Neurological Sciences
https://doi.org/10.1007/s10072-021-05155-9

ORIGINAL ARTICLE

Leber hereditary optic neuropathy and dystonia overlapping
mitochondrial encephalomyopathy with lactic acidosis
and stroke-like episodes due to m.14459G>A mutation
Xiaolin Yu 1,2 & Kunqian Ji 2 & Yan Lin 2 & Xuebi Xu 2 & Wei Wang 2 & Ying Li 1 & Jian-Qiang Lu 3 & Yuying Zhao 2
Chuanzhu Yan 2,4,5

&

Received: 17 August 2020 / Accepted: 26 February 2021
# Fondazione Società Italiana di Neurologia 2021

Abstract
Objective To report a Chinese family with combined m.14459G>A mutation and m.6064A>T mutation of which the female
proband presenting unique Leber hereditary optic neuropathy and dystonia (LDYT) overlapping mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) phenotype.
Methods Clinical information of the pedigree was collected. We performed muscle biopsy and whole-length mitochondrial DNA
(mtDNA) sequencing on the proband. The activity of respiratory chain complexes in immortalized lymphoblasts was determined.
Results The current 23-year-old proband suffered from vision decline at age 15 and developed seizures and dystonia with
bilateral lesions in precentral gyri at age 18. When she was 21, the lesions in bilateral putamen were found with elevated
cerebrospinal fluid lactate. Her mother had optic atrophy; one of her brother died at age 4 with respiratory distress; and the other
8-year-old brother was asymptomatic. Muscle biopsy of the proband was unremarkable. The mtDNA sequencing revealed a
heteroplasmic m.14459G>A mutation and a previously unreported m.6064A>T mutation. The respiratory chain complex I
activity in the proband’s immortalized lymphoblasts was 50% less than the normal control; while there was no statistical
difference between the proband and the normal control in the activity of complex IV.
Conclusions We presented the first case exhibiting LDYT and MELAS phenotype with m.14459G>A mutation, and the decreased complex I activity contributed to the pathogenicity. Our study expanded the clinical spectrum of m.14459G>A mutation.
Keywords Leber hereditary optic neuropathy . Dystonia . MELAS . m.14459G>A mutation

Introduction
Yuying Zhao and Chuanzhu Yan contributed equally to this work.
* Yuying Zhao
zyy72@126.com
* Chuanzhu Yan
czyan@sdu.edu.cn; chuanzhuyan@163.com
1

Department of Geriatrics Medicine, Qilu Hospital, Shandong
University, Jinan, Shandong, China

2

Research Institute of Neuromuscular and Neurodegenerative
Diseases and Department of Neurology, Qilu Hospital, Shandong
University, Jinan, Shandong, China

3

Department of Pathology and Molecular Medicine/Neuropathology,
McMaster University, Hamilton, Ontario, Canada

4

Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao),
Shandong University, Qingdao, Shandong, China

5

Brain Science Research Institute, Shandong University,
Jinan, Shandong, China

Mitochondrial DNA (mtDNA) mutations are associated with
a broad spectrum of clinical disorders. The G to A transition at
nucleotide position 14459 in mtDNA leads to substitution of
alanine to valine at amino acid residue 72 within evolutionarily conserved region of NADH dehydrogenase subunit 6
(ND6) in mitochondrial respiratory chain (MRC) complex I,
which plays important roles in electron transfer, electrochemical gradient maintenance, and reactive oxygen species (ROS)
generation [1]. The clinical phenotypes of complex I deficiency are heterogeneous.
In 1994, m.14459G>A mutation was first reported in a
Hispanic family of which the affected individuals expressed
Leber hereditary optic neuropathy (LHON), early-onset dystonia, or LHON and dystonia (LDYT), and others were
asymptomatic [2]. LHON is characterized by bilateral painless
visual loss, acute or subacute, occurring in the young adult

Neurol Sci

life, and males are predominantly affected [3–5]. To date, the
most prevalent variations for LHON are m.11778G>A,
m.3460G>A, and m.14484T>C mutations, located in MTND4, MT-ND1, and MT-ND6 genes, respectively, accounted
for approximately 90–95% of all the reported cases (http://
www.mitomap.org/). The m.14459G>A mutation is rare for
LHON. A study of 1218 Chinese Han LHON patients
revealed that the m.14459G>A mutation was present in only
one patient (0.08%) [6]. Dystonia is also a phenotype of m.
14459G>A mutation. The patients with m.14459G>A
mutation usually have focal dystonia younger than 5 years
of age, which is gradually progressed to generalized
dystonia [7]. In addition, the carriers with m.14459G>A
mutation could have the phenotype of Leigh syndrome (LS)
with a poor prognosis [8, 9].
Here we describe a Chinese family with combined
m.14459G>A mutation and m.6064A>T mutation, and the
proband developed a LDYT overlapping mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes
(MELAS) phenotype that has not been reported to our
knowledge.

Methods

Respiratory chain enzyme activity assays of
immortalized lymphoblastic cell lines
Leukocytes from the proband and healthy normal control were
transformed with the Epstein-Barr virus as previously detailed
[11]. The generated lymphoblasts were immortalized. The cell
lines were grown in RPMI 1640 media (Gibco) with 10% fetal
bovine serum (FBS).
The enzymatic activities determination including MRC
complex I (NADH-ubiquinone oxidoreductase), II (succinate
dehydrogenase), IV (cytochrome c oxidase), and citrate synthase of immortalized lymphoblasts between the proband and
the normal control were completed by spectrophotometric
method as described before [12].

Statistical analysis
The statistical analysis was performed using SPSS 22.0 software (IBM, USA). Numerical variables were presented with
mean ± standard deviation. The unpaired t test was used to
compare the values between the proband and the normal control. A p value < 0.05 was considered statistically significant.

Results

Subjects
Clinical features
The proband and her family members gave informed consent,
and our study was approved by the Ethic Committees of Qilu
Hospital of Shandong University. A comprehensive medical
history, physical examination, ophthalmic examination, and
neuroimaging data of the proband were collected.

Muscle biopsy
A muscle biopsy from the left biceps brachii was performed
on the proband. Muscle serial frozen sections, 6 μm in thickness, were stained with hematoxylin and eosin (H&E), nicotinamide adenine dinucleotide hydrogen (NADH)-tetrazolium
reductase, modified Gomori trichrome (MGT), cytochrome c
oxidase (COX), succinate dehydrogenase (SDH), SDH/COX.

Mitochondrial DNA sequencing
The total DNA was extracted from peripheral blood, urinary
sediment, buccal smears, and/or biopsied muscle samples of
the proband and her family members by TIANamp Genomic
DNA Kit (TIANGEN, China) according to the manufacturer’s
protocol. The whole mitochondrial genome sequencing from
the proband’s blood sample was performed using the next
generation sequencing. The Sanger screening was used to
identify m.14459G>A and m.6064A>T mutations as previously described [10].

The current 23-year-old female proband (III1, Fig. 1a) had
rough development milestones compared with the peers. She
originally complained of painless vision decline in both eyes
at age 15. In the local hospital, she was diagnosed with optic
neuritis and optic atrophy and received prednisone therapy.
The visual acuity was only slightly promoted. At the age of
18, she suffered from a tonic-clonic seizure on the bus, and
then, she was admitted to our hospital. The electroencephalogram showed short bursts of theta on vertex and bilateral frontal regions. No clear epileptiform activity was found. The
lactic acid level of cerebrospinal fluid was elevated to 2.7
mmol/L (normal value 1.2–2.1 mmol/L). The levels of urine
organic acid, blood lactate, blood amino acid, and
acylcarnitines were normal. Since then, she showed an onset
of dystonia mainly manifested in the right upper limb and left
lower limb. The brain MRI demonstrated symmetric abnormal
high signals in the bilateral precentral gyri on diffusionweighted images (DWI) and T2-weighted images (T2WI)
without post-contrast enhancement, which were roughly unchanged on follow-up MRI performed 3 months later (Fig.
2a–d). Her parents were not consanguineous. Her mother
(II5) had visual acuity of 7/10 and 8/10 in the left and right
eye, respectively, with pale optic disks. One of her brother
(III2) died at age 4 with respiratory distress, and the other 8year-old brother (III3) was asymptomatic up to now.

Neurol Sci

Fig. 1 The pedigree (a) and optical coherence tomography (OCT) examination (b) of the proband. III1 was the proband. The proband’s mother
(II5) had optic atrophy. The proband’s brother (III2) died at age 4 with
respiratory distress. The OCT showed the retinal nerve fiber layer

(RNFL) thickness of the proband at diameter: 3.45 mm from the center
of optic discs, which was diffusely thinner than the normal except the
superior nasal (SN) quadrant

The proband had a height of 160 cm and a weight of 60 kg
at age 22. Neurological examinations revealed dystonia and
mildly reduced muscle strength in the right upper limb and left

lower limb, especially in the former. There was also intention
tremor in the right upper limb. The Babinski sign and meningeal irritation signs were absent. Her score of mini-mental

Neurol Sci

Fig. 2 Brain MRI findings of the proband. There were hyperintense
lesions in the precentral gyri on DWI (a, b) and T2-FLAIR(c, d),
without basal ganglia involvement at age 18. The bilateral precentral

gyrus lesions turned to be isointense on DWI (e); meanwhile, the
hyperintense lesions appeared in putamen on DWI (f), T2WI (g), and
T2-FLAIR (h) at age 22. Arrows indicated the lesions

state examination was 28 with the left hand writing. On ophthalmic examination, the visual acuity was 1/10 in both eyes.
Fundus photography revealed temporal pallor in the optic
disks. The thickness of retinal nerve fiber layer (RNFL) is
diffusely reduced except the superior nasal section on optical
coherence tomography (OCT) examination (Fig. 1b). The visual field tests showed central scotoma. The brain MRI demonstrated hyperintense lesions in the bilateral basal ganglia
and precentral gyri on T2WI and T2-fluid-attenuated inversion recovery imaging (T2-FLAIR); in addition, the DWI signal abnormality was resolved in the precentral gyri (Fig. 2e–
h). It was roughly the same as the manifestation of the brain
MRI performed 5 months ago when she was 21.
Over the past 4 years, she received treatment with coenzyme Q10, vitamin B1, vitamin B2, clonazepam, and levetiracetam with the diagnosis of LDYT and MELAS. She had
tonic-clonic seizures, unstable walking, and involuntary
movement in the right upper limb and left lower limb. The
basic activities of daily living were maintained almost
independently.

activity were observed in subsarcolemmal regions of muscle
fibers (Fig. 3). This muscle sample exhibited no muscle denervation atrophy or fiber type grouping.

Histopathological study

Decreased activity of complex I

A biopsy of left biceps brachii from the proband showed no
necrosis, regenerating or inflammatory features on H&E staining. – There were no convincing ragged red fibers on MGT
staining, or ragged blue fibers on SDH/COX staining; COX
staining revealed no COX-deficient fibers. Slight mitochondrial accumulations and mildly intensive SDH and COX

The activity of MRC complex I from the proband’s immortalized lymphoblastic cells with m.14459G>A and m.6064A>T
mutations is reduced to 50% of the normal control (p < 0.01,
Fig. 4). There is no statistical difference between the proband
and the normal control in the activities of complex II and IV (p
> 0.05, Fig. 4).

Genetic analysis
The whole-length mtDNA sequencing of the proband identified a m.14459G>A mutation and a previously unreported
m.6064A>T mutation. The heteroplasmy of m.14459G>A
mutation was at the levels of 39.1% in blood, 88.1% in urine,
80.8% in buccal mucosa, and 94% in the biopsied muscle. The
proportions of m.6064A>T mutation determined in blood,
urine, buccal mucosa, and muscle were 97.7 %, 96.6%,
100%, and 95.7%, respectively. The mother (II5) had
m.14459G>A and m.6064A>T mutant load at 13.5% and
93%, respectively, in blood. The m.14459G>A and
m.6064A>T mutation rates were 15.5% and 93% in blood
from the younger brother (III3).

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Fig. 3 Histopathological study in frozen sections of the biopsied muscle
of the proband. H&E stain showed a mild variation in fiber size (a).
Slightly red-stained mitochondrial accumulations in subsarcolemmal

regions of few muscle fibers were observed on MGT stain (b). Mildly
intensive activity was observed in subsarcolemmal regions on SDH (c)
and COX stain (d)

Discussion

phenotype with m.14459G>A mutation. This mutation has
been so far reported in patients with LHON, LDYT, dystonia,
or LS, and asymptomatic individuals. A literature review
about the clinical and genetic features of m.14459G>A mutation is summarized in Table 1.
LHON is characterized by midlife onset, acute painless central
vision loss in one eye, and then the contralateral eye within
weeks or months [26]. Some patients also experience vision loss
in both eyes simultaneously. At the acute stage of LHON, fundus
examination could reveal peripapillary telangiectasia and swelling of RNFL near optic discs [5]. The optic atrophy and thinning
of RNFL were observed during chronic stage [5, 26]. The central
visual field and color vision could have a certain recovery even
many years later in some patients. The m.14459G>A mutation
was considered rare for LHON. It has been more than 6 years
since the painless vision declined until the proband received
detailed ophthalmologic examination in our hospital. The presentation of low visual acuity, thinning RNFL, and central scotoma
of the proband was compatible with the diagnosis of LHON at
the chronic stage.
Our proband suffered from dystonia at age 18, whereas the
dystonia associated with m.14459G>A mutation typically developed before 5 years of age and progressed gradually from

In this study, we present the first case of a Chinese female
exhibiting previously unreported LDYT and MELAS

Fig. 4 Mitochondrial respiratory chain complex activities of
immortalized lymphoblasts. The complex I activity of immortalized
lymphoblasts was decreased in the proband. **p < 0.01 compared with
the healthy normal control

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Table 1

The clinical phenotypes in patients with m.14459G>A mutation

Ref

Race

Sex

Onset

Clinical features

Brain images Mutation
load

Koide et al. [13]
Hirayanagi et al. [14]

Japanese
Japanese

M
M
M
M

3y
5y
5y
13y

Dystonia
Dystonia
Dystonia
Truncal ataxia, parkinsonism

PT, CN,MB
PT
PT
PT

homoplasmy
homoplasmy
homoplasmy
heteroplasmy

Brady et al. [15]
Gropman et al. [16]

European
Hispanic

F
F
F
M
F
M
M
3 M+
1F
F

18y
3y
32y
2y
5y
infancy
4y
5y

Ataxia, dystonia
Dystonia
NF1
NF1,hemiparesis
Hemiparesis
Dystonia
Dystonia
Dystonia

BG
PT
temporal
PT
PT
GP, PT
GP, PT
PT, CN

98.4%(M)
homoplasmy
homoplasmy
homoplasmy
homoplasmy
87%(M)
61%(M)
homoplasmy

2y

PT, CN

99%(B)

M
F
F
F
F
F
F
F
M
M
F
F
M

13y
32y
?
5y
42y
19y
34 m
8y
19y
16y
4y
4y
4y

Dystonia, corticospinal tract dysfunction,
ophthalmoplegia
Dystonia, intellectual impairment
LHON
LDYT
Dystonia
LHON
LHON
Dystonia
Dystonia
LHON, hearing loss
LHON
LDYT
LDYT
LDYT

M
M
M
M
M
M
F
F
M
M
F
F
F

16y
17y
17y
3y
9m
3m
6m
2m
18y
6m
3y
1y
15y

LHON
LHON
LHON
LDYT
LS
LS
LS
LS
LHON+LL
LS
LS
LS
LDYT, MELAS

Kurt et al. [17]

Italian-American

Kim et al. [7]

Korea

Jun et al. [2]

Hispanic

Shoffner et al.[5]

Tarnopolsky
et al.[18]
Watanabe
et al.[19]
Saracchi et al.[20]

African-American
Caucasian
Caucasian

Japanese
Not documented

Cui et al.[21]

Chinese

Kirby et al.[8]

Not documented

Ronchi et al.[9]
Funalot et al.[22]
Lee et al.[23]
Wei et al.[24]
Yu et al.[25]
This study

Caucasian
Caucasian
Korea
Chinese
Chinese
Chinese

99%(B)
73%(B)
BG
PT, CN
GP, PT, CN
PT
normal
PT
PT, CN
PT, CN

homoplasmy
50%(B)
homoplasmy
50%(M)
34%(B)
18%(B)
26%(B)

homoplasmy

heteroplasmy
heteroplasmy
homoplasmy
BG
homoplasmy
BG
95%(F)
97%(M)
BG, T, P, MB
97%(M)
BG, T, MB homoplasmy
MB, 3 V
40%(B)
BS, BG
MB, BG
93%(B)
BG
96%(B)
C, PT
39%(B)

M, male; F, female; y, year; m, month; GP, globus pallidus; PT, putamen; CN, caudate nucleus; BG, basal ganglia; P, pons; MB, midbrain; T, thalamus;
WM, white matter; 3 V, near third ventricle; BS, brain stem; C, cerebral cortex; B, blood; M, muscle; F, fibroblast; LL, Leigh-like; NF1, neurofibromatosis
type 1

focal to generalized [5, 7, 13, 14, 16, 17]. Brain MRI of the
patients with m.14459G>A related dystonia may show symmetrical lesions in the putamen, caudate nucleus, or globus
pallidum [2, 5, 7, 13–18].

LDYT is an association of LHON with progressive dystonia. The most frequent genetic defect in LDYT was
m.14459G>A mutation. As mentioned above, in LDYT, the
involvement of visual pathway was generally later in contrast

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to that occurred in the early-onset childhood dystonia [19, 20].
LDYT patients harboring m.14459G>A mutation usually exhibited the characteristic neuroradiological findings of abnormal signal intensity in the bilateral striatum [19–21]. Unlike
the typical cases in literature, our present proband developed
vision decline at age 15 and dystonia at 18. The dystonia
didn’t significantly affect her daily life currently at age 23.
Apart from juvenile-onset LHON and late-onset dystonia,
she presented with seizures in adulthood without cognitive
dysfunction. The lactate level of cerebrospinal fluid was elevated. Additionally, the brain MRI showed only abnormal
signals in the bilateral precentral gyri/cortex without basal
ganglia involvement at the early stage and the hyperintense
signals on DWI that lasted for more than 3 months. The symmetrical lesions in bilateral putamen appeared later; meanwhile, the previous lesions in precentral gyri turned to be
isointense on DWI. Therefore, this patient was diagnosed with
LDYT overlapping MELAS.
In our present study, the genetic sequencing confirmed the
heteroplasmic m.14459G>A mutation in MT-ND6 gene, with
a mutant load of 39.1% in the proband’s blood. This mutation
alters the structure of ND6 polypeptide and leads to the incorrect assembly of MRC complex I subunits, affecting the electron transfer function of complex I in oxidative phosphorylation. By fusing the cytoplasts from Epstein-Barr virus-transformed lymphoblast cell lines to mtDNA-less ρ0 cell lines,
Jun et al. found a reduction in complex I activity of cybrids
harboring the m.14459G>A mutation and speculated that the
mutation might alter the coenzyme Q-binding site of complex
I through polarographic and kinetic analysis [27]. As shown in
Fig. 4, we found decreased complex I activity in the proband’s
immortalized lymphoblastic cells, in accord with the result of
the previous study [27].
Our present study found that the proband’s mother (II5)
manifested a mild visual disturbance with optic atrophy, and
the little brother (III3) was asymptomatic. Gene analysis identified the heteroplasmy of m.14459G>A mutations at levels of
13.5% and 15.5% in their blood, respectively. The low mutant
load might contribute to the phenotypic heterogeneity.
However, this threshold effect of mutation rate cannot
completely explain their phonotypic manifestations, since
some of the other carriers with homoplasmic m.14459G>A
mutation reported in literature were asymptomatic. The
heteroplasmy level of m.14459G>A mutation in some other
affected tissues such as optic nerve pathway and basal ganglia
would be informative but was unknown in our present study
yet. In literature, the reported carriers with m.14459G>A mutation from different races had various mtDNA haplotypes,
nuclear genetic background, and environment factors, which
may modify the clinical presentations as well [9, 22].
Also in our present study, a novel m.6064A>T mutation in
MT-CO1 gene was found in samples extracted from the proband, her mother and little brother. The m.6064A>T mutation

can lead to the substitution of tyrosine to phenylalanine at the
54 amino acid in COI subunit of MRC complex IV. This
mutation was relatively conserved in species, but the activity
of complex IV in immortalized lymphoblast was not decreased. And actually, the unaffected brother harbored almost
homoplasmic m.6064A>T mutation. Therefore, the
m.6064A>T mutation in itself may be non-pathogenic. In addition, this mutation is not a haplogroup-defining variant
which appears to have an effect on the penetrance of LHON.
However, the potential pathogenic role of the secondary mutation cannot be completely ruled out. It is reported that some
secondary mutations may have additive and synergetic effects
on the phenotype of the primary pathogenic mutations [28,
29]. Hence, the potential pathogenic effect of m.6064A>T
mutation still needs to be explored.

Conclusion
In conclusion, we reported a unique overlapping phenotype of
LDYT and MELAS with m.14459G>A mutation in a Chinese
family. The decreased activity of MRC complex I was involved in the mechanism of this particular phenotype. In addition, the co-existing m.6064A>T mutation might influence
the clinical phenotype with m.14459G>A mutation, which
needs to be elucidated in future studies.

Supplementary Information The online version contains supplementary
material available at https://doi.org/10.1007/s10072-021-05155-9.
Acknowledgments The authors thank the proband and her family for
giving consent, samples, and additional information for this study.
Funding This work was supported by the National Natural Science
Foundation of China (No. 81671235 and No. 81701237), People's benefit
project of science and technology in Qingdao (16-6-2-1-nsh), Qingdao
Key Health Discipline Development Fund and the Taishan Scholars
Program of Shandong Province.

Declarations
Conflict of interest The authors declare no competing interests
Ethical approval None

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