Inherited mitochondrial optic neuropathies.
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ABSTRACT:
SUBMITTER: Yu-Wai-Man P
PROVIDER: S-EPMC2643051 | biostudies-literature | 2009 Mar
REPOSITORIES: biostudies-literature
Publications
Inherited mitochondrial optic neuropathies.
Yu-Wai-Man P P Griffiths P G PG Hudson G G Chinnery P F PF
Journal of medical genetics 20081110 3
Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA) are the two most common inherited optic neuropathies and they result in significant visual morbidity among young adults. Both disorders are the result of mitochondrial dysfunction: LHON from primary mitochondrial DNA (mtDNA) mutations affecting the respiratory chain complexes; and the majority of DOA families have mutations in the OPA1 gene, which codes for an inner mitochondrial membrane protein critical for mtD ...[more]
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Project description:In recent years, the term mitochondrial optic neuropathy (MON) has increasingly been used within the literature to describe a group of optic neuropathies that exhibit mitochondrial dysfunction in retinal ganglion cells (RGCs). Interestingly, MONs include genetic aetiologies, such as Leber hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA), as well as acquired aetiologies resulting from drugs, nutritional deficiencies, and mixed aetiologies. Regardless of an inherited or acquired cause, patients exhibit the same clinical manifestations with selective loss of the RGCs due to mitochondrial dysfunction. Various novel therapies are being explored to reverse or limit damage to the RGCs. Here we review the pathophysiology, clinical manifestations, differential diagnosis, current treatment, and promising therapeutic targets of MON.
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Project description:Mitochondrial optic neuropathies constitute an important cause of chronic visual morbidity and registrable blindness in both the paediatric and adult population. It is a genetically heterogeneous group of disorders caused by both mitochondrial DNA (mtDNA) mutations and a growing list of nuclear genetic defects that invariably affect a critical component of the mitochondrial machinery. The two classical paradigms are Leber hereditary optic neuropathy (LHON), which is a primary mtDNA disorder, and autosomal dominant optic atrophy (DOA) secondary to pathogenic mutations within the nuclear gene OPA1 that encodes for a mitochondrial inner membrane protein. The defining neuropathological feature is the preferential loss of retinal ganglion cells (RGCs) within the inner retina but, rather strikingly, the smaller calibre RGCs that constitute the papillomacular bundle are particularly vulnerable, whereas melanopsin-containing RGCs are relatively spared. Although the majority of patients with LHON and DOA will present with isolated optic nerve involvement, some individuals will also develop additional neurological complications pointing towards a greater vulnerability of the central nervous system (CNS) in susceptible mutation carriers. These so-called "plus" phenotypes are mechanistically important as they put the loss of RGCs within the broader perspective of neuronal loss and mitochondrial dysfunction, highlighting common pathways that could be modulated to halt progressive neurodegeneration in other related CNS disorders. The management of patients with mitochondrial optic neuropathies still remains largely supportive, but the development of effective disease-modifying treatments is now within tantalising reach helped by major advances in drug discovery and delivery, and targeted genetic manipulation.
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Project description:PurposeAutosomal-dominant optic atrophy (DOA) is one of the most common inherited optic neuropathies, and it is genetically heterogeneous, with mutations in both OPA1 and OPA3 known to cause disease. Approximately 60% of cases harbor OPA1 mutations, whereas OPA3 mutations have been reported in only 2 pedigrees with DOA and premature cataracts. The aim of this study was to determine the yield of OPA1 and OPA3 screening in a cohort of presumed DOA cases referred to a tertiary diagnostic laboratory.DesignRetrospective case series.ParticipantsOne hundred eighty-eight probands with bilateral optic atrophy referred for molecular genetic investigations at a tertiary diagnostic facility: 38 patients with an autosomal-dominant pattern of inheritance and 150 sporadic cases.MethodsOPA1 and OPA3 genetic testing was initially performed using polymerase chain reaction-based sequencing methods. The presence of large-scale OPA1 and OPA3 genomic rearrangements was assessed further with a targeted comparative genomic hybridization microarray platform. The 3 primary Leber hereditary optic neuropathy (LHON) mutations, m.3460G?>A, m.11778G?A, and m.14484T?C, also were screened in all patients.Main outcome measuresThe proportion of patients with OPA1 and OPA3 pathogenic mutations. The clinical profile observed in molecularly confirmed DOA cases.ResultsTwenty-one different OPA1 mutations were found in 27 (14.4%) of the 188 probands screened. The mutations included 6 novel pathogenic variants and the first reported OPA1 initiation codon mutation at c.1A?T. An OPA1 missense mutation, c.239A?G (p.Y80C), was identified in an 11-year-old black girl with optic atrophy and peripheral sensorimotor neuropathy in her lower limbs. The OPA1 detection rate was significantly higher among individuals with a positive family history of visual failure (50.0%) compared with sporadic cases (5.3%). The primary LHON screen was negative in the patient cohort, and additional molecular investigations did not reveal any large-scale OPA1 rearrangements or OPA3 genetic defects. The mean baseline visual acuity for the OPA1-positive group was 0.48 logarithm of the minimum angle of resolution (units mean Snellen equivalent, 20/61; range, 20/20-20/400; 95% confidence interval, 20/52-20/71), and visual deterioration occurred in 54.2% of patients during follow-up.ConclusionsOPA1 mutations are the most common genetic defects identified in patients with suspected DOA, whereas OPA3 mutations are very rare in isolated optic atrophy cases.
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Project description:Options for the effective treatment of hereditary optic neuropathies have been a long time coming. The successful launch of the antioxidant idebenone for Leber's Hereditary Optic Neuropathy (LHON), followed by its introduction into clinical practice across Europe, was an important step forward. Nevertheless, other options, especially for a variety of mitochondrial optic neuropathies such as dominant optic atrophy (DOA), are needed, and a number of pharmaceutical agents, acting on different molecular pathways, are currently under development. These include gene therapy, which has reached Phase III development for LHON, but is expected to be developed also for DOA, whilst most of the other agents (other antioxidants, anti-apoptotic drugs, activators of mitobiogenesis, etc.) are almost all at Phase II or at preclinical stage of research. Here, we review proposed target mechanisms, preclinical evidence, available clinical trials with primary endpoints and results, of a wide range of tested molecules, to give an overview of the field, also providing the landscape of future scenarios, including gene therapy, gene editing, and reproductive options to prevent transmission of mitochondrial DNA mutations.
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