diagnostico y tratamiento oportuno.
Assuntos
Doenças do Nervo Óptico/diagnóstico , Doença Aguda , Corticosteroides/uso terapêutico , Anti-Infecciosos/uso terapêutico , Criança , Doenças Desmielinizantes/complicações , Diagnóstico Diferencial , Técnicas de Diagnóstico Oftalmológico , Endoftalmite/complicações , Endoftalmite/tratamento farmacológico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Hipertensão Intracraniana/complicações , Neuroimagem , Atrofia Óptica Hereditária de Leber/diagnóstico , Atrofia Óptica Hereditária de Leber/genética , Nervo Óptico/irrigação sanguínea , Doenças do Nervo Óptico/tratamento farmacológico , Doenças do Nervo Óptico/etiologia , Neurite Óptica/diagnóstico , Neurite Óptica/tratamento farmacológico , Neurite Óptica/etiologia , Neuropatia Óptica Isquêmica/diagnóstico , Papiledema/etiologia , Prognóstico , Pseudotumor Cerebral/complicações , Retinite/diagnóstico , Acuidade VisualRESUMO
The similarities and differences between toxic/nutritional and hereditary optic neuropathy and the pathophysiologic mechanisms that they have in common are described. This is based on data from the epidemic suffered in Cuba in 1992, which affected the optic nerves of many individuals and the experience of the authors in dealing with various toxic optic neuropathies, as well as Leber's hereditary optic neuropathy.
Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Atrofias Ópticas Hereditárias/epidemiologia , Fumar/epidemiologia , Cuba/epidemiologia , Humanos , Atrofias Ópticas Hereditárias/diagnóstico , Atrofias Ópticas Hereditárias/fisiopatologia , Atrofia Óptica Hereditária de Leber/diagnóstico , Atrofia Óptica Hereditária de Leber/epidemiologia , Atrofia Óptica Hereditária de Leber/fisiopatologia , Doenças do Nervo Óptico/diagnóstico , Doenças do Nervo Óptico/epidemiologia , Doenças do Nervo Óptico/fisiopatologiaRESUMO
PURPOSE: To study the optic nerve head (ONH) morphology of patients with Leber's hereditary optic neuropathy (LHON) in a large family from Brazil carrying the 11778/ND4 mutation and in a case series of unrelated Italian families bearing different mitochondrial DNA (mtDNA) pathogenic mutations. METHODS: Enrolled in the study were 15 LHON-affected patients (LHON-affected) and 45 LHON unaffected mutation carriers (LHON carriers) belonging to the previously reported Brazilian SOA-BR LHON pedigree and 56 LHON-affected and 101 LHON carriers from 45 unrelated LHON Italian pedigrees molecularly defined. The LHON-affected were subgrouped according to the extent of visual recovery. All individuals underwent optic nerve head (ONH) analysis by optical coherence tomography. RESULTS: In the Brazilian sample, the mean optic disc area was significantly larger in LHON carriers than in the control group (P=0.002). In the Italian sample, the mean optic disc area and vertical disc diameter were significantly higher in LHON carriers than in both LHON-affected (respectively, P=0.008 and P<0.001) and control subjects (P<0.001 in both cases). The LHON-affected with visual recovery had a significantly larger vertical disc diameter when compared with those without visual recovery (P=0.03). CONCLUSIONS: The results, revealing that the ONH size is larger in LHON carriers than in LHON-affected, suggest a protective role for this anatomic trait. Such a hypothesis is reinforced by the observation that, among the LHON-affected, larger discs correlated with visual recovery and better visual outcome. The findings may be relevant for prognosis and provide a mechanism for identifying nuclear-modifying genes implicated in the variability of penetrance in LHON.
Assuntos
Atrofia Óptica Hereditária de Leber/diagnóstico , Disco Óptico/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Análise Mutacional de DNA , DNA Mitocondrial/genética , Progressão da Doença , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia Óptica Hereditária de Leber/genética , Linhagem , Penetrância , Prognóstico , Tomografia de Coerência ÓpticaRESUMO
PURPOSE: The authors previously presented the results of their 2001 field investigation to rural Brazil to investigate a 336-member pedigree of Leber hereditary optic neuropathy (LHON). The present work describes the yearly field investigations 2001 to 2005, utilizing a variety of highly sophisticated psychophysical and electrophysiologic procedures, in asymptomatic LHON carriers, some of whom converted to affected status. METHODS: Careful, repeated examinations of 75 carriers of homoplasmic 11778 LHON mtDNA J-haplogroup mutants were performed as part of the field investigation of this pedigree. All subjects underwent a detailed neuro-ophthalmologic investigation, including formal visual fields (Humphrey; HVF) and fundus photography. In addition, many subjects underwent rigorous psychophysical examination, including Cambridge Research Systems color vision and contrast sensitivity testing, OCT, GDx, and multifocal visual evoked response (mfVER) and multifocal electroretinogram (mfERG). Two patients followed as nonsymptomatic LHON carriers converted to affected status. RESULTS: Many LHON carriers did, in fact, show subclinical or occult abnormalities. Focal edema was often seen involving the arcuate nerve fiber bundles, and this corresponded with areas of relative paracentral or arcuate scotomas on HVF testing. Compared to controls, LHON carriers had significant losses in color vision affecting mostly the red-green system and reduction in spatial but not temporal contrast sensitivity. The mfVER and mfERG data showed that most carriers had depressed central responses and abnormal interocular asymmetries. CONCLUSIONS: In this very large pedigree of 11778 LHON, the carriers frequently showed manifestations of optic nerve impairments. Their occult disease reflected low-grade compromise that waxed and waned. In two cases, these changes led to a crescendo of dramatic impairments that characterize conversion to affected status.
Assuntos
Atrofia Óptica Hereditária de Leber/diagnóstico , Nervo Óptico/patologia , Transtornos da Visão/diagnóstico , Adolescente , Adulto , Brasil , Portador Sadio , Criança , Testes de Percepção de Cores , Sensibilidades de Contraste , DNA Mitocondrial/genética , Eletrorretinografia , Potenciais Evocados Visuais , Feminino , Humanos , Masculino , Atrofia Óptica Hereditária de Leber/genética , Disco Óptico/patologia , Linhagem , Mutação Puntual , Estudos Prospectivos , População Rural , Órgão SubcomissuralRESUMO
CONTEXTO: A neuropatia óptica hereditária de Leber representa uma importante causa de perda visual progressiva, sem dor, em pacientes jovens do sexo masculino. OBJETIVO: Relatar o caso de um paciente jovem com quadro clínico e neurofisiológico sugestivo de neuropatia óptica hereditária de Leber, confirmado pelo teste genético. RELATO DE CASO: Jovem do sexo masculino com 17 anos de idade com perda visual bilateral progressiva tinha história familiar de perda visual progressiva em dois tios maternos. O paciente tinha antecedentes de tabagismo e alcoolismo pesado. O exame neuro-oftalmológico demonstrou acuidade visual de 20/800 em ambos os olhos, com diminuição dos reflexos pupilares direto e consensual e palidez de papilas ópticas no exame de fundo de olho. O exame de potencial visual evocado definiu distúrbio de condução em ambos os nervos ópticos. O exame de campimetria visual revelou perda visual completa em todos os campos visuais de ambos os olhos. O paciente foi diagnosticado com neuropatia óptica bilateral, com a suspeita clínica de neuropatia óptica hereditária de Leber, e o estudo genético para a avaliação das principais mutações encontradas nesta doença revelou a presença da mutação homoplásmica 11778, confirmando, desta forma, o diagnóstico de neuropatia óptica hereditária de Leber.
Assuntos
Humanos , Masculino , Adolescente , DNA Mitocondrial/genética , Atrofia Óptica Hereditária de Leber/diagnóstico , Atrofia Óptica Hereditária de Leber/genética , Análise Mutacional de DNA , Mutação Puntual , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , PrognósticoRESUMO
CONTEXT: Leber's hereditary optic neuropathy is an important cause of progressive painless visual loss among young male patients. OBJECTIVE: To report on a case of a young patient with a clinical and neurophysiological condition suggestive of Leber's hereditary optic neuropathy, confirmed by genetic testing. CASE REPORT: We describe a 17-year-old male with progressive bilateral visual loss. Two maternal uncles had had similar patterns of visual loss. The patient had a history of smoking and alcohol abuse. Neuro-ophthalmological examination revealed visual acuity of 20/800 in both eyes, with decreased direct and consensual pupillary light reflexes. Fundus examination demonstrated pale optic discs. The visual evoked potential test showed signs of conduction disturbances in both optic nerves and campimetric study showed complete visual loss in all fields of both eyes. A diagnosis of bilateral optic neuropathy with a clinical suspicion of Leber's hereditary optic neuropathy was made. A blood sample was submitted to genetic analysis in relation to the principal mutations of this disorder, and homoplasmic mutation in 11778 was detected, thereby confirming the diagnosis of Leber's hereditary optic neuropathy.