A Case of Late-Onset Leber's Hereditary Optic Neuropathy
Release Date: April 2012
Expiration Date: march 1, 2015
This article reviews the case of a 51-year-old man with Leber’s Hereditary Optic Neuroparthy (LHON). In addition, it discusses the role of genetic testing in LHON patients, where the diagnosis may be difficult to confirm.
Carol Aune, B.S., O.D., and James Walters, Ph.D., O.D.
This course is COPE-approved for 1 hour of CE credit. COPE ID is 33939-PS. Please check your state licensing board to see if this approval counts toward your CE requirement for relicensure.
This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.
Drs. Aune and Walters have no relationships to disclose.
LEBER'S HEREDITARY OPTIC
NEUROPATHY (LHON) is a maternally
inherited mitochondrial disorder
that is characterized by painless,
subacute, bilateral vision loss.
The condition occurs primarily in
young, adult males. The average
age of onset ranges between 18
and 35 years; however, delayed
onset has been reported in
patients as old as 73 years of age.
When examining a patient
with LHON, the fundus examination may appear normal at
the onset of vision loss although
the clinician may observe optic
nerve and nerve fiber layer
(NFL) swelling on optical coherence tomography; vascular tortuosity; arteriolar dilation; and
The atrophic phase demonstrates bilateral, temporal optic
pallor that often progresses to
complete optic atrophy. Cell
death is limited to the retinal ganglion cells and is hypothesized to
be a result of apoptosis secondary
to oxidative stress caused by mitochondrial mutations.
LHON is largely a diagnosis
of exclusion, and other causes
of optic neuropathy (i.e., toxic/
nutritional, compressive, ischemic, etc.) must be ruled out.
Regardless of age, genetic testing
in any individual suspected of
LHON should be performed to
confirm the diagnosis.
There is no available treatment
for LHON, but low vision aids
and counseling should be recommended. Also, you should advise
LHON carriers to moderate their
smoking and alcohol intake.
Here, we will examine the case
of a 51-year-old man with LHON.
Additionally, we will discuss the
role of genetic testing in LHON
patients who present with unex
plained bilateral vision loss, where
the diagnosis remains in doubt.
A 51-year-old black male was
referred for electrodiagnostic
testing by his ophthalmologist as
a result of unexplained bilateral
vision loss. His chief complaint
included loss of central vision
in both eyes (O.S. > O.D.) and
decreased color vision O.U.
The patient stated that the
vision in his right eye became
blurred three months earlier, followed by pronounced vision loss
in his left eye one month later.
He informed us that his vision
gradually worsened over a two-month period and then stabilized.
His blurred vision was constant,
and affected all viewing distances.
The patient denied pain while
chewing, scalp tenderness or joint
ache. He also denied any family
history of vision loss.
Recently, the patient was diagnosed with type 2 diabetes mellitus and hypertension. His current
medications included metformin,
quinapril and verapamil.
At the most recent visit to his
ophthalmologist one month earlier, he was diagnosed with unexplained vision loss O.U.; complete
color blindness O.U.; mild, non-proliferative diabetic retinopathy
with no clinically significant macular edema O.S.; and temporal pallor of the optic nerve heads O.U.
The patient was referred for
MRI scans of the brain and orbits
(with and without contrast), which
were unremarkable. The patient
reported discontinuing all alcohol
intake four months prior, but he
used to consume three to four
beers per day. He denied any
tobacco and/or illicit drug use.
The patient was a truck driver for 27 years, but was on medical leave
because of his reduced vision.
The patient's uncorrected
entering visual acuity measured
20/400 O.D and 10/400 O.S.,
with no improvement upon
pinhole testing or refraction.
Confrontation fields revealed
defects in the inferior quadrants
of the right eye and all regions of
the left eye except the superior
temporal quadrant. Other preliminary testing, including pupillary response,
ocular motility and bio-microscopy, were unremarkable.
His intraocular pressure measured 22mm Hg
O.D. and 17mm Hg O.S.
indicated thinning of the
temporal rim of the right
optic nerve and superior rim of the left optic
nerve. We observed a
wedge defect in the inferior NFL of the left eye
as well as mild temporal
optic nerve pallor in
both eyes. We performed
visually evoked response
(VER) and documented
no significant pattern.
However, a flash VER at
2Hz and 8Hz showed a
moderately strong outcome in the right eye and
a severely compromised outcome
in the left eye.
Initial presentation of our patient indicated mild temporal optic nerve pallor in both eyes.
Nine months later: Increased temporal optic nerve pallor in both eyes.
We believed that the patient
had bilateral optic atrophy, with a
suspected hereditary component.
We told him to return to his ophthalmologist, and recommended
genetic testing for LHON.
The patient returned nine
months later for a low vision
evaluation. He stated that his
vision remained unchanged and
reported that he had not returned
to the original referring ophthalmologist for additional testing.
Instead, he went to a different
ophthalmologist who diagnosed
him with bilateral primary open-angle glaucoma; prescribed topical bimatoprost; and referred him
to a neuro-ophthalmologist.
A review of the patient's
records indicated that the neuro-ophthalmologist suspected nutritional amblyopia and ordered
a complete blood count. The
results revealed a slight decrease
in hematocrit, hemoglobin, red
blood cells and B1 levels (for which the patient was started on
B1 oral supplements). However,
routine chemistries, liver function studies, protein electrophoresis, lead, B12 and folate levels
were all normal ruling out nutritional amblyopia. At that time,
the neuro-ophthalmologist suggested that LHON was the top
Humphrey 24-2 visual field threshold testing revealed a significant secocentral scotoma (O.D. > O.S.) and arcuate defects in both eyes.
At the low vision evaluation,
the patient's uncorrected entering visual acuity measured 10/80
O.D. and 10/60 O.S., with no
improvement upon pinhole
testing or refraction. Preliminary
testing included pupillary
response, ocular motility and
biomicroscopy, which were unremarkable. Humphrey 24-2 visual
field threshold testing revealed a
significant secocentral scotoma in
both eyes (O.D. > O.S.). We also
documented an inferior arcuate
defect of the right eye and a superior arcuate defect of the left eye.
NFL analysis on optical coherence tomography revealed thinning of the inferior and superior
temporal quadrants O.U.
A high-definition scan of
the macula showed loss of
the papillomacular NFL
bundle O.U., with no
other macular pathology.
The pattern VER
depressed, and the 2Hz
and 8Hz flash VERs were
repeated. The results
indicated that the left eye
was now more responsive than the right eye.
temporal optic nerve pallor in both eyes as well as
increased thinning of the
superior temporal rim
of the left optic nerve.
The patient refused
optical aids, although
we observed a positive
response to magnification. The patient was
counseled on a probable diagnosis of LHON, because the genetic
testing results for the three primary mutations were still pending.
Two months later, the genetic
testing results revealed a G>A
nucleotide substitution at mitochondrial position 11778 in the
patient's DNA. This finding was
consistent with a definitive diagnosis of LHON.
LHON is one of the most common hereditary optic neuropathies.1 Vision loss usually occurs
in one eye first, and may occur
either suddenly or progressively
over two to three months.3 Vision
loss in the fellow eye typically
occurs nine months later, with
two months being the mean interval between vision loss in each
eye.3 Simultaneous onset may
present in approximately 25%
to 50% of occurences.2,3 Patients
often have no family history of
vision loss, with 40% of cases
occurring in just one family member.2 Males are four times more
likely to be affected than females.2 The worldwide prevalence of
LHON is estimated to be one in
LHON carriers typically are
asymptomatic until the onset of
the acute phase, which causes
central vision blurring as well as
a central or secocentral scotoma
on field testing.2,7 During the
pre-symptomatic phase, carriers
may present with temporal NFL
swelling and peripapillary telangi-ectasic vessels.2,8 During the acute
phase, fundus examination may
be normal in 20% of patients.2
of the macula
loss of the
nerve fiber layer
bundle in both
eyes, with no
The atrophic phase demonstrates bilateral, symmetrical,
temporal optic pallor that often
progresses to complete optic
atrophy.2,7,8,10 Optical coherence
tomography frequently reveals
preferential involvement of the
papillomacular bundle and/or
early involvement of the inferior NFL.8
Final visual acuities usually
are worse than 20/200; however, reports of mild, spontaneous recovery have been
documented.2,3 As with all
optic neuropathies, color vision
defects, especially red/green
anomalies, may be observed. VER
amplitudes often are found to
be reduced or flat. Vision loss
usually is the only symptom of
LHON; but, associated neurological complications, such as peripheral neuropathy, postural tremor,
movement disorders, multiple
sclerosis and cardiac anomalies,
have been reported.2,4
LHON was the first mitochondrial disease to be discovered, and
three primary mutations of the
mitochondrial DNA (m.3460G>A, m.11778G>A, m.14484T>C) have
been found in 90% of all LHON
patients.1-3,8,11,12 These mutations
affect the first site of the mitochondrial respiratory chain.2,11 It
is important to note that these
primary mutations are more common in patients with a family history of multigenerational vision
loss, whereas patients with no
known family history often do not
have a primary mutation.11
In recent years, 45 other mutations in mtDNA also have been
associated with LHON.13 Just
50% of males and 10% of females
with the genetic defect develop
optic neuropathy.4,12 Due to this
incomplete penetrance, it is likely
that other factors are involved in
disease expression. Smoking and
high alcohol intake have been
identified as triggers for visual
loss in individuals carrying a
known Leber's mutation.12 Other
factors, such as poor nutrition,
stress, exposure to toxins and
trauma, have been reported in
Nerve fiber layer analysis on OCT revealed thinning of the inferior and superior temporal quadrants O.U.
The optic nerve is rich in
mitochondria, and neurons are
dependent on mitochondria for
survival. Defects in the respiratory
chain of the mitochondria lead to
increased free radical proliferation and decreased ATP production, which cause oxidative stress.4 It is theorized that neuronal
degeneration is a result of oxidative damage caused by associated
Cell death is limited to the
retinal ganglion cells, and is
hypothesized to be a result of
apoptosis secondary to oxidative
stress (although it is unknown
why only the ganglion cell
layer is affected or why healthy
individuals suddenly develop
symptoms).2,13 The preferential
involvement of the papillomacular bundle is thought to occur
because of its small axons.8
As previously mentioned, there
are no known treatments for
LHON. The LHON Treatment
Trial attempted to use topical brimonidine prophylatically to prevent vision loss in patients' unaffected eyes.7 Brimonidine was
used because of its antiapoptic
properties; however, it was unsuccessful. Other studies have shown
that idebenone, minocycline,
infrared light and multivitamin
supplementation, were ineffective
in improving vision or preventing vision loss.2,3,7,14 Currently,
antioxidant gene therapy is under
Fundus photography of our patient’s left eye at initial presentation. We located a wedge defect in the inferior nerve fiber layer. The posterior pole of the right eye was unremarkable.
The wedge defect in the inferior nerve fiber layer was more evident on red-free photography.
LHON is largely a diagnosis of
exclusion, and diagnostic confusion may occur with compressive,
toxic, nutritional, ischemic or
other hereditary optic neuropathies. All patients suspected of
LHON should undergo MRI,
VER and complete blood testing
to rule out other etiologies.
Ultimately, all LHON suspects
should be considered for genetic
testing to confirm the diagnosis.
Remember, however, absence of
the mutation does not rule out
LHON, because all the mutations
attributed to the disease have not
yet been identified.
Dr. Aune is an optometrist practicing
in Raleigh and Eastern N.C., where she
focuses on ocular pathology, low vision
and specialty contact lenses. Dr. Walters
is an associate professor at the University
of Houston College of Optometry and
clinical director of the Ocular Diagnostic
and Medical Clinic at the University
Eye Institute. He has a background in clinical electrophysiology and a special
interest in retinal pathology.
- Abu-Amero K, Bosley T. Mitochondrial Abnormalities in
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- Yu-Wai-Man P, Chinnery P. Leber Hereditary Optic
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- Orssaud C. Leber's hereditary optic neuropathy. Orphanet
Encyclopedia. Available at: www.orpha.net/data/patho/GB/uk-LHON.pdf (accessed January 25, 2012).
- Kumar M, Tanwar M, Saxena R, et al. Identification of novel
mitochondrial mutations in Leber's hereditary optic neuropathy.
Mol Vis. 2010 Apr 30;16:782-92.
- Shah V, Randhawa S, Mizen T et al. You're too old for that.
Surv Ophthalmol. 2008 Jul-Aug;53(4):403-10.
- Ajax ET, Kardon R. Late-onset Leber's hereditary optic neu-ropathy. J Neuroophthalmol. 1998 Mar;18(1):30-1.
- Newman N. Progression of visual field defects in leber hereditary optic neuropathy: experience of the LHON treatment trial.
Am J Ophthalmol. 2006 Jun;141(6):1061-7.
- Barboni P, Carbonelli M, Savini G, et al. Natural history of
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Ophthalmology. 2010 Mar;117(3):623-7.
- Borruat F, Green W, Graham E. Late onset Leber's optic
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J Ophthalmol. 1992 Sep;76(9):571-3.
- Trobe J, Glaser J, Cassady J. Optic Atrophy: Optic atrophy. Differential diagnosis by fundus observation alone. Arch
Ophthalmol. 1980 Jun;98(6):1040-5.
- Ramos C, Bellusci C, Savini G, et al. Association of optic disc
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- Kirkman M, Yu-Wai-Man P, Korsten A, et al. Gene-environment interactions in Leber hereditary optic neuropathy.
Brain. 2009 Sep;132(Pt 9):2317-26.
- Qi X, Sun L, Hauswirth W, et al. Use of mitochondrial
antioxidant defenses for rescue of cells with a Leber hereditary
optic neuropathy-causing mutation. Arch Ophthalmol. 2007
- Mashima Y, Kigasawa K, Wakakura M, Oguchi Y. Do
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Neuroophthalmol. 2000 Sep;20(3):166-70.