Journal of Neuro-Ophthalmology · 2017 · 0 citations
Diagnosis and Management of Mitochondrial Neuro-Ophthalmologic Disorders: Translating Scientific Advances Into the Clinic
AbstractOnce relegated to a footnote in reviews on neurodegenerative disease, disorders of mitochondrial structure and function, whether the result of nuclear or mitochondrial DNA (mtDNA) abnormalities, are now recognized as major causes of neurodegenerative and multisystem diseases (1,2). Neuro-ophthalmologic manifestations figure prominently among these conditions. Indeed, the vast majority of mitochondrial disorders have some clinically-relevant neuro-ophthalmologic features either as the primary expression of the disease or as a secondary finding that helps define a syndrome and clinch a diagnosis (3). The most common neuro-ophthalmologic manifestations of mitochondrial disorders include vision loss from optic neuropathy or retinal degeneration, chronic progressive external ophthalmoplegia with ptosis, and retrochiasmal visual loss related to stroke-like episodes involving the posterior cerebrum. In his review of the science behind our current understanding of mitochondrial disorders of neuro-ophthalmologic interest (4), Dr. Yu-Wai-Man allows the clinician a glimpse into the complex world of mitochondrial physiology and genetics and how our ever-expanding knowledge might be harnessed into clinical applications for patient care. In this accompanying commentary, I hope to further clarify how this science is highly relevant for both the diagnosis and the management of patients with neuro-ophthalmologic manifestations of mitochondrial diseases. DIAGNOSIS OF MITOCHONDRIAL DISORDERS Advances in molecular genetics have allowed for the development of new technologies that rely on massively parallel next-generation sequencing (NGS) methodologies that are fast becoming the “new” standard for mtDNA genome sequencing (5,6). When screening for nuclear DNA mutations associated with mitochondrial disorders, such as dominant optic atrophy (DOA), NGS screening of one or more genes in question should be performed. Often, phenotypic panels for a variety of nuclear genes in which mutations have been associated with a particular clinical feature are offered commercially, such as an “optic atrophy” panel. If clinical suspicion is very high for a particular phenotypic syndrome with a known gene and sequence analysis is negative, subsequent testing for whole exon deletions and duplications or intronic variants can be performed, although the yield is generally low. Rather than testing separately for a few specific point mutations, next-generation sequence of the entire mtDNA genome now is commonly applied in the detection of mtDNA point mutations associated with mitochondrial diseases such as Leber hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and neuropathy, ataxia, and retinitis pigmentosa (NARP). Most laboratories continue to report a first line screening for LHON to include the 3 primary mtDNA mutations associated with the disease (accounting for about 90% of all cases), but complete analysis of the mitochondrial genome is no longer a difficult or exceptional process, and numerous other disease-causing primary mutations can be identified. Blood is most frequently tested, with newer technologies allowing for accurate detection of heteroplasmy to as low as 1% (6); however, most mtDNA mutations only exert a biochemically deleterious effect at heteroplasmy levels of 70% or more, therefore there is likely little clinical significance in detecting minimal levels of mutant mtDNA. Moreover, it should be emphasized that although newer technologies make mapping an individual's mitochondrial genome feasible, interpretation of what is found still requires an expertise in mitochondrial genetics, physiology, and pathophysiology. For those disorders typically associated with mtDNA deletions/duplications/rearrangements, such as the CPEO syndromes, NGS of the entire mtDNA genome (or Southern blot analysis) should be performed on a tissue other than blood, such as muscle, because of low levels of heteroplasmy in blood and because some mutations are highly tissue-specific (6). The presence of multiple mtDNA deletions or depletion is indicative of a disorder of mtDNA maintenance, and screening the expanding list of nuclear genes that are known to be involved in this complex process should be the next step (7). TREATMENT OF MITOCHONDRIAL DISORDERS Translating bench to bedside in the treatment of mitochondrial diseases has inherent difficulties and barriers to success (2,4,8–14). Demographic limitations include the rarity of many of these disorders with limited numbers of patients for clinical testing, the genetic heterogeneity of a particular phenotype (e.g., multiple different mtDNA or nuclear DNA mutations resulting in optic atrophy), and, conversely, the phenotypic heterogeneity of a specific genotype (e.g., the MELAS 3243 mutation resulting in full-blown MELAS, a syndrome of only maculopathy and diabetes, or an asymptomatic carrier). In some patients (e.g., those with the retinal degeneration of NARP), the amount of damage may be too great for meaningful reversal of the clinical deficit by the time of diagnosis or clinical presentation. In others, the window of opportunity may be too narrow (e.g., the time once visual loss begins in LHON until the second eye becomes involved and the nadir of visual loss is reached). The natural history of the disorder must be predictable and there should be robust objective clinical measures of success. The therapeutic agent must be deliverable in sufficient quantities to the affected tissues, modify a critical number of cells, and have sustained and prolonged effects over time, without causing untoward collateral damage acutely or in the long run. And then there are the ethical concerns for patients, their offspring and even their germlines for generations to come, especially among those receiving therapeutic interventions that involve “genetic engineering.” Current clinical trials on individuals with mitochondrial disorders with prominent neuro-ophthalmologic manifestations that are registered with the NIH ClinicalTrials.gov website are listed in Supplemental Digital Content, Table E1, https://links.lww.com/WNO/A215. It should be emphasized that the listing of a clinical trial on this website does not ensure appropriate clinical trial design and regulation. The assessment of efficacy in LHON patients carries its own additional set of challenges and opportunities. Not all the mtDNA mutations associated with LHON are the same, with the most common 11778 mutation resulting in a poor visual prognosis and a low chance for spontaneous recovery. Even among 11778 patients, there is a better prognosis for those patients who had the onset of visual loss younger than age 20 years and a dramatically better prognosis for those who were 10 years old or less (8), making age of onset an important potential confounder in clinical trials. There are far more asymptomatic LHON carriers, especially among females within the maternal lineage, than actual patients with vision loss, but as of yet, it is impossible to reliably predict who among the carriers will eventually suffer visual loss and when. Currently, it is necessary to wait until the first signs of visual compromise before inclusion in a clinical trial with delivery of therapy. In approximately 50% of LHON symptomatic cases, there is a window of opportunity in which the fellow eye of a recently-affected individual appears clinically relatively-spared, theoretically a window during which an acute intervention can be applied with the dual goals of first eye reversal and second eye vision preservation, although the degree of already irreparable damage in both eyes even in this earliest of stages is currently unknown (8). Since more than 97% of LHON patients will develop bilateral involvement within one year from first eye onset, fairly few patients would be needed in a trial to establish efficacy if the effect of the tested treatment were robust enough to prevent second eye vision loss. Idebenone, a short-chain benzoquinone that both stimulates mitochondrial ATP formation and scavenges free radicals that cause mitochondrial oxidative damage, is currently often offered to patients with LHON visual loss. In a long-term follow-up study of LHON patients systematically treated with varying doses of idebenone, 11778 patients appeared to have an increased frequency of visual recovery, especially if treated early, although idebenone did not protect against second eye involvement in 6 patients (15). In the double-blind, randomized controlled trial of idebenone vs placebo in the treatment of LHON (Rescue of Hereditary Optic Disease Outpatient Study, RHODOS (16)), patients with vision loss up to 5 years were treated with 900 mg/d of idebenone for 24 weeks. Although none of the study primary or secondary endpoints reached statistical significance, when the more visually-favorable 14484-mutation patients were excluded, there was a trend towards better visual outcomes. Additionally, post hoc subgroup analysis of those patients enrolled with discordant visual acuities (and therefore likely in the early stages of LHON) found statistically significant differences in some visual outcomes, translating to about a 4 or 5 Snellen line difference in visual acuity. This suggests that the earlier the treatment, the better the outcome. Given these study results, the safety and tolerability of idebenone, and the lack of any other available therapies, the European Medicines Agency granted marketing approval for idebenone in 2015 for the treatment of LHON under exceptional circumstances. Although not yet FDA approved, many patients in the United States obtain idebenone over the Internet, and most neuro-ophthalmologists recommend its use at least within the first year of LHON visual loss. Obviously, cost-benefit analyses will be necessary when considering the implementation and reimbursement of therapies with partial efficacy. Natural history longitudinal trials of LHON patients treated with idebenone are currently ongoing in Europe and will likely begin soon at centers in the United States. Other oral agents currently being tested in patients with LHON and other mitochondrial disorders are included in Supplemental Digital Content, Table E1, https://links.lww.com/WNO/A215. The long awaited and highly anticipated clinical trials of gene therapy for LHON patients are now a reality. As discussed by Yu-Wai-Man (4), gene therapy to correct pathogenic mtDNA mutations such as those causing LHON is more technologically challenging than delivering the normal gene to the nucleus to complement a nuclear genetic abnormality. Although basic science research continues to investigate ways of directly inserting genetic material into the mitochondrial genome (17), allotopic rescue for LHON has progressed to human clinical applications (2,8,18,19). Clinical safety and efficacy trials using allotopic rescue in LHON patients harboring the 11778 mutation are currently underway in many international sites (Table 1). All studies to date include patients with the 11778 mutation who receive unilateral intravitreal injection of the wild type ND4 gene associated with an AAV2 vector (20–22). Additionally, all studies to date report good safety and tolerability, although transient ocular hypertension and treatment-responsive ocular inflammation are common (22). In one such study from China of 9 patients with the 11778 mutation (20), there was improvement in both eyes of 6 patients after 9 months of follow-up. However, 8 of the 9 patients had their LHON vision loss under the age of 16 years, 4 under the age of 10, likely confounding the results given the better prognosis for young LHON patients. The Miami group's ongoing dose-escalation safety and efficacy trial involves testing 3 different groups of patients at different stages of LHON vision loss with 3 different concentrations of the ND4 gene. A suggestion of efficacy was reported in 2 of the first 5 enrolled patients (21). In a French safety study, 15 patients with vision loss worse than 20/200 in both eyes were treated with 4 escalating concentrations of the ND4 gene into the eye with the worse visual acuity. At 48 weeks of follow-up, the 5 LHON patients in the subgroup who had lost vision within 2 years of treatment showed more visual acuity improvement in the treated eyes than in the sham eyes, whereas there was no significant recovery among those eyes of patients with disease duration of more than 2 years (22). Two multicentered, multinational Phase III studies are currently enrolling LHON 11778-positive patients at 7 sites to receive the third-largest dose from the French Phase I/IIa study, again through a unilateral intravitreal injection with randomized contralateral sham injection. In RESCUE, subjects older than age 15 are included if their vision loss occurred in one or both eyes within the prior 6 months. In REVERSE, subjects older than age 15 are included if their vision loss occurred in both eyes more than 6 months but less than 12 months prior. Studies for binocular delivery are currently in the planning stages, but much will depend on whether current clinical trials demonstrate sufficient efficacy, continued safety, and lasting effects, all within the constraints of cost and practicality. The treatment of patients with DOA also offers some challenges and opportunities. Clinically, meaningful endpoints are even more difficult to define in DOA patients given the wide variability of visual impairment, even among members of the same family. The degree of visual impairment is typically not as severe as with LHON, and most DOA patients manage to function quite well, with many even retaining their independence and capacity to drive (2,8,23). Although the confounder of spontaneous recovery should be less of an issue in DOA studies than in LHON trials, DOA patients' slow, insidious and unpredictable progression will require large numbers of patients and more exacting methods of assessing optic nerve function and structure. In a pilot study of 7 DOA patients treated with varying doses of idebenone for at least 1 year (24), there was some improvement of visual function reported in 5 patients, but larger, double-blind, placebo-controlled, and randomized studies will be required before idebenone can be recommended in this population of patients. As regards gene therapy, because most of the DOA causative OPA1 mutations result in haploinsufficiency, DOA should be an ideal disorder for complementation of the responsible abnormal nuclear gene by direct delivery of the normal gene to the retinal ganglion cells where, unlike with mtDNA disorders, allotopic expression would not be necessary. However, there are currently no gene therapy clinical trials for DOA patients registered with ClinicalTrials.gov. Some of the clinical trials for the treatment of other disorders with neuro-ophthalmologic manifestations, such as the CPEO syndromes, MELAS and Wolfram disease, are listed in Table 1. OTHER FORMS OF MANAGEMENT AND PREVENTION OF MITOCHONDRIAL DISORDERS The management of any patient with neuro-ophthalmologic symptoms and signs must always include symptomatic and supportive treatment. Low-vision rehabilitation for LHON and DOA patients is essential, especially as regards facilitation of reading, communicating, gainful employment, navigation and potentially driving (8). For patients with ptosis and ocular misalignment from the CPEO syndromes, ophthalmic surgical procedures can be helpful, although careful assessment of corneal exposure is paramount. Cardiac conduction interventions and correction of endocrine imbalance can be life-saving. Hearing loss may be improved with hearing aids and even cochlear implants (25). All patients with mitochondrial disorders should be advised to refrain from tobacco use and heavy alcohol consumption, and to avoid medications with suspected mitochondrial toxicity (such as certain antibiotics and antiretroviral therapies) whenever possible (8). Obviously, when dealing with patients with genetically-transmitted diseases such as the mitochondrial disorders, an understanding of the basics of nuclear and mitochondrial DNA inheritance remains essential, and genetic counseling should be performed by professionals comfortable with these issues. Patient-based and maintained websites, such as LHON.org, provide much-needed resources for education, support groups, referrals and links to social media. What about ameliorating or even preventing the disease altogether by germline genetic editing or replacement techniques? For DOA patients with a recognized OPA1 mutation, for example, in vitro fertilization can be selectively performed using oocytes not harboring the pathogenic mutation as determined by pre-implantation genetic diagnosis, and prenatal diagnosis is also possible. Commonly heteroplasmic disorders such as NARP may benefit from techniques to shift the level of mtDNA heteroplasmy toward the wild type in oocytes before in vitro fertilization and implantation, but clinical implementation awaits further refinements of these techniques (4,10). In both heteroplasmic and homoplasmic mtDNA disorders, including LHON, mitochondrial replacement in vitro fertilization techniques offer the opportunity to not only produce a child not at risk for the disease individually, but to halt the germline transmission of the mother's mtDNA disease for all generations to come (26,27). As comprehensively discussed by Yu-Wai-Man (4), the future clinical use of these techniques has raised many ethical and societal issues and the debate is ongoing. The United Kingdom appears to be taking the lead in moving these disease-preventing procedures forward into clinical application, but other regulatory agencies around the world are already weighing in on these issues (28). In 2016 in the United States, the Institute of Medicine, at the request of the FDA, issued a report concluding that it would be “ethically permissible” to embark on human clinical trials of mitochondrial replacement therapies subject to rigorous safety and efficacy imperatives (29,30). However, only months earlier, a federal statute was signed into law that prohibits the FDA from considering research applications of modification of the human germline (29,31). As Yu-Wai-Man (4) concludes, “progress cannot be stopped… and scientists need to engage with the public and politicians to introduce a framework that will allow new genetic technologies to be tested and refined.”
https://doi.org/10.1097/wno.0000000000000471