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.
background. Am J Hum Genet 2007, 81:228–233.
Am J Ophthalmol 2004, 137:271–277.
Shankar SP, Fingert JH, Carelli V, et al.: Evidence for
Kirkman MA, Yu-Wai-Man P, Korsten A, et al.: Gene-
a novel x-linked modifier locus for Leber hereditary
environment interactions in Leber hereditary optic
optic neuropathy. Ophthalmic Genet 2008, 29:17–24.
neuropathy. Brain 2009, 132:2317–2326.
Savini G, Barboni P, Valentino ML, et al.: Retinal
This large, recent study analyzed the environmental risk
nerve fiber layer evaluation by optical coherence
tomography in unaffected carriers with Leber’s he-
Ramos C, Bellusci C, Savini G, et al.: Association of
reditary optic neuropathy mutations. Ophthalmology
optic disc size with development and prognosis of
Leber’s hereditary optic neuropathy. Invest Ophthal-
Ventura DF, Quiros P, Carelli V, et al.: Chromatic
and luminance contrast sensitivities in asymptom-
This study shows that optic disc size, as measured by OCT,
atic carriers from a large Brazilian pedigree of
may be relevant to LHON penetrance and prognosis in af-
11778 Leber hereditary optic neuropathy. Invest
Ophthalmol Vis Sci 2005, 46:4809–4814.
Sanchez RN, Smith AJ, Carelli V, et al.: Leber hereditary
Ventura DF, Gualtieri M, Oliveira AG, et al.: Male prev-
optic neuropathy possibly triggered by exposure to
alence of acquired color vision defects in asymptom-
tire fire. J Neuroophthalmol 2006, 26:268–272.
atic carriers of Leber’s hereditary optic neuropathy.
De Marinis M: Optic neuropathy after treatment
Invest Ophthalmol Vis Sci 2007, 48:2362–2370.
with anti-tuberculous drugs in a subject with Leb-
Gualtieri M, Bandeira M, Hamer RD, et al.: Psy-
er’s hereditary optic neuropathy mutation. J Neurol
chophysical analysis of contrast processing seg-
Leber’s Hereditary Optic Neuropathy Sadun et al.
Ikeda A, Ikeda T, Ikeda N, et al.: Leber’s hereditary
hereditary optic neuropathy. Arch Soc Esp Oftalmol
optic neuropathy precipitated by ethambutol. Jpn J
Eng JG, Aggarwal D, Sadun AA: Idebenone treatment
Pott JW, Wong KH: Leber’s hereditary optic neu-
in patients with Leber hereditary optic neuropathy
ropathy and vitamin B12 deficiency. Graefes Arch
[abstract]. Invest Ophthalmol Vis Sci 2009, 50
Clin Exp Ophthalmol 2006, 244:1357–1359.
Mashima Y, Kigasawa K, Wakakura M, et al.: Do
Chinnery P, et al.: Results of a 6-months randomized,
idebenone and vitamin therapy shorten the time
placebo-controlled trial (RHODOS) with idebenone
to achieve visual recovery in Leber hereditary
(Catena®) in Leber’s Hereditary Optic Neuropathy
optic neuropathy? J Neuroophthalmol 2000,
(LHON) [poster WIP-3]. Presented at the 135th Annual
Meeting of the American Neurological Association. San
Newman NJ, Biousse V, David R, et al.: Prophylaxis
for second eye involvement in Leber hereditary
Guy J, Qi X, Koilkonda RD, et al.: Efficiency and
optic neuropathy: an open-labeled, nonrandom-
safety of AAV-mediated gene delivery of the human
ized multicenter trial of topical brimonidine purite.
ND4 complex I subunit in the mouse visual system.
Am J Ophthalmol 2005, 140:407–415.
Invest Ophthalmol Vis Sci 2009, 50:4205–4214.
Wheeler L, WoldeMussie E, Lai R: Role of alpha-2
Ellouze S, Augustin S, Bouaita A, et al.: Optimized
agonists in neuroprotection. Surv Ophthalmol 2003,
allotopic expression of the human mitochondrial
ND4 prevents blindness in a rat model of mito-
Lai RK, Chun T, Hasson D, et al.: Alpha-2 adreno-
chondrial dysfunction. Am J Hum Genet 2008,
ceptor agonist protects retinal function after acute
retinal ischemic injury in the rat. Vis Neurosci 2002,
40.•• Perales-Clemente E, Fernández-Silva P, Acín-Pérez
R, et al.: Allotopic expression of mitochondrial-
Ghelli A, Porcelli AM, Zanna C, et al.: Protection
against oxidant-induced apoptosis by exogenous
undemonstrated mechanism or impossible task?
glutathione in Leber hereditary optic neuropathy
Nucleic Acids Res 2010 Sep 7 (Epub ahead of
cybrids. Invest Ophthalmol Vis Sci 2008, 49:671–676.
Sala G, Trombin F, Beretta S, et al.: Antioxidants
This careful study demonstrates how apparent comple-
partially restore glutamate transport defect in Leber
mentation of the mitochondrial dysfunction by using the
hereditary optic neuropathy cybrids. J Neurosci Res
approach of allotopic expression may be due to selection
Mahidol University: A randomized, double-blind,
Figueroa-Martínez F, Vázquez-Acevedo M, Cortés-
placebo-controlled trial of curcumin in Leber’s he-
Hernández P, et al.: What limits the allotopic ex-
reditary optic neuropathy (LHON). In: ClinicalTrials.
pression of nucleus-encoded mitochondrial genes?
gov [Internet}. Bethesda, MD: National Library of
The case of the chimeric Cox3 and Atp6 genes.
Mitochondrion 2010 Sep 18 (Epub ahead of print).
Marella M, Seo BB, Thomas BB, et al.: Successful
Huang CC, Kuo HC, Chu CC, et al.: Rapid visual
amelioration of mitochondrial optic neuropathy
recovery after coenzyme q10 treatment of Leber
using the yeast NDI1 gene in a rat animal model.
hereditary optic neuropathy. J Neuroophthalmol
Wenz T, Diaz F, Spiegelman BM, Moraes CT: Acti-
Geromel V, Darin N, Chrétien D, et al.: Coenzyme Q
vation of the PPAR/PGC-1α pathway prevents a
(10) and idebenone in the therapy of respiratory
bioenergetic deficit and effectively improves a mi-
chain diseases: rationale and comparative benefits.
tochondrial myopathy phenotype. Cell Metab 2008,
Cortelli P, Montagna P, Pierangeli G, et al.: Clinical
44.•• Giordano C, Montopoli M, Perli E, et al.: Estrogens
and brain bioenergetics improvement with idebe-
ameliorate mitochondrial dysfunction in Leber’s
none in a patient with Leber’s hereditary optic
hereditary optic neuropathy. Brain 2010, in press.
neuropathy: a clinical and 31P-MRS study. J Neurol
This study demonstrated the role of estrogens in compen-
sating for mitochondrial dysfunction in LHON and explains
Carelli V, Barboni P, Zacchini A, et al.: Leber’s he-
reditary optic neuropathy (LHON) with 14484/
Porcelli AM, Angelin A, Ghelli A, et al.: Respiratory
ND6 mutation in a North African patient. J Neurol
complex I dysfunction due to mitochondrial DNA
mutations shifts the voltage threshold for opening
Barnils N, Mesa E, Munoz S, et al.: Response to
of the permeability transition pore toward resting
idebenone and multivitamin therapy in Leber’s
levels. J Biol Chem 2009, 284:2045–2052.
Product Name: VS1003B-B/LSR-ROHS (BGA49 RoHS) References of “Threshold level” columns: 1) Report the biggest content rate (ppm) of the substance at the homogeneous material level . Optionally also the total weight of the substance in the product. Weight = total weight of the substance in the product. Content rate [ppm] = Content rate of the substance in the homogeneous material th
INDUCED ABORTION IN INDIA Shweta Rana Chauhan* In a society, a woman who is pregnant is pressurized to abort andone who is not pregnant is pressured to control her fertility. The women insocieties such as that found in India do not have the choice to remainsingle and, having gotten married, they cannot choose when to have thesexual relations that make them pregnant. Nor is the choice to con