Professional Documents
Culture Documents
ISSN 2053-180X
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
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).
Kayabasi et al.
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.
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.
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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