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Journal of Pediatric Genetics 3 (2014) 271–280 DOI 10.3233/PGE-14108 IOS Press

Congenital optic nerve anomalies and hereditary optic neuropathies Gena Heidary∗ Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

Received 20 November 2014 Revised 24 November 2014

Abstract. Congenital and hereditary optic nerve anomalies represent a significant cause of visual dysfunction. While some optic nerve abnormalities affect the visual system alone, others may be associated with neurologic and systemic findings. Correct identification of the optic nerve disease therefore is crucial both for developing a treatment plan with respect to visual rehabilitation, but also for initiating the appropriate multidisciplinary evaluation. The purpose of this review is to highlight common examples of congenital and inherited optic nerve abnormalities in an effort to familiarize the clinician with salient clinical features of these diseases and to review important systemic testing when relevant. Keywords: Optic nerve, coloboma, optic nerve hypoplasia, hereditary optic neuropathy, Aicardi syndrome, optic nerve drusen, optic nerve pit, morning glory disc

2. Congenital optic nerve anomalies

amongst the top ten reasons for children in the United States to attend a school for the blind [1]. Initial signs that may suggest optic nerve abnormalities include nystagmus (abnormal to-and-fro movement of the eyes) in infancy when there is bilateral involvement of the eyes or strabismus (eye misalignment) when there is unilateral involvement of an eye [2]. In this section, congenital optic nerve anomalies including optic nerve coloboma, optic nerve hypoplasia, and optic nerve head drusen will be discussed. Further, a focus on appropriate ancillary testing in the setting of optic nerve anomalies will be discussed in an effort to familiarize the clinician with systemic and neurologic associations that may be found in patients who harbor optic nerve disease [3].

Congenital optic nerve anomalies are a significant cause of visual impairment in children and rank

2.1. Optic nerve coloboma

∗ Corresponding author: Gena Heidary, MD, PhD, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Fegan 4, Boston, MA 02115, USA. Tel.: +1 617-355-6401; Fax: +1 617-730-0392; E-mail: [email protected]. edu.

Optic nerve colobomas develop from a failure of the proximal optic fissure to close during early development of the optic nerve. The manifestations are broad and may include defects extending anteriorly from

1. Introduction Vision loss secondary to developmental or hereditary abnormalities of the optic nerves represents an important cause of visual dysfunction. While some of these conditions may affect vision alone, others may be associated with significant neurologic or systemic abnormalities. The purpose of this review is to highlight common examples of congenital and inherited optic nerve abnormalities in an effort to familiarize the clinician with salient clinical features of these diseases and to review important systemic testing when relevant.

2146-4596/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved

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Accepted 24 November 2014

G. Heidary / Optic nerve anomalies and hereditary optic neuropathies

ion and less commonly as an autosomal recessive process [4]. Clinicians should be familiar with syndromes associated with the presence of optic nerve coloboma. A common associated genetic syndrome is CHARGE whose acronym stands for the following clinical features: coloboma, heart defect, atresia choanae, retarded development, genitourinary and ear anomalies [7]. Recently, mutations in the chromodomain helicase DNA-binding protein 7 gene (CHD7) were identified as causative in CHARGE syndrome [8]. The condition is inherited in an autosomal dominant fashion with marked phenotypic variability [9]. Genetic testing is available when considering the diagnosis of CHARGE. When CHARGE is suspected, a multidisciplinary evaluation including genetics, otolaryngology, cardiology, renal and often neurology may be involved to establish the diagnosis and manage patients with this condition. Fig. 1. Optic nerve and chorioretinal coloboma left eye. Fundus photograph of the left eye with colobomatous defect involving the inferior half of the optic nerve and adjacent choroidal tissue. The fovea appears to be intact.

the iris to the lens, optic nerve, and retina/choroid posteriorly [4]. With respect to the optic nerve, a colobomatous defect may appear as a notch in the inferior neuroretinal rim of the optic nerve or as a complete excavation of the optic nerve head (Fig. 1). Unilateral or bilateral eye involvement may be seen. Additional ophthalmic features may include a smaller or microphthalmic eye and/or cysts associated with the colobomatous defect [5]. The effect on visual acuity will be determined by the extent of involvement of the papillomacular bundle or “20/20” seeing part of the eye. Importantly, clinicians should not include eyelid colobomas amongst the defects associated with optic nerve colobomas as the underlying developmental causes of these two entities are distinct and unrelated. Management of optic nerve colobomas includes routine ophthalmologic examinations in an effort to maximize visual function. The clinician should be aware of the possibility of retinal detachment in the area of the colobomatous defect when it involves the adjacent choroid; therefore, monitor the patient and counsel the parents regarding this possibility accordingly [6]. Optic nerve colobomas usually occur sporadically but may be inherited in an autosomal dominant fash-

2.2. Optic nerve pit An optic nerve pit describes a defect of optic nerve which may appear as a grayish excavation in the nerve and which typically occurs in the temporal aspect of the optic nerve (Fig. 2). In contrast to optic nerve colobomas, optic nerve pits are not considered to result from developmental changes in fetal closure of the optic fissure. Optic nerve pits may occur unilaterally or bilaterally and have been reported to result in visual field loss, which may progress over time [10]. In addition to visual field loss, optic nerve pits are associated with serous retinal detachments of the retina adjacent to the optic nerve pit. A proposed mechanism for retinal detachment involves continuity between the pit and the subretinal space creating a schisis-like cavity [11]. Patients should be counseled that these defects might be associated with serous retinal detachment [12] and seek urgent evaluation should there be a sudden change in vision. 2.3. Optic nerve hypoplasia Optic nerve hypoplasia is among the most common optic nerve anomalies associated with childhood visual impairment. This defect is characterized by small optic nerve often with a surrounding hypopigmented halo or the “double-ring” sign [13] (Fig. 3). The impact on vision varies tremendously from excellent to profoundly impaired and cannot be completely predicted on the basis of the optic nerve appearance alone [14].

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Fig. 2. Optic nerve pit right eye. Fundus photograph of the right eye with grayish excavation on the temporal border of the optic nerve. The fovea is intact without a serous retinal detachment.

This optic nerve anomaly may occur unilaterally or more commonly bilaterally. When unilateral, children may present with strabismus of the affected eye; when bilateral, children often present earlier with nystagmus during infancy [15]. Although the true prevalence of optic nerve hypoplasia is unknown, this anomaly is the third most commonly cited cause of early visual morbidity in children in the United States after cortical visual impairment and retinopathy of prematurity [16]. A review of epidemiologic evidence suggests a strong relationship between primiparity, young maternal age and the occurrence of optic nerve hypoplasia although the basis of this association is yet to be determined [17]. Optic nerve hypoplasia may occur in association with neurologic and endocrinologic abnormalities. In every child with optic nerve hypoplasia, a consideration of the condition termed “septo-optic dysplasia” or “de Morsier syndrome” must be made. This condition is characterized by defects in forebrain development including the absence of the septum pellucidum and agenesis of the corpus callosum as well as pituitary and hypothalamic dysfunction [13]. Septo-optic dysplasia is more likely to occur in patients with bilateral optic nerve hypoplasia although it does occur in patients with unilateral optic nerve involvement [18]. The condition typically occurs sporadically and is rarely familial. Mutations in several transcription factors important in

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Fig. 3. Optic nerve hypoplasia right eye. Fundus photograph of the right optic nerve with small optic nerve and peripapillary halo or “double ring” sign.

forebrain development have been implicated in septooptic dysplasia including OTX2, HESX1, and the SOX family transcription factors SOX2 and SOX3 [19]. In addition to a complete ophthalmic evaluation, patients should undergo neuroimaging including magnetic resonance imaging (MRI) brain and orbits to assess for features of septo-optic dysplasia. Neuroimaging findings may provide insight into developmental prognosis as well. Studies have demonstrated that the extent of corpus callosal dysgenesis portends a worse developmental prognosis [13]. Each child with presumed septo-optic dysplasia requires an endocrinologic evaluation. This should be performed even if the pituitary is anatomically normal on neuroimaging. Growth hormone deficiency is most common although pan hypopituitarism has been described. Because of the severe impact on cognitive development if hypothyroidism is missed and the potential mortality from cortisol deficiency, it is imperative that a thorough evaluation be pursued [20, 21]. 2.4. Aicardi syndrome Aicardi syndrome is characterized by the classic triad of infantile spasms, dysgenesis of the corpus callosum and pathognomonic “punched out” chorioretinal lacunae that surround the optic nerve (Fig. 4) [22].

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G. Heidary / Optic nerve anomalies and hereditary optic neuropathies

G. Heidary / Optic nerve anomalies and hereditary optic neuropathies

Fig. 4. Aicardi syndrome right eye. Characteristic “punched out” chorioretinal lacunae surrounding the right optic nerve.

The ophthalmologist may become initially involved during consultation for an infant who is found to have corpus callosal defects on imaging by either head ultrasound or MRI. The condition is considered to be essentially X-linked lethal in males although there is a male child with XXY genotype [23] and one child with XY genotype reported with Aicardi syndrome [24]. Children will have profound developmental delay and epilepsy, although more recent reports suggest that the level of mental impairment may vary [22, 25]. 2.5. Morning glory optic nerve This is a sporadic condition that clinically appears as a large optic nerve with a central glial tuft and peripapillary chorioretinal pigmentary changes (Fig. 5) [26]. This anomaly appears to result from an excavation of the optic nerve head that involves the entire optic nerve in contrast to the optic nerve coloboma, which involves a failure of the neuroretinal rim to close. The morning glory description is used, as the central glial tuft is reminiscent of the central white of a morning glory flower [27]. Clinically patients will present with a poorly seeing eye and strabismus. The degree of vision loss is usually profound. Commonly, this occurs unilaterally but bilateral cases have been reported [28]. Often it may be difficult to distinguish morning glory optic nerve anomaly from optic nerve coloboma. Findings on

Fig. 5. Morning glory optic nerve. Characteristic central glial tuft, radially oriented vessels emanating from the optic nerve, and surrounding chorioretinal pigmentary changes.

MRI that may help to solidify the diagnosis of morning glory optic nerve include the following: excavation of the posterior optic nerve with a funnel-shape and discontinuity of the sclera in the area of the optic nerve defect [29]. Additional work up for these patients should always include neuroimaging. A MRI brain and magnetic resonance angiography head are recommended because of the association between morning glory optic nerve anomaly and basal encephalocele and/or the vascular disease moyamoya syndrome [28, 30]. 2.6. Papillorenal syndrome This condition describes optic nerve changes characterized by an excavated optic cup without central vasculature, radially oriented vessels emanating from the periphery of the optic nerve, and cilioretinal vessels emanating from the edge of the nerve supply the retina (Fig. 6) [31]. Clinically, the level of visual impairment varies and therefore the identification of this optic nerve change may occur incidentally. Papillorenal syndrome displays autosomal dominant inheritance. Mutations in the PAX2 gene on 10q24.3–25.1 have been implicated and genetic testing is available to confirm the diagnosis.

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Fig. 6. Papillorenal syndrome involving right optic nerve. Note vacant central aspect of the optic nerve with vessels directed radially from the edge of the disc rather than from the central aspect of the optic nerve.

The most significant association with the optic nerve changes are renal anomalies, vesicoureteral reflux or other genitourinary anomalies. In addition, sensorineural hearing loss and midbrain/hindbrain anomalies have been reported [32]. Evaluation should include renal consultation with consideration of urinalysis and renal ultrasound. In addition, children would benefit from formal audiologic evaluation and potentially neuroimaging. 2.7. Optic nerve head drusen Optic nerve head drusen have been described as calcium or hyaline bodies, which accumulate within the substance of the optic nerve. The pathogenesis is unclear although it has been proposed to be secondary to a dysplastic optic nerve or small scleral canal and its blood supply leading to chronic axoplasmic flow disturbance and accumulation of this substance over time [33]. When familial, the occurrence of optic nerve head drusen is transmitted in an autosomal dominant fashion. Clinically, optic nerve head drusen may not be visible initially but give the appearance of optic nerve edema, yielding the term “pseudopapilledema.” Optic nerve may develop optic nerve drusen over time and be visually asymptomatic (Fig. 7). The critical clinical

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Fig. 7. Optic nerve head drusen or pseudopapilledema right eye. The border of the optic nerve appears irregular and areas of calcific changes can be seen on clinical exam along the superonasal border of the nerve. Note that the retinal vessels are clearly delineated without obscuration.

goal is to distinguish optic nerve head drusen (pseudopapilledema) from true papilledema because they may have similar features on clinical exam but are distinct in the workup and underlying etiology. Identification of optic nerve head drusen may be done with B-scan ultrasound, fundus autofluorescence and on dedicated computed tomography scan of the orbits. For children, to limit radiation exposure from computed tomography, the B-scan ultrasonography is the preferred method to confirm the presence of optic nerve head drusen [34, 35]. With age, optic nerve head drusen may be associated with visual field defects [36]. In addition, accumulation of optic nerve head drusen may be associated with ischemic optic neuropathy [33] or choroidal neovascularization [37].

3. Hereditary optic neuropathies Hereditary optic neuropathies are characterized by symmetric, bilateral central vision loss. Autosomal dominant, autosomal recessive and mitochondrial inheritance patterns have been observed for these conditions. Although the genetic basis for many of these conditions has been identified, often the initial strategy for making a diagnosis may be difficult. A useful

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G. Heidary / Optic nerve anomalies and hereditary optic neuropathies

paradigm is to stratify the clinical findings based on isolated visual dysfunction versus visual dysfunction in association with neurologic or systemic disease [38]. This review will examine the most common types of hereditary optic neuropathy using the rubric outlined above.

Dominant optic atrophy (DOA) or Kjer’s optic atrophy is an autosomal dominantly inherited condition that occurs with an estimated prevalence of 1 in 35,000 and is the most commonly inherited hereditary optic neuropathy [39, 40]. The disease is characterized by onset of vision loss during the first decade of life with progressive visual decline thereafter. The disease course is slowly progressive with an anticipated course of retaining vision in the legally blind range of 20/200. Characteristic findings on clinical exam include initially temporal atrophy of the optic nerves and later more global atrophy (Fig. 8). This optic nerve appearance is not specific for dominant optic atrophy and reflects the optic nerve appearance in many hereditary optic neuropathies. Patients will have evidence of dyschromatopsia or color deficiency and on visual field testing will be noted to have central scotomata or visual field deficits [39]. Optical coherence tomography will demonstrate thinning of the retinal nerve fiber layer reflecting progressive loss of neuronal tissue that comprises the optic nerve [41–43]. Spontaneous recovery is exceedingly rare [44]. Genetic mutations in the OPA1 gene (OMIM 165500) on 3q29 are causative for the majority of patients with DOA [45]; multiple additional loci have been associated with DOA with causative mutations identified in the OPA3 gene [46]. In those patients who harbor OPA3 mutations, optic atrophy may be associated with the presence of early onset cataracts [47]. Evaluations of pedigrees with a large number of affected family members have suggested incomplete penetrance and variable expressivity [48]. Genetic testing for OPA1 and OPA3 is commercially available. In addition to the classic DOA phenotype, which involves isolated optic atrophy, a clinical syndrome called “DOA-plus” exists. Patients, in addition to optic atrophy, also demonstrate sensorineural hearing loss, progressive external ophthalmoplegia, ataxia, and peripheral neuropathy. In a large population study of 104 patients with OPA1 mutations, 20% were noted to exhibit the multisystemic phenotype [49].

Fig. 8. Optic atrophy in OPA1-associated dominant optic atrophy of the right eye. The optic nerve appears with significant temporal pallor and mild cupping of the optic nerve.

Evaluation of patients with DOA should include genetic testing to confirm the diagnosis, audiologic evaluation for hearing loss, and neurologic evaluation when DOA-plus phenotype is suspected. Treatment of DOA is limited. In one open label pilot study of 8 patients, use of the co-enzyme Q10 related medication idebenone demonstrated some improvement in visual acuity, color vision and visual field deficits [50]. Management should be aimed towards registration with the appropriate social services for the visual impaired and formal low vision evaluation to provide appropriate tools to aid in maximizing visual function. 3.2. Leber hereditary optic neuropathy Leber hereditary optic neuropathy (LHON, OMIM 535000) is a mitochondrially inherited optic neuropathy that occurs with an estimated prevalence of in Europe of 1 in 45,000 [51]. This disease is clinically characterized by an acute/subacute, painless vision loss that predominantly affects young adult men with a peak incidence during the second and third decades. Vision loss may initially occur in one eye followed by the other and in 25% of cases, it may occur simultaneously. The tempo of vision loss is rapid with a precipitous and profound loss of visual acuity to the level of legal blindness

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3.1. Dominant optic atrophy

G. Heidary / Optic nerve anomalies and hereditary optic neuropathies

3.3. Optic atrophy with associated neurologic or systemic disease Increasingly with the advent of genetic testing, it is becoming clear that there are constellations of hereditary optic neuropathies that collectively affect mitochondrial function. The manifestations are myriad including optic atrophy in association with deafness, cardiac dysfunction, endocrinologic abnormalities,

and neurodegenerative disease. Responsible genes are encoded both by the mitochondria and also nuclearly encoded. The number of associated conditions continues to increase. The following section will highlight several examples of optic atrophy associated with systemic or neurologic disease. 3.4. Wolfram syndrome Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and deafness) is an autosomal recessive condition with an estimated prevalence of 1 in 100,000 in the United States. Two causative genes have been identified: WFS1 or wolframin on 4p16.1 [62] and CISD2 on 4q22 [63]. Both genes encode proteins that localize to the endoplasmic reticulum. The condition was first described by Wolfram and Wagener as a syndrome of diabetes mellitus and optic atrophy. The clinical phenotype of Wolfram syndrome may become apparent in an asynchronous fashion but includes endocrinologic dysfunction, optic atrophy, and hearing loss. In their case series, Lessell and Rosman [64] found that the mean age of onset of diabetes mellitus was 5.5 yr, optic atrophy and hearing loss 11 yr. The first insight into diagnosis may come from an ophthalmologic examination in which optic atrophy is identified in a young child with a known history of diabetes mellitus. Vision may deteriorate to the range of legal or complete blindness. Neurologic sequelae develop during the second decade of life including cognitive impairment, psychosis, and cerebellar dysfunction. Ultimately, death may ensue secondary to brainstem dysfunction [65]. Currently, there is no cure for this condition. When Wolfram disease is suspected, patients should undergo genetic testing, ophthalmic evaluation, endocrinologic and audiologic evaluations. 3.5. Costeff syndrome Costeff syndrome or 3-methylglutaconic aciduria type III is a rare, recessively inherited disorder characterized by optic atrophy, spastic paraplegia and chorea [66]. The syndrome is thought to have arisen as a founder effect mutation, which predominantly affects patients of Iraqi Jewish descent. Optic atrophy ensues early and is accompanied by developmental delays early in infancy followed by progressive neurologic dysfunction later [66]. Mutations in the OPA3 gene

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or worse [52]. Initially, the optic nerve may have a hyperemic appearance nasally with telangiectasias of the optic nerve head. Later in the course, the optic nerve will appear pale. Patients will harbor visual field loss centrally and exhibit dyschromatopsia or color vision deficits. Over the clinical course of the disease, there may be spontaneous improvement of visual acuity that may occur even within years from the initial onset of vision loss [52]. Causative mutations in the mitochondrial genome have been identified. Three LHON mutations account for the majority of disease: m.11778G >A, m.3460G >A, m.14484T >C. These genetic changes affect proteins relevant for complex I of the respiratory chain complex [53]. Spontaneous recovery from vision loss is believed to occur most commonly in patients harboring the 14484 mutation and far more rarely in patients with the 3460 or 17778 mutations [52]. In association with LHON, patients may have additional systemic symptoms including peripheral neuropathy or cardiomyopathy; in some pedigrees, more severe neurologic dysfunction has been reported including brainstem dysfunction [54] or pediatric onset dystonia [55]. In women, a multiple sclerosis-like phenotype with LHON has been described known as Harding syndrome or LHON-MS [56, 57]. Therefore, once a diagnosis of LHON is made, consultation with neurology and cardiology may be helpful. Regarding treatment, a placebo-controlled prospective study as well as a retrospective study using the coenzyme Q10 idebenone for treatment of patients with LHON have been somewhat favorable although not definitive [58–60]. Management should be aimed towards registration with the appropriate services for children and adults with visual impairment. Low vision services should be sought to maximize remaining vision. Patients should be advised to avoid exposures, which may exacerbate vision loss with particular emphasis on smoking cessation [61].

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responsible for dominant optic atrophy have also been implicated in this recessively inherited optic atrophy syndrome [67].

[5]

[6]

3.6. C12orf65-associated optic atrophy [7]

Mutations in the C12orf65 [65] gene which localizes to 12q24.31 are now being identified as a novel cause of hereditary optic neuropathy. This was initially described in 2010 in two families with a Leigh syndrome like phenotype who developed nystagmus, vision loss and optic atrophy. Neuroimaging findings of bilateral T2 hyperintense lesions within the brainstem were observed reminiscent of what is observed in the neurodegenerative disease Leigh syndrome [68]. Subsequently, mutations in the same gene were associated with optic atrophy and spastic paraplegia [69]. The number of reported patients and families with this form of hereditary optic neuropathy continues to expand and therefore genetic testing for mutations in the C12orf65 [65] gene should be considered in patients with optic atrophy in the setting of associated neurologic disease [70–72].

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[12]

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4. Summary Significant visual morbidity may be associated with congenital and hereditary optic nerve anomalies. For the clinician, focus should be placed on maximizing visual potential with proper refraction, low vision aids, and registration with the appropriate services for visual impairment. Recognition of the specific optic nerve finding and its associated systemic manifestations is critical. When appropriate, a multidisciplinary evaluation, which may include genetic testing, should be initiated.

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Congenital optic nerve anomalies and hereditary optic neuropathies.

Congenital and hereditary optic nerve anomalies represent a significant cause of visual dysfunction. While some optic nerve abnormalities affect the v...
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