RESUMEN
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.
Asunto(s)
Sensibilidad de Contraste , Tamización de Portadores Genéticos , Atrofia Óptica Hereditaria de Leber/genética , Adolescente , Adulto , Discriminación en Psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valores de Referencia , Pruebas de Visión , Agudeza Visual , Vías VisualesRESUMEN
AIMS: To determine if asymptomatic carriers from a previously identified large pedigree of the Leber's hereditary optic neuropathy (LHON) 11778 mtDNA mutation have colour vision deficits. METHODS: As part of a comprehensive analysis of over 200 members of a large Brazilian LHON pedigree spanning seven generations, colour vision tests were obtained from 91 members. Colour vision was tested one eye at a time using the Farnsworth-Munsell 100 (FM-100) hue colour vision test. The test was administered under uniform conditions, taking into account: ambient light levels, daylight colour temperature of 6700 kelvin, and neutral uniform background. Tests were scored using the FM-100 MS-Excel computer scoring program. Defects were determined and categorised as tritan, deutan, or protan. Categorisation of each dyschromatopsia was based on review of demonstrated axis computer generated plots and age adjusted error scores which coincided with Verriest 95% confidence intervals. Only the axis with the greatest magnitude error score was used to classify the defect. 55 of the 91 test subjects were LHON mtDNA 11778 J haplotype mutation carriers, proved by mtDNA analysis. The remaining 36 subjects were age matched non-blood relatives (off pedigree), who served as controls. RESULTS: 27 of 55 carriers (49.10%) were shown to have colour vision defects in one or both eyes. 13 of the 27 (48%) abnormal tests in the carrier group were tritan defects and the remaining 14 (52%) were deutan defects. Nine of the 27 (33%) abnormals in the carrier group were identified as having bilateral defects. Six of these were deutan, and the remaining three were tritan dyschromatopsias. Only six of the 36 (16.66%) age matched controls were found to have any type of dyschromatopsia. Five (83.3%) of these were deutan defects. The remaining one was a tritan defect. The difference between the two groups using a chi(2) test with one degree of freedom was statistically significant with a p value less that 0.001. CONCLUSIONS: Until now, LHON has always been characterised by a sudden, devastating vision loss. Asymptomatic carriers, those without vision loss, were considered unaffected by the disease. It now appears that asymptomatic carriers of the LHON mutation are affected by colour vision defects and may manifest other subtle, yet chronic, changes.
Asunto(s)
Defectos de la Visión Cromática/genética , ADN Mitocondrial/genética , Atrofia Óptica Hereditaria de Leber/genética , Brasil , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Tamización de Portadores Genéticos , Humanos , Mutación , LinajeRESUMEN
We studied 62 patients aged 48 years as an average and diagnosed with bilateral optical neuropathy during an epidemics in Pinar del Río province. Of these patients, 42 showed the optical form whereas 20 had the mixed form of optical neuropathy. We researched into the levels of formate and folate in serum and cerebrospinal fluid samples and we found a marked deficiency of folates in more than 50% of samples and high formate concentration levels in almost 25% of samples. We concluded that nutritional shortages that lead to a reduction of folates, and the intake of small amounts of methanol in alcoholic drinks could lead to lacking energetic states which would facilitate that the optical nerve be affected and the epidemic optical neuropathy appear.
Asunto(s)
Brotes de Enfermedades , Deficiencia de Ácido Fólico/complicaciones , Ácido Fólico/sangre , Ácido Fólico/líquido cefalorraquídeo , Formiatos/sangre , Formiatos/líquido cefalorraquídeo , Enfermedades del Nervio Óptico/epidemiología , Consumo de Bebidas Alcohólicas , Femenino , Humanos , Masculino , Metanol/efectos adversos , Persona de Mediana Edad , Enfermedades del Nervio Óptico/sangre , Enfermedades del Nervio Óptico/líquido cefalorraquídeo , Enfermedades del Nervio Óptico/inducido químicamente , Factores de Riesgo , Solventes/efectos adversosRESUMEN
Se estudiaron 62 pacientes con neuropatía óptica bilateral, diagnosticados durante una epidemia en la provincia Pinar del Río, con una edad media de 48 años. De ellos, 42 tenían la forma óptica y 20 la forma mixta. Se investigaron los niveles de formato y folatos en muestras de suero y líquido cefalorraquídeo. Se encontró una marcada deficiencia de folatos en más de 50 por ciento de las muestras y los niveles de formato con una elevación de su concentración en casi 25 por ciento de las muestras. Se concluyó que deficiencias nutricionales que ocasionan la disminución de folatos y la ingestión de pequeñas cantidades de metanol en las bebidas alcohólicas, podían contribuir a la producción de estados energéticos deficitarios que facilitarían la afectación del nervio óptico y la aparición de la neuropatía óptica epidémica(AU)
Asunto(s)
Humanos , Masculino , Femenino , Neuritis Óptica/epidemiología , Formiatos/sangre , Formiatos/líquido cefalorraquídeo , Ácido Fólico/sangre , Ácido Fólico/líquido cefalorraquídeoRESUMEN
We studied 62 patients aged 48 years as an average and diagnosed with bilateral optical neuropathy during an epidemics in Pinar del RÝo province. Of these patients, 42 showed the optical form whereas 20 had the mixed form of optical neuropathy. We researched into the levels of formate and folate in serum and cerebrospinal fluid samples and we found a marked deficiency of folates in more than 50 of samples and high formate concentration levels in almost 25 of samples. We concluded that nutritional shortages that lead to a reduction of folates, and the intake of small amounts of methanol in alcoholic drinks could lead to lacking energetic states which would facilitate that the optical nerve be affected and the epidemic optical neuropathy appear.
Asunto(s)
Humanos , Masculino , Femenino , Persona de Mediana Edad , Ácido Fólico/sangre , Ácido Fólico/líquido cefalorraquídeo , Deficiencia de Ácido Fólico/complicaciones , Brotes de Enfermedades , Enfermedades del Nervio Óptico/epidemiología , Formiatos , Consumo de Bebidas Alcohólicas , Enfermedades del Nervio Óptico/sangre , Enfermedades del Nervio Óptico/inducido químicamente , Enfermedades del Nervio Óptico/líquido cefalorraquídeo , Metanol , Factores de Riesgo , SolventesRESUMEN
BACKGROUND: Blindness from an optic neuropathy recently occurred as an epidemic affecting 50,000 patients in Cuba (CEON) and had clinical features reminiscent of both tobacco-alcohol amblyopia (TAA) and Leber's hereditary optic neuropathy (Leber's; LHON). Selective damage to the papillomacular bundle was characteristic, and many patients also developed a peripheral neuropathy. Identified risk factors included vitamin deficiencies as well as exposure to methanol and cyanide. In all 3 syndromes, there is evidence that singular or combined insults to mitochondrial oxidative phosphorylation are associated with a clinically characteristic optic neuropathy. PURPOSE: First, to test the hypothesis that a common pathophysiologic mechanism involving impairment of mitochondria function and, consequently, axonal transport underlies both genetic optic nerve diseases such as Leber's and acquired toxic and nutritional deficiency optic neuropathies. According to this hypothesis, ATP depletion below a certain threshold leads to a blockage of orthograde axonal transport of mitochondria, which, in turn, leads to total ATP depletion and subsequent cell death. Second, to address several related questions, including (1) How does impaired energy production lead to optic neuropathy, particularly since it seems to relatively spare other metabolically active tissues, such as liver and heart? (2) Within the nervous system, why is the optic nerve, and most particularly the papillomacular bundle, so highly sensitive? Although there have been previous publications on the clinical features of the Cuban epidemic of blindness, the present hypothesis and the subsequent questions have not been previously addressed. METHODS: Patients in Cuba with epidemic optic neuropathy were personally evaluated through a comprehensive neuro-ophthalmologic examination. In addition, serum, lymphocytes for DNA analysis, cerebrospinal fluid (CSF), sural nerves, and eyes with attached optic nerves were obtained from Cuban patients, as well as from Leber's patients, for study. Finally, we developed an animal model to match the low serum folic acid and high serum formate levels found in the CEON patients, by administering to rats low doses of methanol after several months of a folic acid-deficient diet. Optic nerves and other tissues obtained from these rats were analyzed and compared with those from the Cuban patients. RESULTS: Patients from the Cuban epidemic of optic neuropathy with clinical evidence of a selective loss of the papillomacular bundle did much better once their nutritional status was corrected and exposure to toxins ceased. Patients with CEON often demonstrated low levels of folic acid and high levels of formate in their blood. Histopathologic studies demonstrated losses of the longest fibers (in the sural nerve) and those of smallest caliber (papillomacular bundle) in the optic nerve, with intra-axonal accumulations just anterior to the lamina cribrosa. Our animal model duplicated the serologic changes (low folic acid, high formate) as well as these histopathologic changes. Furthermore, ultrastructural examination of rat tissues demonstrated mitochondrial changes that further matched those seen on ultrastructural examination of tissues from patients with Leber's. CONCLUSION: Mitochondria can be impaired either genetically (as in Leber's) or through acquired insults (such as nutritional or toxic factors). Either may challenge energy production in all cells of the body. While this challenge may be met through certain compensatory mechanisms (such as in the size, shape, or number of the mitochondria), there exists in neurons a threshold which, once passed, leads to catastrophic changes. This threshold may be that point at which mitochondrial derangement leads to such ATP depletion that axonal transport is compromised, and decreased mitochondrial transport results in even further ATP depletion. Neurons are singularly dependent on the axonal transport of mitochondria. (
Asunto(s)
Mitocondrias/metabolismo , Enfermedades del Nervio Óptico/etiología , Adulto , Anciano , Animales , Cuba , Brotes de Enfermedades , Exposición a Riesgos Ambientales , Femenino , Ácido Fólico/sangre , Formiatos/sangre , Humanos , Masculino , Estado Nutricional , Atrofias Ópticas Hereditarias/sangre , Atrofias Ópticas Hereditarias/metabolismo , Atrofias Ópticas Hereditarias/patología , Enfermedades del Nervio Óptico/inducido químicamente , Enfermedades del Nervio Óptico/epidemiología , Enfermedades del Nervio Óptico/metabolismo , Enfermedades del Nervio Óptico/patología , Ratas , Ratas Long-Evans , Toxinas BiológicasRESUMEN
OBJECTIVE: To search for mitochondrial DNA (mtDNA) mutations previously associated with Leber's hereditary optic neuropathy (LHON) in patients with an optic neuropathy that appeared in epidemic form in Cuba. METHODS: Twelve Cuban patients underwent a comprehensive neuro-ophthalmologic examination and were found to have a characteristic optic neuropathy, Cuban epidemic optic neuropathy (CEON). At the same time, one patient was diagnosed with typical LHON that occurred during the epidemic. Blood samples were taken from these patients as well as from 3 controls with normal neuro-ophthalmologic examinations. These samples were blindly analyzed for 9 LHON-associated mtDNA mutations by molecular genetic methods. RESULTS: CEON bore clinical and epidemiological similarity to LHON, however, family histories, systemic symptoms (especially weight loss and polyuria), and symptoms of peripheral neuropathy permitted a clinical distinction. None of the 12 patients with CEON or 3 controls had any of the LHON-associated mtDNA mutations. Only the patient with clinical LHON, who did not meet the case definition for CEON, harbored the 11778 mtDNA mutation. CONCLUSIONS: Known mtDNA mutations are not found frequently in CEON patients but they may contribute to some cases of Cuban optic neuropathy. CEON may represent an acquired variety of mitochondrial dysfunction induced by nutritional deficiencies, toxins, or both. Alternatively, CEON patients may also harbor as yet undiscovered mtDNA mutations that contribute to their genetic susceptibility.
Asunto(s)
ADN Mitocondrial , Atrofias Ópticas Hereditarias/genética , Enfermedades del Nervio Óptico/epidemiología , Enfermedades del Nervio Óptico/genética , Cuba/epidemiología , Análisis Mutacional de ADN , Brotes de Enfermedades , Femenino , Humanos , Masculino , Mutación , Atrofias Ópticas Hereditarias/epidemiología , Atrofias Ópticas Hereditarias/etiología , Enfermedades del Nervio Óptico/etiología , Reacción en Cadena de la Polimerasa , Factores de RiesgoRESUMEN
OBJECTIVE: To characterize and establish a clinical definition of the optic neuropathy that appeared in epidemic form in Cuba in 1992 and 1993. METHODS: At the invitation of the Cuban Ministry of Health, Havana, members of ORBIS International and the Pan American Health Organization, assembled teams that traveled to Cuba in May 1993. We were initially briefed by Cuban national experts in the areas of virology, nutrition, toxicology, ophthalmology, neurology, and public health. We then examined 20 patients on our own. Thirteen of these patients underwent a comprehensive neuro-ophthalmologic examination, including neurologic examination, ophthalmologic examination, visual fields, optic nerve function studies, contrast sensitivity studies, and funduscopy. We returned 4 months later to perform an additional 12 comprehensive neuro-ophthalmologic and follow-up examinations. RESULTS: Only seven of the 13 patients who were alleged to have the optic form of the epidemic and who were rigorously and systematically examined on the first visit demonstrated a bilateral optic neuropathy. These seven patients had several features that included decreased visual acuity, poor color vision, central scotomas, decreased contrast sensitivity, saccadic eye movements, and most prominent and distinctive of all, nerve fiber layer wedge defects of the papillomacular bundle. Our clinical definition was then implemented by the Cuban ophthalmologists and epidemiologists. On returning 4 months later, we found that all newly presented patients were correctly diagnosed to have the epidemic disease. With the new case definition and the application of a few simple psychophysical tests, the false-positive rate of diagnosis became much lower. After vitamin therapy, we reexamined the patients seen on our initial visit, and all showed marked improvement. CONCLUSIONS: The Cuban epidemic was characterized by an optic neuropathy with features that were similar to those of tobacco/alcohol amblyopia and Leber's optic atrophy. Recent political, economic, and social changes in Cuba may have contributed to the nutritional and/or toxic compromise of mitochondrial function of an acquired nature, which led to selective retinal ganglion cell damage. We have termed this condition Cuban epidemic optic neuropathy.
Asunto(s)
Brotes de Enfermedades , Fondo de Ojo , Enfermedades del Nervio Óptico/diagnóstico , Enfermedades del Nervio Óptico/epidemiología , Adulto , Cuba/epidemiología , Femenino , Humanos , Incidencia , Masculino , Enfermedades del Nervio Óptico/terapiaRESUMEN
We made two trips to Cuba, as part of an invited international delegation, to investigate an epidemic of optic neuropathy-induced blindness. We worked closely with Cuban scientists and clinicians in their efforts to understand and then deal with 50,000 cases of blindness and an entire population at risk. This gave an unparalleled opportunity to understand the Cuban system of ophthalmologic health care and, in particular, to appreciate the responses of the scientific and health care communities to this crisis. Several features of the very different Cuban medical and scientific infrastructure were both problematic and advantageous as they affected the Cuban efforts to understand, contain and treat this remarkable epidemic.