1/21. Mapping and genomic characterization of the gene encoding diacylglycerol kinase gamma (DAGK3): assessment of its role in dominant optic atrophy (OPA1).The family of diacylglycerol kinases (DAGKs) is known to play an important role in signal transduction linked to phospholipid turnover. In the fruitfly drosophila melanogaster, a human DAGK ortholog, DGK2, was shown to underlie the phenotype of the visual mutant retinal degeneration A (rdgA). Previously, the gene encoding a novel member of the human DAGK family, termed DAGK3, was cloned and demonstrated to be abundantly expressed in the human retina. Based on these findings we reasoned that DAGK3 might be an excellent candidate gene for a human eye disease. In the present study, we report the genomic organization of the human DAGK3 gene, which spans over 30 kb of genomic dna interrupted by 23 introns. In addition, we have mapped the gene locus by fluorescence in situ hybridization to 3q27-28, overlapping the chromosomal region known to contain the gene underlying dominant optic atrophy (OPA1), the most common form of hereditary atrophy of the optic nerve. Mutational analysis of the entire coding region of DAGK3 in 19 unrelated German OPA1 patients has not revealed any disease-causing mutations, therefore excluding DAGK3 as a major cause underlying OPA1.- - - - - - - - - - ranking = 1keywords = nerve (Clic here for more details about this article) |
2/21. Acquired mitochondrial impairment as a cause of optic nerve disease.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. (- - - - - - - - - - ranking = 1419.149517581keywords = nerve disease, nerve (Clic here for more details about this article) |
3/21. Optic nerve enhancement on magnetic resonance imaging in arteritic ischemic optic neuropathy.Although optic nerve enhancement may be seen in magnetic resonance imaging of radiation-induced ischemic optic neuropathy, similar enhancement in ischemic optic neuropathy has not been previously reported in the English-language neuroophthalmologic literature. We report three cases of optic nerve enhancement in biopsy-proven arteritic ischemic optic neuropathy. Clinicians should consider giant cell arteritis in the differential diagnosis of an optic neuropathy with optic nerve enhancement on magnetic resonance imaging.- - - - - - - - - - ranking = 7keywords = nerve (Clic here for more details about this article) |
4/21. Oval-shaped cornea, lens duplication, and optic nerve hypoplasia associated with myelomeningocele.Oval-shaped cornea associated with true lens duplication and separate capsules is a rare anomaly. It can occur as an isolated finding(1,2) or be associated with other ocular and facial maldevelopments.(3-5) We report a novel association of an hourglass cornea, lens duplication, and optic nerve hypoplasia with myelomeningocele in a male infant.- - - - - - - - - - ranking = 5keywords = nerve (Clic here for more details about this article) |
5/21. The mitochondrial ND6 gene is a hot spot for mutations that cause Leber's hereditary optic neuropathy.Leber's hereditary optic neuropathy (LHON) is a common cause of bilateral optic nerve disease. The majority of LHON patients harbour one of three point mutations of the mitochondrial dna (mtDNA) complex I, or NADH:ubiquinone oxidoreductase (ND) genes (G11778A in ND4, G3460A in ND1, T14484C in ND6). As a consequence, screening for these mutations has become part of the routine clinical investigation of young adults who present with bilateral optic neuropathy, and the absence of these mutations is interpreted as indicating there is a low likelihood that an optic neuropathy is LHON. However, there are many individuals who develop the clinical features of LHON but who do not harbour one of these primary LHON mutations. We describe two LHON pedigrees that harbour the same novel point mutation within the mtDNA ND6 gene (A14495G). This mutation was heteroplasmic in both families, and sequencing of the mitochondrial genome confirmed that the mutation arose on two independent occasions. This is the seventh mutation in the ND6 gene that causes optic neuropathy, indicating that this gene is a hot spot for LHON mutations. Protein modelling studies indicate that all of these pathogenic mutations lie within close proximity to one another in a hydrophobic cleft or pocket. This is the first evidence for a relationship between a specific disease phenotype and a specific structural domain within a mitochondrial respiratory chain subunit. These findings suggest that the mtDNA ND6 gene should be sequenced in all patients with LHON who do not harbour one of the three common LHON mutations.- - - - - - - - - - ranking = 282.62990351619keywords = nerve disease, nerve (Clic here for more details about this article) |
6/21. Leber hereditary optic neuropathy associated with antiretroviral therapy for human immunodeficiency virus infection.PURPOSE: Antiretroviral therapy has reduced the morbidity and mortality associated with human immunodeficiency virus (hiv) infection. However, side effects are increasingly recognized, including a commonly reported toxic mitochondrial myopathy. We report such a case of Leber hereditary optic neuropathy in a patient with antiretroviral therapy for hiv infection and speculate on a possible toxic etiologic role in the development of Leber hereditary optic neuropathy by a shared mitochondrial mechanism. methods: Case Report. Bilateral optic disk abnormalities observed in a 38-year-old hiv positive man with a family history of Leber hereditary optic neuropathy were documented with fundus photography, color vision testing, and visual field testing. Mitochondrial dna testing was used to confirm the genetic predisposition to Leber hereditary optic neuropathy. RESULTS: Progressive bilateral optic nerve pallor temporally associated with the administration of antiretroviral medication was observed. Diagnostic testing revealed progressive visual field and color vision loss as well as a mitochondrial dna mutation consistent with Leber hereditary optic neuropathy. CONCLUSION: Antiretroviral therapy may be associated with the onset of Leber hereditary optic neuropathy in genetically predisposed patients.- - - - - - - - - - ranking = 1keywords = nerve (Clic here for more details about this article) |
7/21. Leber's hereditary optic neuropathy differentially affects smaller axons in the optic nerve.PURPOSE: Leber's hereditary optic neuropathy (LHON), though known to be due to 1 of 3 pathogenic mtDNA point mutations (nucleotide positions 11,778, 3460, and 14,484), usually manifests itself acutely in young adulthood with a stereotypical presentation of dyschromatopsia, loss of central vision, and loss of the papillomacular bundle nerve fiber layer. Histopathologic investigations have demonstrated devastating losses of axons with relative sparing of the most peripherally placed fibers in the optic nerves. This study was designed to morphometrically investigate the nerve fiber spectrum from ultrastructural studies of optic nerves obtained from 2 patients with LHON. methods: Two cases of LHON were molecularly characterized and the optic nerves from these cases studied by light microscopy and electron microscopy. Montages were made of electron micrographs cut orthogonal to fibers obtained from the periphery of each optic nerve, and these were then used for the measurement of each axon (short and long axis) and its myelin sheath. From this, a spectrum of nerve fiber layer was generated, yielding axon caliber profiles that could be compared between optic nerves. RESULTS: The total depletion of optic nerve fiber population in the 2 cases of LHON varied from 95% to 99%. Those fibers that were spared were limited to the peripheral optic nerve. The nerve fiber layer spectra of these remaining fibers showed a marked diminution of the first peak of axons of less than 1 micron in diameter, with relative emphasis of a second peak of axons of about 2 microns in diameter. In comparison to normal controls, this reflected a preferential loss of the smallest axons corresponding to the P-cell population. CONCLUSIONS: The clinical features of dyschromatopsia and central scotoma (with preservation of pupils) in LHON suggests the selective loss of the P-cell population known to subserve these (and not pupil) functions. This also correlates well with the fundus findings of early losses of the papillomacular bundle. The present study extends these findings to demonstrate a relative preservation of the M-cells in the optic nerve as reflected by the nerve fiber spectral profile. This selective loss of smaller fibers and their corresponding smaller retinal ganglion cells may, in addition to explaining the clinical features in LHON, provide valuable insights as to the exact pathophysiologic mechanisms by which mitochondrial impairment may induce apoptosis in vulnerable neurons.- - - - - - - - - - ranking = 17keywords = nerve (Clic here for more details about this article) |
8/21. Disc excavation in dominant optic atrophy: differentiation from normal tension glaucoma.OBJECTIVE: In patients with dominant optic atrophy (DOA, Kjer type), excavation of the optic nerve develops, and these patients may be misdiagnosed as having normal tension glaucoma (NTG). This study examined disc morphologic features in patients with DOA and explored features that help distinguish this condition from NTG. DESIGN: Noncomparative, observational case series. PARTICIPANTS: patients with DOA who were seen at the Duke University eye Center between 1987 and 1996 and who had bilateral optic nerve photographs. methods: Retrospective chart review of the results of visual acuity testing, visual field testing by Goldmann perimetry, color vision testing, intraocular pressure measurement, and observation of bilateral optic nerve photographs. MAIN OUTCOME MEASURES: Appearance of the optic disc and peripapillary zone in patients with DOA. RESULTS: Nine patients were identified. The mean age at the time of evaluation was 28 years (range, 11-62 years). Most patients had a mild to moderate reduction in visual acuity. color vision as tested with Hardy-Rand-Rittler plates was reduced (4.0/10 /- 4.2/10). A cup-to-disc ratio of more than 0.5 was observed in at least one eye of eight patients. A temporal wedge-shaped area of excavation was observed in 14 of the 18 eyes studied. Moderate to severe temporal pallor was observed in all of the eyes. pallor of the remaining (noncupped) neuroretinal rim was also observed consistently, ranging from mild to moderate. A gray crescent and some degree of peripapillary atrophy were noted in all eyes. CONCLUSIONS: Several clinical features, including early age of onset, preferential loss of central vision, sparing of the peripheral fields, pallor of the remaining neuroretinal rim, and a family history of unexplained visual loss or optic atrophy, help to distinguish patients with DOA from those with NTG.- - - - - - - - - - ranking = 3keywords = nerve (Clic here for more details about this article) |
9/21. Behr's syndrome and 3-methylglutaconic aciduria.We examined three patients from two families of Jewish-Iraqi origin who had progressive reduction of visual acuity and childhood onset of bilateral optic nerve atrophy without additional retinal abnormalities. They had neurologic symptoms compatible with Behr's syndrome. Neurologic signs included increased tendon reflexes, a positive Babinski sign, progressive spastic paraplegia, dysarthria, head nodding, and horizontal nystagmus. Neurologic involvement varied between affected siblings. The patients excreted excessive amounts of 3-methylglutaconic acid and 3-methylglutaric acid in their urine. We compared the characteristic ophthalmic features and the spectrum of neurologic signs encountered in this recently delineated autosomal recessive clinical entity with those of previously described entities associated with 3-methylglutaconic aciduria. patients with early-onset optic atrophy should be examined for neurologic signs and screened for organic aciduria. A detailed ophthalmic examination is important in patients with neurologic abnormalities compatible with Behr's syndrome.- - - - - - - - - - ranking = 1keywords = nerve (Clic here for more details about this article) |
10/21. Occurrence of a multiple sclerosis-like illness in women who have a Leber's hereditary optic neuropathy mitochondrial dna mutation.Eight women are described who presented with bilateral, usually sequential, optic neuropathy, six of whom later developed a neurological syndrome indistinguishable from multiple sclerosis (MS). magnetic resonance imaging, performed in five of the patients with an MS-like illness and in the two others with optic neuropathy alone, showed widespread white matter lesions as seen in MS. All of these women had matrilineal relatives with Leber's hereditary optic neuropathy, although this was not always apparent at presentation, and the most common mitochondrial dna mutation associated with this disorder was detected in each of the women and their affected relatives. On the basis of observations made in these patients, the clinical features of Leber's hereditary optic neuropathy in males, and evidence for mitochondrially encoded peptides involved in the immune response in rodents, we propose that optic nerve damage in this disease could be immunologically mediated and that mitochondrial genes may contribute to susceptibility to MS.- - - - - - - - - - ranking = 1keywords = nerve (Clic here for more details about this article) |
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