emery and rimoin's principles and practice of medical genetics || optic atrophy

Optic AtrophyGrace C Shih and Brian P Brooks

Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Bethesda, MD, USA

C H A P T E R

134

This article is a revision of the previous edition article by Veronique J Arnould-Devuyst, Irene Hussels Maumenee, Bruce R Korf, volume 3, pp 3115–3132, © 2007, Elsevier Inc.

GLOSSARYDyschromatopsia – difficulty or inability to discriminate

colors, sometimes of a particular type (e.g. tritan deficiency is difficulty with discrimination along the blue–yellow axis).

Ganglion cells – the innermost neural retina cells whose axons form the optic nerve.

Nystagmus – an involuntary, rhythmic or wandering movement of the eyes that may be caused by early-onset visual dysfunction and/or brain pathology.

Optic nerve – the second cranial nerve, consisting of axons from ganglion cells of the retina and glial tissue. These axons largely synapse in the lateral geniculate nucleus of the thalamus, after partially decussating at the optic chiasm.

Papillomacular bundle – the mitochondria-rich ganglion cell axons which synapse with macular neural retinal.

Scotoma – a complete or relative inability to discriminate a light stimulus at a particular location of the visual field.

134.1 INTRODUCTION

The optic nerve is composed of over 1 million axons that originate in the retinal ganglion cells (the innermost cel-lular layer of the retina) and synapse largely in the lateral geniculate nucleus of the thalamus. These axons gather at the posterior portion of the eye, where—along with central nervous system glial tissue—they form the optic disc. It is largely from clinical examination of the optic disc that optic atrophy—a loss of retinal ganglion cell axons—is diag-nosed. The optic nerve travels through the posterior orbit and through the optic canal of the skull. The two nerves meet at the anterior floor of the third ventricle to form the optic chiasm; there, the nasal fibers from each eye decus-sate to the opposite side of the brain, whereas the temporal fibers remain ipsilateral. In general, anything that causes harm to retinal ganglion cells or injures their axons along this course will lead to optic atrophy. Injury may be pri-mary (e.g. the accumulation of metabolic products in some lysosomal storage diseases) or secondary (e.g. compression of the optic nerve by overgrowth of bone in the optic canal).

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Hereditary optic atrophies may occur primarily as isolated disorders or as part of a systemic syndrome. Because some “primary optic nerve diseaes” can some-times include systemic features, this distinction is not always crisp. This chapter will focus on the two most common primary optic atrophies encountered in clini-cal genetics practice, namely, dominant optic atrophy (DOA, OMIM#1655000, OPA1) and Leber hereditary optic neuropathy (LHON, OMIM#535000), although some attention will be given to rarer forms of optic atrophy. Although LHON and DOA differ in their clini-cal presentation and their genetics (Table 134-1), both result from abnormal mitochondrial function. Readers are referred to Chapter 11 for a discussion of basic mito-chondrial physiology and genetics.

134.2 “PRIMARY” OPTIC ATROPHIES

134.2.1 Dominant Optic Atrophy (Kjer Type) (MIM#165500, OPA1, *605290)

Using Danish pedigrees, Kjer defined the clinical fea-tures of dominant optic atrophy (DOA), distinguishing it from Leber hereditary optic neuropathy (LHON) (1). Although he differentiated two dominant forms—one congenital with nystagmus and one infantile with no nystagmus—he questioned whether this division repre-sented the phenotypic range for the same genetic con-dition. DOA is typically a bilateral, symmetric, primary optic atrophy, with an insidious onset in childhood. Progression is generally slow, resulting in variable visual acuity and field loss with a dyschromatopsia (classicaly, yellow-blue/tritan type) and optic nerve pallor (2). The prevalence of DOA is approximately 1:35,000 (English cohort) to 1:12,000 (Danish cohort), making it one of the most common forms of inherited optic atrophy (3).134.2.1.1 Clinical Features. DOA typically has an insid-ious to subacute onset in the first decade of life. It has been described in children as early as age 2 years and is often detected when the child starts school; it can occasionally

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2 CHAPTER 134 Optic Atrophy

TABLE 134-1 Comparison of the Clinical Features of Dominant Optic Atrophy and Leber Hereditary Optic Atrophy

Leber Hereditary Optic Atrophy (LHON) Dominant Optic Atrophy, Kjer Type

Inheritance Mitochondrial DNA, maternal Autosomal DominantTypical age of onset 2nd–3rd decade 1st–2nd decadePresentation Acute, painless visual loss Chronic, painless, insidious visual lossGene(s) MTND4 (m.11778G>A)

MTND1 (m.3460G.A)MTND6 (m.14484T>C)Collectively account for >90% cases

OPA1, 3q28–q29

End stage Optic nerve pallor, legal blindness Optic nerve pallor, legal blindnessTreatment None None

start later in life. A British study had, for example, two peaks of age of onset of the symptoms: 5 and 21–30 years (4). Similarly, Johnston et al. found that 58% of indi-viduals had symptoms before the age of 10 (5). Since the identification of mutations in the nuclear-encoded OPA1 gene in a significant percentage of patients with DOA (6) (see below), some clinical reports have focused on patients with confirmed mutations, whereas others have included both mutation-positive and mutation-negative patients. How (if at all) this affects the interpretation of these clinical data is still a subject of debate.

Bilateral loss of visual acuity is the main presenting symptom in DOA. The visual prognosis is relatively good: distance vision typically ranges from 20/70 to 20/100, but can be as good as 20/20 (subclinical), or as poor as light perception (although this is uncommon) (2,4). Visual acuity is usually symmetric, with a typical disparity between the impaired distance vision and the comparatively conserved near vision. DOA is typically slowly progressive, although this may not be univer-sally true (3a,7). Given that DOA predominantly affects the papilomacular bundle (which serves central vision), visual field deficits are usually central or cecocentral, with relative sparing of the retinal periphery. Although a tritan color deficit is classic for DOA, Votruba et al. found that over 80% of individuals have a mixed color deficit (4); color vision defects may precede loss of acu-ity. These same authors note that there is significant intra- and inter-familial variability in phenotype.

Pallor of the temporal optic nerve is the major finding on fundus examination (Figure 134-1). Eliott et al. found that there was no strict correlation between acuity and the degree of optic nerve pallor (8). Recently, Barboni and colleagues noted that the optic nerve heads of DOA patients are generally smaller than in age-matched con-trols (9). Retinal nerve fiber thickness, as measured with optical coherence tomography (OCT), is most severely affected in the temporal quadrant, with relative sparing of the nasal quadrant (10,11). The macular reflex may be unremarkable, decreased, or absent. In contrast to LHON, no vascular changes are described. Barboni et al. argue that the loss of nerve fiber layer thickness over time is similar to the normal aging process, although theirs was

a cross-sectional rather than a longitudinal study (11). The full field electroretinograms (ERG) is typically normal, but the pattern ERG shows a reduced N95 component, in agreement with primary ganglion cell dysfunction (4).

Approximately 20% of patients with OPA1 muta-tions will develop a more severe disease variant, called “dominant optic atrophy plus” (DOA+), with additional neuromuscular features. In addition to cases featuring sensorineural deafness, ataxia, myopathy, peripheral neuropathy, and progressive external ophthalmoplegia (12), Yu-Wai-Man et al. uncovered two novel clinical presentations of DOA: spastic paraparesis was present in two families with DOA, while a phenotype similar to that of multiple sclerosis was exhibited in another fam-ily. Defective cytochrome C oxidative phosphorylation in skeletal muscle is a subclinical feature of patients with OPA1-related dominant optic atrophy, indicating a systemic expression of the OPA1 defect (13). Retinal nerve fiber layer thinning is more pronounced in patients with DOA+ phenotypes (10). Yu-Wai-Man hypothesized that the involvement of other tissue types in DOA+ may be a direct consequence of the greater accumulation of secondary mitochondrial DNA abnormalities, the latter potentiating an already compromised mitochondrial oxi-dative reserve due to the mutant OPA1 protein.

The differential diagnosis includes neuropathies and retinopathies with optic atrophy. LHON, recessive optic atrophy, toxic optic neuropathy, demyelinating diseases, hereditary macular dystrophies have to be considered (14).

Histopathologically, optic atrophy is characterized by general atrophy of the ganglion cell layer as well as partial atrophy of the optic nerve, without atrophy of the outer retinal layers. There is increased collagen in association with a decreased number of neurofibrils and myelin sheaths in the optic nerves, optic chiasm, and optic tracts (15).134.2.1.2 Genetics and Pathogenesis. DOA is inher-ited in an autosomal dominant fashion (1); however, recent evidence has suggested that OPA1 may actually result from semi-dominant inheritance (16). In 2000, two groups simultaneously reported on mutations in the OPA1 gene in DOA (6). Although the penetrance of OPA1 mutations approaches 100%, the expressivity of the phe-notype is quite variable. Pathogenic OPA1 mutations

CHAPTER 134 Optic Atrophy 3

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count for about 60% of all cases (17). The OPA1 rotein localizes to the mitochondria (1) and encodes a TPas related to the dynamin family of proteins (6). In neral, OPA1 mutations are predicted to result in a loss

f protein function, although dominant negative effects f missense mutation alleles have also been proposed. veral lines of evidence suggest that mutations in OPA1 sult in deficient mitochondrial function and bioenerget-s. Skeletal muscle from patients with OPA1 mutations owed reduced mitochondrial adenosine triphosphate

roduction (13). Magnetic resonance spectroscopy simi-rly shows a reduced ATP peak in patients with OPA1 utations (18). Decreased mitochondrial DNA content found in peripheral blood of some patients with OPA1 utations (19). Amati-Bonneau et al. show increased itochondrial network fragmentation and decreased itochondrial membrane potential in skin fibroblasts om patients with R445H mutations in OPA1 (20). Ela-ouri et al. have recently presented evidence that OPA1

important in maintenance of the mitochondrial DNA,

(A)

(B)

GURE 134-1 Dominant optic atrophy. (A) Right eye (OD). (B) ft eye (OS). This 37-year-old man has 20/30 vision in both eyes, tritan color defect, and exhibits the characteristic temporal pallor d atrophy of the disc.

as silencing of the OPA1 gene in vitro resulted in mito-chondrial DNA depletion due to deficient replication (21). In a Drosophila model, Yarosh et al. found that vitamin E and superoxide dismutase were able to reverse the dOpa1 phenotype, suggesting a role of reactive oxygen species in disease pathogenesis (22).

There is evidence of locus heterogeneity in DOA. OPA1 is located on 3q28–29 (6,23). Kivlin et al. described a large North American family of German descent that showed a maximum lod score of 2 at a recombination fraction of 0.18 using the Kidd blood group antigen, which was later assigned to 18q12 mapped a locus (OPA4, OMIM %605293) (24). This locus was further refined by Kerrison et al. (25). Reynier and colleagues identified two different heterozygous mutations in the OPA3 gene (see below) in two families with DOA and cataract (26). Barbet et al. have reported a three-generation French pedigree with DOA that maps to 22q12.1–q13.1 (OPA5, OMIM %610708) (27).134.2.1.3 Management. No clinically proven treat-ment is available. Caution should be observed in trans-lating findings from animal models into humans. Family screening, genetic counseling, and possible molecular diagnosis are indicated.

134.2.2 Leber Hereditary Optic Neuropathy (MIM 535000)

Leber hereditary optic atrophy (LHON) was first described by Theodor Leber in 1871 as a nosologically distinct optic neuropathy. It has long been postulated to be caused by a defect in mitochondrial metabolism, and the first mitochondrial DNA (mtDNA) mutation was found by Wallace’s group in 1988 (see Chapter 11) (28).

LHON has to be distinguished from Leber congenital amaurosis, an autosomal recessive chorioretinal dystro-phy that presents with poor vision at birth. This latter disorder can be associated with variable amounts of optic atrophy. Prevalence of LHON is estimated as 1 in 31,000 to 1 in 50,000, which is comparable to DOA.134.2.2.1 Clinical Features. LHON is classically char-acterized by painless visual loss typically beginning in one eye, and eventually progressing to the other eye over an average interval of 2 months (29). Although rare unilateral cases have been reported (30), the rule is that the second eye will be affected within one year of ini-tial presentation. Up to 25% of cases may present with bilateral visual loss. The deterioration of vision ranges from acute to subacute, and is followed by stability after 3–4 months. Most cases present in the second or third decade of life and approximately 90% of carriers who develop visual loss will do so by age 50 (31). Vision loss, however, can occur at any age and LHON should be included in the differential of acute sequential and/or bilateral optic neuropathy even in older and younger individuals. While approximately 20–60% of at-risk males experience visual loss, only 4–32% of at-risk


females develop visual loss (29). This incomplete pen-etrance and difference in gender susceptibility has been observed across multiple ethnic groups (32). The precise reason for these observations is unclear.

Careful electrophysiological and psychophysical test-ing has revealed abnormalities in color discrimination, subtle edema of the nerve fiber layer, subclinical central scotomas, abnormal multifocal ERGs, and abnormal visual evoked potentials prior to the onset of overt symp-toms (33). Given the ethical and social consequences of presymptomatic diagnosis (e.g. inability to obtain dis-ability or long-term care insurance), care should be taken in approaching the examination of asymptomatic family members of an affected individual.

Classically, the disease occurs as “thunder in a dry sky,” i.e. as an isolated vision loss without prodromal symptoms, although migraine-like headaches occur in up to 33% of the affected patients (34). During the acute phase, circum-papillary telangiectatic blood vessels, hyperemia of the disc, vascular tortuosity of the retinal blood vessels, and intracellular edema of the nerve fiber layer without leak-age on fluorescein angiography are typical (Figure 134-2). Affected individuals develop a central or cecocentral sco-toma and impaired color vision. Pupillary responses may be relatively preserved for the degree of vision loss (35). However, some patients experience symptoms while pre-senting with of a normal eye exam, sometimes leading to an erroneous initial diagnosis of functional vision loss. Over time, the optic nerve becomes increasingly pale. The final visual outcome is variable, ranging from 20/50 to no light perception. Vision loss is generally permanent, although there may be some mild recovery of “islands” within the visual field over time. Kirkman et al. have docu-mented significant effects of LHON on patients’ quality of life, as scored on the Visual Function Index (VF-14) questionnaire (36). Some genotype–phenotype correlation has been reported (see below).

With the advent of OCT, one can now correlate phys-ical abnormalities of the retina and optic cup with the severity of visual acuity changes in patients with LHON. Spectral domain OCT allows for high resolution imag-ing and quantitative analyses of the retinal layers, thus allowing for sequential analysis of the progression of dis-ease in LHON patients, as well as distinguishing between retinal disorders of the inner retinal layers and disorders of the outer retinal layers, such as LHON and DOA (37). The retinal nerve fiber layer (RNFL) is thickened in early (<6 months duration) LHON, and severely thinned in late (>6 months duration) LHON, with inferior and temporal fibers (papillomacular bundle) being the first and most severely affected (38). Additionally, males with LHON demonstrate a more diffuse retinal nerve fiber layer involvement than females on OCT imaging (33a). When assessed by Heidelberg Retina Tomograph (HRT), the eyes of LHON patients demonstrated significantly larger cup parameters, smaller rim volume, and thin-ner mean RNFL thickness than controls (39). Newman et al. found presymptomatic changes in static automated perimetry in patients with LHON (40).

Magnetic resonance imaging (MRI) of LHON patients typically demonstrates an acute enlargement of the ante-rior visual pathways without enhancement, as well as increased T2 signal from the optic nerves to the lateral geniculate bodies. Follow-up imaging a few months later often demonstrate persistent bright T2 signal in normal-sized or atrophied anterior visual pathways (41). LHON lesions may be distinguished from those of multiple sclerosis because they tend to be less than 5mm in diameter, lack sharp boundaries, and do not enhance with gadolinium (42).

Although limited reports of histopathology of the LHON optic nerve exist, Kerrison et al. noted optic atro-phy and double-membrane bound inclusions consist-ing of calcium in retinal ganglion cells in tissue from a

(A) (B) (C) (D)

FIGURE 134-2 Leber optic neuropathy. (A) OD. (B) OS. This 23-year-old man presented with a three-month history of decrease in vision when first seen. His initial examination disclosed hyperemic discs typical of the acute optic neuritis stage of the disease. The vision dropped to its low-est a few weeks later (20/200 OD and CF at 4ft OS). (C) OS. (D) OS. Two years later, fundus examination reveals the subsequent typical total bilateral optic atrophy, while his vision had increased to 20/25 in both eyes. He was found to have the 11778 mutation.

symptomatic 81-year-old woman (43). Molecular analy-sis confirmed homoplasmy for her mitochondrial muta-tions in ocular tissue.

In most instances, LHON manifests as an isolated optic atrophy, but cardiac and neurologic manifesta-tions may occur. Cardiac conduction abnormalities may become symptomatic and occasionally even life-threat-ening (44); they consist of pre-excitation syndromes, specifically Wolff–Parkinson–White and Lown–Ganong–Levine syndromes, or prolongation of the corrected QT interval, which has been observed in the female carri-ers. Because these conduction anomalies can be severe, an ECG should be obtained. The reported neurological abnormalities are uncommon and diverse in presenta-tion (45). Nikoskelainen et al. performed neurological


exams on 38 men and 8 women with LHON and suggest a pathological relationship between LHON and vari-ous movement disorders, multiple sclerosis-like illness, and deformities of the vertebral column—a relationship dubbed “Leber’s plus” (46). The multiple sclerosis-like phenotype associated in some patients with LHON—particularly those with an m.11778 G>A mutation (see below)—is sometimes referred to as “Harding’s syn-drome” (42,47). Vanopdenbosch et al. have suggested, in fact, that carrying a primary LHON-related mutation is a risk factor for developing MS (48). While no consen-sus exists on the utility of neuroimaging in patients with LHON, asking carefully about neurologic symptoms and/or documenting a systemic neurologic exam may be reasonable precautions.
FIGURE 134-3 Mitochondrial DNA with primary and secondary point mutations responsible for Leber hereditary optic neuropathy. (Modifiedfrom Newman, N. J. Leber’s Hereditary Optic Neuropathy: New Genetic Considerations. Arch. Neurol. 1993, 50, 540–548, with permission.)


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4.2.2.2 Genetics and Molecular Mecha-sms. LHON is the prototypical disease caused by tations in maternally-inherited mitochondrial DNA.

such, all children of a woman carrying an LHON tation are expected to inherit the same mutation, ereas children of men with LHON are not at risk of

heriting the mutation. Despite this prediction, over half patients present with no family history (49).Between 90 and 95% of patients with LHON har-r one of three primary mutations in the mitochon-ial DNA: m.3460G>A (in MTND1), m.11778G>A MTND4), or m.14484T>C (MTND6). All three tations are in genes coding for subunits of Complex

n the electron transport chain. Numerous other rare tochondrial DNA mutations have been reported, me of which have not been proven to be pathogenic e Yu-Wai-Man et al. for a recent review) (14). The 11778G>A mutation is the most prevalent change in st populations, although m.14484T>C accounts for

arly 90% of French Canadian cases of LHON.

URE 134-4 Behr optic atrophy in a 24-year-old man with pallor the optic nerve head and unexplained tremor since early child-od. A, OD. B, OS.

Molecular analysis has suggested a correlation between specific mitochondrial mutations and visual recovery (31). The 14484 mutation has the best prognosis, with a recovery rate, defined as a VA of 20/60 or better in both eyes, of 37%. The 3460 mutation recovery rate is variable but may reach 22%. The 11778 mutation has the worst prognosis with recovery seen in only 5% of patients.

Why do only a subset of males and a minority of females carrying a bone fide LHON mutation develop overt disease; and when they develop disease, why is it usually isolated to the optic nerve? While the precise answers to these questions are unclear, both environ-mental and genetic (nuclear and mitochondrial) factors may play a role. The optic nerve—particularly the papil-lomacular bundle—is highly dependent on ATP produc-tion from mitochondria, perhaps making it particularly susceptible to metabolic insult. Many other tissues, however, also have a strong reliance on mitochondrial ATP production, so this answer is, at best, incomplete. Some mitochondrial DNA mutations are present in only a fraction of a cell’s mitochondria (heteroplasmy). A cell must accumulate some threshold of abnormal mitochon-dria—usually thought to be 60–80%—before it devel-ops problems in bioenergetics (50). The most common mitochondrial DNA mutations are most often, however, homoplasmic (at least in the tissues assayed). Hudson et al. found that the haplogroup on which a mitochon-drial mutation occurs (see Chapter 11) may influence the clinical outcome (51). Specifically, individuals with m.11778G>A and m.14484T>C were more likely to have significant visual loss when on the J haplogroup, while m.3460G>A were more susceptible to disease on the H haplogroup.

One attractive hypothesis that would help explain the proclivity of male carriers for developing disease is that a locus on the X-chromosome modifies the LHON phe-notype. Bu and Rotter studied more than 1200 individu-als from 31 large pedigrees to create a two-locus model for visual deficits in LHON, with the X-locus acting in synergy with the primary mitochondrial DNA mutation (52). Several groups have performed mapping studies and identified candidate loci on the X-chromosome—some of which overlap (53). To date, the precise gene (or genes) responsible for this process have not been identi-fied and some groups have failed to confirm significant disease modification by an X-linked locus.

Another possibility is that the LHON phenotype is influenced by hormonal factors. Evidence suggests that estrogens may metabolically ameliorate mitochondrial dysfunction in this disease process (54). Giordano et al. found that LHON cybrid cells treated with 17β-estradiol activated the antioxidant enzyme superoxide dismutase 2, additionally resulting in decreased apoptotic rate, decreased production of reactive oxygen species, and decreased the number of mitochondria with hyper-fragmented morphology. Addidtionally, 17β-estradiol induces a general activation of mitochondrial biogenesis,

and increases in vitro cell viability. Estrogen receptor β was also verified to localize to the mitochondrial network of human retinal ganglion cells via immunofluorescence and Western blot analyses.

Another variable affecting disease expression may be environmental factors, particularly those known or thought to be toxic to mitochondrial function. Kirman et al. studied 196 affected and 206 unaffected carriers, from 125 LHON pedigrees known to harbor one of the three most common LHON mitochondrial DNA muta-tions (55). Using a structured questionnaire, they found a strong, dose-dependent association between tobacco use and vision loss, with a clinical penetrance of greater than 90% in men who smoked. Alcohol intake tended—at least in its extreme—to predispose to vision loss, but this did not reach statistical significance. Case reports have suggested that cyanide (a known inhibitor of the mito-chondrial respiratory chain), cocaine, MDMA (ecstasy), telithromycin (56), erythromycin (57), anti-tuberculosis medications (58), nutritional deficiencies (59), occupa-tional solvent exposure (60), borreliosis (61), anemia

FIGURE 134-5 Hereditary optic nerve hypoplasia. Both sibs pres-ent with bilateral small and pale optic discs. A, 18-year-old young man (right eye). B, Nine-year-old brother (left eye).


(62) and trauma (especially recent head trauma) may also affect disease expression.134.2.2.3 Treatment. To date, there is no proven treat-ment for LHON. The timing and variable disease course associated with this disease makes the evaluation of any treatment through objective studies extremely difficult. Deciding what clinical outcome variables are most rele-vant (e.g. acuity, visual field, OCT findings) is not trivial. In the case of localized treatments such as gene therapy, deciding when and whether to treat the affected eye or the unaffected eye is also an important consideration.

Newman et al. evaluated the effectiveness of brimo-nidine purite eye drops in a nonrandomized, open label prospective pilot trial of nine patients (63). The goal of this trial was to determine whether the reported neuro-protective effects of brimonidine would reduce the rate of second eye involvement, after presentation with vision loss in one eye. The trial was complicated by the find-ing that seven patients had subtle findings of second eye involvement at the time of presentation (40). Based on their results, the authors conclude that brimonidine used at the concentration tested was not effective in prevent-ing second eye involvement.

The short-chain synthetic benzoquinone, idebenone, is a potent antioxidant and inhibitor of lipid peroxi-dation that interacts with the mitochondrial electron transport chain, allowing the “bypass” of complex I. Mashima et al. first described the remission of LHON in a 10-year-old boy with idebenone administration in 1992 (64). A subsequent, small, noncontrolled trial has suggested that oral administration of idebenone, when coupled with vitamins B12 and C supplementation, may speed up visual recovery in affected patients (65). Since then, a multi-center randomized placebo-con-trolled trial of 900 mg idebenone per day in 85 LHON patients demonstrated that idebenone was safe and well-tolerated, and suggests that patients with discor-dant visual acuities are the most likely to benefit from idebenone treatment (66). A retrospective study of early and prolonged idebenone treatment in patients with acute LHON has similarly demonstrated that idebenone administration may significantly improve the frequency of visual recovery and possibly change the natural his-tory of the disease (67).

Because most data suggest that the pathogenesis of LHON is due to a loss of function in electron transport chain proteins, gene replacement is an attractive thera-peutic strategy. So long as the protein is targeted by the cell to the mitochondrial inner membrane, nuclear or epi-somal gene replacement (allotopic expression) would be predicted to be effective (68). In vitro studies suggest that gene replacement in cells from LHON patients improves mitochondrial function (68b,69). Animal studies have suggested that expression of wild-type complex I sub-units is safe. Lam et al. have recently reported on the clin-ical characteristics of LHON patients with the G11778A mutation in anticipation of a gene therapy trial (70).


FIGURE 134-6 Optic nerve malformations. A and B, Optic nerve hypoplasia associated with deMorsier syndrome. C, Marked optic nerve hypoplasia. D, “Morning Glory anomaly” of the disc.

Because tobacco and alcohol may act as mitochon-drial toxins, avoiding smoking and excess alcohol intake is a reasonable precaution in patients who present with LHON or who are known/suspected carriers of an LHON mutation (55).

134.2.3 X-Linked Optic Atrophy (MIM %311050, OPA2)

A rare, early-onset, slowly progressive form of optic atrophy limited to males and accompanied by develop-mental delay and neurologic symptoms has been rec-ognized since the 1970s. Using some of these original pedigrees, Assink et al. performed multipoint linkage analysis, placing the locus for this condition on Xp11.––p11.21 (71). The developmental delay and neurologi-cal abnormalities reported in these earlier studies may not be a consistent part of the phenotype, as Katz et al. describe a US family with similar ophthalmologic fea-tures but no neurological abnormalities, which poten-tially maps to the same locus (72).

134.2.4 Costeff Optic Atrophy Syndrome/Type III 3-Methylglutaconic Aciduria (MIM*606580, OPA3)

Type III 3-methylglutaconic aciduria (MGA, MIM 258501)—which is synonymous with OPA3—is an

autosomal recessive disease characterized by increased urine excretion of 3-methylglutaconic acid and 3-methylglutaric acid, early-onset bilateral optic atro-phy and subsequent neurological and cognitive deficits. Anikster et al. used linkage analysis in 40 Iraqi Jewish patients to localize the OPA3 locus to 19q13.2–13.3 (73). They identied a cDNA clone, FLJ22187, corre-sponding to a two exon gene in which a point mutation co-segregating with the phenotype was observed. The transcript of this gene is widely expressed, including in the skeletal muscle, brain and kidney. The OPA3 protein is localized to the mitochondria (74). It is unclear whether patients who have 3-methylglutaconic aciduria, but not the full-blown Costeff syndrome, may harbor mutations in the OPA3 gene (75).

Reynier et al. found that a form of autosomal domi-nant optic atrophy with cataract (MIM 258501) is allelic to OPA3 (26). These authors posit that the two missense mutations they identify in their cohort may lead to disease via a mechanism other than haploinsuf-ficiency, as the carrier parents of patients with Costeff optic atrophy syndrome—who appear to be haplo-insufficient—are asymptomatic. This hypothesis is somewhat at odds, however, with the observation in a murine model containing a missense mutation in Opa3 (76), where heterozygous mice are asymptomatic, but homozygous mice mirror the Costeff syndrome phe-notype. Yu-Wai-Man et al. did not observe any OPA3


mutations in their cohort of 188 patients with either autosomal dominant or sporadic optic atrophy (77).

134.2.5 OPA4 (MIM %605293)

OPA4 is the designation of autosomal dominant optic atrophy mapping to 18q12.2–12.3 described by Kerrison et al. (25) and previously linked to the Kidd blood group. These patients have a range of visual acuities from nor-mal to legal blindness.

134.2.6 OPA5 (MIM %610708)

Barbet et al. describe a dominant optic atrophy in two unrelated French families that showed linkage to 22q12.1–q13.1 (27). The visual acuity loss in these patients began between the first and third decade of life and slowly progressed.

134.2.7 Autosomal Recessive Congenital/Early Infantile Optic Atrophy (MIM %258500, OPA6)

Barbet et al. reported on a consanguineous French family where four living individuals were affected by an early-onset, but slowly progressive, optic neuropathy (78). A genome-wide scan for homozygous regions idenitified a potential disease locus at 8q21–22. The authors exclude coding sequence changes in the CNGB3, DECR1, and PDP1 genes in this region.

134.2.8 Non-Syndromic Autosomal Recessive Optic Atrophy; Optic Atrophy 7 (OPA7, MIM #612989)

This form of autosomal recessive juvenile-onset optic atro-phy is characterized by severe bilateral visual acuity loss, optic disc pallor, and central scotoma. Identified by Hanein et al. (2009) in a large multiplex Algerian family and 3 other Maghreb families, onset usually occurs between 4 and 6 years of age. All but one of the affected individuals demonstrated strictly normal peripheral visual fields.

Affected individuals may or may not demonstrate par-tial deficiency in mitochondrial complex activity. One affected individual demonstrated partial deficiency of complex I, hypertrophic cardiomyopathy, mild hearing loss, and minor brain MRI alterations, all of which sug-gest mitochondrial dysfunction.

This form of optic atrophy is caused by a homozy-gous mutation in the transmembrane protein 126A gene (TMEM126A, MIM 612988). This mitochondrial pro-tein, found in higher eukaryotes, is located at 11q14.1. The gene product contains 4 transmembrane domains, as well as a central domain conserved with TMEM126B (79). In contrast to OPA1 mutations, cells carrying OPA7 mutations do not demonstrate mitochondrial fragmentation and/or depletion of mitochondrial DNA,

thus suggesting that TMEM26A and OPA1 are not func-tionally related.

134.3 COMPLEX OPTIC ATROPHIES

134.3.1 Behr Syndrome (MIM %210000)

Recessive bilateral optic atrophy of early onset with variable, severe neurologic signs, especially pyramidal, was described by Behr in 1909. This clinical entity is probably a heterogeneous group of disorders, whose root causes are mostly unknown; as such, a true “Behr syndrome” as a distinct clinical and genetic entity may not exist (see discussion below). Some have disputed that the cause of vision loss in some cases may not have been related to optic atrophy per se, as a retinal dys-trophy was not ruled out. Alternative names are Behr complicated form of optic atrophy and complicated infantile optic atrophy.

The disorder has its onset in childhood, between the ages of 1 and 9 years, and is typically stable after an initial and variable period of progression. It is character-ized by bilateral optic atrophy, seen on fundus examina-tion as mild pallor of the disc, more marked temporally and rarely complete. The visual acuity is usually poor and measures about 20/400. There will be moderate to severe dyschromatopsia. Nystagmus is present in half the cases, and strabismus coexists in two thirds. Visual field defects can be present as central scotomas or temporal ones, which are rarely complete. The ERG is unremark-able in those patients where testing has been performed.

The neurological abnormalities resemble Friedreich ataxia: increased tendon reflexes, presence of Babinsky’s sign, hypertonia, mild ataxia and spasticity, and mental retardation.

Autopsy of one affected child showed optic atrophy as well as atrophy of the optic tracts. There were exten-sive degenerative changes in the lateral geniculate nuclei (LGN); disruption of the normal lamination of the LGN was present with dropout of neurons and gliosis. Changes in other thalamic nuclei and in the pallida were evident, but there was no demonstrable lesion in the cortex to correlate with the associated mental retarda-tion. Horoupian and collaborators (80) interpreted the findings as showing a primary degeneration of the LGN with retrograde degeneration leading to optic atrophy.

Recessive inheritance is suggested by the involvement of siblings, with equal frequency in children of both sexes and by an increased frequency of consanguinity among the unaffected parents; however, an autosomal dominant inheritance pattern has also been described (81). The gene has not been mapped.

A major complexity in classifying Behr syndrome as a separate clinical and genetic entity is that the phenotypic expression is quite similar to other forms of optic atrophy with neurological signs. For exam-ple, some patients classified as having a “Behr-like”


syndrome were subsequently found to have type III 3-methylglutaconic aciduria and mutations in OPA3 (73,82). The degree to which Behr syndrome overlaps with type III 3-methylglutaconic aciduria is made even more uncertain by the fact that the abnormal urine profile may not be picked up by routine urine organic analysis (83). No other genetic cause of Behr syndrome has been identified to date, although case studies of OPA1 muta-tions in Behr syndrome patients may suggest that classical Behr syndrome should be re-classified under the umbrella of dominant optic atrophy-plus phenotypes (84).

As with other inherited optic atrophies, there is no proven effective treatment and care is supportive.

134.3.2 Wolfram Syndrome (WFS1: OMIM 222300; WFS2: OMIM 604928; Mitochondrial: OMIM 598500)

DIDMOAD is an acronym for diabetes insipidus, juvenile-onset diabetes mellitis, optic atrophy and senorineural deafness. Also known as Wolfram syn-drome, the phenotypic variability of this autosomal reces-sive condition has led to other acronyms (e.g. DMOA) that include some, but not all, of the “classic” findings. In addition, patients may present with neurological deterio-ration (ataxia, peripheral neuropathy, myoclonus, psy-chiatric disease), gut dysmotility, primary and secondary hypogonadism, anterior pituitary dysfunction and uro-logical findings (hydronephrosis, hydroureter, dilation of the urinary bladder) (85). The presence of optic atro-phy and juvenile-onset diabetes mellitus are considered mandatory for the diagnosis. Barrett et al. estimated the population frequency to be about 1 in 770,00, with a 1 in 354 carrier frequency (85a).

Juvenile-onset diabetes mellitus may be the first manifestation of the syndrome, appearing between 2 and 20 years of age, usually within the first decade. Unlike classic type 1 diabetes, patients with Wolfram syndrome do not develop antibodies against islet cells; HLA-associated risk predictions are also different (86). The French Wolfram Group, headed by Cano et al, compared 26 Wolfram syndrome patients to 52 type-I diabetes mellitus patients matched for age of diabe-tes onset. This study demonstrated a lower daily insu-lin requirement and lower hemoglobin A1c levels in Wolfram Syndrome patients, despite their use of a less intensive insulin regimen (87). Additionally, the study by Cano et al. demonstrated decreased prevalence of diabetic retinopathy, nephropathy, and other micro-vascular complications in patients with Wolfram Syn-drome compared to type 1 diabetics. Fifty patients with Wolfram syndrome-related diabetes (WSD) were com-pared with the data of 24,164 patients with type 1 dia-betes, and this demonstrated that WSD was diagnosed earlier than type 1 diabetes, with a lower prevalence of ketoacidosis (88). Additionally, this study demonstrated a correlation between WFS1 mutations (see below) and

age of diabetes onset, and identified glucose toxicity as an accelerating factor in disease progression. C-peptide stimulation indicated a small remaining insulin secre-tory reserve. Additionally, compared to wild-type beta cells, WFS1 deficient cells demonstrate impaired granular acidification, which is normally required for the priming of secretory granules preceding exocytosis. This may sug-gest a molecular mechanism for the profound impairment of glucose-induced insulin secretion in WFS1-knockout mouse models (89). WFS1-deficient beta cells exhibit increases in markers indicative of endoplasmic reticulum (ER) stress, thus causing beta cell loss through impaired cell cycle progression and increased apoptosis (90).

Progressive visual loss due to primary optic atrophy usually follows the diabetes mellitus symptoms and starts between the ages of 2 and 24 years, most often before age 15 years, with an average age of onset of 11 years. Visual impairment is severe, resulting in acu-ities of 20/2000–20/6000 (0.01–0.003), but ranges from 20/200 to hand motion. There is progressive, marked, diffuse pallor of the optic disc, which may be absent at the time of first complaints of vision loss. In a study of fifteen Wolfram syndrome patients, the prevalence of optic atrophy was 93.3%, color loss was 92.9%, cata-ract was 66.6%, pigmentary retinopathy was 30%, and diabetic retinopathy was 20% (91). Visual field testing in some cases demonstrates concentric and/or periph-eral vision loss (92). In the retina, electrooculograms and ERGs are usually normal in the presence of reduced cone/rod dark adaptation, although Dhalla et al. report a case with pigmentary retinopathy (93). Neuropathologi-cal specimens demonstrate loss of retinal ganglion cells, myelinated axons in the optic nerve, chiasm, and tract, as well as neuron loss in the lateral geniculate nucleus (94). Diabetic retinopathy is extremely rare; the overall course is milder than that seen in isolated diabetes mellitus, with a lower prevalence of microvascular disease (87).

Hearing loss is present in about 66% of individuals with Wolfram syndrome, with the preferential involve-ment of high frequencies (95). Hearing impairment ranges from congenital deafness to a milder, progressive sensori-neural hearing loss, and median age of onset is 12.5 years (85a). Among individuals with inactivating WFS1 muta-tions, five females demonstrated significantly greater hear-ing impairment than four males, thus suggesting a role for hormonal factors in hearing loss modulation (96). Neuro-pathological findings in Wolfram syndrome patients dem-onstrate loss of the organ of Corti in the basal turn of the cochlea, as well as focal atrophy of the stria vascularis, correlating well with high-frequency hearing loss (94).

Diabetes insipidus (DI), present in 51–87% of indi-viduals (85b,97), is most often central in origin and usu-ally presents in the second decade of life. Brain MRI may show absence of the typical T1-hyperintense signal from the posterior pituitary along with atrophy and gliosis in the supraoptic and paraventricular nuceli (PVN) of the hypothalamus (98). Necropsy has demonstrated similar


findings, as well as accumulation of vasopressin precur-sors in the PVN (99).

Neurological abnormalities, including neurodegen-eration, are present in more than half of patients with Wolfram syndrome (85a). Widespread neurodegenera-tive changes, with a median age of onset of 15 years, are considered part of the syndrome and are supported by abnormal MRI findings, making Wolfram syndrome part of a multisystem neurodegenerative disorder. Progressive neurological findings are the result of generalized brain atrophy, with the involvement of cranial nerves, the brain stem, pons, cerebellum, and posterior hypothalamus (85a,98a,100). The most prominent atrophy was demon-strated in the cerebellum, medulla, pons, optic nerves, and posterior hypothalamus (101). Neuroimaging may also show atrophy of other brain regions in the setting of neu-rodegeneration, although this atrophy does not always result in patient symptoms (98a). Cognitive impairment, corresponding to cortical abnormalities on MRI, may also be observed in up to 32% of patients with neurologi-cal signs (102). DI and hearing loss have been correlated with degenerative damage of the hypothalamus and the vestibulocochlear nuclei (94). Ataxia has been correlated with Purkinje cell loss and gliosis in the cerebellar white matter (103). In a postmortem study, Hilson et al. demon-strate gross shrinkage and neuron loss in the pontine base and inferior olivary nucleus, as well as minimal neurohy-pophyseal tissue in the pituitary and decreased numbers of axons in the paraventricular and supraoptic nuclei, with relative sparing of the cerebellum (94).

Gastrointestinal complaints have also been noted in a large number of Wolfram syndrome patients, with 25% of patients complaining of constipation, chronic diar-rhea, and other bowel dysfunctions. Some of these cases have been attributed to gluten intolerance, which is 20 times more frequent in patient populations who have had several years’ history of diabetes mellitus (104).

Autosomal recessive inheritance with incomplete pen-etrance is supported by reports of families with more than one affected sibling, and consanguinity is noticed in 15%–32.5% of the cases. Many of the described cases are sporadic.

Wolfram syndrome is genetically heterogeneous and is currently subdivided into three genetic forms: WFS1 (MIM *606201), WFS2 (MIM#604928), and a pos-sible mitochondrial syndrome (MIM#598500). WFS1 is located on 4p16.1 and encodes a transmembrane ER glycoprotein called wolframin, which may function as a calcium channel or a regulator of calcium conductance in the ER (105). Khanin et al. found mutations in 90% of their patients with Wolfram syndrome (106). Wolframin is ubiquitously expressed, with particularly high levels in the pancreas, heart, brain and in insulinoma beta-cell lines (107). Disease likely results from loss of wolfra-min function (108). Diabetes mellitus development in DIDMOAD is attributed to impaired homeostasis of beta cells, and studies indicate that wolframin may help

fold proinsulin, a protein precursor of insulin, into the mature hormone that controls blood glucose levels (109). Additionally, WFS1 is up-regulated in mouse pancre-atic beta cells during glucose-induced insulin secretion, whereas WFS1 knockdown in beta cells resulted in ER stress and cell dysfunction. These authors hypothesized that Wolfram syndrome thus involves chronic ER stress in pancreatic beta cells. Interestingly, a heterozygous mutation of WFS1 may explain some cases of autosomal dominant, non-syndromic sensorineural, low-frequency hearing loss (110). Sandhu et al. reported that two single nucleotide polymorphisms (rs10010131, rs6446482) are associated with risk for type 2 diabetes mellitus (111).

In contrast, WS2 localizes to the long arm of chro-mosome 4 (4q22–24) and is caused by mutations in the CISD2 gene (MIM222300), which codes for an ER intermembrane protein (112). Unlike classic Wolfram syndrome, the patients—all from consanguineous Jor-danian families—did not exhibit DI and also presented with severe upper gastrointestinal bleeding/ulceration (113). Chen et al. demonstrated that, in the mouse, Cisd2 localizes to the outer mitochondrial membrane and is involved in the control of life span (114).

The third, a mitochondrial syndrome, was initially suggested by Rotig et al. in a patient with early-onset diabetes mellitus, optic atrophy and deafness, who har-bored a 7.6 kb mitochondrial deletion (115). Barrientos et al. provided evidence that mutations in the 4p16 region predispose individuals to multiple mitochondrial DNA deletions in families with Wolfram syndrome (116), although Domenech et al. did not find mitochondrial DNA abnormalities in their Spanish cohort of six WS1 families (117). Hofmann et al. found, when comparing mitochondrial DNA variants identified in DIDMOAD patients with those found in LHON patients and healthy controls, that a high percentage of DIDMOAD patients harbored secondary LHON mutations, and that both DIDMOAD and LHON patients were concentrated in two different mitochondrial haplotypes (118). He thus concluded that different clusters of mitochondrial DNA variants may act as predisposing haplotypes, increas-ing the risk of either DIDMOAD or LHON. However, the characteristics distinguishing the three genetic sub-types have been questioned, as the CISD2 gene of Wol-fram syndrome 2 has been implicated in mitochondrial dysfunction as well (114a). As such, the relationship between either of the autosomal loci for Wolfram syn-drome and mitochondrial mutations is unclear.

Treatment of Wolfram syndrome is symptomatic. The diabetes mellitus is treated with insulin. Physicians should monitor patients carefully for signs of urological complications. As wolframin is a transmembrane protein with multisystem localization, other tests to consider include dynamic pituitary gland tests, such as an insulin tolerance test and lutenising hormone releasing hormone (LH-RH) test, as well as a water deprivation test to deter-mine posterior pituitary gland function (119). Depending


on the degree of hearing impairment, hearing loss may be managed with hearing aids or cochlear implantation. No treatment is available for the basic defect.

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Biographies

Grace Shih is a medical student at Vanderbilt University School of Medicine. She graduated cum laude with a BS in biology from Duke University in 2008. As a 2011–2012 Howard Hughes Medical Institute Cloister program research scholar at the National Institutes of Health, she worked in the laboratory of Brian Brooks, MD, PhD.

Brian P Brooks obtained his MD and PhD from the University of Pennsylvania. His residency training in ophthalmology and fellowship training in pediatric ophthalmology were completed at the University of Michigan. Dr Brooks completed a clinical genetics fellowship at the Metro-politan Washington DC Medical Genetics program centered at the National Human Genome Research Institute. Dr Brooks is one of the few physicians in the United States boarded in both ophthalmology and clinical genetics. He is currently Chief, Unit on Pediatric, Develop-mental, and Genetic Ophthalmology in the Ophthalmic Genetics and Visual Function Branch of the National Eye Institute. In 2010, he was awarded the Presidential Early Career Award for Science and Engineering by President Barak Obama, the nation’s highest honor for young investigators.

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