Brain & Development 41 (2019) 803–807
www.elsevier.com/locate/braindev

Case Report

Transition from Leigh syndrome to MELAS syndrome in a
patient with heteroplasmic MT-ND3 m.10158T>C
Atsuko Kori a, Ikumi Hori a, Tatsushi Tanaka a, Kohei Aoyama a, Koichi Ito a,
Ayako Hattori a, Kyoko Ban b, Yasushi Okazaki c, Kei Murayama d, Shinji Saitoh a,⇑
a

Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Japan
b
Department of Pediatrics, Yokkaichi Municipal Hospital, Japan
c
Intractable Disease Research Center, Juntendo University, Japan
d
Department of Metabolism, Chiba Children’s Hospital, Japan
Received 7 March 2019; received in revised form 16 May 2019; accepted 22 May 2019

Abstract
An m.10158T>C mutation in MT-ND3, encoding a subunit of respiratory complex I, causes early-onset Leigh syndrome (LS),
mitochondrial encephalomyopathy with lactic acid and stroke-like episodes (MELAS) syndrome, and LS and MELAS overlapping
syndrome, presumably dependent on the ratio of heteroplasmy. Herein, we report a 4-year-old girl with heteroplasmic m.10158T>C
mutation, showing an evolving age-dependent phenotype from LS to MELAS syndromes. She showed mild developmental delay
during infancy, which was associated with magnetic resonance imaging lesions in the brain stem and basal ganglia. At the age of
4 years, she developed rapid neurological deterioration and intractable seizures, which was associated with recurrent multiple cerebral lesions as well as basal ganglia lesions. Her cerebral lesions were located predominantly in white matter and appeared at multiple areas simultaneously, unique characteristics that are distinct from typical MELAS. Two patients with LS-MELAS overlapping
syndrome with m.10158T>C have been previously reported, however, this is the first patient with m.10158T>C showing significant
age-dependent changes in clinical features and neuro-images, implying an age-dependent role of complex I in the developing brain.
Ó 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Keywords: Mitochondrial disease; Respiratory complex I; Neuroimaging

1. Introduction
Respiratory complex I is the largest multiprotein
enzyme complex of the respiratory chain, and its main
function is the transport of electrons from NADH to
ubiquinone with simultaneous shunting of protons.
Complex I consists of at least 46 distinct subunits, seven

⇑ Corresponding author at: Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences,
1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
E-mail address: ss11@med.nagoya-cu.ac.jp (S. Saitoh).

of which are encoded by mitochondrial DNA (mtDNA),
such as NADH dehydrogenase subunit 3 (ND3) [1]. An
m.10158T>C mutation in the MT-ND3 gene was first
reported in 2003 [2], and 17 patients with an
m.10158T>C mutation have been reported to date.
Initially, the m.10158T>C mutation was identified in
patients with Leigh syndrome with poor prognosis
[1–6]. These patients demonstrated an early onset, very
rapid disease progression, and lethal consequences in
early childhood [4]. Indeed, nine of ten LS patients died
within one year of life [1–6]. It is of note that these LS
patients are associated with homoplasmy or a very high

https://doi.org/10.1016/j.braindev.2019.05.006
0387-7604/Ó 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

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A. Kori et al. / Brain & Development 41 (2019) 803–807

ratio of heteroplasmy (>83%) of the m.10158T>C mutation in muscle. Additionally, two patients with LS and
mitochondrial encephalomyopathy with lactic acid and
stroke-like episodes (MELAS) overlapping syndrome
[7,8], and three patients with MELAS have been
reported [6,9]. The non-LS patients tend to exhibit a
lower ratio of heteroplasmy in muscle or blood and an
older age of onset, but the small number of patients precludes any definite conclusions. Herein, we describe a 4year-old girl carrying an m.10158T>C mutation in MTND3 with 82% heteroplasmy in blood, who showed
motor development delay at 1 year and 6 months, and
rapid neurological deterioration and intractable seizures
at 4 years. Magnetic resonance imaging (MRI), initially
involving only the brain stem and basal ganglia, found
multiple cerebral lesions of predominantly white matter,
indicating a transition from LS to a MELAS phenotype.
2. Case report
The proband was a 4-year-old girl. She was born at
38 weeks and 6 days of gestation, with a birth weight
of 2790 g, by normal delivery. Her elder sister was
healthy and there is no family history of neuromuscular
diseases. Her parents were healthy and unrelated. She
presented to our hospital at 2 years and 1 month
because she was not able to walk alone. Neurological
examination was normal except for a mild decrease in
muscle tone. Laboratory examination showed increased
venous lactic acid (61.1 mg/dl) and lactate/pyruvate
ratio (30.5). The lactic acid and lactate/pyruvate ratio
of cerebrospinal fluid was also increased (48.9 mg/dl
and 23.7, respectively). MRI revealed FLAIR/T2WI
high signal and T1WI low signal lesions in bilateral globus pallidus, periaqueductal gray matter of midbrain,
cerebral peduncles, and superior colliculi (Fig. 1A, B),
which are typical findings in LS. Respiratory chain
enzyme activity of skin fibroblasts was low only at complex I (19%; citrate synthase ratio). To identify the
pathogenic mutation in this patient, we performed targeted gene panel sequencing (panel information available on request). The targeted regions including
nuclear-encoded mitochondrial disease genes and whole
mitochondrial genome were captured using the Agilent
SureSelect custom target enrichment kit (Agilent Technologies) following Agilent protocols. The paired-end
reads sequencing was performed on an Illumina MiSeq
according to the manufacturer’s protocols. We finally
identified a pathogenic mutation m.10158T>C (618 of
754 reads; 81.96% in blood). This mutation was not
detectable with Sanger sequencing from parents blood
DNA whereas the patient had high ratio of heteroplasmy (data not shown). Although focal aware seizures
of limbs appeared at 2 years and 4 months, seizures were
well controlled by levetiracetam (30 mg/kg/day) and the
patient had been in a stable condition for approximately

two years. At 4 years, recurrent focal aware seizures of
the right upper limb followed by loss of consciousness
and apneic attack occurred. MRI showed new lesions
in the cortex as well as in bilateral basal ganglia
(Fig. 1C). Administration of multi-vitamin, carbamazepine, clonazepam, and L-arginine failed to control
seizures, and the patient exhibited rapid functional
decline and neurodegenerative regression over four
months. She became less able to assume a sitting position, swallowing function declined, and tube feeding
was introduced. Her speech gradually regressed, and
she became less able to turn over. She showed various
seizure types including generalized clonic seizures, clusters of focal seizures of various origins, and apneic
attacks. Sometimes, the patient displayed epilepsia partialis continua such as twitching of the corners of the
mouth or right thumb, that continued almost an entire
day. Her seizures tended to appear in cluster, and the
seizure frequency fluctuated. Each time a seizure cluster
occurred, new MRI lesions were identified in various
areas of cerebral cortex and white matter (Fig. 1D–F).
Diagnostic study was approved by the ethics committee of Juntendo University and Chiba Children’s Hospital, and was performed after receiving written informed
consent from the parents of the patient.
The parents of the patient assented to be reported in
this literature.
3. Discussion
Characteristic brain MRI findings in LS are bilateral
and symmetrical lesions in the basal ganglia and brainstem, while characteristic brain MRI findings in
MELAS are asymmetrical lesions in the cortex and subcortical white matter of the occipital, temporal, and
frontal lobes. In terms of clinical features, LS develops
in infancy and is characterized by developmental delay,
seizures, and hypotonia, while MELAS develops in
childhood and is characterized by stroke-like symptoms
and hyperlactatemia. Our case exhibited developmental
delay during infancy, and brain MRI revealed lesions in
the brainstem and basal ganglia, which is consistent with
LS. However, at the age of four, rapid neurological
regression with refractory seizures was observed that
was associated with new cerebral lesions, resembling
the stroke-like symptoms of MELAS. Therefore, we
concluded the phenotype had changed from LS to
MELAS in an age-dependent manner.
The clinical features of previously reported cases with
an m.10158T>C mutation in MT-ND3 and the case presented here are summarized in Table 1. Previous reports
have reported a significant correlation between phenotype and the age of onset (Table. 1) [1–9]. The median
age of onset in LS cases was 3 months, while the median
age of onset in MELAS cases was 26 years. Two patients
with m.10158T>C were reported to develop LS and

A. Kori et al. / Brain & Development 41 (2019) 803–807

805

Fig. 1. Age-dependent changes in brain magnetic resonance imaging (FLAIR image): (A) MRI showed high signal lesions in the left globus pallidus
and bilateral superior colliculi at the age of 2 years and 1 month. (B) High intensity of the bilateral basal ganglia at 3 years and 6 months. The new
lesions identified in (C) the cortex of the frontal and bilateral occipital lobes at 4 years; (D) the frontal cortex, subcortical white matter and right
occipital cortex at 4 years and 2 months, (E) the corpus callosum and left frontal cortex at 4 years and 3 months, and (F) the bilateral frontal lobes at
4 years and 5 months.

MELAS simultaneously [7,8], with a median age of
onset of 8.5 years, which is between the median ages
of onset of LS and MELAS, respectively. There is no
published account of a phenotype changing over time
in patients with m.10158T>C, such as we report here
with our patient. Yet, it is possible that in the two previously reported patients with overlapping syndrome,
LS symptoms in infancy were present but not observed.
The age-dependent changes have been reported in
MELAS/LS overlap syndrome with other mitochondrial DNA mutations. Therefore, we should be aware
that a patient with a mitochondrial DNA mutation
including m.10158T>C may show age-dependent phenotype changes. The medians of heteroplasmy ratio in
blood and muscle were higher in LS than MELAS cases,
while homoplasmy was not shown in patients with
MELAS phenotype (Table. 1). It has been suggested
that heteroplasmy ratio may correlate with clinical

presentation and brain image findings in patients with
an m.10158T>C mutation [10]. Our patient is unique
because she showed transition from LS to MELAS.
Her heteroplasmy ratio in blood was 82% and comparable to that of the LS and overlap syndrome, but not
MELAS. Therefore, her intermediate phenotype would
support the correlation between heteroplasmy ratio
and clinical severity in patients with an m.10158T>C
mutation.
In MRI of patients with an m.10158T>C mutation,
38% of LS cases had cerebral lesions, 33% of MELAS
cases had basal ganglion lesions, and 100% of cases with
overlapping LS and MELAS had both cerebral lesions
and basal ganglion lesions (Table. 1). These MRI findings imply overlapping brain involvement irrespective
of clinical presentation. In our patient, brain MRI
showed the T2WI/FLAIR high signal lesions with
brainstem and basal ganglia at 2 years and 1 month,

17%

50%

0%

NA

0%

0%

Appendix A. Supplementary data
Supplementary data to this article can be found
online at https://doi.org/10.1016/j.braindev.2019.05.
006.

NA
+
+

2

3

1

LS/MELAS

MELAS

Present case

NA: Not applicable.
*
Homoplasmy is treated as 100%.

Alive

33%
100%
100%

100%

100%

88%
(83–100%, 6)
98%
(95–100%, 2)
80%
(69.5–89.5%, 3)
NA
12
LS

3 months
(neonatal-1 year)
8.5 years
(7–10 years)
26 years
(20–63 years)
1.5 years

11%
(6.5 months)
100%

38%

100%

96%
(48–100%, 5)
70%
(n = 1)
4.2%
(3–5.3%, 2)
82%

Percentage of cases
of homoplasmy
in blood
Heteroplasmy
ratio in muscle,
median (range, n)*
Heteroplasmy
ratio in blood,
median (range, n)*
Basal
ganglion
lesion
Cerebral
lesion
Survival rate
(Median age
of death)
Number
of cases

Median age
of onset

which is typical for LS. At the age of 4, brain MRI
showed multiple recurrent cerebral lesions predominantly in the white matter, which is not typical for
MELAS. Three previously reported patients with an
m.10158T>C mutation also showed MRI high signal
intensity in the white matter. Two are LS cases; one
had high signal in the basal ganglia and the cortexsubcortex of gyrus of cingulum and central region [2],
and the other had high signal in the supratentorial white
matter, cerebral peduncles, periaqueductal gray matter,
and medulla [3]. The third case is a MELAS-like
encephalopathy case, whose MRI showed bilateral cortical and subcortical high-intensity lesions, with red
nuclei, mesencephalic tectum, vermis and cerebellar flocculus also involved [9]. Thus, it may be characteristic of
the m.10158 T > C mutation that white matter lesions
are observed in addition to cortex lesions.
In conclusion, to our knowledge, this is the first
report to show a patient with an MT-ND3
m.10158T>C mutation exhibiting an age-dependent
transition from LS to MELAS, which suggests an agedependent role of complex I in the developing brain.

References

Phenotype

Table 1
Current and previous reported patients with an MT-ND3 mt.10158T>C mutation.

40%

A. Kori et al. / Brain & Development 41 (2019) 803–807
Percentage of cases
of homoplasmy
in muscle

806

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