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IJMBR 2 (2014) 1-6

ISSN 2053-180X

Genetics and treatment of Leber' s hereditary optic


neuropathy (LHON)
Umur Ali Kayabasi*, Tayfun Bavbek and Oguz Glecek
World Eye Hospital, Istanbul, 34778 Turkey.
Article History
Received 09 October, 2013
Received in revised form 17
October, 2013
Accepted 14 November, 2013

Key words:
Leber's Hereditary
Optic Neuropathy,
Mitochondria,
Genetics.

Article Type:
Review

ABSTRACT
The current concepts about Leber's hereditary optic neuropathy (LHON) and
mitochondrial connection are very difficult to understand completely. Even after
twenty years of clinical studies, it is still difficult to completely explain how
LHON mutations cause damage to the optic nerve or why particularly the optic
nerve is at risk, and the information about mitochondria, the mitochondrial
genome, the metabolism of the optic nerve and the phenotypic variability of
LHON are still being discussed. We cannot fully explain the incomplete
penetrance or the male predominance of LHON, the typical onset in young adults
or the bilaterality of visual loss. Evidence points to abnormalities of the
mitochondria as the direct or indirect cause of LHON. Primary LHON mutations
definitely are not present in every family with the LHON phenotype and
multigenerational maternal inheritance. They may be present in only a minority
of patients with LHON phenotype without a clear family history. Therefore, the
mitochondria-LHON connection needs to be examined more closely and
understood better. This is a review that will attempt to provide an update on
different aspects of LHON and current novel treatment options.
2013 BluePen Journals Ltd. All rights reserved

INTRODUCTION
German ophthalmologist, Theodore Leber (1840-1917),
described Leber' s hereditary optic neuropathy (LHON)
for the first time (Puomila et al., 2007). LHON is one of
the most common inherited optic neuropathies, with an
approximate disease prevalence of 1 in 30,000 (Man et
al., 2003). LHON is mostly detected between 15 and 35
years of age, but the range of onset can vary between
childhood and over 60 years (Nikoskelanien et al., 1996;
Howell, 1997). The age of onset is slightly higher in
females (19-55 years, average being 31.3 years) than
males (15-53 years, average being 24.3) (Leber, 1871;
Howell, 1997). LHON affects mostly males, 80% of
patients being male (Spruijt et al., 2007). There may be
differences in male to female ratio between mutations:
3:1 for m.3460G>A, 6:1 for m.11778G>A and 8:1 for
m.14484T>C. The cause of this predominance is still

*Corresponding author. E-mail: kayabasi@yahoo.com.

undetermined.
Almost one in three cases have no definite family
history (Man et al., 2003). Patients present with painless
visual loss and both eyes become affected either
simultaneously (25% of patients) or sequentially (75% of
patients). The time difference between the effection of
two eyes is about 8 weeks (Huoponen, 2001). Unilateral
cases of LHON can rarely be seen (Newman et al.,
1991). 56 weeks after the onset, visual acuity may
severely be reduced to 6/60 or less. Fundus examination
reveals a characteristic appearance and discloses
changes that consist of a circumpapillary telangiectatic
microangiopathy, edema of the retinal nerve fiber layer,
tortuosity of the vessels and disc swelling (Harding et al.,
1995). But, up to 2025% of cases may have a normal
fundus appearance in the acute stage. The characteristic
field defect in LHON is a central scotoma. Visual field
examination reveals central or centrocecal defect. In the
chronic stage, the loss of retinal ganglion cells results in
optic atrophy (Newman et al., 1991; Harding et al., 1995).

Int. J. Mod. Biol. Res.

Rarely, visual recovery is seen even several years later


(Stone et al., 1992). The chances of visual recovery
depends on the type of the mutation, being least with the
m.11778G>A mutation that causes the most severe
visual loss, and highest with the m.14484T>C mutation;
the m.3460G>A mutation discloses an intermediate
prognosis.
Central
visual
field
defect
and
dyschromatopsia can also be permanent (Newman et al.,
1991; Mackey and Howell, 1992; Nikoskelainen et al.,
1994; McFarland et al., 2007; Ortiz et al., 1992). The
majority of patients with LHON are legally blind (Ortiz et
al., 1992). Neurological examination sometimes reveals
LHON plus syndrome which consists of postural tremor,
cerebellar ataxia and loss of deep tendon reflexes
(Flanigan and Johns, 1993; Funakawa et al., 1995;
Newman, 1993; Nikoskelainen et al., 1995). LHON plus
has been detected both in the presence (Van Senus,
1963; Gropman et al., 2004) and absence of mtDNA
mutations (Abu-Amero et al., 2005).
OPTIC NERVE AND MITOCHONDRIA
The concentrations of mitochondria at the optic disc are
high, showing the increased dependence of the optic
nerve on the mitochondria. Studies have shown that
mitochondria were high in the prelaminar and intralaminar
regions (extending into the lamina cribrosa), but low in
the retrolaminar region, revealing that they were mainly in
the unmyelinated part of the optic nerve (Melov et al.,
1997). Some studies point to a defect in the function of
the respiratory chain which can create either a defect in
ATP synthesis or an increase of oxidative stress (Brune,
2003). According to histopathological studies, there is
selective loss in the retinal ganglion cells and the
temporocentral portion of the optic nerve is more affected
(Howell, 1997). According to histological evidence, there
is impaired axonal transport due to mitochondrial
dysfunction (Howell, 1998). Most likely, oxidative stress
affects the oligodendrocytes of the optic nerves and
mitochondria in optic nerve cells which become unable to
produce energy resulting in cell death. The process of
programmed cell death (PCD) is named as apoptosis
(Barron et al., 2004). Some biochemical changes cause
the loss of cell membrane, cell shrinkage, chromatin
condensation and chromosomal DNA fragmentation.
Mitochondria contain pro-apoptotic elements like
Smac/DIABLO,
apoptosis-inducing
factor
and
cytochrome C. These elements are released through
pores in the mitochondrial membrane by apoptotic
signals like free radical damage, growth factor deprivation
and cell stress. Moreover, nitric oxide can also induce
apoptosis by changing the membrane potential of
mitochondria (Wang et al., 2008). The evidence suggests
that pathology of LHON is related to apoptosis. The
change in the optic nerve happens by swelling of

mitochondria and cytochrome C (Danielson et al., 2002).


It was also suggested that ubiquinone and complex I
cause the opening of the mitochondrial pores. These
results show that apoptosis plays a major role in LHON
(Carelli et al., 2002; Ghelli et al., 2003).
MITOCHONDRIAL DNA MUTATIONS AND GENETIC
TESTING IN LHON
Leber reported young men in four families who had visual
loss with a maternal inheritance pattern in 1871 (Leber,
1871; Kerrison and Newman, 1997). Wallace found the
mutation at nucleotide position 11778 in patients with
LHON in 1988. This was reported as a G to A mutation.
Then, short time later, a G to A point mutation at
nucleotide position 3460 and a T to C mutation at
nucleotide 14484 were reported (Huoponen et al., 1991;
Howell et al., 1991; Erickson, 1972; Wallace et al., 1988;
Newman et al., 1991).
The modern era of genetic investigations in LHON
started with these preliminary findings (Mackey and
Howell, 1992; Johns et al., 1992). The three mutations
described above are called 'primary' mutations. And they
are responsible for about 95% of the mutations in LHON
(Mackey et al., 1996; Brown et al., 1997; Wallace et al.,
1999; Nakamura, 1993; Kim et al., 2003). The 11778
mutation is responsible for 5070% cases, the 14484
mutation for 1015% cases and the 3460 mutation for
825% cases (Newman, 1993). Some polymorphic
mtDNA varients have also been detected and they are
thought to affect the clinical expression of the primary
mutations (Carelli et al., 2004; Valentino et al., 2004;
Zhadanov et al., 2005). There are also 'secondary'
mutations and these cannot cause LHON in isolation, but
the presence of them plus one of the primary mutations
seems to lead to LHON. An example is the 11778
primary mutation in addition to secondary mutations
4216,13708 and 15257 causing LHON (Brown et al.,
2002; Chinnery et al., 1999).
If genetic testing for a patient with LHON is necessary,
then the presence of the three primary mutations should
be checked. In case the test is positive, then the result is
reported. If the three primary mutations cannot be found,
then the secondary mutations are tested (Hofhaus et al.,
1996; Battisti et al., 2004; Zanna et al., 2003). Some of
the secondary mutations are m.4216T^C, m.13708G^A
and m.15257G^A. Secondary mutations should be
interpreted cautiously because they may also be found in
the normal general population (Howell et al., 1995;
Hudson et al., 2007). In case secondary mutations are
not found, then very rare mutations listed in Mitomap can
be tested too (Table 1). The majority of mtDNA mutations
are homoplasmic in LHON and because of that,
heteroplasmy level is not important (Abu-Amero and
Bosley, 2006, 2007; Abu-Amero et al., 2007, 2006;

Kayabasi et al.

Table 1. The Mitomap.

AA Consa

Patient
percent

Control
percent

Het.b

R340H
A52T
M64V
S110N
A112T
E143K
L289M
V65A
A72V
M64I
M64I
L60S

H
M
L
H
H
H
H
L
M
L
L
H

69
13
14
Rare
Rare
Rare
Rare
Rare
Rare
Rare
Rare
Rare

0
0
0
0
0
0
0
0
0
0
0
0

+/+/+/+/+/+/+
+/+

T-C

I58V

Rare

C-T

G36S

Rare

Mutation

Nt

AA

MTND4*LHON11778A
MTND1*LHON3460A
MTND6*LHON14484C
MTND1*LHON3635A
MTND1*LHON3700A
MTND1*LHON3733A
MTND1*LHON4171A
MTND4L*LHON10663C
MTND6*LDYT14459A
MTND6*LHON14482A
MTND6*LHON14482G
MTND6*LHON14495G

G-A
G-A
T-C
G-A
G-A
G-A
C-A
T-C
G-A
C-A
C-G
A-G

MTND6*LHON14502C
MTND6*LHON14568T

Penetrancec
% relatives
33-60
14-75
27-80
29 (range 1164)
NA
24-30
46
56
NA
NA
NA
NA
14502:10%
14502+11778:37%
NA

Penetrancec
% males
82
40-80
68
54 (range 25100)
NA
36-44
47
60
NA
89
NA
NA
14502:11%
14502+11778:47%
NA

Percentage
d
recovery
4
22
37-65
Low
UN
Yes
Yes
UN
Low
Yes
UN
Low
UN
UN

H, High amino acid conservation; M, moderate; L, low; NA, not applicable; Ter, termination codon.
Het., Heteroplasmy; +, detected, -, not detected.
NA, not applicable; UN, unknown; penetrance values are rough estimates.
Low, anecdotal low degree of vision recovery; Yes, anecdotal moderate to high degree of vision recovery; UN, unknown; NA, not applicable.

Fraser and Ross-Cisneros, 2008; La Morgia et al.,


2010). In families with the disease, almost 90% of
the carriers are homoplasmic for the mutation and
the remainder may be heteroplasmic. In case the
mutational load is below 60% which is the
threshold for the onset of the disease, the risk is
low (Man et al., 2003; Yu-Wai-Man et al., 2009;
Fraser et al., 2010; Harding et al., 1992). Male
carriers can be told that their offspring will not
inherit the genetic defect, but the female carriers
will transmit the mutation (Cree et al., 2009). It is
very difficult to predict whether a carrier will lose
vision, but some other factors like sex, age and
environment will play a role, too. Male carriers
have a higher risk for developing the disease and

other factors like smoking or heavy alcohol


consumption increase the risk (Harding et al.,
1992; Chinnery et al., 2001; Cree et al., 2009;
Kirkman et al., 2009; Yu-Wai-Man et al., 2011).
TREATMENT
Coenzyme Q10 is an analogue of quinone and
frequently prescribed in mitochondrial disease.
The evidence for its treatment effect is limited.
Idebenone is a similar compound with better
bioavailability (Yu-Wai-Man et al., 2011; Haefeli et
al., 2011; Klopstock et al., 2011). It has a dual
mode of action; it can bypass complex I inhibition

and optimise ATP production (Haefeli et al., 2011;


Klopstock et al., 2011). There are studies showing
that significant visual recovery can be achieved
with Idebenone treatment (Cree et al., 2009). High
dose Idebenone treatment was also tested by
RHODOS (Rescue of Hereditary Optic Disease
Outpatient Study). Eighty-five patients were
involved in the placebo controlled, double-blind
study. The patients were randomised to receive
either high-dose idebenone (900 mg) or placebo
during a 24 week study. No adverse drug
reactions were detected. Patients, especially the
ones treated early after onset, enjoyed better
vision than placebo (Giordano et al., 2011).
Idebenone has currently been under review by

Int. J. Mod. Biol. Res.

Table 2. Other candidate Leber' s hereditary optic neuropathy mutations found as single family or singleton cases.

Mutation
MTND1*LHON4025T
MTND2*LHON5244A
MTND2*LHON4640A
MTND3*LHON10237C
MTND4*LHON11253C
MTND4*LDYT11696G/
MTND6*LDYT14596A
MTND5*LHON12811C
MTND5*LHON12848T
MTND5*LHON13051A
MTND5*LHON13637G
MTND5*LHON13730A
MTND6*LHON14279A
MTND6*LHON14325C
MTND6*LHON14498T
MTATP6*LHON9101C
MTCO3*LHON9804A
MTCYB*LHON14831A

Nt
C-T
G-A
C-A
T-C
T-C
A-G
G-A
T-C
C-T
G-A
A-G
G-A
G-A
T-C
C-T
T-C
G-A
G-A

AA
T240M
G259S
I57M
I60T
I165T
V312I
I26M
Y159H
A171V
G239S
Q434R
G465E
S132L
N117D
Y59C
I192T
A200T
A29T

AA Cons
M
H
L
H
H
L
M
M
H
H
L
M
M
L
M
L
H
M

# Patients
1 family; 3 cases
1 case
1 family; 4 cases
1 family; 2 cases
1 case
1 family; 11 cases
1 family; 2 cases
1 case
1 family; 3 cases
1 family; 3 cases
1 case
1 family; 2 cases
1 case
1 case
1 case
Multiple unrelated singleton cases
1 case

# Controls
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0

Het.
_

+
_
_
_

+
_
_

+
_
_

+
_
_

+/
_
_
_

Recovery
UN
UN
UN
UN
Yes
UN
UN
UN
UN
UN
Yes
UN
UN
UN
UN
UN
UN

H, High amino acid conservation; M, moderate; L, low; NA, not applicable; Ter, termination codon.
Het., Heteroplasmy; +, detected, -, not detected.
NA, not applicable; UN, unknown; penetrance values are rough estimates.
Low, anecdotal low degree of vision recovery; Yes, anecdotal moderate to high degree of vision recovery; UN, unknown; NA, not applicable.

Europeanagencies (Qi et al., 2007). Gene therapy: The


inner membrane of mitochondria is relatively
impermeable and a highly efficient vector (for example,
adenovirus) is necessary to transfect a sufficient
number of mitochondria per cell. A solution for this
problem is to bypass the mitochondrial genome by an
allotopic approach. The specific targeting sequence that
can facilitate its uptake into the mitochondria. This
approach may compensate for the mtDNA mutation and
the retinal ganglion cell loss may be dramatically reduced
(Cree et al., 2009; Qi et al., 2007). In these situations
when the oxidative stress is high, enzyme superoxide
dismutase exerts an anti-apoptotic effect. In a study, a
defective ND4 gene transfect a sufficient number of
mitochondria per cell. A solution for this problem is to
bypass the mitochondrial genome by an allotopic
approach.
The specific targeting sequence that can facilitate its
uptake into the mitochondria. This approach may
compensate for the mtDNA mutation and the retinal
ganglion cell loss may be dramatically reduced (Cree et
al., 2009; Qi et al., 2007). In these situations when the
oxidative stress is high, enzyme superoxide dismutase
exerts an anti-apoptotic effect. In a study, a defective
ND4 gene in a rat with the m.11778A^G mutation was
transfected with the wild type version of the ND4 gene
and visual loss was reversed.

DISCUSSION
LHON is considered a model for the other mitochondrial
diseases. The collected data for LHON may also be
important for other conditions. The nerve cell damage in
LHON has been found to be similar to the damage in
Parkinson' s disease, Alzheimer' s and glaucoma. These
neurodegenerative diseases affect millions in the world.
The onset and time span of LHON is more rapid
compared with other slowly progressing neurodegenerative diseases. For the time being, it is not known
for sure whether the genetic mutations are sufficient
alone to explain the visual loss. The effects of
environmental factors (for example, smoking and excess
alcohol) play an important role, too. The combination of
genetics and environmental factors are subjects for
ongoing research in neurodegenerative diseases. The
results of RHODOS have been encouraging and
idebenone is being used for the treatment trials of LHON.
Other neuroprotective agents and gene therapy will be
the subjects of future studies.
The findings from this research will be very important
for the treatment trials of other mitochondrial diseases.
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