Downloaded from http://jmg.bmj.com/ on March 4, 2015 - Published by group.bmj.

com

162

REVIEW ARTICLE

Leber hereditary optic neuropathy

P Y W Man, D M Turnbull, P F Chinnery
.............................................................................................................................

J Med Genet 2002;39:162–169

Leber hereditary optic neuropathy (LHON) is a PATHOGENIC MUTATIONS

mitochondrial genetic disease that preferentially causes In one retrospective study, over 95% of LHON
blindness in young adult males, affecting about 1 in pedigrees harboured one of three mtDNA point
mutations, G3460A, G11778A, and T14484C,
25 000 of the British population. It is characterised by which all involve genes encoding complex I sub-
bilateral subacute loss of central vision owing to focal units of the mitochondrial respiratory chain.7
degeneration of the retinal ganglion cell layer and optic These primary LHON mutations have so far not
been found in a large sample of normal controls,
nerve. Over 95% of LHON cases are primarily the result without a family history of visual failure
of one of three mitochondrial DNA (mtDNA) point (>1000). However, the relative frequency of each
mutations, G3460A, G11778A, and T14484C, which of these pathogenic mutations varies considerably
world wide. A meta-analysis involving 159 pedi-
all involve genes encoding complex I subunits of the grees from northern Europe and Australia
respiratory chain. An intriguing feature of LHON is that showed that G11778A was the most prevalent
only ∼50% of males and ∼10% of females who harbour LHON mutation (table 1). The predominance of
G11778A is even more marked in the Far East
a pathogenic mtDNA mutation actually develop the where it accounts for ∼ 90% of total LHON cases.8
optic neuropathy. This marked incomplete penetrance Although T14484C is relatively rare in most
and gender bias imply that additional mitochondrial countries,8 9 it is the most common mutation
found among French Canadians (87%). This has
and/or nuclear genetic factors must be modulating the recently been convincingly ascribed to a founder
phenotypic expression of LHON. It is also likely that event.10 11
environmental factors contribute to the onset of visual Primary mutations have not been identified in
a small minority of diagnosed LHON cases, the
failure. However, these secondary precipitating factors most likely explanation being that rare patho-
remain poorly defined at present. In this review, we genic mtDNA variants are segregating in these
describe the natural history of this optic nerve disorder pedigrees. Some of these have recently been iden-
tified and most seem to cluster in the gene encod-
and highlight issues relating to clinical diagnosis, ing the ND6 subunit. It has been suggested by
management, and genetic counselling. We also discuss some investigators that the latter represents a
the findings of recently published studies and the light mutational hot spot for LHON and should be
investigated in pedigrees where none of the three
they shed on the complex aetiology and primary mutations is present.12
pathophysiology of LHON.
.......................................................................... EPIDEMIOLOGY
LHON is by far the most common of the
mitochondrial genetic diseases, with an esti-
mated prevalence of ∼1 in 25,000 in the north east
of England.23 No prevalence data are currently
available for other populations, although 2% of
HISTORY people on the blind register in Australia are
Leber hereditary optic neuropathy (LHON, reported to suffer from LHON.24 The reported
OMIM 535000) was first described as a distinc- median age of onset in LHON varies somewhat
tive clinical entity in 1871 by the German between various case series, but 95% of those who
ophthalmologist Theodore Leber (1840-1917).1 lose their vision do so by their early 50s (table 2).
He described a characteristic pattern of visual However, visual deterioration can occur any time
loss among members of four families and his during the first to the seventh decade of life.
observations were subsequently confirmed in Except for one report which found a slight
See end of article for pedigrees from different populations.2–6 These increase in the age of onset in females carrying
authors’ affiliations early studies highlighted several of the salient the G11778A mutation,9 it is generally accepted
....................... features of LHON including the maternal that neither gender nor mutational status signifi-
Correspondence to: transmission of the disease, the predilection of cantly influences the timing and severity of the
Dr P F Chinnery, males to lose vision, and the almost exclusive
Department of Neurology, involvement of the optic nerve. The non-
School of Neurosciences mendelian pattern of inheritance was to remain .................................................
and Psychiatry, The
Medical School, University a mystery until more became known about the Abbreviations: LHON, Leber hereditary optic
of Newcastle Upon Tyne, mitochondrial genome. The hypothesis that a neuropathy; mtDNA, mitochondrial DNA; MS, multiple
Newcastle upon Tyne, UK; mitochondrial DNA (mtDNA) mutation was the sclerosis; MHC, major histocompatibility complex; VEPs,
[email protected] causative factor in LHON then became firmly visual evoked potentials; ADOA, autosomal dominant
....................... optic atrophy
established.

www.jmedgenet.com
 Downloaded from http://jmg.bmj.com/ on March 4, 2015 - Published by group.bmj.com

LHON 163

Table 1 Reported pathogenic primary mtDNA

mutations in LHON
Mutation Protein Prevalence7 Reference

Common >95%
G3460A ND1 13% 14, 15
G11778A ND4 69% 13
T14484C ND6 14% 16, 17

Rare <5%
G13730A ND5 18
G14459A ND6 19
C14482G ND6 20
A14495G ND6 12
C14498T ND6 21
C14568T ND6 21
T14596A ND6 22

initial visual loss.10 25–27 LHON is also characterised by a marked Figure 1 Acute fundal appearance in LHON.
gender bias, with males more likely to become affected than
females. Finally, up to 60% of LHON probands will give a reli- depends greatly on the patient’s mutational status, with
able history of other maternal relatives being affected. The G11778A carrying the worst overall prognosis (table 2). There
remainder most likely represent cases where family history is is also some evidence that patients with the T14484C mutation
difficult to trace back, given that de novo mutation is rare in are more likely to show improvement if visual loss occurs
LHON.28 before the age of 20.27 31 However, LHON is a devastating disor-
der with the majority of patients showing no functional
CLINICAL FEATURES improvement and remaining within the legal requirement for
Acute phase blind registration.
LHON carriers remain asymptomatic until they experience
blurring or clouding of vision in one eye. In the vast majority Associated features
of cases, visual dysfunction is bilateral, the fellow eye becom- A significant minority of white LHON carriers, especially
ing affected either simultaneously (25%) or sequentially females with the G11778A mutation, develop clinical and
(75%), with a median inter-eye delay of eight weeks.9 Visual neuroimaging features indistinguishable from multiple scle-
acuity usually reaches a nadir four to six weeks after the first rosis (MS), including unmatched oligoclonal bands in the
start of symptoms and is severely reduced to 6/60 or less. The cerebrospinal fluid.32–36 The prevalence of this MS-like illness
characteristic field defect in LHON is a centrocaecal scotoma. in LHON is higher than expected because of chance only and
Other clinical features include the early impairment of colour some investigators have argued for a potential role of autoim-
perception but, more importantly, pupillary reflexes are munity in the pathophysiology of this mitochondrial
preserved and patients usually report no pain on eye disorder.32 37 It is of note that higher levels of antibodies to the
movement. Fundoscopy provides other diagnostic clues and in optic nerve protein tubulin have been found among LHON
classical cases the following abnormalities can be observed: carriers compared to controls.38 However, other reports have
vascular tortuosity of the central retinal vessels, a circumpap- failed to detect any significant association between LHON and
illary telangiectatic microangiopathy, and swelling of the reti- either class I or class II major histocompatibility complex
nal nerve fibre layer (fig 1). However, it must be stressed that (MHC) genotypes.39 40 Overall, the “autoimmunity” hypothesis
in ∼20% of LHON cases, the optic disc looks entirely normal in has not yet been convincingly substantiated. Other clinical
the acute phase.29 abnormalities have also been reported to be more common in
LHON compared to controls. These include postural tremor,
Chronic phase peripheral neuropathy, non-specific myopathy, movement dis-
The retinal nerve fibre layer gradually degenerates and after orders, and cardiac arrhythmias.31 41–46 The jury is still out as to
six months optic atrophy is a universal feature of LHON.30 If a whether these represent real or spurious associations.
patient is only seen at this stage, it can be difficult to exclude However, it is now well recognised that a group of LHON
other possible causes of optic atrophy, especially if there is no pedigrees does exist characterised by optic neuropathy and
clear maternal family history. In these cases, molecular additional severe neurological deficits (spastic dystonia,
genetic testing is warranted. The extent of final visual recovery ataxia, and juvenile onset encephalopathy). These “LHON+”

Table 2 Summary of major reported case series in LHON

No of Median onset
pedigrees (y) Male:female ratio Visual recovery Reference

G3460A 9 29 2.3 : 1 22% 26

8 20 4.3 : 1 25% 9

G11778A 49 28 4.5 : 1 4% 25
66 24 3.7 : 1 25% 9

T14484C 17 27 2.1 : 1 37% 27

23 19 7.7 : 1 58% 10

www.jmedgenet.com
 Downloaded from http://jmg.bmj.com/ on March 4, 2015 - Published by group.bmj.com

164 Man, Turnbull, Chinnery

that none found any significant difference between affected

Table 3 Respiratory chain dysfunction in LHON and unaffected LHON carriers. Balancing the current weight
In vitro60–74 In vivo75–77 of evidence, it seems that LHON is associated with a rather
more subtle respiratory chain defect when compared to other
Complex I Respiratory
activity* rate* MRS* pathogenic mtDNA mutations (such as the A3243G in the
syndrome of mitochondrial myopathy, encephalopathy, lactic
G3460A 60–80% 30–35% 0%
acidosis, and stroke-like episodes (MELAS)).
G11778A 0–50% 30–50% 75%
T14484C 0–65% 10–20% 50%

*% decrease relative to controls. PATHOPHYSIOLOGY

These functional studies also raise important issues regarding
the pathophysiology of LHON (fig 2). The most obvious one
syndromes have been linked to various mtDNA mutations in relates to the focal degeneration of the optic nerve. One could
isolated pedigrees from Holland, Australia, and North argue that only retinal ganglion cells are affected because they
America: A11696G and/or T14596A,22 T4160C,47 and require a sustained level of ATP for normal function. This is
G14459A,19 respectively. So far, none of the three primary supported by a recent study that found a high level of
LHON mutations have been linked to such severe phenotypes. mitochondrial enzyme activity in retinal ganglion cells and
the nerve fibre layer.78 However, two points militate against
Diagnosis this assertion. Firstly, it has been shown quite conclusively
A tentative diagnosis of LHON can usually be made based that photoreceptors have a much higher oxidative demand
solely on the patient’s clinical history. A series of baseline than retinal ganglion cells.79 80 Secondly, it is difficult to recon-
investigations are usually carried out. These include a formal cile why other mitochondrial disorders characterised by more
assessment of visual fields with static or kinetic perimetry and severe complex I defects do not universally cause optic atrophy
fluorescein angiography which in LHON shows no leakage, (J Smeitink, personal communication). Although purely
implying that the microvasculature is not compromised. Elec- speculative, it is possible that retinal ganglion cells are prefer-
trophysiological studies, including electroretinograms and entially involved because they are somehow exquisitely sensi-
visual evoked potentials (VEPs), can be carried out to exclude tive to subtle imbalances in cellular redox state or increased
retinal pathology and confirm optic nerve dysfunction. A more level of free radicals.81
in depth review of the electrophysiological features in LHON is The clinical picture of LHON shows some overlap with that
provided by Sherman and Kleiner.48 CT and MRI scans are of autosomal dominant optic atrophy (ADOA), and in both
usually normal in LHON, although there are some case reports disorders optic nerve dysfunction results from the selective
of non-enhancing high signals within the optic nerve and degeneration of the retinal ganglion cell layer.82 Therefore, it is
sheath distension.49–54 The latter is thought to represent slight of great interest that the causative gene in ADOA has recently
oedema or gliosis in the atrophic phase. Cranial imaging is been identified as being a dynamin related GTPase, located on
sometimes required in those situations where other inflam- chromosome 3q28-29.83 84 This protein has a highly basic
matory or structural causes of acute optic neuropathy need to amino-terminal domain that targets it to the mitochondria
be excluded. In singleton cases with atypical clinical features and preliminary studies in yeast indicate important roles in
and no clear maternal history of blindness, molecular genetic vesicular transport and outer membrane integrity.85–87 These
testing for the three primary LHON mutations will usually findings add further weight to the long held view that the
clarify matters. maintenance of retinal ganglion cells is heavily dependent
upon normal mitochondrial function. The development of
NEUROPATHOLOGY faithful animal models will hopefully provide us with a better
To date, there are no pathological data on the acute phase of insight into the still obscure pathophysiology of LHON.
LHON. Post mortem studies have been carried out mostly on
elderly patients who had experienced visual loss several
decades earlier.55 56 In some of the early reports, the mutational INCOMPLETE PENETRANCE
status of the patient is also unknown although the clinical An intriguing feature of LHON is that only ∼50% of males and
history was highly suggestive of LHON.49 50 57 58 These limita- ∼10% of females who harbour one of the three primary muta-
tions notwithstanding, the neuropathology in LHON seems to tions actually develop the optic neuropathy.5 88–90 This incom-
be limited to the retinal ganglion cell layer with sparing of the plete penetrance and predilection for males to lose vision
retinal pigment epithelium and photoreceptor layer. There is imply that additional genetic and/or environmental factors
marked cell body and axonal degeneration, with associated must modulate the phenotypic expression of LHON. Alterna-
demyelination and atrophy observed from the optic nerves to tively, the gender bias could also result from a combination of
the lateral geniculate bodies. Apoptosis is thought to be subtle anatomical, hormonal, and/or physiological variations
involved although this has yet to be formally proven.59 between males and females.25 56 91

BIOCHEMICAL FEATURES
Since all three primary LHON mutations involve complex I MITOCHONDRIAL GENETIC FACTORS
subunits, one would expect respiratory chain function to be Heteroplasmy
compromised, leading to deficient ATP production and subse- In most LHON pedigrees, the primary mutation is homoplas-
quent degeneration of retinal ganglion cells as a consequence mic (every mtDNA molecule harbours the mutant allele). By
of energy failure. However, both in vitro and in vivo biochemi- contrast, 10-15% of LHON carriers are thought to be
cal studies have produced conflicting results regarding the heteroplasmic, with one mtDNA subpopulation carrying the
extent of respiratory chain dysfunction in LHON (table 3). wild type allele.9 92 It has been suggested that heteroplasmy
These variations could be partly because of the different pro- might influence the expression and inheritance pattern of
tocols used. For example, a wide range of cell types was LHON but there have been no rigorous prospective studies to
assayed in these experiments, including platelets, leucocytes, address this possibility.93–97 Preliminary data suggest that het-
fibroblasts, and skeletal muscle, to name just a few. For obvi- eroplasmy might contribute to incomplete penetrance, with
ous technical reasons, it is not possible to investigate retinal the risk of blindness being minimal if the mutational load is
ganglion cells directly. A striking feature of these studies is less than 60%.98

www.jmedgenet.com
 Downloaded from http://jmg.bmj.com/ on March 4, 2015 - Published by group.bmj.com

LHON 165

Environmental ? ↓ ATP synthesis

factors
? ↑ Free radicals
? Redox imbalance

Primary mtDNA Mitochondrial Retinal

mutation dysfunction ganglion cells

? Apoptosis

Genetic
factors

Mitochondrial Nuclear

? Heteroplasmy ? X linked susceptibility gene

Optic nerve
? MtDNA background ? Other nuclear modifier degeneration
genes

Visual failure

Figure 2 Schematic representation of the pathways leading to optic nerve degeneration in LHON.

MtDNA haplogroups group J on the biochemical features of the T14484C mutation

There still exists some controversy surrounding the patho- has not yet been determined. This would be interesting to
genic role of so-called “secondary” mtDNA mutations in clarify given the much stronger association of haplogroup J
LHON: T4216C, A4917G, G9804A, G9438A, G13708A, with T14484C compared to G11778A. However, as already
G15257A, and G15812A.99–101 These nucleotide substitutions mentioned, these biochemical studies are not without their
are found at a higher frequency in LHON patients relative to own limitations and require cautious interpretation.
controls and some investigators argue that they act in synergy Haplogroup J is one of nine European specific haplogroups
with the primary mutations, increasing the risk of disease and therefore one would expect LHON to be more common in
expression. Based on phylogenetic analysis, it has been shown populations of European extraction. However, this hypothesis
that T4216C, G13708A, G15257A, and G15812A all cluster on is difficult to assess given the current paucity of data regard-
a specific mtDNA background, haplogroup J.102 Several studies ing the prevalence of this mitochondrial disorder in different
have subsequently found that LHON pedigrees, T14484C and ethnic groups. Haplogroup J is not thought to influence age of
to a lesser extent G11778A, are not randomly distributed
onset or final visual outcome in LHON but this requires
along the phylogenetic tree but show a strong preferential
further confirmation in a larger LHON cohort.30 109 The
association with haplogroup J.103–105 This could be because of an
question also remains as to why G3460A pedigrees do not
early founder effect whereby the G11778A and T14484C
show a skewed haplogroup distribution. The hypothesis that
mutations arose early in the evolution of haplogroup J, leading
haplogroup J increases penetrance for the G11778A and
to its over-representation on that mitochondrial lineage.106
However, this explanation is unlikely given that it has been T14484C mutations is not widely accepted and further studies
shown convincingly that all three primary LHON mutations are required to clarify matters.
have arisen multiple times on different mitochondrial
backgrounds.104 Moreover, up to now, none of these mtDNA
mutations have been found in normal controls belonging to
haplogroup J. NUCLEAR GENETIC FACTORS
The most compelling explanation is that the risk of visual Segregation analysis
loss in patients harbouring a primary LHON mutation is The predominance of affected males in LHON cannot be
increased by haplogroup J and by extension one or more of the explained by mitochondrial inheritance. Segregation analysis
polymorphisms that defines it.107 If this specific mtDNA back- of a large number of pedigrees from diverse ethnic groups
ground does have a deleterious effect, one would expect hap- suggests the existence of a recessive X linked susceptibility
logroup J to result in a more pronounced respiratory chain gene acting in synergy with the mtDNA mutation.9 110 111 In the
defect. Cybrid cell lines carrying the G11778A mutation and Bu and Rotter model,110 development of blindness in males is
haplogroup J were shown to have a lower oxygen consump- consistent with the simultaneous inheritance of an X linked
tion and a longer doubling time compared to cell lines with the visual loss susceptibility allele and the LHON mutation.
G11778A mutation alone.67 However, a recently published Females are affected either if they are homozygous at the sus-
study using in vivo MRS failed to detect any deleterious effect ceptibility locus (40%) or heterozygous with skewed X
in brain and skeletal muscle, with haplogroup J not further chromosome inactivation (60%). The gene frequency for the
impairing mitochondrial oxidative metabolism in patients susceptibility locus was proposed to be 0.08 and the estimated
harbouring the G11778A mutation.108 The influence of haplo- penetrance in a heterozygous female 0.11.

www.jmedgenet.com
 Downloaded from http://jmg.bmj.com/ on March 4, 2015 - Published by group.bmj.com

166 Man, Turnbull, Chinnery

Linkage analysis
Attempts to identify this X linked susceptibility locus Table 4 Recurrence risks for relatives of LHON
by standard linkage analysis have so far been probands
unsuccessful.112–114 116 According to the Bu and Rotter model,110 Risk of visual loss (%)
a proportion of heterozygous females will be affected as a
result of unfortunate Lyonisation of the “normal” X chromo- G11778A9 T14484C10
some. Mathematical modelling suggests that visual loss in Sibs
women will only occur if at least 60-83% of retinal ganglion Brother 25 28
cells harbour the visual loss susceptibility allele.117 However, a Sister 8 5
number of studies have failed to show skewed X chromosome Sister’s children
Nephew 41 30
inactivation in the leucocyte fraction of affected female
Niece 17 3
carriers.115 118–120 Despite these negative results, it would be pre- Maternal first cousins
mature to conclude that there are no additional nuclear Male 30 19
genetic factors modulating the expression of the primary Female 7 4
LHON mtDNA mutations. The situation may be highly
complex, with the existence of genetic heterogeneity and the
epistatic interaction of multiple nuclear susceptibility loci.

ENVIRONMENTAL FACTORS mutation. The latter is exceedingly rare and has only been
Five pairs of monozygotic twins harbouring a primary LHON previously reported for the T14484C mutation.28 We recently
mutation have been reported.9 25 28 123–125 In two cases, the twins confirmed the occurrence of a de novo G3460A mutation in a
remained discordant, although there is always the possibility pedigree from the north east of England (P Y W Man, unpub-
that the unaffected sib will lose vision later on in life. The lished data). Since LHON shows strict maternal inheritance,
existence of discordant monozygotic twins does not exclude males can be reassured that none of their children will inherit
the possibility of nuclear genetic factors in LHON but strongly the mtDNA mutation. On the other hand, females will trans-
suggests that environmental factors also contribute to mit the pathogenic mutation to all of their offspring. Since
penetrance. Anecdotal evidence suggests that smoking, most mothers are homoplasmic, their children will only
alcohol, nutritional deprivation, psychological stress, or acute harbour the mutant allele and their lifetime risk of losing
illness can precipitate the onset of blindness in LHON.41 126–131 vision can be derived from established gender and age
However, a recently published case-control study failed to dependent penetrance figures, as detailed below. The situation
confirm the association between heavy smoking or alcohol is rather more complicated for a heteroplasmic mother given
intake and an increased risk of visual loss.132 the theoretical possibility that she could transmit only a low
Potential environmental triggers have not been extensively level of mutant mtDNA to a particular offspring. However,
investigated because of the logistical problems inherent in the genetic counselling is not straightforward for unaffected car-
proper conduct of case-control studies for a rare disease. The riers who are found to be heteroplasmic for a primary LHON
most obvious limitation of these types of retrospective studies mutation. Although, there is a suggestion that a mutational
is the possibility of recall bias given that most patients are threshold of ∼60% is necessary for disease expression, it must
interviewed several years after they lost vision. This makes it be stressed these are only preliminary findings and require
very difficult to obtain reliable data regarding not only possi- further confirmation.98
ble exposure to environmental triggers but also to quantify Some indication of recurrence risks can be provided to
their duration and intensity. A possible solution to this maternal relatives of a LHON proband (table 4). However,
problem will be to set up a longitudinal study involving the robust estimates for the G3460A mutation have not yet been
long term and regular follow up of a large cohort of unaffected determined in a large number of pedigrees and, although
LHON carriers. Although an attractive option, this will almost these are unlikely to differ significantly from the G11778A and
certainly require a multicentre collaborative effort in order to T14484C mutations, any extrapolation should be done with
collect a sufficient number of subjects. caution. It is important for LHON carriers to be made aware
that it is currently not possible to predict accurately whether
CLINICAL MANAGEMENT or when they will become affected. Despite these caveats, the
Prevention two main predictive factors for visual failure remain age and
No generally accepted measures have been shown either to gender. Males have a 50% lifetime risk of blindness compared
prevent or delay the onset of blindness in LHON. In spite of to only 10% for females, but these approximate figures can be
this, for general health reasons, it would be wise to advise further refined based upon the patient’s age. From published
unaffected LHON carriers to moderate their alcohol intake age dependent penetrance data, we know that most patients
and stop smoking. There is therefore no need for long term experience visual loss in their late teens or early 20s and the
follow up of asymptomatic carriers in the clinic. probability of becoming affected is minimal once past the age
of 50.10 31 89
Treatment
There is currently no treatment available that improves the
final visual outcome in LHON. One small, non-randomised CONCLUSIONS
trial claimed that oral administration of a quinone analogue LHON is a mitochondrial genetic disease characterised by
(idebedone) and vitamin supplementation (B12 and C) can bilateral subacute loss of central vision owing to focal degen-
speed up visual recovery.133 However, more rigorous studies are eration of the optic nerve. The vast majority of cases are the
required before such a regimen can be advocated during the result of one of three mtDNA point mutations, G3460A,
acute phase. The long term management of visually impaired G11778A, and T14484C, which all involve genes encoding
patients is mainly supportive. complex I subunits of the respiratory chain. With molecular
genetic testing now routinely available, this has greatly facili-
GENETIC COUNSELLING tated clinical diagnosis, especially in atypical cases. However,
Once a primary LHON mutation has been identified in a many aspects of the complex aetiology of LHON remain poorly
proband, other family members can be offered molecular defined at present. The incomplete penetrance and sex bias
genetic testing to exclude the possibility of a de novo clearly indicate that, although necessary, the mtDNA mutation

www.jmedgenet.com
 Downloaded from http://jmg.bmj.com/ on March 4, 2015 - Published by group.bmj.com

LHON 167

is insufficient on its own for disease manifestation. The iden- 21 Wissinger B, Besch D, Baumann B, Fauser S, Christ-Adler M, Jurklies B,
Zrenner E, Leo-Kottler B. Mutation analysis of the ND6 gene in patients
tification of the secondary factors modulating the phenotypic with Lebers hereditary optic neuropathy. Biochem Biophys Res Commun
expression of LHON is currently an area of intense research. 1997;234:511-15.
Better characterisation of the relationship between mtDNA 22 De Vries DD, Went LN, Bruyn GW, Scholte HR, Hofstra RM, Bolhuis PA,
van Oost BA. Genetic and biochemical impairment of mitochondrial
mutations, mitochondrial biogenesis, and optic nerve dys- complex I activity in a family with Leber hereditary optic neuropathy and
function is also needed to clarify the still unclear pathophysi- hereditary spastic dystonia. Am J Hum Genet 1996;58:703-11.
ology of LHON. Progress in all of these areas is a prerequisite 23 Chinnery PF, Johnson MA, Wardell TM, Singh-Kler R, Hayes C, Brown
DT, Taylor RW, Bindoff LA, Turnbull DM. The epidemiology of
for both improved genetic counselling and the development of pathogenic mitochondrial DNA mutations. Ann Neurol 2000;48:188-93.
future therapeutic strategies. 24 Mackey DA, Buttery RG. Leber hereditary optic neuropathy in Australia.
Aust NZ J Ophthalmol 1992;20:177-84.
25 Newman NJ, Lott MT, Wallace DC. The clinical characteristics of
ACKNOWLEDGEMENTS pedigrees of Leber’s hereditary optic neuropathy with the 11778
This work was supported by the Welcome Trust (PFC, DMT), the mutation. Am J Ophthalmol 1991;111:750-62.
26 Johns DR, Smith KH, Miller NR. Leber’s hereditary optic neuropathy.
Medical Research Council (DMT), and the PPP Healthcare Trust Clinical manifestations of the 3460 mutation. Arch Ophthalmol
(PYWM). Figure 1 was kindly provided by Mr P G Griffiths. 1992;110:1577-81.
27 Johns DR, Heher KL, Miller NR, Smith KH. Leber’s hereditary optic
neuropathy. Clinical manifestations of the 14484 mutation. Arch
..................... Ophthalmol 1993;111:495-8.
Authors’ affiliations 28 Biousse V, Brown MD, Newman NJ, Allen JC, Rosenfeld J, Meola G,
Wallace DC. De novo 14484 mitochondrial DNA mutation in
P Y W Man, D M Turnbull, P F Chinnery, Department of Neurology,
monozygotic twins discordant for Leber’s hereditary optic neuropathy.
School of Neurosciences and Psychiatry, The Medical School, University
Neurology 1997;49:1136-8.
of Newcastle Upon Tyne, UK 29 Riordan-Eva P, Harding AE. Leber’s hereditary optic neuropathy: the
clinical relevance of different mitochondrial DNA mutations. J Med Genet
1995;32:81-7.
REFERENCES 30 Nikoskelainen EK, Huoponen K, Juvonen V, Lamminen T, Nummelin K,
1 Leber T. Ueber hereditaere und congenital angelegte sehnervenleiden. Savontaus ML. Ophthalmologic findings in Leber hereditary optic
Graefes Arch Clin Exp Ophthalmol 1871;17:249-91. neuropathy, with special reference to mtDNA mutations (published
2 Bell J. Hereditary optic atrophy (Leber’s disease). In: Pearson K, ed. The erratum appears in Ophthalmology 1996;103:998). Ophthalmology
treasury of human inheritance. Cambridge: Cambridge University Press, 1996;103:504-14.
1931:345-423. 31 Riordan-Eva P, Sanders MD, Govan GG, Sweeney MG, Da Costa J,
3 Imai Y, Moriwaki D. A probable case of cytoplasmic inheritance in man: Harding AE. The clinical features of Leber’s hereditary optic neuropathy
a critique of Leber’s disease. J Genet 1936;33:163-7. defined by the presence of a pathogenic mitochondrial DNA mutation.
4 Lundsgaard R. A genealogic, genetic and clinical study of 101 cases of Brain 1995;118:319-37.
retrobulbar optic neuritis in 20 Danish families. Acta Ophthalmol 32 Harding AE, Sweeney MG, Miller DH, Mumford CJ, Kellar-Wood H,
1944;21:1-306. Menard D, McDonald WI, Compston DA. Occurrence of a multiple
5 Van Senus AHC. Leber’s disease in the Netherlands. Doc Ophthalmol sclerosis-like illness in women who have a Leber’s hereditary optic
1963;17:1-162. neuropathy mitochondrial DNA mutation. Brain 1992;115:979-89.
6 Seedorff T. Leber’s disease. Acta Ophthalmol 1968;46:4-25. 33 Jansen PH, van der Knaap MS, de Coo IF. Leber’s hereditary optic
7 Mackey DA, Oostra RJ, Rosenberg T, Nikoskelainen E, Bronte-Stewart J, neuropathy with the 11 778 mtDNA mutation and white matter disease
Poulton J, Harding AE, Govan G, Bolhuis PA, Norby S. Primary resembling multiple sclerosis: clinical, MRI and MRS findings. J Neurol
pathogenic mtDNA mutations in multigeneration pedigrees with Leber Sci 1996;135:176-80.
hereditary optic neuropathy. Am J Hum Genet 1996;59:481-5. 34 Kellar-Wood H, Robertson N, Govan GG, Compston DA, Harding AE.
8 Mashima Y, Yamada K, Wakakura M, Kigasawa K, Kudoh J, Shimizu Leber’s hereditary optic neuropathy mitochondrial DNA mutations in
N, Oguchi Y. Spectrum of pathogenic mitochondrial DNA mutations and multiple sclerosis. Ann Neurol 1994;36:109-12.
clinical features in Japanese families with Leber’s hereditary optic 35 Mojon DS, Fujihara K, Hirano M, Miller C, Lincoff NS, Jacobs LD,
neuropathy. Curr Eye Res 1998;17:403-8. Greenberg SJ. Leber’s hereditary optic neuropathy mitochondrial DNA
9 Harding AE, Sweeney MG, Govan GG, Riordan-Eva P. Pedigree mutations in familial multiple sclerosis. Graefes Arch Clin Exp
analysis in Leber hereditary optic neuropathy families with a pathogenic Ophthalmol 1999;237:348-50.
mtDNA mutation. Am J Hum Genet 1995;57:77-86. 36 Olsen NK, Hansen AW, Norby S, Edal AL, Jorgensen JR, Rosenberg T.
10 Macmillan C, Kirkham T, Fu K, Allison V, Andermann E, Chitayat D, Leber’s hereditary optic neuropathy associated with a disorder
Fortier D, Gans M, Hare H, Quercia N, Zackon D, Shoubridge EA. indistinguishable from multiple sclerosis in a male harbouring the
Pedigree analysis of French Canadian families with T14484C Leber’s mitochondrial DNA 11778 mutation. Acta Neurol Scand
hereditary optic neuropathy. Neurology 1998;50:417-22. 1995;91:326-9.
11 Macmillan C, Johns TA, Fu K, Shoubridge EA. Predominance of the 37 Vanopdenbosch L, Dubois B, D’Hooghe MB, Meire F, Carton H.
T14484C mutation in French-Canadian families with Leber hereditary Mitochondrial mutations of Leber’s hereditary optic neuropathy: a risk
optic neuropathy is due to a founder effect. Am J Hum Genet factor for multiple sclerosis. J Neurol 2000;247:535-43.
2000;66:332-5. 38 Smith PR, Cooper JM, Govan GG, Riordan-Eva P, Harding AE, Schapira
12 Chinnery PF, Brown DT, Andrews RM, Singh-Kler R, Riordan-Eva P, AH. Antibodies to human optic nerve in Leber’s hereditary optic
Lindley J, Applegarth DA, Turnbull DM, Howell N. The mitochondrial neuropathy. J Neurol Sci 1995;130:134-8.
ND6 gene is a hot spot for mutations that cause Leber’s hereditary optic 39 Chalmers RM, Govan GG, Schapira AH, Harding AE. HLA class I
neuropathy. Brain 2001;124:209-18. genotypes in Leber’s hereditary optic neuropathy. J Neurol Sci
13 Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas 1996;135:173-5.
LJD, Nikoskelainen EK. Mitochondrial DNA mutation associated with 40 Govan GG, Smith PR, Kellar-Wood H, Schapira AH, Harding AE. HLA
Leber’s hereditary optic neuropathy. Science 1988;242:1427-30. class II genotypes in Leber’s hereditary optic neuropathy. J Neurol Sci
14 Huoponen K, Vilkki J, Aula P, Nikoskelainen EK, Savontaus ML. A new 1994;126:193-6.
mtDNA mutation associated with Leber hereditary optic neuroretinopathy. 41 Charlmers RM, Harding AE. A case-control study of Leber’s hereditary
Am J Hum Genet 1991;48:1147-53. optic neuropathy. Brain 1996;119:1481-6.
15 Howell N, Bindoff LA, McCullough DA, Kubacka I, Poulton J, Mackey D, 42 Meire FM, Van Coster R, Cochaux P, Obermaier-Kusser B, Candaele C,
Taylor L, Turnbull DM. Leber hereditary optic neuropathy: identification of Martin JJ. Neurological disorders in members of families with Leber’s
the same mitochondrial ND1 mutation in six pedigrees. Am J Hum Genet hereditary optic neuropathy (LHON) caused by different mitochondrial
1991;49:939-50. mutations. Ophthal Genet 1995;16:119-26.
16 Mackey D, Howell N. A variant of Leber hereditary optic neuropathy 43 Nikoskelainen EK, Marttila RJ, Huoponen K, Juvonen V, Lamminen T,
characterized by recovery of vision and by an unusual mitochondrial Sonninen P, Savontaus ML. Leber’s “plus”: neurological abnormalities in
genetic etiology. Am J Hum Genet 1992;51:1218-28. patients with Leber’s hereditary optic neuropathy. J Neurol Neurosurg
17 Johns DR, Neufeld MJ, Park RD. An ND-6 mitochondrial DNA mutation Psychiatry 1995;59:160-4.
associated with Leber hereditary optic neuropathy. Biochem Biophys Res 44 Bower SP, Hawley I, Mackey DA. Cardiac arrhythmia and Leber’s
Commun 1992;187:1551-7. hereditary optic neuropathy. Lancet 1992;339:1427-8.
18 Howell N, Halvorson S, Burns J, McCullough DA, Paulton J. When does 45 Mashima Y, Kigasawa K, Hasegawa H, Tani M, Oguchi Y. High
bilateral optic atrophy become Leber hereditary optic neuropathy?. Am J incidence of pre-excitation syndrome in Japanese families with Leber’s
Hum Genet 1993;53:959-63. hereditary optic neuropathy. Clin Genet 1996;50:535-7.
19 Jun AS, Brown MD, Wallace DC. A mitochondrial DNA mutation at 46 Nikoskelainen EK, Savontaus ML, Huoponen K, Antila K, Hartiala J.
nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene Pre-excitation syndrome in Leber’s hereditary optic neuropathy. Lancet
associated with maternally inherited Leber hereditary optic neuropathy 1994;344:857-8.
and dystonia. Proc Natl Acad Sci USA 1994;91:6206-10. 47 Howell N, Kubacka I, Xu M, McCullough DA. Leber hereditary optic
20 Howell N, Bogolin C, Jamieson R, Marenda DR, Mackey DA. mtDNA neuropathy: involvement of the mitochondrial ND1 gene and evidence
mutations that cause optic neuropathy: how do we know? Am J Hum for an intragenic suppressor mutation. Am J Hum Genet
Genet 1998;62:196-202. 1991;48:935-42.

www.jmedgenet.com
 Downloaded from http://jmg.bmj.com/ on March 4, 2015 - Published by group.bmj.com

168 Man, Turnbull, Chinnery

48 Sherman J, Kleiner L. Visual-system dysfunction in Lebers hereditary hereditary optic neuropathy: genetic, biochemical, and phosphorus
optic neuropathy. Clin Neurosci 1994;2:121-9. magnetic resonance spectroscopy study in an Italian family. Neurology
49 Smith JL, Tse DT, Byrne SF, Johns DR, Stone EM. Optic nerve sheath 1991;41:1211-15.
distention in Leber’s optic neuropathy and the significance of the 76 Barbiroli B, Montagna P, Cortelli P, Iotti S, Lodi R, Barboni P, Monari L,
“Wallace mutation”. J Clin Neuroophthalmol 1990;10:231-8. Lugaresi E, Frassineti C, Zaniol P. Defective brain and muscle energy
50 de Gottrau P, Buchi ER, Daicker B. Distended optic nerve sheaths in metabolism shown by in vivo 31P magnetic resonance spectroscopy in
Leber’s hereditary optic neuropathy. J Clin Neuroophthalmol nonaffected carriers of 11778 mtDNA mutation. Neurology
1992;12:89-93. 1995;45:1364-9.
51 Dotti MT, Caputo N, Signorini E, Federico A. Magnetic resonance 77 Lodi R, Taylor DJ, Tabrizi SJ, Kumar S, Sweeney M, Wood NW, Styles
imaging findings in Leber’s hereditary optic neuropathy. Eur Neurol P, Radda GK, Schapira AHV. In vivo skeletal muscle mitochondrial
1992;32:17-19. function in Leber’s hereditary optic neuropathy assessed by P-31
52 Mashima Y, Oshitari K, Imamura Y, Momoshima S, Shiga H, Oguchi Y. magnetic resonance spectroscopy. Ann Neurol 1997;42:573-9.
Orbital high resolution magnetic resonance imaging with fast spin echo 78 Andrews RM, Griffiths PG, Johnson MA, Turnbull DM. Histochemical
in the acute stage of Leber’s hereditary optic neuropathy. J Neurol localisation of mitochondrial enzyme activity in human optic nerve and
Neurosurg Psychiatry 1998;64:124-7. retina. Br J Ophthalmol 1999;83:231-5.
53 Vaphiades MS, Newman NJ. Optic nerve enhancement on orbital 79 Lowry O, Roberts NR, Lewis C. The quantitative histochemistry of the
magnetic resonance imaging in Leber’s hereditary optic neuropathy. J retina. J Biol Chem 1956;220:879-92.
Neuroophthalmol 1999;19:238-9. 80 Kageyama GH, Wong-Riley MT. The histochemical localization of
54 Inglese M, Rovaris M, Bianchi S, Mancardi GL, Ghezzi A, Salvi F, cytochrome oxidase in the retina and lateral geniculate nucleus of the
Cortelli P, Filippi M. MRI, MTI, and DWI study of the optic nerve, brain, ferret, cat, and monkey, with particular reference to retinal mosaics and
and cervical cord from patients with Leber hereditary optic neuropathy. ON/OFF-center visual channels. J Neurosci 1984;4:2445-59.
Neurology 2000;54:A320. 81 Klivenyi P, Karg E, Rozsa C, Horvath R, Komoly S, Nemeth I, Turi S,
55 Saadati HG, Hsu HY, Heller KB, Sadun AA. A histopathologic and Vecsei L. Alpha-tocopherol/lipid ratio in blood is decreased in patients
morphometric differentiation of nerves in optic nerve hypoplasia and with Leber’s hereditary optic neuropathy and asymptomatic carriers of the
Leber hereditary optic neuropathy. Arch Ophthalmol 1998;116:911-16. 11778 mtDNA mutation. J Neurol Neurosurg Psychiatry
56 Sadun AA, Dao J. Annual review in neuro-ophthalmology. The anterior 2001;70:359-62.
visual pathways. J Neuroophthalmol 1994;14:141-54. 82 Kjer B, Eiberg H, Kjer P, Rosenberg T. Dominant optic atrophy mapped
57 Kwittken J, Barest HD. The neuropathology of hereditary optic atrophy to chromosome 3q region. II. Clinical and epidemiological aspects. Acta
(Leber’s disease): the first complete anatomic study. Am J Ophthalmol Orthop Scand 1996;74:3-7.
1958;34:185-207. 83 Delettre C, Lenaers G, Griffoin JM, Gigarel N, Lorenzo C, Belenguer P,
58 Adams JH, Blackwood W, Wilson J. Further clinical and pathological Pelloquin L, Grosgeorge J, Turc-Carel C, Perret E, Astarie-Dequeker C,
observations on Leber’s optic atrophy. Brain 1966;89:15-26. Lasquellec L, Arnaud B, Ducommun B, Kaplan J, Hamel CP. Nuclear gene
59 Howell N. Leber hereditary optic neuropathy: mitochondrial mutations OPA1, encoding a mitochondrial dynamin-related protein, is mutated in
and degeneration of the optic nerve. Vision Res 1997;37:3495-507. dominant optic atrophy. Nat Genet 2000;26:207-10.
60 Parker WD Jr, Oley CA, Parks JK. A defect in mitochondrial 84 Alexander C, Votruba M, Pesch UE, Thiselton DL, Mayer S, Moore A,
electron-transport activity (NADH-coenzyme Q oxidoreductase) in Leber’s Rodriguez M, Kellner U, Leo-Kottler B, Auburger G, Bhattacharya SS,
hereditary optic neuropathy. N Engl J Med 1989;320:1331-3. Wissinger B. OPA1, encoding a dynamin-related GTPase, is mutated in
61 Majander A, Huoponen K, Savontaus ML, Nikoskelainen E, Wikstrom autosomal dominant optic atrophy linked to chromosome 3q28. Nat
M. Electron transfer properties of NADH:ubiquinone reductase in the Genet 2000;26:211-15.
ND1/3460 and the ND4/11778 mutations of the Leber hereditary optic 85 Pelloquin L, Belenguer P, Menon Y, Ducommun B. Identification of a
neuroretinopathy (LHON). FEBS Lett 1991;292:289-92. fission yeast dynamin-related protein involved in mitochondrial DNA
62 Larsson NG, Andersen O, Holme E, Oldfors A, Wahlstrom J. Leber’s maintenance. Biochem Biophys Res Commun 1998;251:720-6.
hereditary optic neuropathy and complex I deficiency in muscle. Ann 86 van der Bliek AM. Functional diversity in the dynamin family. Trends
Neurol 1991;30:701-8. Cell Biol 1999;9:96-102.
63 Smith PR, Cooper JM, Govan GG, Harding AE, Schapira AH. Platelet 87 Labrousse AM, Zappaterra MD, Rube DA, van der Bliek AM. C elegans
mitochondrial function in Leber’s hereditary optic neuropathy. J Neurol dynamin-related protein DRP-1 controls severing of the mitochondrial
Sci 1994;122:80-3. outer membrane. Mol Cell 1999;4:815-26.
64 Degli Esposti M, Carelli V, Ghelli A, Ratta M, Crimi M, Sangiorgi S, 88 Seedorff T. The inheritance of Leber’s disease. A genealogical follow-up
Montagna P, Lenaz G, Lugaresi E, Cortelli P. Functional alterations of the study. Acta Ophtalmol 1985;63:135-45.
mitochondrially encoded ND4 subunit associated with Leber’s hereditary 89 Nikoskelainen EK. Clinical picture of LHON. Clin Neurosci
optic neuropathy. FEBS Lett 1994;352:375-9. 1994;2:115-20.
65 Cock HR, Cooper JM, Schapira AH. The 14484 ND6 mtDNA mutation 90 Brown MD, Wallace DC. Spectrum of mitochondrial-DNA mutations in
in Leber hereditary optic neuropathy does not affect fibroblast complex I Lebers hereditary optic neuropathy. Clin Neurosci 1994;2:138-45.
activity. Am J Hum Genet 1995;57:1501-2. 91 Hollander H, Makarov F, Stefani FH, Stone J. Evidence of constriction of
66 Oostra RJ, Van Galen MJ, Bolhuis PA, Bleeker-Wagemakers EM, Van optic nerve axons at the lamina cribrosa in the normotensive eye in
den Bogert C. The mitochondrial DNA mutation ND6*14,484C humans and other mammals. Ophthal Res 1995;27:296-309.
associated with leber hereditary optic neuropathy, leads to deficiency of 92 Smith KH, Johns DR, Heher KL, Miller NR. Heteroplasmy in Leber’s
complex I of the respiratory chain. Biochem Biophys Res Commun hereditary optic neuropathy. Arch Ophthalmol 1993;111:1486-90.
1995;215:1001-5. 93 Zhu DP, Economou EP, Antonarakis SE, Maumenee IH. Mitochondrial
67 Vergani L, Martinuzzi A, Carelli V, Cortelli P, Montagna P, Schievano DNA mutation and heteroplasmy in type I Leber hereditary optic
G, Carrozzo R, Angelini C, Lugaresi E. MtDNA mutations associated neuropathy. Am J Med Genet 1992;42:173-9.
with Leber’s hereditary optic neuropathy: studies on cytoplasmic hybrid 94 Yen MY, Yen TC, Pang CY, Liu JH, Wei YH. Mitochondrial DNA
(cybrid) cells. Biochem Biophys Res Commun 1995;210:880-8. mutation in Leber’s hereditary optic neuropathy. Invest Ophthalmol Vis
68 Montagna P, Plazzi G, Cortelli P, Carelli V, Lugaresi E, Barboni P, Sci 1992;33:2561-6.
Fiocchi M. Abnormal lactate after effort in healthy carriers of Leber’s 95 Barboni P, Mantovani V, Montagna P, Bragliani M, Cortelli P, Lugaresi
hereditary optic neuropathy. J Neurol Neurosurg Psychiatry E, Puddu P, Caramazza R. Mitochondrial DNA analysis in Leber’s
1995;58:640-1. hereditary optic neuropathy. Ophthal Pediatr Genet 1992;13:219-26.
69 Majander A, Finel M, Savontaus ML, Nikoskelainen E, Wikstrom M. 96 Black GC, Morten K, Laborde A, Poulton J. Leber’s hereditary optic
Catalytic activity of complex I in cell lines that possess replacement neuropathy: heteroplasmy is likely to be significant in the expression of
mutations in the ND genes in Leber’s hereditary optic neuropathy. Eur J LHON in families with the 3460 ND1 mutation. Br J Ophthalmol
Biochem 1996;239:201-7. 1996;80:915-17.
70 Hofhaus G, Johns DR, Hurko O, Attardi G, Chomyn A. Respiration and 97 Tanaka A, Kiyosawa M, Mashima Y, Tokoro T. A family with Leber’s
growth defects in transmitochondrial cell lines carrying the 11778 hereditary optic neuropathy with mitochondrial DNA heteroplasmy
mutation associated with Leber’s hereditary optic neuropathy. J Biol related to disease expression. J Neuroophthalmol 1998;18:81-3.
Chem 1996;271:13155-61. 98 Chinnery PF, Andrews RM, Turnbull DM, Howell N. Leber hereditary
71 Carelli V, Ghelli A, Ratta M, Bacchilega E, Sangiorgi S, Mancini R, optic neuropathy: does heteroplasmy influence the inheritance and
Leuzzi V, Cortelli P, Montagna P, Lugaresi E, Degli Esposti M. Leber’s expression of the G11778A mitochondrial DNA mutation? Am J Med
hereditary optic neuropathy: biochemical effect of 11778/ND4 and Genet (in press).
3460/ND1 mutations and correlation with the mitochondrial genotype. 99 Johns DR, Berman J. Alternative, simultaneous complex I mitochondrial
Neurology 1997;48:1623-32. DNA mutations in Leber’s hereditary optic neuropathy. Biochem Biophys
72 Cock HR, Tabrizi SJ, Cooper JM, Schapira AH. The influence of nuclear Res Commun 1991;174:1324-30.
background on the biochemical expression of 3460 Leber’s hereditary 100 Johns DR, Neufeld MJ. Cytochrome b mutations in Leber hereditary
optic neuropathy. Ann Neurol 1998;44:187-93. optic neuropathy. Biochem Biophys Res Commun 1991;181:1358-64.
73 Cock HR, Cooper JM, Schapira AH. Functional consequences of the 101 Johns DR, Neufeld MJ. Cytochrome c oxidase mutations in Leber
3460-bp mitochondrial DNA mutation associated with Leber’s hereditary hereditary optic neuropathy. Biochem Biophys Res Commun
optic neuropathy. J Neurol Sci 1999;165:10-17. 1993;196:810-15.
74 Brown MD, Trounce IA, Jun AS, Allen JC, Wallace DC. Functional 102 Torroni A, Wallace DC. Mitochondrial DNA variation in human
analysis of lymphoblast and cybrid mitochondria containing the 3460, populations and implications for detection of mitochondrial DNA
11778, or 14484 Leber’s hereditary optic neuropathy mitochondrial mutations of pathological significance. J Bioenerg Biomembr
DNA mutation. J Biol Chem 2000;275:39831-6. 1994;26:261-71.
75 Cortelli P, Montagna P, Avoni P, Sangiorgi S, Bresolin N, Moggio M, 103 Brown MD, Torroni A, Reckord CL, Wallace DC. Phylogenetic analysis
Zaniol P, Mantovani V, Barboni P, Barbiroli B, Lugaresi E. Leber’s of Leber’s hereditary optic neuropathy mitochondrial DNA’s indicates

www.jmedgenet.com
 Downloaded from http://jmg.bmj.com/ on March 4, 2015 - Published by group.bmj.com

LHON 169

multiple independent occurrences of the common mutations. Hum Mutat 118 Pegoraro E, Schimke RN, Garcia C, Stern H, Cadaldini M, Angelini C,
1995;6:311-25. Barbosa E, Carroll J, Marks WA, Neville HE. Genetic and biochemical
104 Torroni A, Petrozzi M, D’Urbano L, Sellitto D, Zeviani M, Carrara F, normalization in female carriers of Duchenne muscular dystrophy:
Carducci C, Leuzzi V, Carelli V, Barboni P, De Negri A, Scozzari R. evidence for failure of dystrophin production in dystrophin-competent
Haplotype and phylogenetic analyses suggest that one European-specific myonuclei. Neurology 1995;45:677-90.
mtDNA background plays a role in the expression of Leber hereditary 119 Pegoraro E, Carelli V, Zeviani M, Cortelli P, Montagna P, Barboni P,
optic neuropathy by increasing the penetrance of the primary mutations Angelini C, Hoffman EP. X-inactivation patterns in female Leber’s
11778 and 14484. Am J Hum Genet 1997;60:1107-21. hereditary optic neuropathy patients do not support a strong X-linked
105 Brown MD, Sun F, Wallace DC. Clustering of Caucasian Leber determinant. Am J Med Genet 1996;61:356-62.
hereditary optic neuropathy patients containing the 11778 or 14484 120 Oostra RJ, Kemp S, Bolhuis PA, Bleeker-Wagemakers EM. No evidence
mutations on an mtDNA lineage. Am J Hum Genet 1997;60:381-7. for ‘skewed’ inactivation of the X-chromosome as cause of Leber’s
106 Howell N, Kubacka I, Halvorson S, Howell B, McCullough DA, Mackey hereditary optic neuropathy in female carriers. Hum Genet
D. Phylogenetic analysis of the mitochondrial genomes from Leber 1996;97:500-5.
hereditary optic neuropathy pedigrees. Genetics 1995;140:285-302. 121 Gale RE, Wheadon H, Boulos P, Linch DC. Tissue specificity of
107 Finnila S, Majamaa K. Phylogenetic analysis of mtDNA haplogroup TJ in X-chromosome inactivation patterns. Blood 1994;83:2899-905.
a Finnish population. J Hum Genet 2001;46:64-9. 122 Sharp A, Robinson D, Jacobs P. Age- and tissue-specific variation of X
108 Lodi R, Montagna P, Cortelli P, Iotti S, Cevoli S, Carelli V, Barbiroli B. chromosome inactivation ratios in normal women. Hum Genet
‘Secondary’ 4216/ND1 and 13708/ND5 Leber’s hereditary optic 2000;107:343-9.
neuropathy mitochondrial DNA mutations do not further impair in vivo 123 Nikoskelainen EK, Savontaus ML, Wanne OP, Katila MJ, Nummelin
mitochondrial oxidative metabolism when associated with the KU. Leber’s hereditary optic neuroretinopathy, a maternally inherited
11778/ND4 mitochondrial DNA mutation. Brain 2000;123:1896-902. disease. A genealogic study in four pedigrees. Arch Ophthalmol
109 Oostra RJ, Bolhuis PA, Zorn-Ende I, de Kok-Nazaruk MM, 1987;105:665-71.
Bleeker-Wagemakers EM. Leber’s hereditary optic neuropathy: no 124 Johns DR, Smith KH, Miller NR, Sulewski ME, Bias WB. Identical twins
significant evidence for primary or secondary pathogenicity of the who are discordant for Leber’s hereditary optic neuropathy. Arch
15257 mutation. Hum Genet 1994;94:265-70. Ophthalmol 1993;111:1491-4.
110 Bu XD, Rotter JI. X chromosome-linked and mitochondrial gene control of 125 Lam BL. Identical twins no longer discordant for Leber’s hereditary optic
Leber hereditary optic neuropathy: evidence from segregation analysis neuropathy. Arch Ophthalmol 1998;116:956-7.
for dependence on X chromosome inactivation. Proc Natl Acad Sci USA 126 Hwang JM, Park HW. Carbon monoxide poisoning as an epigenetic
1991;88:8198-202. factor for Leber’s hereditary optic neuropathy. Korean J Ophthalmol
111 Nakamura M, Fujiwara Y, Yamamoto M. The two locus control of Leber 1996;10:122-3.
hereditary optic neuropathy and a high penetrance in Japanese 127 Tsao K, Aitken PA, Johns DR. Smoking as an aetiological factor in a
pedigrees. Hum Genet 1993;91:339-41. pedigree with Leber’s hereditary optic neuropathy. Br J Ophthalmol
112 Chen JD, Cox I, Denton MJ. Preliminary exclusion of an X-linked gene in 1999;83:577-81.
Leber optic atrophy by linkage analysis. Hum Genet 1989;82:203-7. 128 DuBois LG, Feldon SE. Evidence for a metabolic trigger for Leber’s
113 Carvalho MR, Muller B, Rotzer E, Berninger T, Kommerell G, hereditary optic neuropathy. A case report. J Clin Neuroophthalmol
Blankenagel A, Savontaus ML, Meitinger T, Lorenz B. Leber’s hereditary 1992;12:15-16.
optic neuroretinopathy and the X-chromosomal susceptibility factor: no 129 Cullom ME, Heher KL, Miller NR, Savino PJ, Johns DR. Leber’s
linkage to DXs7. Hum Hered 1992;42:316-20. hereditary optic neuropathy masquerading as tobacco-alcohol
114 Sweeney MG, Davis MB, Lashwood A, Brockington M, Toscano A, amblyopia. Arch Ophthalmol 1993;111:1482-5.
Harding AE. Evidence against an X-linked locus close to DXS7 130 Golnik KC, Schaible ER. Folate-responsive optic neuropathy. J
determining visual loss susceptibility in British and Italian families with Neuroophthalmol 1994;14:163-9.
Leber hereditary optic neuropathy. Am J Hum Genet 1992;51:741-8. 131 Shaikh S, Ta C, Basham AA, Mansour S. Leber hereditary optic
115 Chalmers RM, Davis MB, Sweeney MG, Wood NW, Harding AE. neuropathy associated with antiretroviral therapy for human
Evidence against an X-linked visual loss susceptibility locus in Leber immunodeficiency virus infection. Am J Ophthalmol 2001;131:143-5.
hereditary optic neuropathy. Am J Hum Genet 1996;59:103-8. 132 Kerrison JB, Miller NR, Hsu F, Beaty TH, Maumenee IH, Smith KH,
116 Handoko HY, Wirapati PJ, Sudoyo HA, Sitepu M, Marzuki S. Meiotic Savino PJ, Stone EM, Newman NJ. A case-control study of tobacco and
breakpoint mapping of a proposed X linked visual loss susceptibility locus alcohol consumption in Leber hereditary optic neuropathy. Am J
in Leber’s hereditary optic neuropathy. J Med Genet 1998;35:668-71. Ophthalmol 2000;130:803-12.
117 Bu X, Rotter JI. Leber hereditary optic neuropathy: estimation of number 133 Mashima Y, Kigasawa K, Wakakura M, Oguchi Y. Do idebenone and
of embryonic precursor cells and disease threshold in heterozygous vitamin therapy shorten the time to achieve visual recovery in Leber
affected females at the X-linked locus. Clin Genet 1992;42:143-8. hereditary optic neuropathy? J Neuroophthalmol 2000;20:166-70.

www.jmedgenet.com
 Downloaded from http://jmg.bmj.com/ on March 4, 2015 - Published by group.bmj.com

Leber hereditary optic neuropathy

P Y W Man, D M Turnbull and P F Chinnery

J Med Genet 2002 39: 162-169

doi: 10.1136/jmg.39.3.162

Updated information and services can be found at:

http://jmg.bmj.com/content/39/3/162

These include:

References This article cites 130 articles, 30 of which you can access for free at:
http://jmg.bmj.com/content/39/3/162#BIBL

Email alerting Receive free email alerts when new articles cite this article. Sign up in the
service box at the top right corner of the online article.

Topic Articles on similar topics can be found in the following collections

Collections Eye Diseases (280)
Clinical diagnostic tests (337)
Clinical genetics (239)

Notes

To request permissions go to:

http://group.bmj.com/group/rights-licensing/permissions

To order reprints go to:

http://journals.bmj.com/cgi/reprintform

To subscribe to BMJ go to:

http://group.bmj.com/subscribe/