Leigh syndrome: Resolving the clinical and genetic heterogeneity paves the way for treatment options.

Leigh syndrome is a progressive neurodegenerative disorder, affecting 1 in 40,000 live births. Most patients present with symptoms between the ages of three and twelve months, but adult onset Leigh syndrome has also been described. The disease course is characterized by a rapid deterioration of cognitive and motor functions, in most cases resulting in death due to respiratory failure. Despite the high genetic heterogeneity of Leigh syndrome, patients present with identical, symmetrical lesions in the basal ganglia or brainstem on MRI, while additional clinical manifestations and age of onset varies from case to case. To date, mutations in over 60 genes, both nuclear and mitochondrial DNA encoded, have been shown to cause Leigh syndrome, still explaining only half of all cases. In most patients, these mutations directly or indirectly affect the activity of the mitochondrial respiratory chain or pyruvate dehydrogenase complex. Exome sequencing has accelerated the discovery of new genes and pathways involved in Leigh syndrome, providing novel insights into the pathophysiological mechanisms. This is particularly important as no general curative treatment is available for this devastating disorder, although several recent studies imply that early treatment might be beneficial for some patients depending on the gene or process affected. Timely, gene-based personalized treatment may become an important strategy in rare, genetically heterogeneous disorders like Leigh syndrome, stressing the importance of early genetic diagnosis and identification of new genes/pathways. In this review, we provide a comprehensive overview of the most important clinical manifestations and genes/pathways involved in Leigh syndrome, and discuss the current state of therapeutic interventions in patients.

[Modern opportunities and prospects for studying pathogenesis, diagnosing and treating hereditary optic neuropathies].

OBJECTIVE: To evaluate modern opportunities and prospects for studying pathogenesis and improving diagnostics and treatment of hereditary optic neuropathies (HON). MATERIAL AND METHODS: The article presents summarized data on the pathogenesis, diagnostics, and treatment of HON based on modern methods of assessment. RESULTS: The results of long-term worldwide studies and those performed in the Research Institute of Eye Diseases in collaboration with several other institutions are presented. Genetic testing for mitochondrial and nucleus DNA mutations that have a known association with Leber's hereditary optic neuropathy (LHON) and autosomal dominant optic neuropathy (ADON) allow verification only in half of the cases. Particular features of hereditary diseases, such as incomplete penentrance, variable expression, clinical polymorphism, difficulties in detection of hereditary sings, and genetic heterogeneity, are shown to complicate the diagnosis of HON. Spectral retinal tomography revealed characteristic morphometric changes in the macular region and peripapillary nerve fiber layer in the acute stage of LHON. Hereditary optic neuropathies result from a genetically determined decrease in mitochondrial respiratory chain complexes activity, which is associated with a decrease in ATP production. From that standpoint, studying of mitochondrial oxidative phosphorylation biochemical defects in LHON and ADON is an option for detection of mitochondrial dysfunction. Results of a newly proposed method of mitochondrial membrane potential assessment in skin fibroblasts, which can be used for differential diagnosis of mitochondrial optic nerve diseases, are presented. Possible therapeutic measures for HON are discussed. CONCLUSION: In the prevailing number of cases the described clinical, molecular genetic, and cytological methods ensure proper diagnosis of hereditary optic neuropathies. Prospects of HON treatment, rather ambiguous, are associated with further studying of pathogenesis, development of drugs and gene therapy.

The sights along route 65.

Regeneration of rod visual pigments after photobleaching requires a protein called Rpe65. Several studies clarify its role in visual physiology and pathology, including a new one that shows it is required pigment regeneration in cone cells.

Gene therapy restores vision in a canine model of childhood blindness.

The relationship between the neurosensory photoreceptors and the adjacent retinal pigment epithelium (RPE) controls not only normal retinal function, but also the pathogenesis of hereditary retinal degenerations. The molecular bases for both primary photoreceptor and RPE diseases that cause blindness have been identified. Gene therapy has been used successfully to slow degeneration in rodent models of primary photoreceptor diseases, but efficacy of gene therapy directed at photoreceptors and RPE in a large-animal model of human disease has not been reported. Here we study one of the most clinically severe retinal degenerations, Leber congenital amaurosis (LCA). LCA causes near total blindness in infancy and can result from mutations in RPE65 (LCA, type II; MIM 180069 and 204100). A naturally occurring animal model, the RPE65-/- dog, suffers from early and severe visual impairment similar to that seen in human LCA. We used a recombinant adeno-associated virus (AAV) carrying wild-type RPE65 (AAV-RPE65) to test the efficacy of gene therapy in this model. Our results indicate that visual function was restored in this large animal model of childhood blindness.

From Transcriptomics to Treatment in Inherited Optic Neuropathies.

Inherited optic neuropathies, including Leber Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA), are monogenetic diseases with a final common pathway of mitochondrial dysfunction leading to retinal ganglion cell (RGC) death and ultimately loss of vision. They are, therefore, excellent models with which to investigate this ubiquitous disease process-implicated in both common polygenetic ocular diseases (e.g., Glaucoma) and late-onset central nervous system neurodegenerative diseases (e.g., Parkinson disease). In recent years, cellular and animal models of LHON and DOA have matured in parallel with techniques (such as RNA-seq) to determine and analyze the transcriptomes of affected cells. This confluence leaves us at a particularly exciting time with the potential for the identification of novel pathogenic players and therapeutic targets. Here, we present a discussion of the importance of inherited optic neuropathies and how transcriptomic techniques can be exploited in the development of novel mutation-independent, neuroprotective therapies.

Update on hereditary optic neuropathy.

Although no treatment is available for hereditary optic neuropathies, recent localization and identification of some of the genetic loci have helped the evaluation and management of patients with these disorders. This article discusses the clinical features and known genetic information regarding Leber's hereditary optic neuropathy, dominant optic atrophy, recessive optic atrophy, and Wolfram syndrome.

[Differential diagnosis of optic nerve atrophy]. / Differentialdiagnose der sehnervenatrophie.

Diseases of the visual pathway: early detection and therapy. Manual kinetic perimetry is faster in the detection of lesions of the visual pathway than automated static perimetry. When cases with a comparable reduction of visual acuity are considered, color desaturation is more pronounced in lesions of the visual pathway than in opacities of the optic media. Search for an afferent pupil defect allows the differential diagnosis between functional and unilateral organic visual impairment: in the case of bilateral visual impairment, a combination of VEP and pattern ERG is suitable for this differentiation. In chronic papilledema, secondary atrophy can best be detected in the arcuate retinal nerve fibers. Fistulation of the dural sheath of the optic nerve prevents visual loss in chronic papilledema. A similar operation could be useful in the progressive form of anterior ischemic optic neuropathy. Recently, the mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy was identified. Prolactin secreting pituitary adenomas shrink with bromocriptine treatment.

[The efficacy of transcutaneous electrostimulation of the visual system in partial optic atrophy]. / Effektivnost' chreskozhnoi élektrostimuliatsii zritel'noi sistemy pri chastichnoi atrofii zritel'nykh nervov.

Effects of transcutaneous electric stimulation of the eyes on vision acuity, visual field, electric sensitivity, electric lability, Hanzfeld ERG and macular ERG were studied in 260 patients with partial atrophy of the optic nerve of various origins and with different degrees of visual function loss. Dispersion analysis of random samples showed that changes in each characteristic after electric stimulation depended on the initial value of this parameter: in general, the more manifest were deviations from the norm, the more marked was the improvement of this or that function. A conclusion is made on physiological nature of electric stimulation method used for the treatment of optic nerve atrophy.

Treatment of hereditary optic neuropathies.

The hereditary optic neuropathies are inherited disorders in which optic nerve dysfunction is a prominent feature in the phenotypic expression of disease. Optic neuropathy may be primarily an isolated finding, such as in Leber hereditary optic neuropathy and dominant optic atrophy, or part of a multisystem disorder. The pathophysiological mechanisms underlying the hereditary optic neuropathies involve mitochondrial dysfunction owing to mutations in mitochondrial or nuclear DNA that encodes proteins essential to mitochondrial function. Effective treatments are limited, and current management includes therapies directed at enhancing mitochondrial function and preventing oxidative damage, as well as genetic counselling, and supportive and symptomatic measures. New therapies, including gene therapy, are emerging via animal models and human clinical trials. Leber hereditary optic neuropathy, in particular, provides a unique model for testing promising treatments owing to its characteristic sequential bilateral involvement and the accessibility of target tissue within the eye. Lessons learned from treatment of the hereditary optic neuropathies may have therapeutic implications for other disorders of presumed mitochondrial dysfunction. In this Review, the natural history of the common inherited optic neuropathies, the presumed pathogenesis of several of these disorders, and the literature to date regarding potential therapies are summarized.

[Hereditary optic atrophies]. / Hereditäre Optikusneuropathien.

Hereditary optic neuropathies are caused by mutations either in the nuclear or mitochondrial genome and lead to retinal ganglion cell death mediated by reduced oxidative phosphorylation, fragmentation of the mitochondrial network, and increased sensitivity to apoptosis. Nuclear mutations result in autosomal dominant optic atrophy, autosomal recessive optic atrophy, or X-linked recessive optic atrophy, whereas mitochondrial mutations result in Leber's hereditary optic neuropathy, which is maternally inherited. A tentative diagnosis of a hereditary optic neuropathy can usually be made on the grounds of a thorough patient and family history, visual field and color vision tests, and a detailed assessment of the optic nerve head. The rarity of hereditary optic neuropathies makes it difficult to include these disorders in the differential diagnosis. Molecular genetic testing of a blood DNA sample should be performed on every patient, with implications for future genetic counseling and prediction of the disease course.

[Evaluation of the efficacy of plasma exchange in Leber's disease]. / Evaluation de l'efficacité des échanges plasmatiques dans la maladie de Leber.

Amaurosis congenita of Leber is a hereditary optic neuropathy, usually bilateral, that quickly leads to blindness. There is no effective treatment. The inflammatory aspect of the papillary lesions in the early stage, in addition to the beneficial effect of plasma exchanges reported for other optic neuritides, led us to propose such a therapeutic regimen to 6 young adult men afflicted with the disease. This treatment was initiated early, before optic nerve atrophy occurred. The plasma volume exchanged was 3.2 +/- 0.5 liters/session and 4.2 +/- 1.8 (3 to 7) exchanges were performed. The exchanges were always well tolerated. Three patients subjectively reported improvement immediately following the exchanges but only one had some improvement of his visual acuity. However, a more sensitive evaluation of the ability to distinguish contrasts revealed improvement in patients whose visual acuity remained unchanged. This visual gain was lost 3 months later. Therefore, it appears that plasma exchanges are not the treatment of choice for this disease.

Leber's hereditary optic neuropathy among Japanese.

This article reviews the literature on point mutation of mitochondrial DNA (mtDNA) among Japanese and the authors' research data on pupil reaction in patients with Leber's hereditary optic neuropathy (LHON). Among Japanese, a higher frequency (80-90%) of point mutation at nucleotide position 11778 of mtDNA was found; other point mutations found were at nucleotide positions 3460, 14484, 13708, 7444, and 3394. Although pupil reaction to light stimulus is usually defective in all types of optic neuropathy, in patients with LHON the reaction was well maintained even when vision was reduced. W cells in the retina may be preserved or less damaged, even when the degenerative process progresses in both X and Y cells. Possible treatment is also described.

Leber's hereditary optic neuropathy: historical and contemporary considerations.

Leber's hereditary optic neuropathy (LHON) is a distinct form of optic atrophy with a unique pattern of inheritance. The clinical reports of this disorder remain consistent with the original classic description made by Theodor Leber in 1871. Recent advances in the field of molecular genetics, however, have yielded insights into the etiological determinants underlying the clinical expression of LHON. Disease presentation, both ophthalmoscopically and clinically, are reviewed. Classic and atypical presentations are discussed with genetic testing as the definitive diagnostic measurement. Clinical and histopathological findings have led to the investigation of promising preclinical indicators of LHON symptomatology. Evidence of a multifactorial etiology has implicated a broad spectrum of potential intervention protocols. Teaming of the clinician and laboratory geneticist to identify those at risk is critical, not only for future clinical protocols, but to allow for immediate intervention when an effective therapy becomes available.

Leber's hereditary optic atrophy.

Leber described a particular type of hereditary optic atrophy in 1871. The clinical features of all cases since reported are reviewed. There is characteristically acute visual loss, circumpapillary teleangiectatic micropathy, tortuosity of the retinal vessels and oedema in the retinal nerve fibres. 85% of those affected are male, but affected fathers do not transmit the condition to their children. The exact mode of inheritance is still obscure but it is suggested that inheritance may be mitochondrial; enlarged subsarcolemmal mitochondria in LOA patients have been described. Colour vision defects are observed not only in patients, but also in presumed carriers. Electrophysiological investigations demonstrate optic nerve damage, but are not indicative of any particular pathology. It has been reported that in many cases of LOA the severity of the disease is related to tobacco smoking. Increased cyanocobalamin blood levels in patients and increased cyanide blood levels support this hypothesis.