Ординатура / Офтальмология / Английские материалы / Essentials in Ophthalmology Pediatric Ophthalmology Neuro-Ophthalmology Genetics_Lorenz, Borruat_2008

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gon laser therapy, photodynamic therapy, or surgical ablation is available. However, two specific surgical maneuvers have recently been used in order to treat patients with ODD.

In the past few years, radial optic neurotomy has been proposed to treat a subset of patients with central retinal vein occlusion. A few patients with the progressive form of nonarteritic anterior

ischemic optic neuropathy have also been treated with radial optic neurotomy. Radial optic neurotomy has been successfully used in one patient with ODD who acutely lost vision, resulting in a drastic recovery of visual function in the treated eye [22]. However, this is the only patient reported in the literature, and such an outcome is still anecdotal.

Optic nerve sheath fenestration (ONSF) is aimed at decompressing the retrolaminar optic nerve when excessive fluid is present within the optic nerve sheath. Thus far, the only recommended use of ONSF is in progressive optic neuropathy resulting from increased intracranial pressure. Optic nerve sheath fenestration has been demonstrated to be harmful in treating nonarteritic anterior ischemic optic neuropathy. One group from Slovenia claimed a successful outcome after ONSF in 62 patients with disorders as diverse as idiopathic intracranial hypertension,

anterior ischemic optic neuropathy, low-tension glaucoma, central retinal vein occlusion, amiodarone neuropathy and ODD [25]. In total, 19 eyes with ODD were treated and improved visual acuity was noted in 10/19 eyes and improved computerized visual field in 13/19 eyes, with a median follow-up of 12 months (2 weeks to 2 years). However, details of this study were scarce and no other study has ever examined this therapeutic option in ODD. More studies by other groups are needed to confirm these results.

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4.1 Introduction

Inherited optic neuropathies are a diverse group of conditions in which optic nerve dysfunction and optic atrophy arise as a result of loss of retinal ganglion cells. They are inherited in a Mendelian fashion, as autosomal-dominant, autosomalrecessive or X-linked recessive diseases, or in a non-Mendelian pattern, so-called maternal or

mitochondrial inheritance. They share common clinical features, which comprise a bilateral, symmetrical, painless, reduced visual acuity, colour vision defects, central or centro-caecal visual field loss and pallor of the optic disc. This pattern suggests that papillomacular bundle involvement is also a common feature. Electroretinography shows a normal flash electroretinogram, suggesting normal outer retinal and photore-

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ceptor function. An absent or delayed pattern visually evoked potentials and a reduction of the N95 waveform on the pattern electroretinogram are consistent with a primary ganglion cell dysfunction. The optic neuropathy is generally permanent, may be progressive and is currently irreversible. The underlying pathophysiology remains a subject for considerable research and remains largely unknown in many of these conditions.

However, independent of mode of inheritance, there is tremendous phenotypic variability both within and between families, affecting age and mode of onset, severity of the visual loss, colour deficit and overall prognosis. A number of different genes in both nuclear and mitochondrial genomes underlie these disorders. Some manifest with disease restricted to the eye, whilst others have more widespread systemic associated features, many of which are neurological.

In this chapter the inherited optic neuropathies are classified as follows:

•Primary inherited optic neuropathies with ocular manifestations

•Primary inherited optic neuropathies with significant systemic features

•Optic neuropathies secondary to hereditary degenerative disease.

Discussion will focus on the primary inherited optic neuropathies.

4.2Primary Inherited Optic Neuropathies with Ocular Manifestations

In the primary hereditary optic neuropathies cell death is confined to the retinal ganglion cells (RGCs) of the inner retina. These inherited optic neuropathies comprise autosomal-dominant, autosomal-recessive and X-linked recessive optic atrophy, and the maternally inherited Leber’s hereditary optic neuropathy (Table 4.1). However, some individuals presenting with optic neuropathy may have no family history, in which case it is important to exclude an acquired cause and examine related family members, who may be sub-clinically affected.

4.2.1Autosomal-Dominant Optic Atrophy

4.2.1.1 Clinical Features

Autosomal-dominant optic atrophy (ADOA, OMIM 165500, [26]) is the commonest hereditary optic neuropathy, with an estimated disease prevalence of 1:12,000 to 1:50,000 [28]. The disease presents in childhood, often insidiously making an exact age of onset hard to establish, typically between 4 and 6 years of age. In mild cases it may remain sub-clinical until early adult life and rarely severe cases have been diagnosed as early as 1 year of age. It presents with bilateral, symmetrical visual loss and temporal disc pallor. Investigation may reveal a central or centro-caecal visual field defect and colour vision abnormality. Visual acuity ranges from 6/6 (1.0) to perception of light (which, however, is rare), with a median acuity of 6/36 (0.16). Visual acuity equal to or better than 6/12 (0.5) is seen in about 15% of patients [48]. Nystagmus is uncommon and is seen only if there is severe visual impairment from infancy.

There is considerable variability both within and between families. Visual acuity may decline slowly with age, but rarely is this dramatic [28, 48], and vision does not recover spontaneously. The optic nerve appearances range from subtle temporal pallor to complete atrophy (Fig. 4.1). About 55% of patients may be expected to have subtle or temporal pallor and 44% may have total atrophy [48]. Very rarely the nerve may appear normal. Whilst the intra-ocular pressure is normal and optic disc cupping is not typical, some patients may have a degree of atypical cupping, making the exclusion of normal tension glaucoma all the more difficult [18, 49]. Magnetic resonance imaging of the optic nerve in affected patients reveals a reduced optic nerve-sheath complex throughout the length of the intra-or- bital optic nerve with no signal abnormality and a clearly visible cerebrospinal fluid space. Perimetry shows a central, paracentral or centro-caecal defect, with a reported predominance of defects in the superotemporal visual field. The peripheral fields are usually full, but there may be an inversion of red and blue isopters [26]. The dyschromatopsia may be an acquired tritanopia, but is often a generalized dyschromatopsia [44], and even a

Table 4.1.  Genetics of primary inherited optic neuropathies. (ADOA Autosomal-dominant optic atrophy, ADOAC autosomal-dominant optic atrophy and cataract, AROA autosomal-recessive optic atrophy, LHON Leber hereditary optic neuropathy, OMIM Online Mendelian Inheritance in Man, X-LOA X-linked optic atrophy)

Manifestations Ocular with Neuropathies Optic Inherited Primary  2.4

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Table 4.1.  (continued) Genetics of primary inherited optic neuropathies. (ADOA Autosomal-dominant optic atrophy, ADOAC autosomal-dominant optic atrophy and cataract, AROA autosomal-recessive optic atrophy, LHON Leber hereditary optic neuropathy, OMIM Online Mendelian Inheritance in Man, X-LOA X-linked optic atrophy)

Neuropathies Optic Inherited 54

red-green defect may be seen. Best preserved colour vision and least field loss have been noted in patients with the least degree of clinical optic atrophy. Many of these features are suggestive of preferential involvement of the papillomacular bundle. In this context current evidence suggests that neither the parvocellular nor the magnocellular pathway is preferentially involved [48].

important to exclude other causes of optic neuropathy before making the diagnosis.

4.2.1.4Molecular Genetics and the Genetic Heterogeneity of ADOA

Currently, ADOA is associated with three mapped genetic loci: OPA1, OPA3 and OPA4.

4.2.1.2 Electrophysiology

Pattern visually evoked cortical potentials are absent or delayed, consistent with a conduction defect in the optic nerve. The pattern electroretinogram shows an abnormal N95:P50 ratio, with a reduction in the amplitude of the N95 waveform [20], supporting a ganglion cell defect. A small number of families with ADOA have been reported to have a negative electroretinogram.

4.2.1.3 Histopathology

Histopathology reports of human eyes suggest a primary retinal ganglion cell loss [22, 27] with an ascending optic atrophy and a preserved outer retina.

4.2.1.4.1 OPA1 Locus

Families with dominant optic atrophy were mapped by linkage analysis to a large interval on chromosome 3q28-qter [17] in 1994, subsequently refined to 1.4 cM [47]. A large number of dominant families have been reported to map to the locus on chromosome 3q28-qter, suggesting that it may be the predominant locus for dominant optic atrophy. The former estimated penetrance figure of 98% in dominant optic atrophy has been revised recently in the light of molecular studies, and recent estimates of penetrance vary from family to family and mutation to mutation, being as high as 100% [45], and as low as 43% [46].

Summary for the Clinician

■Inherited optic neuropathies share many common clinical features, such as optic atrophy, dyschromatopsia, central or centro-caecal field defect.

■There is considerable phenotypic variation both within and between families.

■A detailed history of onset of visual loss and family history can be essential in making a diagnosis.

■In many cases it may be highly informative to examine parents and relatives in order to confirm the mode of inheritance.

Sporadic cases of inherited optic neuropathy arise frequently. In such cases it is particularly

4.2.1.4.2 OPA1 Gene and Mutations

The OPA1 gene [2, 15] (GenBank Acc. No. AB011139, OMIM 605290) is 6031 nucleotides long and is composed of 31 exons spanning >114 kb of genomic DNA. OPA1 is ubiquitously expressed on Northern blot analysis of RNA from human tissue, with most abundant expression in retina and brain. Alternative splicing gives rise to eight splice variants [16]. Two splice variants are particularly highly expressed in fetal brain, retina and heart.

There is a wide spectrum of mutations described to date, with over 110 of them reported (http://lbbma.univ-angers.fr). Mutations are dispersed throughout the gene, but there is a concentration of mutations in the GTPase and dynamin central regions, coded for by exons 8–16, and in the C-terminal coding region by exons 27–28. No mutations have been found in exons 4, 4b and 5b, which are alternately spliced. Mutations