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Current Treatment Options in NeurologyDOI 10.1007/s11940-010-0100-y NeuropathyAlfredo A. Sadun, MD, PhD1Chiara La Morgia, MD*,2Valerio Carelli, MD, PhD2 Address1Thornton Professor of Vision, Departments of Ophthalmologyand NeuroSurgery, Doheny Eye Institute and Keck-USC School of Medicine,Los Angeles, CA 90033, USA*,2Department of Neurological Sciences,University of Bologna, Via Ugo Foscolo, 7, 40123 Bologna, ItalyEmail: [email protected] * Springer Science+Business Media, LLC 2010 Leber’s hereditary optic neuropathy (LHON) is a maternally inherited blinding diseasewith variable penetrance. Three primary mitochondrial DNA mutations, affecting therespiratory complex I, are necessary but not sufficient to cause blindness. Reduced ef-ficiency of ATP synthesis and increased oxidative stress are believed to sensitize theretinal ganglion cells to apoptosis. Different therapeutic strategies are considered tocounteract this pathogenic mechanism. However, potential treatments for the visualloss are complicated by the fact that patients are unlikely to benefit after optic atrophyoccurs. There is no proven therapy to prevent or reverse the optic neuropathy in LHON.
Results from a recent trial with idebenone hold promise to limit neurodegeneration andimprove final outcome, promoting recovery of visual acuity. Other therapeutic optionsare under scrutiny, including gene therapy, agents increasing mitochondrial biogene-sis, and anti-apoptotic drugs.
Leber’s hereditary optic neuropathy (LHON) is a ND6 and 3460/ND1. These three mutations, affect- maternally inherited disease characterized by severe ing respiratory complex I, account for about 95% of visual loss, which usually does not manifest until LHON cases [••]. Patients inherit their multi- young adulthood [••]. It was first formally de- copy mtDNA entirely from the mother (via the oo- fined by Theodor Leber in 1871, though initially cyte). The mitochondria may carry only wild-type it was mistakenly thought to be X-linked in its or only LHON mutant mtDNA (homoplasmy), or genetics. In 1988, Wallace and colleagues [deter- a mixture of mutant and wild-type mtDNA (hetero- mined that the maternal transmission was due plasmy). Only high loads of mutant heteroplasmy to a mitochondrial DNA (mtDNA) mutation affect- or, most frequently, homoplasmic mutant mtDNA ing nucleotide position (np) 11778/ND4. Later, in the target tissue put the subject at risk for blind- mtDNA mutations were also found at nps 14484/ Except for patients carrying the 14484/ND6 mu- atic, even though they may show subclinical changes tation, who present with a more benign disease such as retinal nerve fiber layer (RNFL) thickening course, most patients remain legally blind. Typically, on optical coherence tomography (OCT) or subtle a man in his second or third decade of life will pres- dyschromatopsia [–A subgroup of these unaf- ent with abrupt and profound loss of vision in one fected mutation carriers may convert and become af- eye, followed weeks to months later by similar loss fected, suffering an abrupt and serious loss of central of vision in the other eye. The ophthalmologist will find little on ocular examination except evidence of All three LHON mutations affect different subunits poor optic nerve function. LHON may occur later in of complex I, the first site of the mitochondrial elec- life and affects women as well. Environmental fac- tron transport chain. Complex I dysfunction due to tors may trigger the visual loss but do not fully ex- the LHON mutations may lead to a combination of re- plain why only certain individuals within a family duced adenosine triphosphate (ATP) synthesis, in- creased oxidative stress, and predisposition for cellsto undergo apoptosis [, ]. The severity of the bio-chemical phenotype is higher for the 3460/ND1 and the 11778/ND4 mutations and milder for the LHON may be the most frequently occurring mito- chondrial disease. The prevalence of visual loss from The exact mechanisms translating the mitochondri- LHON has been reported to be approximately 1 in al dysfunction due to LHON mutations into the selec- 30,000 in Northeast England, 1 in 40,000 in The Neth- tive death of retinal ganglion cells (RGCs) remains an erlands, and 1 in 50,000 in Finland [••]. However, area of contention. In particular, it is debated whether the disease remains underestimated: many patients LHON is due mostly to a bioenergetic defect or to are not adequately diagnosed or are given an inade- chronic oxidative stress, or how a combination of both quate description of optic atrophy, and many are sim- these impairments may play a role in the context of ply misdiagnosed. Furthermore, most individuals the peculiar RGC system. However, it seems plausible carrying the LHON mutation remain unaffected, that these mechanisms lead to changes in mitochon- though a subset of them may develop the disease later drial membrane potential, lowering the threshold for in life. The minimum prevalence for the LHON the mitochondrial permeability transition pore m t D N A m u t a t i o n s i s p r o b a b l y a b o u t 1 5 p e r (MPTP) opening and initiating mitochondrially driven 100,000, which is similar to many autosomal Histopathologic descriptions of molecularly char- Penetrance for the disease (percent affected of total acterized LHON patients have demonstrated a dramat- number of mutation carriers) is much higher for men ic loss of RGCs and their axons, which constitute the than for women. For example, in a well-studied, very nerve fiber layer and optic nerve []. The centrally lo- large Brazilian 11778/ND4 pedigree, about 45% of cated, small-caliber fibers of the papillomacular bun- the males and 10% of the females lost vision ].
dle (PMB) were most damaged, and the larger axons Penetrance also varies greatly between families and on the periphery were most spared. Mitochondria ac- even within the same pedigree. Factors that affect pen- cumulate in the RNFL, especially in the unmyelinated etrance may include heteroplasmy, environmental fac- portion anterior to the lamina cribrosa, as this is the tors, and the mitochondrial DNA background, as well area with the greatest energy requirements [, ••].
as nuclear modifying genes ••, It is for this The particularly high energy demands of the unmy- last reason that the likelihood of visual loss has been elinated RNFL may explain why the optic nerve, reported to be greater if the mother is affected, even which represents the coalescence of these fibers as they course towards the brain, is the target tissue inLHON ].
PathophysiologyThe primary etiologic cause of LHON is an mtDNA mutation, which is a necessary determinant but not The patient classically presents with painless, subacute sufficient to lead to visual loss. In fact, most individu- loss of vision in one eye. The visual acuity is usually als carrying the mtDNA mutation remain asymptom- worse than 20/400, and there is optic nerve dysfunc- Leber’s Hereditary Optic Neuropathy Sadun et al.
tion manifested as large and dense central or cecocen- the absence of other systemic or constitutional symp- tral scotomas on visual fields. Fundus examination in toms. After the patient has lost vision in the second LHON may show telangiectatic capillaries and pseu- eye, the diagnosis becomes much easier. In addition doedema of the optic disc with surrounding swelling to all the points above, the features of both eyes can of the RNFL. Over time, there is loss of the PMB with now be compared. Bilaterally symmetric optic neurop- corresponding atrophy of the temporal optic nerve, athies are almost always due to mitochondrial disease.
which eventually will extend to the other quadrants, This becomes even more certain with bilaterally sym- leading to diffuse optic atrophy , , ]. The vi- metrical central or cecocentral scotomas on visual field sual loss in LHON is usually permanent, although a testing []. Mitochondrial optic neuropathies fall in- subgroup of patients may spontaneously recover some to three categories: 1) LHON, 2) dominant optic atro- visual acuity. This recovery is particularly frequent phy (DOA), and 3) nutritional and toxic optic with the 14484/ND6 mutation [, ••].
neuropathies []. The disease segregation in One remarkable aspect of LHON is the tissue DOA will involve paternal as well as maternal trans- specificity. The optic nerve is singularly involved, mission. Furthermore, the visual loss occurs at a youn- with preferential loss of the smallest fibers that ger age (usually before age 10) and progresses slowly constitute the PMB [Loss of vision is usually over many years, often leveling off at 20/100 or 20/ the only clinical manifestation, notwithstanding 200. This is easily distinguishable from LHON [, reports of patients with cardiac, skeletal, or neuro- Nutritional and toxic etiologies must also be inves- tigated by a careful history •]. Folate and vita- min B deficiencies are usually associated with a very LHON patients present with subacute visual loss and poor diet over a long course. There may also be an as- optic neuropathy. Fundus examination will usually sociated anemia. Toxic agents that can produce a mito- rule out any retinopathy. Hence, the differential diag- chondrial optic neuropathy include several antibiotics nosis begins with the optic neuropathies. Usually, the subacute tempo of the visual loss is very helpful. Com-pressive lesions involving the optic nerve have a slowlyprogressive course. So too does chronic papilledema from brain tumors or idiopathic intracranial hyperten- LHON can usually be diagnosed clinically. Confirma- sion (pseudotumor cerebri). Glaucoma also is a much tion can be made by blood testing of the mtDNA to slower and progressive process and the optic disc cup- reveal one of the three common mutations. Even if ping is usually obvious. Ischemic optic neuropathies this test is negative, however, LHON may still be con- produce a very abrupt loss of vision, but the optic disc sidered, as about 5% of cases are not due to the three appearance, including peripapillary hemorrhages, is common LHON mutations. Complete mtDNA se- distinctive. Hence, a young adult with painless sub- quence analysis may be recommended if the clinical acute visual loss is likely to have an inflammatory or diagnosis of LHON remains as a strong indication, infiltrative optic neuropathy. These etiologies are or if there is evidence of maternal transmission of revealed by fundus examination and neuroimaging.
blindness. DNA testing of primary LHON mutations An infiltrative optic neuropathy is usually evident by is especially useful in atypical presentations or in the the thickened appearance of the optic disc and by absence of a clear family history of LHON or optic at- the leakage of dye during fluorescein angiography.
rophy of unknown etiology limited to the maternal MRI studies of the brain help reveal any infiltrative side of the pedigree. Ophthalmologic and psycho- or inflammatory lesions of the optic nerve, or lesions physical tests are also useful. In LHON, there is ab- elsewhere, as in multiple sclerosis.
sence of dye leakage at the optic disc on fluorescein However, as in many neuro-ophthalmologic dis- angiography , ••]. In the acute phase of the disease, eases, the most revealing part of the examination OCT demonstrates thickening of the RNFL around the comes from the history. In addition to the tempo of optic nerve; on subsequent examinations, it reveals visual loss, the patient with LHON can often provide a history of visual loss in family members along the Unaffected mutation carriers may show subclini- maternal line ••]. The history will also confirm cal abnormalities. Examination and testing of 75 Table 1. Agents that may prompt conversion in Leber’s hereditary opticneuropathy EthambutolAminoglycosidesChloramphenicolLinezolidZidovudine (AZT) and other antiretroviral drugs Smoke (including tobacco)EthanolPesticidesCyanideMethanol asymptomatic carriers in a large Brazilian family mic 11778/ND4 mutation and J-haplogroup) showed a with the 11778/ND4 mutation revealed microangi- doubling of disease risk with high consumption of either opathy and swelling of the RNFL in about 15% of alcohol or tobacco , A subsequent multicenter sur- the eyes [These mutation carriers also exhibited vey of a cohort of 402 LHON patients, carrying the three corresponding relative central visual field defects on primary mutations, also found a significant role in dis- Humphrey visual field tests. Furthermore, they often ease risk for tobacco, in particular, and alcohol use showed subtle deficits in color vision and contrast []. Smoke in general (not just tobacco smoking) sensitivity, as well as thickening of the RNFL on may also trigger LHON, as some reported cases have been associated with exposure to smoke from tire firesor malfunctioning stoves Further triggers of LHON may be antibiotics such Environmental risk factors may be important triggers of as ethambutol, chloramphenicol, linezolid, aminogly- the conversion to active LHON in unaffected carriers.
cosides, and antiretroviral drugs (for HIV) (Table One study of a large Brazilian LHON pedigree (332 indi- All of these are known for interfering with mitochon- viduals, 97 on the maternal line, all carrying a homoplas- & There are currently no proven treatments to prevent or reverse the & While awaiting further progress with experimental therapeutic strat- egies, individuals (affected or still unaffected) who carry the LHONmutation need a frank discussion that includes genetic counselingand information on risk factors and on currently available treatmentoptions (Table Leber’s Hereditary Optic Neuropathy Sadun et al.
Table 2. Conversation with patients affected by Leber’s hereditary OpticNeuropathy (LHON) Frankly discuss the nature of LHON and poor visual prognosis.
Offer genetic counseling: Men cannot transmit; women affected and carriers are certain to transmit; variable penetrance; male prevalence.
Counsel patients about risk factors:• Advise against smoking tobacco.
• Caution against exposure to any smoke, including fires.
• Recommend minimizing use of alcohol.
• Recommend a healthy diet, including B vitamins and high-quality proteins.
Discuss novel and unproven therapies, including idebenone.
Caution patients against international scams that suggest stem cell treatment Anecdotal reports on the therapeutic use of vitamins (especially folic acidand vitamins B2 and B12) and nutritional supplements (includingvitamins C and E) did not prove their efficacy in LHON. Although theadministration of vitamin B12 has not been a successful treatment forLHON, it may be helpful in the setting of a B12 deficiency that precip-itates the visual loss in LHON [ Topical brimonidine, an alpha-2 agonist, also failed in a small clinicaltrial as a prophylactic agent aimed to avoid the involvement of the felloweye in LHON []. It had been hoped that brimonidine, by upregulatingBcl-2, could inhibit the MPTP opening, thus forestalling mitochondriallyinduced apoptosis The study was halted early because of in-sufficient enrollment and because none of the patients achieved thetarget of mitigating visual loss [].
& Most treatment options in LHON have targeted the excessive produc- tion of reactive oxygen species , ]. Antioxidants such as glutathi-one, Trolox (a derivative of vitamin E), and coenzyme Q-10 havedemonstrated modest protective effects in vitro. A current clinical trialin Thailand is investigating the efficacy of curcumin, another com-pound with antioxidant properties, in treating LHON patients Coenzyme Q10 is a mitochondrial cofactor that shuttles electrons fromcomplexes I and II to complex III. Coenzyme Q10 (or ubiquinone) is available as a nutritional supplement. A few case reports of treatmentwith coenzyme Q10 have been published, but the lack of any successfulcase series gives rise to skepticism about this treatment ]. Onelikely limitation of treatment with exogenous coenzyme Q10 relates toits poor delivery crossing lipid membranes to mitochondria.
Idebenone, a coenzyme Q10 derivative, is reported to have higher de-livery to mitochondria as well as a higher efficiency in crossing theblood-brain barrier []. Successful treatment with idebenone has beendescribed in a few case reports and retrospective case series [, –].
One such study evaluated the treatment of 28 Japanese patients withLHON who carried all three mutations The authors divided thesepatients into two groups: an untreated group and a group treated with acombination of idebenone, riboflavin (vitamin B2), and ascorbic acid(vitamin C). The two cohorts of LHON patients had an equal distribu-tion of mtDNA mutation types. The visual recovery was significantlyearlier for treated patients carrying the 11778/ND4 mutation and waslimited to small openings that appeared in the paracentral visual field(fenestrations) We recently reported a case series of seven LHON patients, treated withidebenone alone (about 450 mg/d) []. Most eyes showed recovery ofvisual acuity, color vision, and visual fields. One 11778/ND4 LHON patientimproved from counting-fingers vision in both eyes to visual acuities of 20/20 and 20/30 with associated shrinkage of the central scotomas from a di-ameter of about 20 degrees to less than 5 degrees [].
Most recently, the Rescue of Hereditary Optic Disease Outpatient Study(RHODOS) was concluded. In this large, double-blind, randomized,placebo-controlled clinical trial in a series of 85 LHON patients, treatedpatients were given idebenone (900 mg/d) for 24 weeks. The preliminarypress release highlighted that patients taking idebenone had better finalvisual acuity than the placebo group [].
& Other strategies proposed to bypass the complex I dysfunction in LHON are based on a gene-therapy approach. It is important toemphasize that none of these approaches is currently used inpatients; they remain experimental pending further evidence of theirsafety and usefulness.
& LHON is due to mutations affecting the mtDNA-encoded subunits of complex I (11778/ND4, 3460/ND1, 14484ND4). One strategy of genetherapy is the so-called nuclear allotopic expression of a mitochondrialgene. Briefly, in order to express a wild-type version of the mtDNA-encoded ND subunits in the nucleus, they first need to be recoded Leber’s Hereditary Optic Neuropathy Sadun et al.
according to the slightly different coding system of nuclear DNA. Then,the recoded wild-type ND subunit is engineered to carry the mito-chondrial import signal and is delivered by an AAV vector to the nucleusof the target cells (RGCs). Thus, the nuclear-encoded wild-type NDsubunit will be expressed in the cell cytoplasm and transported to mi-tochondria, where it is assumed to co-assemble in complex I. This wild-type ND subunit will be competing with the mitochondrial-encodedmutant ND subunit, thus potentially complementing the biochemicaldefect , ]. However, serious doubts have been cast on this ap-proach recently, and caution must be exercised before the stage ofclinical trials in patients is reached ••, & Another strategy is based on the xenotopic expression of an alter- native oxidase, such as the Saccharomyces cerevisiae single subunitNADH oxidase Ndi1, in mammalian cells. This can re-establish theelectron flow to coenzyme Q bypassing the complex I defect, butwithout coupled proton translocation, thus missing the energy-con-serving function of complex I By this means, the downstreamrespiratory chain is fed again with the electron flow, re-establishing asufficiently efficient oxidative phosphorylation. This gene therapyapproach has been successfully tried in an experimental animalmodel mimicking LHON [ Drugs activating mitochondrial biogenesis and anti-apoptotic agents & Other therapeutic strategies are proposed to provide a compensatory mechanism to prevent the loss of vision in unaffected individualscarrying the mutation, and to inhibit the apoptotic program in RGCsonce the acute phase has started.
& The compensatory mechanism is based on activating mitochondrial biogenesis. To this end, drugs such as bezafibrate and rosiglitazoneare being tested in vitro; they act as peroxisome proliferator-activatedreceptor γ (PPARγ) activators and, through PPARγ coactivator α(PGC1α), enhance mitochondrial biogenesis []. A similar resultmay be achieved by estrogens or estrogen-related compounds, whichrecently have been shown to activate mitochondrial gene expression,including antioxidant enzymes, and to increase mtDNA copy num-ber ••].
& A class of drugs that includes as a prototypic example cyclosporine A can abort the apoptotic program by holding closed the MPTP [].
These drugs may be beneficial in the very early stages of LHON bymodifying the natural disease progression.
No potential conflicts of interest relevant to this article were reported.
Papers of particular interest, published recently, have beenhighlighted as:• Carelli V, Ross-Cisneros FN, Sadun AA: Mitochon- regated into magnocellular and parvocellular drial dysfunction as a cause of optic neuropathies.
systems in asymptomatic carriers of 11778 Leb- Prog Retin Eye Res 2004, 23:53–89.
er’s hereditary optic neuropathy. Vis Neurosci Fraser JA, Biousse V, Newman NJ: The neuro-oph- thalmology of mitochondrial disease. Surv Ophthalmol Sadun AA, Win PH, Ross-Cisneros FN, et al.: Leber’s hereditary optic neuropathy differen- This is the most comprehensive recent review of LHON and tially affects smaller axons in the optic nerve.
Trans Am Ophthalmol Soc 2000, 98:223–232. dis- Wallace DC, Singh G, Lott MT, et al.: Mitochon- drial DNA mutation associated with Leber’s he-reditary optic neuropathy. Science 1988, 14.•• Barboni P, Carbonelli M, Savini G, et al.: Natural history of Leber’s hereditary optic neuropathy: Sadun AA, Carelli V, Salomao SR, et al.: A very large longitudinal analysis of the retinal nerve fiber layer Brazilian pedigree with 11778 Leber’s hereditary by optical coherence tomography. Ophthalmology optic neuropathy. Trans Am Ophthalmol Soc 2002, 100:169–178. discussion 178–179.
This is the first study on the stages of swelling and atrophy ofthe retinal nerve fiber layer in LHON as measured by OCT Sadun AA, Carelli V, Salomao SR, et al.: Extensive Sadun AA, Salomao SR, Berezovsky A, et al.: Sub- investigation of a large Brazilian pedigree of clinical carriers and conversions in Leber heredi- 11778/haplogroup J Leber hereditary optic neu- ropathy. Am J Ophthalmol 2003, 136:231–238.
psychophysical study. Trans Am Ophthalmol Soc Carelli V, Achilli A, Valentino ML, et al.: Haplogroup effects and recombination of mitochondrial DNA: Barboni P, Savini G, Valentino ML, et al.: Retinal novel clues from the analysis of Leber hereditary nerve fiber layer evaluation by optical coherence optic neuropathy pedigrees. Am J Hum Genet 2006, tomography in Leber’s hereditary optic neuropa- thy. Ophthalmology 2005, 112:120–126.
Hudson G, Carelli V, Spruijt L, et al.: Clinical ex- Sadun F, De Negri AM, Carelli V, et al.: Ophthal- pression of Leber hereditary optic neuropathy is mologic findings in a large pedigree of 11778/ affected by the mitochondrial DNA-haplogroup Haplogroup J Leber hereditary optic neuropathy.
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