Mezuki et al. BMC Neurology (2017) 17:217
DOI 10.1186/s12883-017-1001-4

CASE REPORT

Open Access

Isolated and repeated stroke-like episodes
in a middle-aged man with a mitochondrial
ND3 T10158C mutation: a case report
Satomi Mezuki1,2* , Kenji Fukuda1, Tomonaga Matsushita1, Yoshihisa Fukushima1, Ryu Matsuo2, Yu-ichi Goto3,
Takehiro Yasukawa4, Takeshi Uchiumi4, Dongchon Kang4, Takanari Kitazono2 and Tetsuro Ago2*

Abstract
Background: Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome,
is the most common phenotype of mitochondrial disease. It often develops in childhood or adolescence, usually
before the age of 40, in a maternally-inherited manner. Mutations in mitochondrial DNA (mtDNA) are frequently
responsible for MELAS.
Case presentation: A 55-year-old man, who had no family or past history of mitochondrial disorders, suddenly
developed bilateral visual field constriction and repeated stroke-like episodes. He ultimately presented with cortical
blindness, recurrent epilepsy and severe cognitive impairment approximately 6 months after the first episode. Genetic
analysis of biopsied biceps brachii muscle, but not of peripheral white blood cells, revealed a T10158C mutation in the
mtDNA-encoded gene of NADH dehydrogenase subunit 3 (ND3), which has previously been thought to be associated
with severe or fatal mitochondrial disorders that develop during the neonatal period or in infancy.
Conclusion: A T10158C mutation in the ND3 gene can cause atypical adult-onset stroke-like episodes in a sporadic manner.
Keywords: Cognitive impairment, MELAS, Mitochondrial ND3 gene, T10158C, Sporadic

Background
It is well established that point mutations and deletions
of mitochondrial DNA (mtDNA) cause mitochondrial
disorders. While mtDNA point mutations are usually
maternally inherited, deletions usually occur sporadically. Mitochondrial myopathy, encephalopathy, lactic
acidosis and stroke-like episodes (MELAS), is the most
common phenotype of mitochondrial disease. The strokelike episodes often develop in childhood or adolescence,
and usually before the age of 40 [1]. Among the reported
mutations in mtDNA, an A to G mutation at nucleotide
position 3243 (A3243G) in the mitochondrially encoded
tRNA leucine 1 (MT-TL1) gene, which encodes a transfer
* Correspondence: smezuki@intmed2.med.kyushu-u.ac.jp;
agou@intmed2.med.kyushu-u.ac.jp
1
Stroke Center, St. Mary’s Hospital, 422 Tsubukuhonmachi, Kurume 830-8543,
Japan
2
Department of Medicine and Clinical Science, Graduate School of Medical
Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582,
Japan
Full list of author information is available at the end of the article

RNA for leucine, has been found in more than 80% of
MELAS patients [2]. The A3243G mutation ultimately
leads to multiple defects of the mitochondrial respiratory
chain (MRC) [3]. Complex I deficiency accounts for many
cases of MRC defects and results in a wide range of mitochondrial diseases [4]. It has been thought that mutations
in Complex I subunits often manifest a severe or fatal
mitochondrial disorder from the neonatal period to infancy, known as Leigh syndrome [3].
Here we describe the case of a 55-year-old man
who sporadically and suddenly developed repeated
stroke-like episodes, ultimately presenting with cortical blindness, recurrent epilepsy and severe cognitive
impairment. We identified a T10158C mutation in the
NADH dehydrogenase subunit 3 (ND3) gene in this
patient. We discuss the significance of this mutation
in the development of sporadic adult-onset stroke-like
encephalopathy.

© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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Mezuki et al. BMC Neurology (2017) 17:217

Case presentation
A previously healthy 55-year-old Japanese man became
aware of flashing lights in his visual field. A month later
he visited a doctor with a complaint of sudden visual
field constriction. Magnetic resonance images (MRI)
revealed abnormal signals in the bilateral occipital lobe,
and he was transferred to our hospital. At the time of
admission, the height of the patient was 167 cm and his
weight was 57 kg. His blood pressure was 158/70 mmHg,
and his heart rate was 72 beats per minute and regular.
His body temperature was 36.8 °C. Although his vision
was slightly misty, he was well orientated and his higher
brain function was normal. He had afferent tunnel
vision, but no other obvious neurological deficits. Blood
tests, including serum autoantibodies and soluble IL-2
receptor antibody, indicated no apparent abnormalities
except that the ratio of lactate (47.5 mg/dl) to pyruvate
(2.09 mg/dl) was significantly increased (L/P ratio 22.7).
Cerebrospinal fluid (CSF) examination showed a normal
cell count (1/μl) and a slightly elevated protein concentration (55 mg/dl). His CSF L/P ratio was also increased
(lactate 27.6 mg/dl, pyruvate 1.30 mg/dl and L/P ratio
21.2). Levels of adenosine deaminase and 14–3-3 protein
in CSF were within normal limits. Both fluid-attenuated
inversion recovery (FLAIR) and diffusion-weighted
images (DWI) revealed multiple high-intensity signals in
the cortical and subcortical areas of the bilateral occipital lobe, the mesial temporal lobes, and the left frontal
lobe (Fig. 1). Apparent diffusion coefficient (ADC)
images showed normal- to slightly low-intensity signals
in the areas with the abnormal signals shown by FLAIR
and DWI (Fig. 1). Magnetic resonance angiography and
venography (MRA and MRV) showed no abnormalities
(Fig. 1). Furthermore, magnetic resonance spectroscopy
(MRS) demonstrated elevated lactate concentrations in
the bilateral occipital lesion (Fig. 2, arrows). Electroencephalography showed periodic slow waves and sharp
waves bilaterally, but no periodic synchronous discharge
was detected. No abnormalities were revealed by ophthalmological examinations, audiography, echocardiography,
electromyography, or glucose tolerance tests. Histopathological studies of biopsied right biceps brachii muscle
showed no mitochondrial myopathic features, including
ragged-red fibers or intense succinate dehydrogenase activity. However, genetic analysis of the biopsied muscle by
complete sequencing of mtDNA revealed a T10158C missense mutation in the ND3 gene (Fig. 3). Pyrosequence
analysis, a method used to quantify heteroplasmy [5],
showed that 76% of the mtDNA in the biopsied muscle of
the patient had the mutation (Fig. 4). The mutation was
not found in DNA obtained from his peripheral white
blood cells.
After the first episode, he had repeated stroke-like
episodes accompanied by abnormal MRI signals in

Page 2 of 5

Fig. 1 Fluid-attenuated inversion recovery (FLAIR) images and diffusionweighted images (DWI) show multiple high-intensity signals (arrows) in
the cortical and subcortical areas of the bilateral occipital and the mesial
temporal lobes, and the left frontal lobe. Apparent diffusion coefficient
(ADC) images show normal- to slightly low-intensity signals in the areas
with the abnormal signals shown by FLAIR and DWI (arrows). Magnetic
resonance angiography and venography (MRA and MRV) show
no abnormalities

various areas, mainly in the occipital lobes. Within 6
months he manifested cortical blindness, recurrent
epilepsy and severe cognitive impairment (Fig. 5).

Discussion and conclusions
Here we described a middle-aged man who suddenly
developed repeated stroke-like episodes and eventually
presented with cortical blindness, recurrent epilepsy and
severe cognitive impairment within about 6 months. We
considered that ischemic stroke, sinus thrombosis,
posterior reversible encephalopathy syndrome, central
nervous system (CNS) vasculitis, encephalopathies, malignant lymphoma, and Creutzfeldt-Jacob disease could
be excluded based on laboratory examinations, including
blood and CSF, physiological examinations, MR imaging,
and clinical course. Instead, we identified a significant
increase in the ratio of lactate to pyruvate in both his
blood and CSF and a heteroplasmic T10158C mutation
in the ND3 gene, encoded on mtDNA, in his right biceps brachii muscle but not in peripheral white blood
cells. We therefore suggest that a possible diagnosis for
the patient could be isolated mitochondrial encephalopathy associated with the mutation.
The gene product of ND3, NADH dehydrogenase subunit 3, is a structural component of the multimeric

Mezuki et al. BMC Neurology (2017) 17:217

Page 3 of 5

Fig. 2 Magnetic resonance spectroscopy (MRS) reveals markedly elevated lactate (Lac) concentrations in the regions of interest in the high-intensity
area of the bilateral occipital lesion (arrows). It also reveals decreased N-acetyl acetate (NAA) and slightly elevated choline (Cho) in these areas

enzyme Complex I of the MRC, and is involved in the
active/de-active enzymatic transition of Complex I [6].
Because Complex I drives ATP generation in the mitochondria, any genetic abnormalities of its components
could directly cause severe impairment of energy generation and subsequent cellular or organ failure, particularly in the CNS. Currently, three ND3 mutations that
can lead to MRC defects are known: T10158C [7–9],
T10191C [10–12] and G10197A [4, 13]. Although it has
been reported that most of the cases harboring these

Fig. 3 Identification of the T10158C mutation in the ND3 gene by
sequencing mitochondrial DNA obtained from the right biceps
brachii muscle

mutations manifested mitochondrial encephalopathy
during the neonatal period or in infancy [7, 12], Mukai
et al. recently reported two adult cases with the
T10158C mutation that developed repeated stroke-like
episodes [8, 9] and are very similar to the present case.
Their cases and ours had common clinical characteristics: 1) the patients developed repeated stroke-like episodes later than middle-age, 2) the CNS was affected in
an isolated manner and 3) they had no recognized family
history of mitochondrial disorders.
Adult-onset stroke-like episodes are a common feature
of MELAS syndrome where more than 80% patients harbor the A3243G mutation [2]. In contrast to MELAS patients with the A3243G mutation, it is generally
understood that patients with mutations in Complex I
are likely to manifest severe and fatal mitochondrial disorders, such as Leigh syndrome, in the neonatal to infant
period [14]. However, the fact that these three cases harbor the T10158C mutation in the ND3 subunit of Complex I, causing late-onset stroke-like episodes similar to
MELAS, highlights the complexity of the relationship between the causative mutation and clinical manifestation.
Various mtDNA mutations can cause either multiple
or single organ disorders due to their heteroplasmic
characteristics. These three adult-onset cases with the
T10158C mutation manifested isolated encephalopathy, presenting with stroke-like episodes, but not
myopathy or other organ dysfunctions. This is despite

Mezuki et al. BMC Neurology (2017) 17:217

Page 4 of 5

Fig. 4 Pyrosequence analysis of mitochondrial DNA extracted from biopsied muscle

the fact that the mutation was identified in biopsied
muscles with an approximately 80% mutation load
[8]. This may be attributable to “threshold effects”: it
is thought that threshold values of mutational load
presenting phenotypic changes may be around 60%
for mtDNA deletions, while around 90% for mtDNA
point mutations [15]. We therefore speculate that the
mutational load in the affected CNS lesions in the
present case may be over 90%. Alternatively, the mutation may disrupt the functions of the CNS more
easily than those of other organs, such as muscles,
even with a similar mutational load of around 80%.
We would need to perform a brain biopsy and genetic analysis to determine this.
Pathogenic mtDNA mutations can be maternally
inherited or occur sporadically. Although it is thought

that point mutations are usually inherited maternally
[1], there were no recognized family histories of mitochondrial disorders, with either infantile- [7] or adult[8, 9] onset, in the reported cases with the T10158C
mutation. This indicates that the T10158C mutation
may occur de novo in the germline cells of the patients’ mothers and may attain high-level heteroplasmy, presenting encephalopathy very rapidly in
some cases [7], or slowly over 40 years in others. We
infer the presence of additional unknown factors that
accelerate or slow the dysfunction or accumulation of
mtDNA with the T10158C mutation [16].
Our study supports the hypothesis that the T10158C
mutation in the mitochondrial ND3 gene can sporadically cause isolated and repeated stroke-like episodes,
with an onset later than middle-age [8, 9].

Fig. 5 FLAIR images at days 11, 39, 63 and 191 show high intensity signals appearing recurrently in various cortical and subcortical areas, mainly
in the bilateral occipital lobe, and that atrophic changes develop progressively over approximately 6 months

Mezuki et al. BMC Neurology (2017) 17:217

Abbreviations
ADC: Apparent diffusion coefficient; CNS: Central nervous system;
CSF: Cerebrospinal fluid; DWI: Diffusion-weighted images;
MELAS: Mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes; MRC: Mitochondrial respiratory chain; MRI: Magnetic resonance
images; MRS: Magnetic resonance spectroscopy
Acknowledgements
We are grateful to Taeko Hotta, a chief engineer in the Department of Pathological
Sciences, Graduate School of Medical Sciences, Kyushu University, for her help in
conducting the gene analysis.

Page 5 of 5

6.

7.

8.

9.
Funding
None.
Availability of data and materials
All data and material supporting the conclusions of this article is included in
the article. Identifying/confidential information has not been and shall not
be shared.
Authors’ contributions
SM drafted the manuscript. SM, KF, TM and YF examined and treated the patients
serially over time. YT, RM, TK and TA provided direction and critically revised the
manuscript. YG, TU and DK conducted the gene analysis and diagnosis. TA revised
the manuscript and gave the final approval of the version to be published. All
authors have read and approved the final manuscript.
Ethics approval and consent to participate
This report was approved by the institutional review board (St. Mary’s Ethics
Committee, approval No.16–0205), and informed consent for participation
was obtained from the patient.

10.

11.

12.

13.

14.
Consent for publication
Written informed consent was obtained from the patient for publication of
this report and accompanying images. Copies of the written consent are
available for review by the Editor-in-Chief of this journal.

15.
16.

Competing interests
The authors declare that they have no competing interests.

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Author details
1
Stroke Center, St. Mary’s Hospital, 422 Tsubukuhonmachi, Kurume 830-8543,
Japan. 2Department of Medicine and Clinical Science, Graduate School of
Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka
812-8582, Japan. 3Department of Mental Retardation and Birth Defect
Research, National Institute of Neuroscience, NCNP, 4-1-1 Ogawa-Higashi,
Kodaira, Tokyo 187-8551, Japan. 4Department of Pathological Sciences,
Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi,
Higashi-ku, Fukuoka 812-8582, Japan.
Received: 21 June 2017 Accepted: 5 December 2017

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