Dominant optic atrophy: Refining the clinical diagnostic criteria in light of genetic linkage studies

ObjectiveTo describe the clinical findings and refine the clinical diagnostic criteria for dominant optic atrophy based on eight British families in which the diagnosis was confirmed by linkage analysis.Design and participantsCase series; 92 subjects in 8 pedigrees had both eyes examined.InterventionFamily members received a domiciliary examination based on best-corrected visual acuity, color vision using Ishihara and Hardy Richter Rand (HRR) plates, confrontation field testing using a red target, and optic disc evaluation using a direct ophthalmoscope. Genomic DNA was extracted from leukocytes or buccal mucosal cells and genotyped using 12 fluorescently labeled microsatellite markers from the region 3q27–q29.Main outcome measuresSubjects were classified clinically as definitely or possibly affected on the basis of the domiciliary examination before genetic analysis, and these results were compared with the haplotype analysis.ResultsClinically, 43 subjects were identified as definitely affected, 4 as possibly affected, and 45 as unaffected. Visual acuity in affected subjects ranged from 6/6 to count fingers and declined with age. On genetic analysis, a haplotype was identified in each family, which was found in all definitely affected members but not in those regarded as unaffected. The four possibly affected individuals also bore the haplotype that segregated with the disease.ConclusionsSimple clinical tests are highly efficacious in diagnosing dominant optic atrophy. Contrary to accepted criteria, symptoms begin before the age of 10 years in only 58% of affected individuals. Visual acuity in affected subjects is highly variable. A mild degree of temporal or diffuse pallor of the optic disc and minimal color vision defects, in the context of a family with dominant optic atrophy, are highly suggestive of an individual being affected, even if the visual acuity is normal. This widens the generally accepted diagnostic criteria for this disease.     

Dominant infantile optic nerve atrophy

The authors present an account of a family with an autosomal dominant infantile atrophy of the optic nerve. In three generations two men and three women were affected. With the clinical picture of simple atrophy of the optic nerve with a different degree of expressivity corresponded functional and fluoroangiographic changes. Disorders of colour vision were within the range of deuteroanomaly, deuteroanopia. The proband suffered also from tritanopia. The disease did not call for amaurotic training.     

Dominant optic atrophy: Culprit mitochondria in the optic nerve

Dominant optic atrophy (DOA) is an inherited mitochondrial disease leading to specific degeneration of retinal ganglion cells (RGCs), thus compromising transmission of visual information from the retina to the brain. Usually, DOA starts during childhood and evolves to poor vision or legal blindness, affecting the central vision, whilst sparing the peripheral visual field. In 20% of cases, DOA presents as syndromic disorder, with secondary symptoms affecting neuronal and muscular functions. Twenty years ago, we demonstrated that heterozygous mutations in OPA1 are the most frequent molecular cause of DOA. Since then, variants in additional genes, whose functions in many instances converge with those of OPA1, have been identified by next generation sequencing. OPA1 encodes a dynamin-related GTPase imported into mitochondria and located to the inner membrane and intermembrane space. The many OPA1 isoforms, resulting from alternative splicing of three exons, form complex homopolymers that structure mitochondrial cristae, and contribute to fusion of the outer membrane, thus shaping the whole mitochondrial network. Moreover, OPA1 is required for oxidative phosphorylation, maintenance of mitochondrial genome, calcium homeostasis and regulation of apoptosis, thus making OPA1 the Swiss army-knife of mitochondria. Understanding DOA pathophysiology requires the understanding of RGC peculiarities with respect to OPA1 functions. Besides the tremendous energy requirements of RGCs to relay visual information from the eye to the brain, these neurons present unique features related to their differential environments in the retina, and to the anatomical transition occurring at the lamina cribrosa, which parallel major adaptations of mitochondrial physiology and shape, in the pre- and post-laminar segments of the optic nerve. Three DOA mouse models, with different Opa1 mutations, have been generated to study intrinsic mechanisms responsible for RGC degeneration, and these have further revealed secondary symptoms related to mitochondrial dysfunctions, mirroring the more severe syndromic phenotypes seen in a subgroup of patients. Metabolomics analyses of cells, mouse organs and patient plasma mutated for OPA1 revealed new unexpected pathophysiological mechanisms related to mitochondrial dysfunction, and biomarkers correlated quantitatively to the severity of the disease. Here, we review and synthesize these data, and propose different approaches for embracing possible therapies to fulfil the unmet clinical needs of this disease, and provide hope to affected DOA patients.     

Correlation between optic disc atrophy and aetiology: anterior ischaemic optic neuropathy vs optic neuritis

BACKGROUND: The morphologic features of swollen disc in the acute stage of optic neuritis and anterior ischaemic optic neuropathy (AION) have been extensively investigated in contrast to the morphologic features of optic disc atrophy after these events. OBJECTIVE:: A prospective study to evaluate the morphologic features of optic disc atrophy 6 months or more after optic neuritis and nonarteritic AION. PATIENTS AND METHODS: A total of 35 optic discs after nonarteritic AION (n=27) and 24 after optic neuritis (n=19) in otherwise healthy subjects have been evaluated by direct fundoscopic examination with a +90 diopters lens and optic disc photography. The average age of patients at the onset of AION was 57.8 years (range: 38-80) and at the onset of optic neuritis was 32.6 (range: 19-46). The female:male ratio was 18 : 17 in the former and 15 : 9 in the latter. The evaluated parameters included: degree of rim pallor (0 to +3), location of rim pallor, height of rim above the retina, depth and width of cup, peripapillary retinal artery to vein (A : V) ratio, and peripapillary pigment epithelial atrophy. A comparison was made also with 17 age-matched normal discs of 17 patients. Statistical significance was calculated with chi(2) and Fisher's exact test. RESULTS: Most of the discs after AION were paler (+2: 70%, +3: 26%) than after optic neuritis (normal colour: 8%, +1: 58%, P< or =0.007). Rim segmental involvement after AION was usually either superior 'altitudinal' (53%) or inferior 'altitudinal' (29%), whereas after optic neuritis, it was usually either temporal-central (papillomacular) (42%) or diffuse temporal (42%, P<0.0001). Discs had lower A : V ratio (1 : 3, 40%) after AION compared with optic neuritis (1 : 3, 8%) (P=0.007). There were no significant differences between the two groups in height of the rim, cupping, and peripapillary atrophy. CONCLUSIONS:: A combination of the degree of rim pallor, location of rim pallor, and A : V ratio may be of value in assessing the aetiology of optic disc atrophy when no previous clinical data are available and a compressive lesion has been ruled out.     

Anterior optic nerve blood flow decreases in clinical neurogenic optic atrophy

Anterior optic nerve blood flow was studied in nine patients with unilateral neurogenic optic atrophy using noninvasive techniques. Disk reflectometry measurements from temporal sites demonstrated a significant reduction in the index of blood volume in atrophic optic nerves as compared with the contralateral optic nerves (P less than 0.00001). Laser Doppler measurements from the same temporal sites detected a significant reduction in the speed of blood (P less than 0.002). On average, blood volume was decreased by 49% +/- 11% and blood speed by 30% +/- 17%. Combining the results of these two techniques yielded a relative index of blood flow that showed a significant reduction in the atrophic nerves (P less than 0.0001), averaging 64% +/- 14% temporally. Nasally there was less reduction in blood flow. The results correlated well with clinical assessment of the degree of optic nerve damage (rho = 0.92, P less than 0.002). This study demonstrates that clinical neurogenic optic atrophy induces significant reductions in overall anterior optic nerve blood flow that are detected by these noninvasive techniques.     

Cataract in gyrate atrophy: clinical and morphologic studies

The clinical appearance of the cataract in nine phakic patients with gyrate atrophy of the choroid and retina is described. The gross and microscopic examination of three cataractous lenses removed from patients 31 years to 47 years of age is reported. Clinically, the lens opacities appeared primarily along the confluence of the sutures posteriorly, interfering with vision because of their location in the visual axis. Histologically the region of the posterior sutures was filled with liquified and degenerated lens material typical of senile cataractous changes. By the second decade, cataract is a uniform finding in patients with gyrate atrophy and appears to be unique as compared with cataracts associated with other forms of retinal degeneration.     

Misdiagnosis of Leber's hereditary optic neuropathy (LHON): role of clinical and molecular genetic examinations

Background: Leber's hereditary optic neuropathy is associated with point mutations in the mitochondrial DNA (mtDNA) that appear to be pathogenic for this disease. These mutations affect nucleotide positions 3460, 11 778 and 14 484. Materials and methods: We reviewed the clinical and molecular genetic characteristics of 29 visually symptomatic patients with the clinical diagnosis of LHON. Results: Nine patients really suffered from LHON, but in 20 patients other ocular diseases could be proven. Degeneration of the retina and choroid was most common (seven patients), followed by vascular optic disease (six patients). Three patients suffered from tobacco-alcohol amblyopia, two from optic neuritis and two from autosomal dominant optic neuropathy. Conclusions: The clinical diagnosis of LHON is strengthened by a proven maternal inheritance and clinical signs such as a severe decrease in visual acuity, central or centrocecal scotomas in the perimetry and pseudoedema of the optic disc, followed by optic atrophy. Pathognomonic clinical signs of LHON are twisted vessels and ectatic capillaries in the fundus of these patients and their relatives of the maternal line, i. e., peripapillary microangiopathy. A careful analysis of the patients' pedigrees, anamnesis and the functional and morphological results of the clinical examinations helps to avoid misdiagnosis of the disease. However, the expensive and time-consuming molecular genetic analysis is always necessary to confirm or exclude the diagnosis of LHON.      

Regression of drusen or vitelliform material heralding geographic atrophy: correlation between clinical observations and basic science

Graefe's Archive for Clinical and Experimental Ophthalmology -     

Dominant optic nerve atrophy with progressive hearing loss and chronic progressive external ophthalmoplegia (CPEO)

This paper describes a family where chronic progressive external ophthalmoplegia is associated with dominant optic atrophy and progressive sensorineural deafness. This may be a possible association in the same family of two diseases: progressive external ophthalmoplegia and dominant optic atrophy with progressive hearing loss. However, we believe that this family represents an unusual manifestation of ophthalmoplegia plus.     

X-linked retinoschisis: a clinical and molecular genetic review

X-linked retinoschisis is a leading cause of macular degeneration in male children. It is characterized by a high degree of clinical variability. Clinical features include a stellate foveal retinoschisis, with or without peripheral retinoschisis. The schisis occurs within the inner retina, primarily at the level of the nerve fiber layer. The disease-causing gene, X-linked retinoschisis 1, has recently been identified, and is expressed in photoreceptor and bipolar cells. This gene codes for retinoschisin, a secreted protein containing a discoidin domain which may be involved in cellular adhesion or cell-cell interactions. The identification of this gene allows for improved diagnosis and contributes to the understanding of this condition. Visual prognosis is variable, as X-linked retinoschisis exhibits a high degree of phenotypic variability. Although there is no treatment to halt the progressive maculopathy, clinical management is directed toward treatment of amblyopia and surgical correction of certain complications. X-linked retinoschisis is an important condition to study, both to improve the clinical management of this disorder, and to better understand retinal function and development. Herein, we review the clinical, histopathologic, and molecular genetic and treatment options of X-linked retinoschisis.     

慢性青光眼和非青光眼视神经萎缩黄斑厚度的比较

目的 对比慢性青光眼和非青光眼视神经萎缩的黄斑厚度的差异,找出两者的异同.方法 选取2012年1月至2014年9月在我院门诊和住院治疗的患者为研究对象,其中慢性青光眼11例17眼为青光眼组,非青光眼视神经萎缩患者20例26眼为非青光眼组;选择同期正常老年女性23名44眼为对照组,对三组均进行黄斑区OCT 3D模式扫描,并对黄斑的平均及各方位厚度进行分析.结果 黄斑厚度青光眼组为(243.76±16.93)μm,非青光眼组为(245.45±12.80) μm,对照组为(273.06±14.86) μm,青光眼组较对照组黄斑厚度下降28.58 μm,非青光眼组较对照组黄斑厚度下降27.81 μm(均为P＜0.05);黄斑中央区厚度三组无明显差异(均为P＞0.05);青光眼组、非青光眼组与对照组相比,黄斑内环、外环各区均有变薄,差异均有统计学意义(均为P＜O.05).青光眼组与非青光眼组相比,黄斑厚度除颞外区存在差异外,其他各区数据对比差异均无统计学意义(均为P＞0.05).结论 慢性青光眼与非青光眼视神经萎缩患者黄斑厚度均变薄,黄斑厚度扫描并不能鉴别两者.     

视神经萎缩和视神经炎时VEP潜时异常的比较

目的 :比较视觉诱发电位 (VEP)检查在视神经萎缩和视神经炎两种疾病时的区别。方法 :3 7例 66眼视神经萎缩和 14厘 2 6眼视神经炎患者接受了给撤图型VEP (P -VEP)和闪光VEP (F -VEP)检查 ,其中最佳矫正视力低于 0 0 3者仅接受F -VEP检查。结果 :视神经萎缩时的P -VEP潜时均值延迟程度低于视神经炎 (P <0 0 5 ) ,但F -VEP恰好相反。视神经萎缩和视神经炎时的P -VEP和F -VEP潜时异常率分别是 74%和 65 % ,90 %和 42 % (P <0 0 5 )。视神经萎缩和视神经炎时仅在F -VEP检查时表现出潜时异常的患眼百分率 ,在全部患眼和视力低于 0 0 3患眼分别是 2 3 %和 9% ,12 %和 5 %。结论 :视神经萎缩时的P -VEP潜时延迟程度低于视神经炎 ,但F -VEP相反 ;因此 ,视神经萎缩时F -VEP联合应用的检查价值比视神经炎时高。另外 ,两种疾病时F -VEP联合应用的检查价值不仅仅在具有不能接受P -VEP检查的视力患眼中存在 ,而且在具有能接受P -VEP检查的视力患眼中也仍然存在。     

Choroidal rupture and optic atrophy.

The association between post-traumatic optic disc pallor and traumatic choroidal rupture is poorly understood. To further define this relationship, nine cases of indirect traumatic choroidal rupture and post-traumatic optic disc pallor were compared with cases of indirect choroidal rupture without disc pallor in terms of severity of ocular injury, fundus findings, and visual outcome. The type and severity of the injury did not appear to influence the risk of optic disc pallor. Optic disc pallor was associated with a slightly poorer long term visual acuity than eyes without pallor (p = 0.059). The presence of a relative afferent pupillary defect was strongly associated with optic disc pallor (p = 0.016). Peripapillary retinal pigment epithelial abnormalities were a common finding, suggesting peripapillary trauma as a cause for optic disc pallor.     

Creutzfeldt-Jakob disease and optic atrophy.

A 49-year-old man developed ataxia, myoclonic jerks, cortical blindness, and dementia. In 3 1/2 months, he rapidly deteriorated and died. Clinical and autopsy diagnosis confirmed Creutzfeldt-Jakob disease. The eyes were examined and bilateral optic atrophy was noted. No other ocular changes were noted. Optic atrophy had not been noted before death.     

Adult-onset cyclic esotropia and optic atrophy

A 37-year-old man developed periodic esotropia with 4-day cycles. He was unique because of his age, negative family history for strabismus, bilateral optic atrophy, and absence of light perception in the deviating eye. Adult-onset cyclic esotropia in a blind eye is reported. This afferent defect may lead to secondary changes in the central nervous system, and fusional potential is not necessary for cyclic esotropia to occur.