(2023) 23:165
Scarcella et al. BMC Neurology
https://doi.org/10.1186/s12883-023-03198-3

BMC Neurology

Open Access

CASE REPORT

Ischemic optic neuropathy as first
presentation in patient with m.3243 A > G
MELAS classic mutation
Simone Scarcella1,2†, Laura Dell’Arti3†, Delia Gagliardi1,2, Francesca Magri4, Alessandra Govoni1, Daniele Velardo1,
Claudia Mainetti4, Valeria Minorini3, Dario Ronchi1,4, Daniela Piga2, Giacomo Pietro Comi1,4, Stefania Corti1,2 and
Megi Meneri1,2*   

Abstract
Background Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a systemic disorder in which multi-organ dysfunction may occur from mitochondrial metabolism failure. Maternally inherited mutations in the MT-TL1 gene are the most frequent causes for this disorder. Clinical manifestations may include
stroke-like episodes, epilepsy, dementia, headache and myopathy. Among these, acute visual failure, usually in association with cortical blindness, can occur because of stroke-like episodes affecting the occipital cortex or the visual
pathways. Vision loss due to optic neuropathy is otherwise considered a typical manifestation of other mitochondrial
diseases such as Leber hereditary optic neuropathy (LHON).
Case presentation Here we describe a 55-year-old woman, sister of a previously described patient with MELAS
harbouring the m.3243A > G (p.0, MT-TL1) mutation, with otherwise unremarkable medical history, that presented
with subacute, painful visual impairment of one eye, accompanied by proximal muscular pain and headache. Over
the next weeks, she developed severe and progressive vision loss limited to one eye. Ocular examination confirmed
unilateral swelling of the optic nerve head; fluorescein angiography showed segmental perfusion delay in the optic
disc and papillary leakage. Neuroimaging, blood and CSF examination and temporal artery biopsy ruled out neuroinflammatory disorders and giant cell arteritis (GCA). Mitochondrial sequencing analysis confirmed the m.3243A > G
transition, and excluded the three most common LHON mutations, as well as the m.3376G > A LHON/MELAS overlap
syndrome mutation. Based on the constellation of clinical symptoms and signs presented in our patient, including the muscular involvement, and the results of the investigations, the diagnosis of optic neuropathy as a stroke-like
event affecting the optic disc was performed. L-arginine and ubidecarenone therapies were started with the aim
to improve stroke-like episode symptoms and prevention. The visual defect remained stable with no further progression or outbreak of new symptoms.
Conclusions Atypical clinical presentations must be always considered in mitochondrial disorders, even in welldescribed phenotypes and when mutational load in peripheral tissue is low. Mitotic segregation of mitochondrial
DNA (mtDNA) does not allow to know the exact degree of heteroplasmy existent within different tissue, such as retina

†

Simone Scarcella and Laura Dell’Arti equally contributed to this work.

*Correspondence:
Megi Meneri
megi.meneri@unimi.it
Full list of author information is available at the end of the article
© The Author(s) 2023, corrected publication 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0
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and optic nerve. Important therapeutic implications arise from a correct diagnosis of atypical presentation of mitochondrial disorders.
Keywords Optic neuropathy, Mitochondrial disease, MELAS, Stroke-like episodes, NAION

Background
Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is one of the most
common maternally inherited mitochondrial diseases
[1–4].
Although childhood represents the typical age of onset,
in a small percentage of cases the disease starts adulthood and is commonly associated with better prognosis
and a relatively less aggressive clinical course [4]. The
prevalence in the Caucasian population is reported to be
around 0.24% [5].
An A to G transition in the 3243 position of mitochondrial DNA (mtDNA) is responsible for up to 80% of cases
[1]. Position 3243 is placed within the MT-TL1 gene,
which encodes for the mitochondrial leucine transfer
RNA (tRNA) Leu(UUR). Besides that, other different pathogenic mutations have been described [1, 2, 6]. As result
of the classic m.3243A > G mutation, altered mitochondrial protein translation occurs. Complex I and complex
IV synthesis seems to be particularly affected, resulting
in a reduced electron transport chain (ETC) function and
energy deficit, especially in the most metabolically active
tissues [2]. Hence, multi-organ dysfunction occurs with
heterogeneous clinical manifestations, depending on the
degree of mutational load harboured by the different tissues and organs, and considering respectively their energetic needs [3, 6]. Metabolically active tissues are indeed
particularly affected. Neurological and muscular symptoms are the most frequent expression of the disease
with epilepsy, stroke-like episodes, dementia, headache,
sensorineural hearing impairment and myopathy being
particularly characteristic [2, 7]. Lactic acidosis and short
stature represent typical features too. Moreover, cardiac,
gastrointestinal, endocrine systems can be involved as
well [4].
Different plausible theories have been proposed to
explain the pathogenic mechanism underlying strokelike episodes (SLEs) in MELAS. According to a metabolic hypothesis, a local breakdown of the mitochondrial
energy metabolism occurs, either in neurons, glial cells,
or in cells constituting the blood brain barrier (BBB)
[2, 3]. A vascular hypothesis exists as well: angiopathy
seems to play an important role in the outbreak of a SLE.
Regional energy deficiency can indeed stimulate mitochondrial proliferation in the smooth muscle and in the
endothelial cells of small blood vessels leading to angiopathy, narrowing of the vessel diameter, thus impairing the

microvasculature of several organs [2, 3]. In addition, SLE
could represent a risk factor for ischemic stroke, due to
a vascular impairment caused by microangiopathy [2, 3].
Increased signal on diffusion-weighted imaging represents a characteristic finding in the magnetic resonance
imaging (MRI) of the acute stroke-like events, accompanied by high signal on T2-weighted and fluid-attenuated
inversion recovery (FLAIR) sequences [7]. Interestingly,
apparent diffusion coefficient (ADC) signal can be both
increased, decreased, or mixed. This fact suggests the
coexistence of cytotoxic and vasogenic edema within a
SLE lesions [7].
Visual impairment represents a possible manifestation of MELAS. Retinal dystrophy, pigmentary retinopathy, ptosis, ophthalmoplegia, optic atrophy, and
corneal polymegathism are well described ophthalmologic expressions of the syndrome that can cause visual
defects [1, 8]. Acute visual failure in MELAS is otherwise associated with cortical blindness as a consequence
of stroke-like episodes affecting the occipital cortex
or other parts of the visual pathway [2, 3]. Conversely,
optic neuropathy is considered a typical manifestation
of other mitochondrial diseases such as Leber hereditary
optic neuropathy (LHON). LHON/MELAS or LHON/
MELAS/Leigh overlap syndromes are reported to exist
within literature, most of all caused by uncommon
mtDNA mutations [1, 8, 9]. Description of visual disturbance due to stroke-like episodes affecting the retina or
the optic nerve in a carrier of the m.3243A > G MELAS
canonical mutation lacks so far [10].

Case presentation
A 55-year-old woman with known medical history of
arterial hypertension, hypercholesterolemia and aortic
stenosis, presented with a subacute episode of visual loss
started as an arcuate visual field defect in the left eye (LE)
and evolved in the next days in a larger central defect.
Visual symptoms were accompanied by the onset headache and diffuse muscular pain, in particular with proximal musculature involvement. Her younger brother was
diagnosed a few years earlier with MELAS for relapsing
episodes of intestinal pseudo-obstruction, followed by
SLEs. In a short period of time he experienced a rapidly
progressive cognitive decline, unfortunately leading to his
death [4]. He carried a high mutational load, estimated by
Real-time PCR, with an amount of 52% in muscle tissue,
28% in urinary epithelial and 18% in peripheral blood.

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Instead, her sister here presented resulted to be a carrier
of the m.3243A > G variant, with 12% of mutation load
in urinary epithelial cells and no alteration detected in
peripheral blood leukocytes. She did not undergo muscular biopsy. Two days after the onset of symptoms she
underwent ophthalmologic examination that revealed
optic disc swelling for which prednisone 50 mg/day was
started, then reduced to 25 mg/day after twelve days
of therapy. One week after symptoms onset she developed left ear tinnitus, orbital pain exacerbated by ocular movements and throbbing temporal pain extended
to the auricular and masseteric region worsened by
chewing. Diffuse muscular pain with asthenia were still
reported as well. Two weeks after the onset of symptoms
the case was referred to our hospital for evaluation. She

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was taking oral olmesartan 40 mg daily, hydrochlorothiazide 20 mg daily, prednisone 25 mg daily. She has not
had any intercurrent infections or assumption of drugs
with putative mitochondrial toxicity. Therapy with ubidecarenone and L-Arginine were immediately started at
admission. L-Arginine was administered intravenously
for the first five days at 0.5gr/kg daily. Ubidecarenone
was started and continued with a posology of 300 mg/
day subdivided in three administrations. Visual acuity was 20/20 in the right eye (RE) and 20/20 in the LE.
Visual field exam confirmed a dense diffuse scotoma in
the affected eye (Fig. 1A). Ophthalmologic evaluation
confirmed left eye optic neuropathy consisting in unilateral swelling of the optic nerve head, with cotton wool
spots, splinter haemorrhages and venous congestion. The

Fig. 1 A Humphrey 30–2 visual field detected a normal visual field in the right eye (RE) and a dense diffuse scotoma in the left eye (LE). B Fundus
colour picture: normal RE, LE optic disc swelling with cotton wool spots, splinter haemorrhages and venous congestion. C-D Autofluorescence
images (FAF, Heidelberg Spectralis, 30 and 55 degrees lenses): bilateral mild pigmentary changes of the posterior pole, characteristic of MELAS.
E Fluorescein angiography (FA, Heidelberg Spectralis, 30 degree lens) showed segmental perfusion delay in the optic disc, focal telangiectasia
and papillary leakage, F Indocyanine angiography ( Heidelberg Spectralis, 55 degree lens) ruled out delayed filling of the choroid, while late phase
FA ruled out other signs of ocular inflammation

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right optic disc was normal and showed a physiological
excavation. Mild pigmentary changes of the posterior
pole, characteristic for MELAS, were detected bilaterally
(Fig. 1B). Autofluorescence images confirmed this finding (Fig. 1C,D). Fluorescein angiography (FA) showed
segmental perfusion delay in the optic disc, focal telangiectasia and papillary leakage, while indocyanine angiography ruled out delayed filling of the choroid. Late phase
FA ruled out other signs of ocular inflammation such as
vasculitis (Fig. 1E,F). OCT scans detected retinal nerve
fiber layer (RNFL) thickening only in the LE and an initial
thinning of macular ganglion cell layer (GCL) (Fig. 2A).
Visual evoked potential showed a reduction in amplitude
with prolonged P100 in the left eye. Brain MRI did not
show optic nerve inflammation or any other pathological feature, while spectroscopy revealed abnormal lactate peak in the CSF. To rule out atypical presentation
of multiple sclerosis (MS), neuromyelitis optica (NMO)
and neuromyelitis optica spectrum disorders (NMOSD),
spinal cord MRI was also performed nineteen days after
the onset of symptoms and did not show demyelinating
lesions at all. Short tau inversion recovery (STIR) and diffuse weighted imaging (DWI) sequences were performed
too without any findings supporting inflammatory or
SLE-related lesions. Serum myelin oligodendrocyte glyco
(MOG) and aquaporin auto-antibodies were found to
be negative. Erythrocyte Sedimentation Rate (ESR) and
C Reactive Protein (CRP) were assessed for the first
time after ten days of steroids therapy and were both

Page 4 of 7

negative. Fludeoxyglucose positron emission tomography
(FDG-PET) and temporal artery biopsy were performed
without any findings that might support large-vessel vasculitis of inflammatory processes. Other possible risk
factors for non-arteritic anterior ischemic optic neuropathy (NAION) such as anaemia, diabetes, nocturnal
dip, sleep apnoea were investigated and excluded. Serum
lactate was 1.7 mmol/L. CSF analysis was unremarkable. CSF infection was excluded and oligoclonal bands
were absent. mtDNA sequencing analysis was performed
and ruled out the possible presence of mitochondrial
mutations known to be associated with MELAS/LHON
overlap syndrome. Mitochondrial sequencing analysis
confirmed the m.3243A > G transition, and excluded the
three most common LHON mutations, as well as the
m.3376G > A, described in literature for being associated
with LHON/MELAS overlap syndrome.
At the follow up visit after four months, visual field
defects remained stable (Fig. 2B), while the swelling of
the optic disc resolved leaving an atrophic optic nerve
head (Fig. 2C,D; Fig. 3).

Discussion and conclusions
Here we present a unique phenotype of MELAS
related optic neuropathy in a patient with a common
m.3243A > G mutation. The visual defect and the ophthalmologic alteration compatible with ischemic neuropathy may represent the consequence of energy
deficiency in the optic nerve due to a MELAS vascular

Fig. 2 A Optical coherence tomography (OCT) scans detected retinal nerve fiber layer (RNFL) thickening only in the LE and an initial thinning
of macular ganglion cell layer (GCL). B At the follow-up visit after four months, visual field defects remained almost stable, while the swelling
of the optic disc resolved leaving an atrophic optic nerve head. C Fundus colour picture and D OCT after four months since the onset of symptoms

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Fig. 3 Timeline of the case report

related SLE. mtDNA sequencing was important to confirm MELAS diagnosis and to rule out possible mutations
which account for MELAS/LHON overlap syndrome.
However, some aspects regarding the onset of the visual
defect were atypical for a LHON: severe unilateral optic
nerve head swelling, segmental perfusion delay and leakage of the optic disc on FA were more consistent with
an ischemic optic neuropathy, in addition orbital pain
exacerbated by ocular movements combined with throbbing temporal pain worsened by chewing were suggestive of an arteritic aetiology. The diffuse muscular pain
that she reported was a typical manifestation that could
either be associated to the myopathy existing within
MELAS, either to inflammatory phenomena affecting
muscles during GCA. PET and temporal artery biopsy
were indeed fundamental to exclude a large vessel disease
vasculitis. ESR and CRP were unreliable since they were
first assessed after ten days of steroids therapy. Excluding
such type of vasculitis, it was possible to start prednisone
titration in a patient harbouring a syndrome known to
be associated with possible endocrinological dysfunction (such as diabetes) which could also be aggravated by
steroids.
Although visual evoked potential showing a reduction
in amplitude with prolonged P100 in the left eye represents a typical finding of demyelinating lesion affecting
the optic nerve, brain MRI did not show any altered signal of the optic nerve, which would otherwise be present
in the context of MS, NMO and NMOSD presentation.
SLEs are commonly accompanied by elevated lactate levels in serum and CSF analysis, along with increased lactate
at MR-spectroscopy in the central nervous system (CNS)
regions affected by the SLE event [2, 3, 7]. In this case, only
MR spectroscopy revealed abnormal lactate peak in the
CSF, not confirmed then by its physical–chemical analysis or by its serum levels assessment. Moreover, it must
be considered that vasoconstriction and angiopathy might
have played a more important role in the outbreak of this

SLE, compared to the contribution of the disrupted mitochondrial energy production. Hypoperfusion and ischemia
of the anterior optic nerve might better explain the clinical
picture here described. (NAION) is manifested as isolated,
sudden, nevertheless painless, monocular vision loss with
oedema of the optic disc [11]. Subacute progressive worsening of vision over a period of a few days or a few weeks is
a common outcome of NAION [11]. Diagnosis of NAION
relies mainly on clinical features with the demonstration
of vision loss with a relative afferent pupillary defect and
oedema of the optic disc. Vision loss severity is highly variable and can include both visual-field defects with a preserved visual acuity but also profound vision losses. Disc
pallor often replaces the oedema that typically resolves
over a period of 6 to 11 weeks. Imaging of the optic nerve
is one of the most important exams within the diagnostic
work-up of ischemic optic neuropathy. Although the exact
pathogenesis of NAION remains unproven, it appears to be
a multifactorial disease. It is presumed to be due to a transient disruption in the circulation of the optic nerve head
leading to hypoperfusion and ischemia. The exact cause
of this transient disturbance remains unclear, but several
hypotheses have been proposed including generalised
hypoperfusion, nocturnal hypotension, local autoregulation failure, vasospasm, venous occlusion, and thrombosis. Systemic hypertension has been documented in up to
50% of patients [12]. In our patient, who presented risk factors for NAION, the perfusion of the optic disc could have
been partially compromised by hypertension and worsened
because of SLE secondary to a microangiopathy or transient local energetic breakdown in mitochondrial function.
MELAS-like retinal anomalies detected on fundoscopy and
fundus autofluorescence (FAF) imaging, further support
this theory [13, 14]. Moreover, OCT reduction of GCL is
an already described finding within MELAS retinal assessment [15]. Based on the constellation of clinical symptoms
in our patient and the results of the investigations performed, we diagnosed an ischemic optic neuropathy in a

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(2023) 23:165

middle-aged woman harbouring MELAS classic mutation,
possibly secondary to a stroke-like event affecting the optic
nerve. The pathogenesis of this SLE could be in our opinion
better explained by the angiopathy existent within MELAS,
thus needed to be separated from the pathogenesis of a
classic NAION. In our opinion, the simultaneous onset
of diffuse muscular pain, typical for myopathic involvement within mitochondrial disorders, further supports this
hypothesis. L-arginine and ubidecarenone therapies were
therefore started to improve stroke-like episode symptoms
and prevention of new ones, as well as avoiding the involvement of the other eye. After the initiation of therapy we did
not assist to further progression of symptoms or to the outbreak of new possible ones.
This is the second case of a possible SLE described in
a carrier of mutation m.3243A > G with swollen optic
disc; previously, a case with bilateral transient optic disc
oedema was described [10]. However, differently from
our case, the recovery of the visual acuity was complete.
Considering that SLE may be at least partially reversible,
the authors speculated that a similar phenomenon had
occurred in their patient [10].
In conclusion, atypical clinical presentations must be
always considered in mitochondrial disorders, even in
well-described phenotypes and even if mutational load
in peripheral tissue (that are easily accessible for analysis) is low. Indeed, the stochastic mitotic segregation of
mtDNA molecules does not allow to foresee the exact
degree of heteroplasmy existent within different tissues,
such as retina and optic nerve. As a consequence, important therapeutic implications arise from a correct diagnosis of atypical presentations of mitochondrial disorders.
In conclusion, mitochondrial gene mutations may present not only with different and less frequently atypical phenotypes, but they may also be considered as an
adjunctive risk factor for ischemic events. In this case, we
think that better knowledge of the genetic background
could help not only in a correct diagnosis, but also for a
tempestive and tailored therapy.
Abbreviations
ADC	Apparent diffusion coefficient
BBB	Blood barrier brain
CNS	Central nervous system
CRP	C reactive protein
CSF	Cerebrospinal fluid
DWI	Diffusion weighted imaging
ESR	Erythrocyte sedimentation rate
ETC	Electron transport chain
FA	Fluorescein angiography
FAF	Fundus autofluorescence
FDG-PET	Fludeoxyglucose positron emission tomography
FLAIR	Fluid-attenuated inversion recovery
GCA​	Giant cell arteritis
GCL	Ganglion cell layer
LE	Left eye

Page 6 of 7

LHON	Leber hereditary optic neuropathy
MELAS	Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like
episodes syndrome
MOG	Myelin oligodendrocyte glycoprotein
MRI	Magnetic resonance imaging
MS	Multiple sclerosis
mtDNA	Mitochondrial DNA
MT-TL1	Mitochondrially encoded tRNA leucine 1
NAION	Non-arteritic ischemic optic neuropathy
NMO	Neuromyelitis optica
NMOSD	Neuromyelitis optica spectrum disorders
OCT	Ocular coherence tomography
PCR	Polymerase chain reaction
RE	Right eye
RNFL	Retinal nerve fiber layer
SLE	Stroke-like episode
STIR	Short tau inverion recovery
tRNA	Transfer RNA

Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s12883-​023-​03198-3.
Additional file 1. Supplementary materials. Family history and pedigree.
Acknowledgements
This work was partially supported by Italian Ministry of Health (Ministero della
Salute), Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico Grant
Ricerca Corrente 2022 to GPC. We would like to thank “Associazione Centro
Dino Ferrari” for its support.
Authors’ contributions
SS and MM: drafted the manuscript for intellectual content and collected and
analyzed the data. DG, LD, DV, CM, VM, DP and MM: collected and analyzed
the data and revised the manuscript for intellectual content. FM, MM, AG,
GPC,DR and SC: revised the manuscript for intellectual content. All authors
contributed to the article and approved the submitted version.
Funding
This work was partially supported by Italian Ministry of Health (Ministero della
Salute), Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico Grant
Ricerca Corrente 2022 to GPC.
Availability of data and materials
The original contributions presented in the study are included in the article/
supplementary material, further inquiries can be directed to the corresponding authors.

Declarations
Ethics approval and consent to participate
Not available.
Consent for publication
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Competing interests
The authors declare no competing interests.
Author details
1
Neuroscience Section, Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Via Francesco Sforza 35,
20122 Milan, Italy. 2 Neurology Unit, Foundation IRCCS Cà Granda Ospedale
Maggiore Policlinico, Milan, Italy. 3 Ophthalmological Unit, Fondazione IRCCS
Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy. 4 Neuromuscular
and Rare Diseases Unit, Department of Neuroscience, Fondazione IRCCS Cà
Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.

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Received: 17 October 2022 Accepted: 22 March 2023

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