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

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include missense and nonsense substitutions, deletions, insertions and complex rearrangements. The majority of these result in protein truncation and the functional loss of one allele, suggesting that they may give rise to haploinsufficiency of OPA1. The identification of a 560to 860-kb microdeletion on chromosome 3q28 that results in the complete loss of one copy of the OPA1 gene [33] would support haploinsufficiency as an important likely disease mechanism. Missense mutations are less common and may cause disease by a dominant-negative mechanism. Unusually, one family has been reported demonstrating apparent semi-dominance [38], with heterozygous mutations in OPA1.

4.2.1.4.3 OPA1 Protein

The OPA1 gene encodes a 960-amino-acid mitochondrial, dynamin-related, guanosine triphosphatase (GTPase) protein (SwissProt 060313). The protein comprises a mitochondrial leader sequence within the highly basic amino-termi- nal, a GTPase domain, a central dynamin domain that is conserved across all dynamins, and a carboxy terminus of unknown function. The carboxy terminus differs from that of other dynamin family members in lacking a proline-rich region, a GTPase effector domain and a pleckstrin homology domain. OPA1 protein is widely expressed throughout the body: in heart, skeletal muscle, liver, testis, and most abundantly in brain and retina. In the eye, OPA1 is present in the cells of the retinal ganglion cell layer, inner and outer plexiform layers and inner nuclear layer [1].

Although the precise function of the OPA1 protein is unknown, current evidence points to a role in the maintenance of mitochondrial morphology. Functional insights are being gained from studies of homologous proteins, patient mutation data, the cellular sub-localization of OPA1 and in vitro expression and knockdown studies.

4.2.1.4.4Functional Studies of OPA1

OPA1 is the human homologue (33% homology) of the yeast dynamin-related GTP-bind-

ing protein Mgm1, which is involved in mitochondrial genome maintenance. Mitochondrial morphology is maintained through a balance of fusion and fission [12]. Mutations in Mgm1 have been shown to disrupt mitochondrial fusion, and overexpression of mutant or wild-type Mgm1 causes the mitochondria to become fragmented within the cell.

Data from ADOA patients with OPA1 mutations has shown that in some the mitochondrial DNA content is lower and oxidative phosphorylation in the calf muscle is defective [30]. The structure of the mitochondrial network in monocytes is reportedly altered compared to normal control subjects, although this is still controversial [2, 15].

Opa1 localization to mitochondria has been experimentally confirmed by co-localization with Hsp60 in HeLa cells [15]. The subcellular distribution of Opa1 overexpressed in COS-7 cells largely overlaps that of endogenous cytochrome c, a mitochondrial marker. Subcellular localization of Opa1 has also been investigated in primary culture of dissociated rat cerebellar cells, where it shows labelling, distributed in a vesicular pattern in the somas of MAP-2-positive neurons and a weaker signal in the dendrites. However, in these cells the authors observed that the Opa1 signal did not completely overlap with that of cytochrome c, suggesting that the distribution of endogenous Opa1 in the brain might not be confined to mitochondria [34].

Furthermore, Opa1 is an intermembrane space protein, closely associated with the inner mitochondrial membrane, although it has been reported that different isoforms of Opa1 (produced by alternative splicing) may be sublocalized to the inner and outer mitochondrial membranes of HeLa cells [42].

Opa1 protein undergoes processing by mitochondrial endopeptidases, which recognize their cleavage motifs at the amino-terminus of Opa1 [34]. Western blot analysis of Opa1 in mouse brain and HEK 293 cells detected the presence of various sized proteins, with a major band at ~ 90 kDa isolated from the mouse brain, which is estimated to be a product of processing of the unprocessed 100-kDa protein. A major band of approximately 90 kDa was also detected in total protein extracts from human tissues (heart, lung, kidney, spinal cord, skeletal muscle, retina, cer-

ebellum and testes). The enzyme PARL (prese- nilin-associated rhomboid-like protease), which is located in the mitochondrial inner membrane, may cleave and activate Opa1. Since a number of Opa1 isoforms have been identified, Opa1 may be bior multi-functional, and its activity may depend on which isoform predominates.

Experiments carried out in HeLa cells have shown that downregulation of Opa1 by small interfering RNAs (siRNA) results in mitochondrial fragmentation and dispersion throughout the cytosol, dissipation of the mitochondrial membrane potential, disorganization of the cristae and release of cytochrome c followed by caspasedependent apoptotic nuclear events [35]. Following an initial leak of Opa1, a consequence of mitochondrial outer membrane permeabilization, there is re-structuring of the mitochondrial cristae, exposing and releasing the sequestered pools of Opa1 and cytochrome c. The loss of Opa1 then causes a block in mitochondrial fusion, providing an explanation for the observed mitochondrial fragmented phenotype. In retinal ganglion cells Opa1 knockdown results in mitochondrial network aggregation and occurs at a higher rate than in cerebellar ganglion cells [23].

Overexpression of wild-type or mutant forms of Opa1 protein (in particular mutations affecting GTPase activity) causes mitochondria to fragment and accumulate to various extents in the cells near the nucleus [34]. However, mitochondrial fragmentation due to Opa1 overexpression is blocked by downregulation of the fission molecule Drp1 [12].

It is increasingly apparent that a collection of mitochondrial shaping proteins function together with Opa1 to maintain the dynamic control of mitochondrial morphology. Such proteins include pro-fusion GTPases, such as mitofusin (Mfn) 1 and 2, and pro-fission GTPases, such as dynamin-related protein 1 (Drp1) and Fis 1. Opa1 and Mfn1 work synergistically to regulate mitochondrial fusion [13]. Opa1 is unable to promote mitochondrial fusion in the absence of Mfn1, and Mfn1 cannot induce mitochondrial elongation in the absence of Opa1. Opa1 and Mfn1 may have a protective role within the cell. Acting as anti-apoptotic GTPases, they may protect the cell from spontaneous apoptosis and the detrimental effects and consequences of apoptotic stimuli.

4.2.1.4.5 Pathophysiology

OPA1 is the first dynamin-related protein implicated in human disease. It remains unclear why ADOA manifests with a restricted ocular phenotype, particularly since it is ubiquitously expressed throughout the body, albeit most abundantly in the retina and brain. It may be that the loss of one allele decreases the amount of OPA1 protein below a critical threshold for normal mitochondrial function, and this may compromise retinal ganglion cell survival. Neurons in particular, owing to their high energy demands, may be particularly susceptible to changes in mitochondrial function. OPA1 protein may have different functions in the mitochondria of different tissues, particularly as the eight mRNA splice forms are differentially expressed. Haploinsufficiency may increase tissue susceptibility to apoptotic stimuli, in particular those stimuli that are especially relevant to the retinal ganglion cell, such as exposure to UV light and reactive oxygen species. There are no reported therapeutic interventions for ADOA and supportive intervention and genetic counselling are important in patient management. The development of an animal model for OPA1 ADOA may lead the way to a fuller understanding of the pathophysiology [50].

Summary for the Clinician

■Over 100 mutations in the OPA1 gene have been reported and genotype–phe- notype correlations are not marked, with the exception of deafness associated with the R455H OPA1 mutation.

■OPA1 is a nuclear gene targeted to the inner mitochondrial membrane, where it appears to have a role in mitochondrial fusion.

■Evidence suggests that retinal ganglion cells are lost by apoptosis in OPA1 ADOA.

■Mitochondrial shaping proteins, such as OPA1, are a newly discovered and important group of proteins, increasingly being associated with human inherited eye disease.

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4.2.1.4.6The Wider Role of OPA1 in Optic Neuropathy?

Polymorphisms in the OPA1 gene have been associated with normal-tension glaucoma in a British population [6], although no role for OPA1 has been identified in primary open-angle glaucoma. This has led to the hypothesis that normal-ten- sion glaucoma may be an unrecognized hereditary optic neuropathy of mitochondrial aetiology. However, research in geographically distinct populations has produced conflicting results and the role of OPA1 in normal-tension glaucoma is far from clear.

4.2.1.5 OPA4 Locus

A second dominant optic atrophy locus, OPA4, has been mapped on chromosome 18q12.2-q12 [25]. The gene has not been identified yet. The phenotype has many similarities to that of OPA1 (see Table 4.1).

4.2.1.6OPA3 Locus: AutosomalDominant Optic Atrophy and Cataract (ADOAC)

4.2.1.6.1 Clinical Features

Cataract has recently been described in association with dominantly inherited optic atrophy in two families, which maps to the OPA3 locus on chromosome 19q13.2-q13.3 (ADOAC, OMIM 165300) [39] (Table 4.1). The reported age at diagnosis of OPA3 cataract is from 4 years up to 56 years of age, with varied cataract morphologies (predominantly blue-dot/cerulean, but also anterior and posterior cortical, anterior and posterior sub-capsular).

4.2.1.6.2OPA3 Gene and Mutations Associated with ADOAC

The OPA3 gene (MIM 606580) consists of a 5´-UTR of 150 bp, an open reading frame of 179 amino acids and >970 nucleotides of 3´ untranslated sequence. Northern blot analysis

demonstrates a primary transcript of approximately 5.0 kb that is ubiquitously expressed, most prominently in skeletal muscle, kidney and brain [4]. Two heterozygous missense mutations in OPA3 have been reported in these patients: 277G>A (G93S) and 313C>G (Q105E) [39] (Table 4.2).

4.2.1.6.3The OPA3 Protein and Mitochondria

The OPA3 protein is predicted to be a 20-kDa peptide. The sequence contains a mitochondrial targeting peptide, NRIKE, at amino acid residues 25–29 and a carboxy-terminal coiled-coil domain of unknown function. The protein is predicted, with a probability of 0.87, to be exported to the mitochondrion. Whilst the function of the protein remains unknown, it may have a significant role in mitochondrial processes. OPA3 protein is located on the inner mitochondrial membrane in mouse liver [14]. OPA3 is speculated to have an anti-apoptotic role. Although no abnormalities were found in the respiratory chain, in the mitochondrial membrane potential or in the organization of the mitochondrial network of fibroblasts in ADOAC patients, an increased susceptibility to staurosporine-induced apoptosis has been demonstrated [39].

4.2.2 Recessive Optic Atrophy

4.2.2.1 Clinical Features

Recessive optic atrophy (OMIM 258500) presents at birth or by the age of 3 or 4 years with profound visual deficit, sensory nystagmus and marked optic nerve pallor. There may be parental consanguinity. Visual field assessment shows variable constriction and a paracentral scotoma. There are very few reports of isolated primary recessive optic atrophy and some authors believe that many cases are a variant of dominant optic atrophy with partial penetrance. In general, recessive optic neuropathies are seen much more commonly in association with multisystem diseases.

4.2.2.2 OPA5 Locus

The first recessive optic atrophy locus OPA5 (OMIM 258500) has been mapped to chromosome 8q21-q22 in a French consanguineous family [7]. The optic atrophy is of very early onset in childhood and is slowly progressive, but nystagmus is not a feature. Colour vision testing revealed red-green colour loss.

4.2.3 X-Linked Optic Atrophy

4.2.3.1 Clinical Features

Isolated X-linked optic atrophy (OMIM 311050) is extremely rare. Affected males my have mental retardation and neurological abnormalities, including dysarthria, tremor, dysdiadochokinesia and abnormal reflexes. The female carriers are normal. The age of onset of optic atrophy has been reported to be early childhood, and there may be a slow loss of visual acuity with age. Defects may be seen on colour vision testing.

4.2.3.2 OPA2 Locus

X-linked optic atrophy (OPA2) has been linked to Xp11.4-p11.2 [5].

4.2.4Mitochondrial Disease: Leber’s Hereditary Optic Neuropathy

4.2.4.1 Clinical Features

Leber’s hereditary optic neuropathy (LHON, OMIM 535000) is the most common mito-

chondrial optic neuropathy and it is also the first disease to have been linked to mitochondrial DNA [51]. The minimum prevalence of visual loss due to LHON has been estimated in the UK as 3.22:100,000 [32]. Visual loss occurs most frequently in the second to third decades, with a mean age of 27 years and a reported range of 1–70 years. The initial symptom is acutely blurred central vision in one eye or noticeable colour desaturation. The two eyes are affected sequentially in 75% of cases and simultaneously in 25%. The progression of visual loss for the first eye appears longer than for the second eye and the two eyes are separated by a mean of 2 months (range 6–22 weeks) [41], although the interval has been reported to be as long as 8 years. The visual loss develops over a matter of weeks and is severe, dropping to 6/60, counting fingers or occasionally even no perception of light by 4–6 weeks. Only 5% of patients have vision better than 6/60 [41]. The onset of visual loss may occasionally be accompanied by headache or ocular discomfort (24% of patients) [40] and an Uhthoff’s phenomenon (worsening of vision with exercise, hot baths, or hot drinks) may be reported. There is variability in expression even within families [31].

The visual field loss, which is initially central, rapidly becomes centro-caecal and results in a large scotoma. In the acute stages 30%–60% of eyes show circumpapillary telangiectatic microangiopathy, or swelling of the nerve fibre layer around the disc with microvascular anomalies, but there is absence of leakage from the disc and aberrant vessels on fluorescein angiography (Fig. 4.2). Increased tortuosity of capillaries, medium-sized arteries and venules, with arterio-venous shunting in the peripapillary vasculature, is observed. Over the next few months the swelling typically resolves, the telangiectasia

disappears and optic atrophy develops (with loss of the nerve fibre layer). Microangiopathy is uncommon after 6 months. Optic atrophy has been noted as early as 1 month from the onset of visual symptoms. It is universal after 6 months [41]. Visually evoked responses are delayed and the flash electroretinogram is normal. MRI in the acute phase may show enhancement and magnetic resonance spectroscopy with phosphorous-31 shows impaired metabolism in muscle and brain [29].

layer, increased tortuosity of capillaries, medium arteries and venules and arterio-venous shunting. Such individuals may also show colour perception abnormalities and mild abnormalities of pattern-reversal visual-evoked responses. The long-term significance of such findings is uncertain, since the presence of telangiectatic vessels is not universal even in affected individuals, with only 58% of patients with the bp 11778 mutation, and 33% with the bp 14484 mutation manifesting this “typical” phenotype.

4.2.4.2Findings in Unaffected Relatives

Abnormal findings are reported in the eyes of unaffected relatives who carry primary pathogenic mitochondrial mutations. These findings include swelling in the peripapillary nerve fibre

4.2.4.3 Systemic Manifestations

In most patients with LHON the visual loss is the only manifestation of the disease. However, cardiac pre-excitation syndromes have also been reported in up to 9% of patients, including those with Wolff-Parkinson-White syndrome and long

Q-T interval. Systemic neurological abnormalities, including multiple-sclerosis-like symptoms, have also been reported in patients with LHON, particularly with the bp 11778 mutation [36]. MRI of these patients shows appearances typical of multiple sclerosis. Other neurological findings, including spastic paraparesis, dementia, deafness, dorsal column dysfunction and heredofamilial ataxias, have been reported in LHON patients and their families.

4.2.4.4 Molecular Genetics

ThematernalinheritancepatternofLHONisnonMendelian, and the disease is due to point mutations in mitochondrial DNA (mtDNA). Since mitochondria are maternally inherited this means that there can be no male-to-male transmission in a LHON pedigree – a point that may be use-

ful in assessing families with inherited optic neuropathy.

Human mtDNA is a closed, circular molecule of 16,569 bp and there are thousands of copies per cell. The mitochondrial genome is essential for aerobic metabolism, as the vast majority of cellular adenosine triphosphate is generated by the proteins of the oxidative phosphorylation cascade, of which complexes I–V reside in the mitochondrial inner membrane. Complexes I–IV are key components of the electron transport chain. The respiratory chain is, however, assembled from both mitochondrial and nuclear gene products, thus the generation of ATP depends on the coordination of two physically distinct genomes.

The first mtDNA mutation in LHON at nucleotideposition(np)11,778wasdemonstrated in 1988 by Wallace et al. [51]. Three “primary” mtDNA mutations account for 90%–95% of

(14% of cases) (Table 4.3).

4.2.4.5LHON-Associated Mitochondrial Mutations

LHON-associated mutations can be classified as “primary” or “secondary” pathogenic mutations. Primary mutations (above) are found almost exclusively in multiple LHON families and alter evolutionarily conserved amino acids. There may be other, rarer primary mutations, but their significance has not been established in the population, and they may only occur in a few pedigrees worldwide. (These mutations include T14596A, C14498T, G13730A, G14459A, C14482G and A14495G.) The majority of genes believed to cause LHON encode subunits of complex I. Arguably, a group of so-called secondary mutations may also be involved in the pathogenesis of LHON, but they also occur at a lower prevalence in control populations, and may represent polymorphisms. The secondary mutations usually occur in association with a primary mutation or other secondary mutations. They generally cause the mutation of a less highly conserved amino acid. (Secondary pathogenic mutations may include np G13708A, G15812A, A4917G, T4216C, G9804A, G9438A and G15257A.)

in LHON as the three primary mutations have a remarkably similar phenotype. The T14484C mutation is associated with the best visual outcome (6/24 or better in 71% of patients). Some 50%–60% of reported patients with the T14484C mutation have some recovery of vision. A younger age of onset of visual loss with this mutation and other mutations is also associated with a better visual outcome, especially if the onset is before the age of 20 years. Visual recovery can occur more than a year later [40]. Mutation at position G11778A is associated with

the disease, and a number of other factors have been investigated. Heteroplasmy (the presence of both mutant and normal mtDNA) may be a factor, but there is contradictory evidence on its role, as some individuals with 100% mutant mtDNA never suffer loss of vision. The role of the haplotype J (G15812A, G15257A, G13708A and T4216C) has been implicated in disease expression in European kindred. There is likely to be an interplay between mitochondrial and nuclear genetic factors as well as environmental factors. Environmental triggers, which have been investigated, include tobacco,

alcohol, systemic illness, nutrition and head trauma. Even here there is still some controversy, with one case–control study [24] suggesting no role for tobacco or alcohol.

tive phosphorylation and deficient generation of ATP may have a direct or indirect role, involving generation of free radicals and toxicity. The respiratory dysfunction may lead to axoplasmic stasis and swelling.

Summary for the Clinician

■The T14484C mutation is associated with the best visual outcome.

■Mutation at positions G11778A is associated with the lowest chance of recovery.

Summary for the Clinician

■LHON is attributable to one of three common mutations in mitochondrial DNA in 95% of European pedigrees: 11778 (69% of cases), 3460 (13% of cases) and 14484 (14% of cases).

4.2.4.7Evidence for an X-Linked Susceptibility Factor

There has been considerable debate as to why more men than women are clinically affected by LHON. Mutation type does not predict male-to- female ratio of affected patients. Estimated male- to-female ratio is between 3:1 and 5.6:1, and up to 80%–90% of cases in some series are male. Hudson et al. (2005) [21] recently defined an X- chromosomal haplotype bounded by markers in the proximal half of the short arm of the X chromosome (Xp11) that appears to have a modulating effect on expression. The effect of the modulating haplotype was independent of the mtDNA genetic background and appeared to explain the variable penetrance and sex bias that characterizes LHON.

4.2.4.8The Pathophysiology of LHON

The pathophysiology of LHON is still not fully understood. The clinical picture points to retinal ganglion cell loss and there is evidence that the small axons of the papillomacular bundle, found centrally in the optic nerve, are particularly vulnerable [11]. Why this should be is not entirely clear, but histochemical studies of optic nerve show that this region has a high requirement for mitochondrial function [10]. Histopathological reports from patients with visual loss with LHON show axonal degeneration in the optic nerve. Abnormal oxida-

Therapeutic intervention in LHON has so far been disappointing, with a variety of agents having been tried on empirical grounds, including, co-enzyme Q, idebenone, succinate, l-carnitine, vitamin B2, thiamine, vitamin C and vitamin E. It is important to offer genetic counselling and a range of support to affected individuals and their families. The development of mouse models of complex I deficiency will further help our understanding of the pathophysiology of LHON [9] and may assist the development of therapies tailored to address the metabolic or genetic defect. Gene therapy by allotypic expression may have a role in future treatment strategies [19].

Summary for the Clinician

■No therapeutic intervention to date has been shown to be effective.

■The role of accurate clinical and molecular diagnosis and genetic counselling should not be underestimated.

■Patients with ADOA may have only moderate visual loss and some functional vision.

■Patients with LHON are likely to have very significant visual loss.

■Despite the lack of firm conclusive supportive evidence patients with LHON are well advised to avoid excess alcohol, tobacco and environmental toxins.

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4.3Primary Inherited Optic Neuropathies with Significant Systemic Features

4.3.1Autosomal-Dominant Optic Atrophy and Neurological Defects

There are a number of pedigrees described in the literature with dominant optic atrophy and other neurological abnormalities, such as sensorineural deafness, ataxia, ophthalmoplegia, polyneuropathy or myopathy. Of these myriad of associations the aetiology is unknown for the vast majority, which are isolated families, and in many the mode of inheritance may even be mitochondrial. Three syndromes stand out: (1) dominant optic atrophy, deafness, ophthalmoplegia and myopathy, (2) autosomal-dominant progressive optic atrophy and deafness, and (3) autosomal-domi- nant progressive optic atrophy with progressive hearing loss and ataxia.

The constellation of dominant optic atrophy and deafness has been associated with the R445H mutation in the OPA1 gene by a number of groups [3, 43]. The hearing loss in these pedigrees is severe and may occur at birth. Many of the patients have optic atrophy with reduced vision by the first decade. Optic atrophy, deafness, ophthalmoplegia and myopathy have been associated with the same OPA1 mutation [37]. The hearing loss is moderate with onset in the first or second decades and the onset of visual loss is between 2 and 9 years of age. Ophthalmoplegia and myopathy occur in midlife.

4.3.2Autosomal-Recessive Optic Atrophy “Plus”

As with syndromic dominant optic atrophies, pedigrees have been reported with recessive or putative X-linked optic atrophy and a variety of syndromes with features including progressive hearing loss, spastic quadriplegia, ataxia, tetraplegia, areflexia, polyneuropathy, mental deterioration and dementia. In some cases it is also possible that they represent mitochondrial diseases.

4.3.3 Costeff’s Syndrome

The OPA3 gene (MIM 606580; chromosome 19q13.2-q13.3) has recently been found to be mutated in patients of Jewish Iraqi extraction with type III 3-methylglutaconic aciduria (MGA, MIM 258501): optic atrophy plus syndrome or Costeff’s syndrome [4]. MGA is a recessive neuro-ophthalmological syndrome that consists of early-onset bilateral optic atrophy and lateronset spasticity, extrapyramidal dysfunction and cognitive deficit. Two homozygous mutations in OPA3 are reported: IVS1+1G-C 11 and 320337del 12, both causing “loss of function”.

4.3.4 Behr’s Syndrome

Optic atrophy in Behr’s syndrome (OMIM 210000) is associated with pyramidal tract signs, ataxia, mental retardation, urinary incontinence and pes cavus. Visual loss is moderate or severe, often with nystagmus, with onset before the age of 10years. Children often also have a spastic ataxic gait.

4.3.5Wolfram Syndrome, DIDMOAD

Optic atrophy in Wolfram Syndrome (Fig. 4.3) is associated with juvenile diabetes mellitus and diabetes insipidus and neurosensory hearing loss [8]. (DIDMOAD stands for diabetes insipidus, diabetes mellitus, optic atrophy and deafness.) Diabetes mellitus develops in the first decade and precedes the optic atrophy, which may cause only mild visual loss to begin with but later leads to profound field constriction and acuity loss. The deafness is severe. A wide range of degenerative neuroendocrine abnormalities has been reported, suggesting widespread central nervous system involvement. The WFS1 gene is on chromosome 4p16.1; 90% of patients with Wolfram syndrome have mutations in WFS1. A second locus on chromosome 4q22-q24 has been identified by linkage. In some pedigrees there also appears to be a mitochondrial factor.

drial or X-linked fashion.

■There is considerable overlap between the clinical phenotypes and modes of inheritance.

■Three genetic loci are mapped currently for autosomal-dominant optic atrophy (ADOA): OPA1, OPA4 and OPA3.

■Of these the OPA1 gene is likely to account for the majority of ADOA. Over 100 mutations have been reported to date in the OPA1 gene.

■In OPA3 optic atrophy has been associated with cataract.

■Recessive and X-linked optic atrophies are very rare.

■Leber’s hereditary optic neuropathy is inherited in a maternal fashion and is due to mutation in mitochondrial DNA.

4.4 Conclusions

The optic neuropathies are revealing new insights into a possible central role for mitochondrial dysfunction in optic nerve disease. It is still

of basic mechanisms of ganglion cell development, physiology and metabolism and further our understanding of the pathophysiology of optic nerve disease. It will also improve diagnosis, counselling and management of patients, and eventually lead to the development of new therapeutic modalities.

References

1.Aijaz SS, Erskine L, Jeffery G et al (2004) Developmental expression profile of the optic atrophy gene product: OPA1 is not localised exclusively in the mammalian retinal ganglion cell layer. Invest Ophthalmol Vis Sci 45:1667–1673

2.Alexander C, Votruba M, Pesch U et al (2000)

OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nature Genet 26:211–215

3.Amati-Bonneau P, Guichet A, Olichon A et al (2005) OPA1 R445H mutation in optic atrophy associated with sensorineural deafness. Ann Neurol 58:958–963