Yokota et al. BMC Neurology
(2020) 20:247
https://doi.org/10.1186/s12883-020-01818-w

CASE REPORT

Open Access

Late-onset MELAS syndrome with mtDNA
14453G→A mutation masquerading as an
acute encephalitis: a case report
Yuki Yokota1, Makoto Hara1* , Takayoshi Akimoto1, Tomotaka Mizoguchi1, Yu-ichi Goto2,3, Ichizo Nishino4,
Satoshi Kamei1,5 and Hideto Nakajima1

Abstract
Background: A unique patient with MELAS syndrome, who initially masqueraded as having acute encephalitis and
was eventually diagnosed with MELAS syndrome harboring a mtDNA 14453G → A mutation, is described.
Case presentation: A 74-year-old Japanese man was admitted to another hospital due to acute onset of cognitive
impairment and psychosis. After 7 days he was transferred to our hospital with seizures and deteriorating psychosis.
The results of primary ancillary tests that included EEG, CSF findings, and brain MRI supported the diagnosis of an
acute encephalitis. HSV-DNA and antibodies against neuronal surface antigens in the CSF were all negative. With
the assistance of the lactate peak on the brain lesions in the magnetic resonance spectroscopy image and genetic
analysis of the biopsied muscle, he was eventually diagnosed with MELAS syndrome harboring mtDNA 14453G →
A mutation in the ND6 gene.
Conclusions: This case provides a caveat that MELAS syndrome can manifest in the symptoms and ancillary tests
masquerading as an acute encephalitis caused by infection or autoimmunity. This is the first adult patient seen to
harbor the mtDNA14453G → A with a unique onset, which broadens the phenotypic spectrum of MELAS syndrome
associated with ND6 gene mutation.
Keywords: MELAS, Late-onset, ND6 gene, Encephalitis

Background
Mitochondrial encephalomyopathy with lactic acidosis
and stroke-like episodes (MELAS), which is clinically
characterized by stroke-like episodes accompanied with
headache, seizures, hemiparesis, cortical blindness, hearing disability, and diabetes mellitus [1, 2], is caused by
genetic defects in mitochondrial proteins involved in
oxidative phosphorylation (OXPHOS) [3]. Previous reports of MELAS have revealed that mutations in both
mitochondrial DNA (mtDNA) and nuclear genes
* Correspondence: hara.makoto@nihon-u.ac.jp
1
Division of Neurology, Department of Medicine, Nihon University School of
Medicine, 30-1, Oyaguchi-Kamicyo, Itabashi-ku, Tokyo 173-8610, Japan
Full list of author information is available at the end of the article

essential for mtDNA maintenance are pathogenic [4, 5].
The mtDNA mutations can be categorized into two
groups: one type of mutation affects general mitochondrial protein biosynthesis (tRNA and rRNA genes), a
representative of which is associated with the nucleotide
3243A → G mutation in the mitochondrial tRNALeu
gene [6]; the other type of mutation causes amino acid
substitutions in enzyme complexes involved with
OXPHOS (protein-encoding genes) [3, 4].
The dysfunction of respiratory complex I (type I
NADH dehydrogenase: ND), which plays an important
role in OXPHOS complexes, is considered to be one of
the principle mechanisms underlying mitochondrial diseases that include MELAS [7]. An increasing number of

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pathogenic mutations in ND subunits encoding genes
ND1, ND3, ND4, ND5, and ND6 have been described in
MELAS [4]. Ravn et al. described the relationship between the 14453G → A mutation within the ND6 gene
and severe MELAS in a pediatric patient with myoclonic
epilepsy, focal seizure, and ataxia with dystonia [8].
Here we report a unique case of 74-year-old man,
whose condition initially masqueraded as acute encephalitis and who was eventually diagnosed with MELAS
harboring the 14453G → A mutation.

Case presentation
A 74-year-old right-handed Japanese man was admitted
to another hospital, due to the acute onset of cognitive
impairment and psychosis, accompanied by headache
and pyrexia. He was treated promptly with intravenous
acyclovir. Due to the deterioration of his cognitive function and mental status, he was transferred to our hospital 7 days after the onset of his symptoms. He had
normal development and growth before coming of age.
His past medical history included hypertension, dyslipidemia, angina pectoris, and chronic renal failure. He had
an unremarkable family history, including a lack of
neuromuscular diseases, encephalitis, and mitochondrial
disease.
At admission, his height was 161.8 cm and weight
was 52.6 kg. On physical examination, his body
temperature was 38.0 degrees Celsius. A chest auscultation revealed normal respiratory sound and normal
heart rate with no murmur. Neurological examination
showed mild disturbance of consciousness: GCS 14
(E4 V4 M6), attention disorder, disorientation, psychosis that included abnormal behavior and talkativeness, and left unilateral spatial neglect. On the first
day of hospitalization, he presented with no muscle
weakness. Ophthalmological examination revealed no
abnormal findings in bilateral fundus and oculomotor
control. Brain magnetic resonance imaging (MRI) revealed high-intensity lesions in the right parietotemporal area on fluid attenuated inversion recovery
(FLAIR) (Fig. 1 a–c) images and diffusion weighted
images (DWI) (Fig. 1 d–f). On the lesions, the apparent diffusion coefficient (ADC) image demonstrated
hypo-intensity in the cortical area and high-intensity
in the subcortical area (Fig. 1 g–i). A cerebrospinal
fluid (CSF) sample included 26 white cells/mm3, 70
mg/dL of total protein, and 62 mg/dL of glucose (100
mg/dL of serum glucose). Electroencephalography revealed periodic lateralized epileptiform discharges
(PLEDs), which manifested as high-amplitude, periodic, sharp, transient waves occurring every 1.0–1.5 s
over the right temporo-occipital region (Fig. 2). We
initially diagnosed the patient with acute encephalitis
with an infectious (e.g. herpes simplex virus

Fig. 1 MR imaging findings. Fluid attenuated inversion recovery
(FLAIR), (a-c), diffusion weighted imaging (DWI), (d-f), and apparent
diffusion coefficient (ADC), (g-i) images of the case at first
presentation. FLAIR revealed high-intensity lesions in cortical and
subcortical areas of right parieto-temporal lobes. Cortical areas were
hyperintense on DWI and hypointense on ADC (arrows). Subcortical
areas were hyperintense on DWI and hyperintense on ADC
indicating vasogenic edema (asterisks)

encephalitis; HSVE) or autoimmune origin and continued treatment with acyclovir, while adding intravenous methylprednisolone pulse therapy. On hospital
day 4, we discontinued acyclovir due to the receipt of
negative real-time PCR results for herpes simplex
virus DNA in the CSF. Moreover, autoimmune encephalitis associated with antibodies against neuronal
surface antigens (e.g. anti-N-methyl-d-aspartate receptor antibodies) was adequately excluded due to the
negative results of autoantibody screening of the CSF
with an in-house tissue-based assay using rat brain
sections. Moreover, onconeural antibodies including
Hu, Yo, Ri, CV2, Ma, amphiphysin, PCA-2, Tr, SOX1,
titin, and recoverin all tested negative using line blot
assay (EUROIMMUN).
The patient also developed mild muscular weakness in
the left upper and lower extremities after the admission,
as evaluated using the Medical Research Council (MRC)
Scale, with a score of 3/5. His mental status deteriorated
with increasing confusion and aggressive behavior and,
therefore, we started a low-dose of continuous intravenous midazolam to sedate the patient. The cortical and
subcortical lesions seen on DWI and FLAIR were seen
to have progressed to the occipital area on the follow-up

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Fig. 2 EEG findings. Electroencephalography (EEG) performed on admission revealed poorly organized background activity with periodic
lateralized epileptiform discharges (PLEDs), which manifested as high- amplitude, periodic, sharp, transient waves occurring every 1.0–1.5 s(S) over
the right temporo-occipital area

MRI. Magnetic resonance spectroscopy (MRS) also revealed an elevated and inverted lactate peak with a normal N-acetyl-aspartate level (Fig. 3a) and 123I-IMP single
photon emission computed tomography (SPECT) revealed increased uptake in the lesions that were involved
on MRI (Fig. 3b). Repeated CSF analyses clarified the elevated level of lactate. These ancillary test results facilitated the possible diagnosis of MELAS, even though the
episode was the first neurological event in the patient’s
life. With the diagnosis of suspected MELAS, the oral
coenzyme Q10 (90 mg/day), L-arginine hydrochloride
(7.5 g/day), and vitamin B1 (225 mg/day) were administrated as additional therapies. On day 12, a muscle biopsy of the left biceps brachii was performed for the
histopathological diagnosis and analyses of the mitochondrial genetic mutation. Modified GomoriTrichrome staining of the specimens revealed some
ragged-red fibers (Fig. 4) and analyses of the mitochondrial gene revealed an mtDNA 14453G → A point mutation (Fig. 5); this was accompanied by the
mtDNA189A → G and 16129G → A point mutations,
which were located in the D-loop region of the mtDNA.
With continued treatment, the patient’s disturbed
consciousness and mental state gradually improved,
but the mild left hemiparesis (MRC scale 4/5 for
upper limbs and 4/5 for lower limbs) and cognitive
impairment remained (modified Rankin Scale 2). On
day 110, he was transferred to the rehabilitation hospital and his Barthel Index score was shown to have
improved substantially (from a score of 10 to 80)
after intensive rehabilitation. A summary of the

clinical course of this patient is shown in Additional
Fig. 1.

Discussion and conclusions
MELAS is, in the main, well characterized to manifest as
stroke-like episodes, seizures, and headache. Also, adult
patients may frequently have a hearing disability, cortical
blindness, or diabetes mellitus [1]. The stroke-like episodes often develop in childhood or adolescence and
usually before the age of 40 years [9]. We have described
a late-onset stroke-like episode that initially manifested
as disturbed consciousness and psychosis with acute febrile seizure. The results of ancillary tests including
pleocytosis in the CSF and localized lesions in the lateral
temporal lobe on MRI indicated acute encephalitis possible caused by HSVE or an autoimmune event [10]. The
negative results for the presence of HSV-DNA and antibodies against neuronal surface antigens in the CSF
prompted a further differential diagnosis that included
MELAS. The patient was eventually diagnosed with
MELAS and was found to harbor a 14453G → A point
mutation in mtDNA with the assistance of MRS results
and typical pathological findings from biopsied muscle.
Reports of several patients with MELAS who share
the syndrome and radiological manifestations of
HSVE have been published [11–16], although some
extended reviews of the clinical features of molecularly confirmed MELAS did not mention diagnostic
confusion with HSVE [2, 17]. The previously reported
[11–16] and present cases share clinical characteristics
such as relatively late-onset, initial involvement of the

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Fig. 3 MR spectroscopy and 123I-IMP SPECT findings. Magnetic resonance spectroscopy (MRS, A) revealed a markedly elevated lactate
concentration, which was detected as an inverted double peak (arrow) in the regions of interest on the high-intensity area within the right
parietal lesion; a normal N-acetyl aspartate (NAA) level was also observed. On three-dimensional stereotactic surface projection (3D-SSP) analysis
of 123I-IMP single photon emission tomography (SPECT, B), regional cerebral blood flow (rCBF) was compared with the blood flow of the normal
control group using a Z test. Color-coding represents the statistical significance (Z score) of the increase in rCBF. Z score maps of the brain
surface and tomographic views demonstrated that rCBF in the right temporo-occipital area was remarkably increased

temporal lobes and insular lesions on MRI, and immediate induction of ACV. However, all of previous
cases harbored a 3243A → G mutation of mtDNA
(Table 1). Johns et al., who also described three adult
patients with MELAS that initially masqueraded as
HSVE, insist that clinical features including the absence of pyrexia, lack of prominent alterations in consciousness, and normal CSF cell count assist in
distinguishing MELAS from typical HSVE [11]; in
contrast, Gooriah et al. [15] reported a patient with
pyrexia, and Hsu et al. [13] described a patient with
acute onset pyrexia, headache, and seizures, who
showed remarkable pleocytosis in the CSF and unremarkable findings on MRI. The case reported here
developed acute cognitive impairment and psychosis,

which suggested limbic encephalitis, with pyrexia
showing mild pleocytosis at onset. On the other hand,
Graus et al. recently reported the clinical diagnostic
criteria for autoimmune encephalitis and mentioned
that mitochondrial diseases can be offered as a differential diagnosis from autoimmune encephalitis [18].
Indeed, the present case initially met the criteria for
‘possible autoimmune encephalitis’, which is defined
in the report, in terms of main symptoms, radiological features, and CSF pleocytosis. Autoantibody
screening with an in-house tissue-based assay using
the patient’s CSF was valuable enable prompt exclusion of the encephalitis due to the presence of autoantibodies for synaptic proteins. These findings may
suggest a caveat for physicians in that MELAS

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Fig. 4 Pathological findings on the biopsied muscle. Modified
Gomori-Trichrome staining of the biopsied muscle demonstrated
that the specimen had some ragged-red fibers (arrow)

patients can initially share symptoms with those of
HSVE or autoimmune encephalitis, showing mild
neuroinflammatory signs.
The mutations of the ND6 gene lead to disruption
of the mitochondrial respiratory chain involved in the
OXPHOS complex, provoking an increase in the sensitivity of complex I to inhibitors binding to the ubiquinone site [19] and drastic reduction in complex I
activity [8, 19]. Table 2 lists 16 previously reported
pathogenic point mutation sites in the ND6 gene,
which are associated with neuromuscular disease [8,
20–33]. According to previous reports, the common
clinical manifestation of mutations in the ND6 gene
is Leber’s hereditary optic neuropathy (LHON).

Page 5 of 9

Several cases presenting with LHON/dystonia, Leigh
disease, or MELAS have also been reported. Ravn
et al. described a pediatric patient presenting with
MELAS, who harbored a mtDNA 14453G → A mutation. A comparison of the clinical features of MELAS
with 14453G → A are summarized in Table 3. The
mutation load of the mtDNA extracted from biopsied
muscle in the report of the previous patient was 82%
[8], while that of present case was 53%. In terms of
the ‘threshold effect’ theory in mitochondrial disease,
Miyabayashi et al. [34] reported that the phenotypic
threshold value of mutational load in muscle fibers
taken from MELAS patients is 60%. Alternatively, Ng
et al. [35] described patients with ND5 point mutation manifesting MELAS or Leigh syndrome at highly
variable and relatively low mutational loads of
mtDNA extracted from muscle fibers (median 62%,
range 28–90%). As the brain is one of the most
oxygen-dependent organs reliant mostly on mitochondrial energy supply [36], mitochondrial dysfunctions
affect the central nervous system more easily and severely than other tissues. These principles support the
suggestion that the mutation load of around 50%
from biopsied muscle in the present case could fulfill
the phenotypic threshold required to exhibit MELAS,
although the heteroplasmy level of the brain tissue,
which may be a better predictor of course and severity, are unknown.
Some studies also described a correlation between the
proportion of mutant mtDNA in the affected tissues and
the age of onset [37, 38] and also the severity of the disease [37]. On the contrary, Yokota et al. revealed that
heteroplasmy at the single-cell level was widely varied

Fig. 5 Sequence of part of the patient’s ND6 gene (muscle). Identification of the 14453G > A missense mutation (arrow), which resulted in
Ala74Val in the ND6 gene, by sequencing mitochondrial DNA obtained from the biopsied muscle

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Table 1 Literature review of MELAS syndrome masquerading as acute encephalitis
Author
(year)

Age/ Symptoms at onset
Sex

Focus on MRI

Johns DR
(1993)

41/F Headache, seizure
44/
M

CSF cell
(/mm3)/
protein
(mg/dL)/
lactic acid
(mg/dL)

Treatment

mtDNA References
mutation

Lt. temporal lesion with edema and ND
mass effect

ACV, DXA, PHT

3243

Rt. temporoparietal lesion

Acellular/
100/ND

ACV, PHT

3243

16/F Confusion, visual difficulties,
severe headache, nausea,
vomiting

Lt. occipital lesion

2/36/ ND

ACV

3243

Sharfstein
SR (1999)

55/F Aphasia, delirium

Edema in the Lt. temporal and
parietal lobes

3/63/ ND

ACV, PHT

3243

12

Hsu YC
(2012)

47/
M

Acute onset pyrexia, headache,
generalized seizure, agitation

Unremarkable

7750/431.8/ CTRX, VCA, VPA →
ND
PHT

3243

13

Gieraerts C 36/
(2013)
M

Anomic aphasia, difficulties of
comprehension

Both temporal lobes, insular
regions, posterior straight, and
cingulate gyri with sparing of the
lentiform nuclei

Normal
cells/65.8/
46.9

ACV

3243

14

Gooriah R
(2015)

29/
M

Gradual onset of confusion,
Rt. temporoparietal region, Rt.
headache, irritability, personality insular cortex and the pole of the
change, tonic-clonic seizures,
Lt. temporal lobe
pyrexia

1/62/ ND

ACV

3243

15

Caldarazzo
Ienco E
(2016)

45/
M

Confusion, headache,
generalized seizures

Both temporal lobes

Normal
Antiviral, antibiotic
cells/ 83/80 therapy,
corticosteroid, →
carnitine, CoQ10

3243

16

Present
case

74/
M

Acute cognitive impairment,
psychosis, headache, pyrexia

Rt. parieto-temporal areas

26/70/58.0

ACV, mPSL, →
CoQ10, L-arginine,
Vitamin B1

14453

Present
study

Lt. visual field defect, apraxia of
the Lt. limbs, dressing apraxia

11

ACV acyclovir, CoQ10 coenzyme Q10, CTRX ceftriaxone, DXA dexamethasone, F female, Lt left, M male, mPSL methyl prednisolone, ND not described, PHT
phenytoin, Rt right, VCA vancomycin, VPA valproic acid.

Table 2 Reported pathogenic mtDNA mutations associated with neuromuscular disease involving the ND6 gene
Nucleotide position and changes

Amino acid changes in ND6

Phenotype

References

14258G → A

P139L

LHON

20

14279G → A

S132L

LHON

21

14325 T → C

N117D

LHON

22

14453G → A

A74V

MELAS

8

14459G → A

A72V

LHON /dystonia

23

14482C → A

M64I

LHON

24

14482C → G

M64I

LHON

25

14484 T → C

M64V

LHON

26

14487 T → C

M63V

Leigh disease

27

14495A → G

L60S

LHON

28

14498 T → C

Y59C

LHON

29

14502 T → C

I58V

LHON

30

14568C → T

G36S

LHON

31

14582A → G

V31A

LHON

20

14596A → T

I26M

LHON /dystonia

32

14600G → A

P25L

Leigh disease

33

LHON Leber’s hereditary optic neuropathy, MELAS mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, mtDNA mitochondrial DNA

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Table 3 Comparison of the clinical features of MELAS with 14453G → A mutation
Author
(year)

Age, y /Sex

Mutation

Locus

Mutation rate
Muscle /Blood

Phenotype

Clinical features

mRS
Peak /Current

FU
(Months)

Ravn (2001)

7/F

5628 T → C
13535A → C
14453G → A

MTTA
ND5
ND6

NR
NR
82%/78%

MELAS

Myoclonic epilepsy,
partial seizure,
ataxia with dystonia

5/NR

NR

Present case

74/M

189A → G
14453G → A
16129G → A

D-loop
ND6
D-loop

45%/NE
53%/NE
81%/NE

MELAS

Cognitive impairment,
psychosis, left hemiparesis

5/2

8

F female, FU following up period, MELAS mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, M male, mRS modified Rankin Scale,
NE not examined, NR not reported, y years

among the primary fibroblasts derived from MELAS patients who harbored mtDNA3243A → G [39], which
suggests that the mean heteroplasmy level in the affected
organ may not represent the disease burden. Further investigation is required to determine why the present case
showed later onset of the syndrome and an overall
milder clinical course than those of the case reported by
Ravn et al. (Table 3). Ravn et al. also argued that the reason their case, which had a mtDNA 14453G → A mutation, caused a severe phenotype is that one or more of
the accompanied mutations synergistically modified the
pathological phenotype [8]. The present case was found
to have a mtDNA 14453G → A mutation in ND6; this
was accompanied by the mtDNA189A → G and
16129G → A point mutations, which were located in the
D-loop region of the mtDNA. The D-loop region, which
is located in the main noncoding area of mtDNA, is involved in replication, transcription, and organization of
the mitochondrial genome [40]. Wang et al. described a
relationship between pediatric-onset cyclic vomiting syndrome with migraine and a mtDNA 16129G → A mutation [41], although the present case manifested a
different syndrome from the one reported. Moreover,
the present case also harbored a novel mtDNA189A →
G mutation, the pathogenic role of which has not yet
been determined [4]. In the present case, mutations in
the D-loop regions accompanied by a mtDNA
14453G → A mutation might have modified the syndrome, which consisted of a unique stroke-like episode
masquerading as acute encephalitis (MELAS) (Table 3).
However, the underlying relationship between the mutation site in the ND6 gene and the clinical phenotypes
such as LHON, LHON/dystonia, or MELAS remains to
be elucidated.
In conclusion, the present case is a unique example of
late-onset MELAS with a 14453G → A mutation accompanied by mutations in the D-loop regions of mitochondrial DNA, the clinical onset of which masqueraded as
acute encephalitis with an HSVE or autoimmune cause,
which broadens the phenotypic spectrum of MELAS associated with an ND6 gene mutation.

Supplementary information
Supplementary information accompanies this paper at https://doi.org/10.
1186/s12883-020-01818-w.
Additional file 1. Summary of the clinical course. The clinical course
of the patient is summarized. The patient developed acute onset
psychosis with pyrexia and was transferred to our hospital after
deterioration of the syndrome. He also presented with left hemiparesis
after admission. Acyclovir (ACV) and intravenous methyl prednisolone
were initially administered for acute encephalitis that included herpes
simplex virus encephalitis with an autoimmune cause. The findings from
magnetic resonance spectroscopy (MRS), which revealed markedly
elevated lactate concentration in the regions of interest, assisted the
possible diagnosis of MELAS. With a suspected diagnosis of MELAS, oral
coenzyme Q10, L-arginine hydrochloride, and Fursultiamine were administered as additional treatments. On day 12, a muscle biopsy of the left biceps brachii was performed for the histopathological diagnosis and
analyses of the mutation in the mitochondrial gene, which eventually
lead to a confirmed diagnosis of MELAS with a mitochondrial DNA
14453G > A point mutation. The remaining left hemiparesis with gait disability gradually improved. Eight months after onset, the Barthel Index
and modified Rankin Scale were substantially improved (from scores of
10 to 80, and 5 to 2, respectively) by intensive rehabilitation with no clinical recurrence.
Additional file 2.

Abbreviations
ADC: Apparent diffusion coefficient; CSF: Cerebrospinal fluid; DWI: Diffusionweighted images; EEG: Electroencephalography; FLAIR: Fluid-attenuated
inversion recovery; GCS: Glasgow coma scale; HSVE: Helps simplex virus
encephalitis; LHON: Leber hereditary optic neuropathy; MELAS: Mitochondrial
encephalomyopathy with lactic acidosis and stroke-like episodes;
MRC: Medical Research Council; MRI: Magnetic resonance imaging;
MRS: Magnetic resonance spectroscopy; mtDNA: Mitochondrial DNA;
NADH: Nicotinamide adenine dinucleotide; ND: Nicotinamide adenine
dinucleotide dehydrogenase; OXPHOS: Oxidative phosphorylation;
PLEDs: Periodic lateralized epileptiform discharges; SPECT: Single photon
emission computed tomography; 3D-SSP: Three-dimensional stereotactic
surface projection

Acknowledgements
Not applicable.

Authors’ contributions
YY and MH drafted the manuscript. YY, MH, TA, and TM prepared patient’s
clinical data. YY, MH, YG, IN, SK, and HN analyzed and interpreted the patient
data. TA, TM, YG, and IN performed the histological examination. YG and IN
performed the genetic testing. SK and HN supervised this study. All authors
revised the manuscript for intellectual content. All authors approved the final
manuscript.

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Funding
This study was supported partly by Intramural Research Grant (29–4) for
Neurological and Psychiatric Disorders of NCNP, and Takeda Science
Foundation (to MH). The funding bodies supplied the manuscript with
funding for data acquisition and analyses, writing the manuscript, and
publication.

Page 8 of 9

14.

15.
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.
Ethics approval and consent to participate
The case was discussed with the institutional ethics committee. Ethics
approval was not required.

16.

17.
18.
19.

Consent for publication
We obtained written consent for publication from the patients and patient’s
legal representative (patient’s wife).
Competing interests
The authors declare that they have no competing interests.
Author details
1
Division of Neurology, Department of Medicine, Nihon University School of
Medicine, 30-1, Oyaguchi-Kamicyo, Itabashi-ku, Tokyo 173-8610, Japan.
2
Medical Genome Center, National Center of Neurology and Psychiatry,
Tokyo, Japan. 3Department of Mental Retardation and Birth Defect Research,
National Institute of Neuroscience, National Center of Neurology and
Psychiatry, Tokyo, Japan. 4Department of Neuromuscular Research, National
Institute of Neuroscience, National Center of Neurology and Psychiatry,
Tokyo, Japan. 5Center for Neuro-infection, Department of Neurology, Ageo
Central General Hospital, Saitama, Japan.

20.

21.

22.

23.

Received: 25 March 2020 Accepted: 3 June 2020

24.

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