|

Revised: 23 December 2018

|

Accepted: 2 January 2019

ORIGINAL ARTICLE

AARS2 leukoencephalopathy: A new variant of mitochondrial
encephalomyopathy
Yi Tang1

|

Qi Qin1

|

1

Innovation Center for Neurological
Disorders, Department of Neurology, Xuan
Wu Hospital, Capital Medical University,
Beijing, China
2

Center of Alzheimer's Disease, Beijing
Institute for Brain Disorders, Beijing
Key Laboratory of Geriatric Cognitive
Disorders, Neurodegenerative Laboratory
of Ministry of Education of the People's
Republic of China, Beijing, China
Correspondence
Yi Tang, Department of Neurology &
Innovation center for neurological disorders,
Xuan Wu Hospital, Capital Medical
University, Beijing, China.
Email: [email-masked]
and
Qi Qin, Innovation Center for Neurological
Disorders, Department of Neurology, Xuan
Wu Hospital, Capital Medical University,
Beijing, China.
Email: [email-masked]
Funding information This study was
supported by National Key R&D Program
of China (2017YFC1310102) and National
Natural Science Foundation of China
(81671040).

Yi Xing1

|

Dongmei Guo1

|

Li Di1

|

Jianping Jia1,2

Abstract
Background: Mutations in the mitochondrial alanyl‐transfer (t)RNA synthetase 2
(AARS2,OMIM:612035) have been linked to leukoencephalopathy recently. Till
now, there have been 19 cases reported so far. However, the clinical and genetic
characteristics of this disease are not fully understood. We reported an adult‐onset
male leukoencephalopathy patient related to novel AARS2 gene mutations and reviewed all previous cases regarding the clinical and genetic features of AARS2
leukoencephalopathy.
Methods: The spectrum of clinical symptoms and the genetic analysis of the presented patient were identified and investigated. Besides this case, we assessed previously reported cases with AARS2 gene mutations.
Results: Here, we present a 30‐year‐old man with progressive motor deficits in the
right lower limb and severe cerebellar ataxia for one year. MRI revealed extensive
white matter lesions in periventricular regions and along the corticospinal tract.
Genetic analysis revealed two new heterogeneous missense mutations in AARS2:
c.179C>A and c.1703_1704del. We described the ragged red fiber (RRF) for the
first time, suggesting that AARS2‐related leukoencephalopathy be a new variant of
mitochondrial encephalomyopathy. Gradual improvement in motor function was observed with intravenous coenzyme complex treatment. We also summarized our case
and all previously reported cases to provide an overview of AARS2‐related late‐onset
leukoencephalopathy. Then, we compared clinical and neuroimaging features of
AARS2‐related leukoencephalopathy with three other frequently diagnosed types of
adult‐onset leukoencephalopathy to provide insight into diagnostic strategies.
Conclusion: The characteristic MRI abnormalities and clinical symptoms described
here may help to distinguish AARS2‐related leukoencephalopathy from other adult‐
onset leukoencephalopathies. The combination of encephalopathy and myopathy
strongly suggest that AARS2‐related leukoencephalopathy is a new variant of mitochondrial encephalomyopathy. The response to coenzyme complex will shed light
on future therapy investigation.
KEYWORDS
AARS2 leukoencephalopathy, alanyl‐transfer (t)RNA synthetase 2, leukoencephalopathies, mitochondrial
encephalomyopathy

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original
work is properly cited.
© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
Mol Genet Genomic Med. 2019;7:e582.		
https://doi.org/10.1002/mgg3.582

wileyonlinelibrary.com/journal/mgg3

| 1 of 12

|   

2 of 12

1

|

IN TRO D U C T ION

Adult‐onset leukoencephalopathies are a rare group of neurological diseases disorders characterized by progressive
degeneration of cerebral white matter (Euro et al., 2015).

TANG et al.

They are associated with a variety of clinical phenotypes
dominated by dementia, psychiatric changes, movement
disorders, and upper motor neuron signs (Lakshmanan
et al., 2017). The differential diagnosis of adult‐onset leukoencephalopathies is often challenging due to the high

F I G U R E 1 Brain MRI scans of patients with various types of leukoencephalopathy. (a) Brain MRI of P20 (the presented case) with AARS2‐
related leukoencephalopathy. T1‐weighted, T2‐weighted, axial scans show symmetrical and extended white matter abnormalities at bilateral
periventricular areas and corpus callosum involvement mainly in the posterior part. Fluid‐attenuated inversion recovery (FLAIR)‐weighted, axial
scans present symmetrical, longitudinal, striped, and intense signals present on both sides of the corticothalamic level. The diffusion‐weighted
image (DWI) and apparent diffusion coefficient (ADC) image show patchy areas of restricted diffusion in the abnormal white matter. PET MRI
of the patient shows that decreased metabolism is pronounced in the white matter lesions. (b) T2‐weighted, axial scans of Patient 3 at age 33 years
(left) demonstrates pronounced leukoencephalopathy at bilateral periventricular areas. Axial T2‐weighted MRI of Patient 4 at age 24 years
(middle) shows that abnormal signals are found in the frontal and parietal lobe white matter and the pyramidal tract at the internal capsule. FLAIR
MRI image of Patient 7 at age 30 (right) shows that the affected white matter is rarefied. (c) In a patient with ALSP (left), axial T2‐weighted
MRI shows confluent slightly asymmetric frontoparietal‐predominant white matter hyperintensity, with more atrophy compared with AARS2
leukoencephalopathy. In a patient with X‐ALD (middle), axial postgadolinium contrast sequences show diffuse white matter signal T2‐weighted
hyperintensity and volume loss of the posterior frontal, posterior callosal and parieto‐occipital regions. In a patient with MLD (right), an axial
T2‐weighted sequence demonstrates widespread symmetrical white matter signal hyperintensity sparing the subcortical U fibers and radiating
transmedullary bands

TANG et al.

heterogeneity of etiologies (Lakshmanan et al., 2017). With
advances in the genetic testing, several causative gene mutations have been shown to be responsible for the etiology
of adult‐onset leukoencephalopathies (Lynch et al., 2017;
Renaud, 2012). Of these gene mutations, mitochondrial
alanyl‐tRNA synthetase 2 gene (AARS2, OMIM:612035)
is a nuclear gene, accounting for AARS2 loading of alanine onto tRNA during mitochondrial translation. AARS2
mutations can result in two very different phenotypes with
different tissue involvement: some mutations particularly
affect the heart (Calvo et al., 2012; Gotz et al., 2011), thus
producing a fatal, early‐onset cardiomyopathy, whereas
others are associated with late‐onset leukoencephalopathy
without cardiac involvement, and ovarian failure also been
described in female.

  

| 3 of 12

Leukoencephalopathy due to AARS2 mutations is a syndrome with progressive cerebral white matter degeneration
(Kaye & Moser, 2004). Since first identified in 2014, only
19 AARS2‐related leukoencephalopathy cases have been
reported in English literature until now (Dallabona et al.,
2014; Dong et al., 2018; Hamatani et al., 2016; Lee et al.,
2017; Peragallo, Keller, van der Knaap, Soares, & Shankar,
2018; Szpisjak et al., 2017; Taglia et al., 2018). Owing to
the low number of known cases, most clinicians have limited knowledge about the clinical presentation and neuroimaging features of AARS2‐related leukoencephalopathy.
In addition, there are many different kinds of leukoencephalopathies, which makes a definitive diagnosis difficult.
Here, we report the first description of typical ragged red
fiber (RRF) identified by muscle biopsy in a male patient

F I G U R E 2 Muscle biopsy and genetic analysis of our patient. (a) Morphologic analysis of muscle biopsy, with succinate dehydrogenase
(SDH) staining, hematoxylin‐eosin staining (HE) and Gomori trichrome (GT) staining. A typical RRF was indicated by arrow. (b) Sequencing of
AARS2 in the presented case shows both mutations c.179C>A and c.1703_1704del

Sex

Female

Male

Female

Female

Female

Female

Female

Male

Female

Male

Male

Male

P1

P2

P3

P4

P5

P6

P7

P8

P9

P10

P11

P12

15

Mid 20s

Late
30s

40

27

30

22

40

15

33

7

15

Age at
onset
(years)

Cognitive decline
and psychosis

Rapid motor
decline

Cognitive decline

Anxiety and
cognitive decline

Psychosis

Cognitive decline
and psychosis

Spastic paraparesis and
depression

Cognitive decline
and depression

Tremor

Cognitive decline
and depression

Ataxia

Gait ataxia,
cognitive
decline, tremor

First neurological symptoms

+

+

−

−

+

−

+

−

+

+

+

+

Cerebellar
symptoms

+

+

+

+

+

+

−

+

+

+

+

+

Cognitive
impairment

+

+

−

−

+

+

+

+

+

+

−

+

Psychiatric
symptoms

Clinical and genetic characteristics of patients with AARS2‐mutations reported in literature

Case
number

TABLE 1

+

+

−

+

+

+

+

−

+

+

−

Pyramidal
signs

Male

Male

Male

+

Male

+

+

+

+

+

Male

+

Ovarian
failure

c.892_894del;
c.2234_2235
del

c.1188G>A*;
c.1709delG

c.1188G>A*;
c.1709delG

c.1041‐1G>A*;
c.595C>T

c.578T>G;
c.595C>T

c.1145C>A;
c.2255 + 1G>
A*

c.595C>T;
c.2611dup

c.595C>T;
c.390_392del

c.230C>T;
c.595C>T

c.1609C>T &
c.2350del;
c.595C>T

c.2893G>A;
c.1213G>A

c.149T>G;
c.1561C>T

AARS2
mutation

p.298_298delGln;
p.Ser745Cysfs*60

p. Gly570Afs*21

p. Gly570Afs*21

p. Arg199Cys

p.Leu193a;
p.Arg199Cys

p.Thr382Lys

p.Arg199Cys;
p.Thr871Asnfs*21

p.Arg199Cys;
p.Phe131del

p.Ala77Val;
p.Arg199Cys

p.Gln537 &
p.Glu784Serfs*9;
p.Arg199Cys

p.Gly965Arg;
p.Glu405Lys

p.Phe50Cys;
p.Arg521a

Amino acid change

11

11

11

11

10

9

8

8

8

8

8

8

(Continues)

Reference

4 of 12

|   
TANG et al.

Sex

Male

Male

Female

Female

Female

Female

Male

Male

P13

P14

P15

P16

P17

P18

P19

P20

29

35

33

23

32

44

17

Mid 40s

Age at
onset
(years)

(Continued)

Case
number

TABLE 1

Axatia

Dystonia

Ovarian failure
and cognitive
decline

Ataxia and spastic
gait

Cognitive decline

Gait ataxia and
cognitive decline

Tremor

Right upper limb
dystonia

First neurological symptoms

+

+

−

+

−

+

+

−

Cerebellar
symptoms

+

+

+

−

+

+

+

+

Cognitive
impairment

−

−

−

−

−

−

+

+

Psychiatric
symptoms

+

+

+

+

−

+

+

+

Pyramidal
signs

Male

Male

+

+

+

+

+

Male

Ovarian
failure

c.179C>A;
c.1703_1704del

c.963C>A;
c.452T>C

c.963C>A;
c.452T>C

c.595C>T;
c.2611_2612
insA

c.595C>T;
c.236T>A

c.595C>T;
c.390_392del

c.2265dupA;
c.650C>T

c.595C>T
(homozygous)

AARS2
mutation

p.Arg199Cys;
p.Val730Met

Tyr321*;
p.Met151Thr

Tyr321*;
p.Met151Thr

p.Arg199Cys;
p.Thr871Asnfs

p.Arg199Cys;
p.Met79Lys

p.Arg199Cys;
p.Phe131del

p.Arg756 fs;
p.Pro217Leu

p. Arg199Cys

Amino acid change

Presented
case

12

12

14

14

14

13

11

Reference

TANG et al.
  

| 5 of 12

+

+

+

P18

P19

P20

+

+

P16

+

P15

P17

+

+

P13

P14

+

−

P11

+

P10

P12

−

−

+

P7

P8

+

P6

P9

+

+

P3

+

+

P2

P4

+

P1

P5

White Matter
Rarefaction

Case
number

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

Corticospinal
Tracts

+

+

+

−

−

+

+

+

+

+

+

+

−

+

−

−

−

+

+

+

Corpus
Callosum

+

−

−

−

+

−

+

−

+

−

−

+

−

+

−

−

−

−

−

+

Atrophy

Clinical examinations of patients with AARS2‐mutations

MRI abnormalities

TABLE 2

+

−

−

−

−

+

−

−

−

−

−

−

−

+

−

−

−

+

−

−

U‐fibers

Normal

Normal

Normal

n.i.

n.i.

n.i.

Normal

Normal

Normal

Normal

Normal

n.i.

Normal

Normal

n.i.

n.i.

n.i.

n.i.

n.i.

Normal

Cardiac
ultrasound

Normal

n.i.

n.i.

n.i.

n.i.

Normal

Normal

Normal

Normal

Normal

Normal

n.i.

Normal

Normal

Normal

n.i.

n.i.

Normal

Normal

Normal

ECG

Typical RRF

n.i.

n.i.

n.i.

n.i.

n.i.

n.i.

n.i.

n.i.

n.i.

n.i.

n.i.

n.i.

Normal

Isolated COX
deficiency

n.i.

n.i.

n.i.

n.i.

Isolated COX
deficiency

Muscle biopsy

Increased

n.i.

n.i.

n.i.

n.i.

n.i.

Normal

Normal

Normal

Normal

Normal

Increased

n.i.

n.i.

n.i.

n.i.

Normal

Normal

Normal

Normal

Plasma
lactate level

Normal

n.i.

n.i.

n.i.

n.i.

n.i.

Normal

Normal

Normal

Normal

Normal

Low estradiol, FSH & LH↑

Normal

Normal

low estradiol, normal FSH &LH

FSH, LH and prolactin↑

FSH & LH↑

Low estradiol, FSH & LH↑

n.i.

Low estradiol, FSH & LH↑

Sex hormone levels

6 of 12

|   
TANG et al.

  

TANG et al.

with AARS2‐related leukoencephalopathy, suggesting that
AARS2‐related leukoencephalopathy be a new variant of mitochondrial encephalomyopathy. We summarized the main
findings of our case and all previously reported 19 cases to
provide an overview of the genetic, clinical, and neuroimaging characteristics of AARS2‐related late‐onset leukoencephalopathy. Then, we compared clinical and neuroimaging
features of AARS2‐related leukoencephalopathy with three
other frequently diagnosed types of adult‐onset leukoencephalopathy to provide insight into diagnostic strategies.

2

|

CA S E RE P O RT

A 30‐year‐old Chinese man was admitted with complaints of
progressive motor deficits in the right lower limb for 1 year
and dysarthria for 2 months. The patient's motor symptoms
had developed 1 year earlier, along with an unsteady gait.
Subsequently, he had gradually developed weakness and
numbness of the right limbs, rigidity and aphasia, with occasional dysphagia and dysarthria. The patient had a 6‐year
history of drug abuse and had taken methamphetamine on
ten occasions in the previous 6 months. His symptoms were
considered to be encephalopathia toxica in a local hospital
and were treated with 500 mg of methylprednisolone per day
followed by 30 mg prednisone per day. No improvement
was observed. There was no family history of cerebellar
symptoms.
Neurological examination revealed normal mental status
and normal cranial nerve functions. The strength of the right
lower limb was 4/5 with brisk tendon reflexes, bilateral ankle
clonus, and bilateral Rossolimo and Chaddock signs. The patient also showed spastic gait and positive Romberg's sign,
with slight decrease in pinprick sensation in the lower extremities. The patient was unable to perform the finger‐nose
tests and rapid alternating movements.
Laboratory evaluation showed normal routine studies.
Examination of the cerebrospinal fluid revealed 507.7 mg/dl
protein (normal range 15–45 mg/dl) and normal IgG index.
Autoimmune, infectious, endocrinologic, neoplastic, and
paraneoplastic screenings were unremarkable. However,
serum levels of alanine aminotransferase and lactic acid
(instant state, resting state, 1 min, and 10 min) were all increased. Brain magnetic resonance imaging (MRI) showed
abnormal signals in the bilateral periventricular white matter,
the posterior part of the corpus callosum and symmetrically
along the corticospinal tract without gadolinium enhancement. In addition, a thin posterior corpus callosum, enlarged
lateral ventricle, and widened bilateral parietal sulcus were
demonstrated. The diffusion‐weighted image (DWI) shows
patchy areas of restricted diffusion in the abnormal white
matter, confirmed by low signal of the corresponding areas on
the apparent diffusion coefficient (ADC) map. The restricted

| 7 of 12

diffusion areas exist for more than 1 year. PET‐MRI showed
hypometabolism in the posterior part of the cerebral white
matter (Figure 1a). A typical RRF was identified in muscle
biopsy for the first time (Figure 2a).
Targeted gene sequencing of AARS2 identified two variations: c.179C>A and c.1703_1704del (Figure 2b). These two
mutations have not been previously described, and they were
not found in the ExAC database (http://exac.broadinstitute.
org/gene). The patient was compound heterozygote for these
pathogenic mutations, which were transmitted maternally
and paternally, respectively (Figure 2b).
The treatment was generally supportive. After the application of intravenous coenzyme complex 200 U one time per
day for 10 days, the patient showed gradual improvement in
motor function. He could walk 1,000 m alone and remained
stable on six‐month follow‐up. However, the patient showed
rapidly deterioration of cerebellar ataxia and motor deficits
in 1 year.

3

|

LITERATURE REVIEW

To date, AARS2 mutations have been reported in 19 patients with late‐onset leukoencephalopathy. To provide an
overview of the clinical characteristics of AARS2‐related
late‐onset leukoencephalopathy, we searched the MEDLINE
database to October 2018 using the terms “AARS2” or “alanyl‐tRNA synthetase 2 gene” and reviewed all identified articles and articles referenced therein, including non‐English
articles (Dallabona et al., 2014; Dong et al., 2018; Hamatani
et al., 2016; Lee et al., 2017; Peragallo et al., 2018; Szpisjak
et al., 2017; Taglia et al., 2018). We identified 19 previous
cases and combined them with the current case to provide a
summary of the genetic, clinical, and neuroimaging features
of AARS2‐related leukoencephalopathy.

3.1

|

Clinical features

The detailed clinical features of the case presented here and
the previously reported patients (9 males and 11 females) are
summarized in Table 1. The patients had adult‐onset signs
of neurologic deterioration with an average age of onset of
27.3 years. All 20 patients exhibited rapid deterioration after
onset. Psychiatric symptoms, such as changes in personality, delusions, anxiety and depression, usually preceded
neurological symptoms. The neurological dysfunctions are
composed of motor deterioration, including cerebellar ataxia
and pyramidal signs, and progressive cognitive decline with
features of frontal lobe dysfunction, such as poor attention,
inactivity, and other neurological changes. Among these
symptoms, cognitive decline was the most frequent (18
patients [90%]). Pyramidal signs (15 patients [75%]) and
cerebellar ataxia (13 patients [65%]) were also prominent

|   

TANG et al.

−
−

−

+

+

+

−

+
+

−
−

−

−
−

−
+

−

Visual
involvement

3.2

+
+
+
+
ARSA
AR
Up to
70 years
MLD

2/million,
20% adult
onset

+

−
−
+
−
ABCD1
X linked
Childhood
to
adulthood
X‐ALD

Up to 40/
million,
5% adult
onset

+

−
+
+
CSFR1
AD
Mean
40 years
ALSP

52 reported
cases

+

+

−
+
+
+
+
AARS2
AR
20 reported
cases
Mean
20 years
AARS2‐L

Inheritance
Disorder

Prevalence

Cognitive
involvement

|

Genetic analysis

|

Neuroimaging features

Genetic analysis revealed that in all 20 cases the mutations
followed autosomal recessive inheritance. Nineteen patients
were compound heterozygotes for AARS2 mutations and only
one male patient was homozygous. The pathogenic gene mutations were derived from the paternal and maternal side.
All nucleotide and amino acid changes are summarized in
Table 1. Among these nucleotide changes, c.595C>T was
the most common (nine patients). The most prominent amino
acid changes were p.Arg199Cys. P20 (the present case) carried two new heterogeneous missense mutations, c.179C>A
and c.1703_1704del.

3.3

Affected
gene(s)

Movement
disorder

Pyramidal
weakness/
spasticity

Cerebellar
ataxia

Peripheral
neuropathy

Psychiatric
symptoms

+

−

−

clinical features. Psychiatric dysfunction, such as anxiety
and depression (11 patients [55%]), was often observed. All
women with the condition had primary or secondary amenorrhea related to ovarian failure. General physical examination
usually revealed no abnormalities and no evidence of cardiac
dysfunction.

Age of
onset

TABLE 3

Clinical features of patients with AARS2‐mutations and other common types adult‐onset leukoencephalopathies

Primary/
secondary
amenorrhea

Adrenal
insufficiency

Hyper‐pigmentation

8 of 12

The MRI abnormalities of the 20 patients are summarized
in Table 2. All patients exhibited T2‐W hyperintense, T1‐W
hypointense white matter signal abnormalities. Typically,
the abnormalities were predominantly present in the frontal
and parietal periventricular and deep white matter, sparing
a segment of white matter in between. White matter structures were affected in a tract‐like manner, with involvement
of interhemispheric connections through the corpus callosum
and descending pathways. The cases with involvement of the
corpus callosum may show either a single lesion in the splenium or the entire corpus callosum in an inhomogeneous
manner. Among the other patients, the lesion involved the
entire corpus callosum in an inhomogeneous manner. The
abnormalities were confined to white matter structures and
were progressive over time. No gadolinium enhancement
was observed. Cerebellar atrophy was variable, and cerebral
atrophy, if present, was mild.

3.4 | Muscle biopsy and cardiac
function analysis
Morphologic analysis of muscle biopsy and cardiac function
analysis of the patients with AARS2 mutations are summarized
in Table 2. Cardiac ultrasonography and electrocardiogram
revealed no evidence of cardiac dysfunction. Patients P1, P6,
P7, and P20 (the presented case) underwent skeletal muscle
biopsy to further investigate possible mitochondrial defects.
Patients P1 and P6 showed isolated cytochrome c oxidase
deficiency. Our group identified a typical RRF in the patient
with AARS2‐related leukoencephalopathy for the first time.

  

TANG et al.

TABLE 4

Neuroimaging features of AARS2‐related leukoencephalopathy and three other common adult‐onset leukodystrophies
Pattern of white matter
involvement

Findings in the
corpus callosum

Atrophy

Symmetry

Unique MRI features

AARS2‐L

Predominantly frontoparietal periventricular

Atrophy in the
posterior part

Mild cerebral and cerebellar
atrophy

Symmetric

White matter
rarefaction

ALSP

Predominantly frontoparietal periventricular

Thinning

Prominent cerebral atrophy

Asymmetric

Calcifications

X‐ALD

Predominantly
parieto‐occipital

Atrophy in the
splenium

Spinal cord atrophy

Asymmetric

Contrast enhancement

MLD

Predominantly frontal
periventricular

Thinning

Cerebral atrophy

Symmetric

Spared U fibers

Disorder

|

3.5

Laboratory findings

The laboratory findings, including the results of routine hematology and biochemistry tests, were normal among all 20
patients (Table 2). None of the patients had elevated CSF lactate levels; however, patients P9 showed increased plasma
levels of lactate. Most women with ovarian failure showed
low estradiol levels and high levels of follicle‐stimulating
hormone (FSH) and luteotropic hormone (LH).

4

| 9 of 12

|

D IS C U SSION

Herein, we present the case of a 30‐year‐old man with
progressive motor deficits in the right lower limb and severe cerebellar ataxia for 1 year. MRI revealed extensive
white matter lesions in bilateral periventricular regions
and the posterior part of corpus callosum and along the
corticospinal tract. Genetic analysis revealed two new
heterogeneous missense mutations in AARS2: c.179C>A
and c.1703_1704del. The serum lactic acid level was elevated. It is noteworthy that this is the first reported case
of AARS2‐related leukoencephalopathy with a typical RRF
identified by muscle biopsy.
As AARS2‐related encephalopathy is a newly reported
encephalopathy, clinicians have scant knowledge about the
clinical presentation and neuroimaging features. By reviewing all published cases, the following findings are strongly
indicative of AARS2‐related leukoencephalopathy: late‐onset
and rapidly progressing encephalopathy; cerebellar ataxia
and cognitive decline; white matter signal abnormalities in
periventricular regions, posterior part of the corpus callosum
and symmetrically along the corticospinal tract. In the presence of these symptoms, the diagnosis should be confirmed
by genetic analysis.
Adult onset leukoencephalopathy is a category of neurological disorders with high heterogeneity. It is always
difficult to make definite diagnosis, even for experienced
neurologists. Therefore, we compared AARS2‐related
leukoencephalopathy with three other types of common

adult‐onset leukoencephalopathies to provide insight into
diagnostic strategies, including leukoencephalopathy
with axonal spheroids and pigmented glia (ALSP) (Lynch
et al., 2016), X‐linked adrenoleukodystrophy (X‐ALD)
(Mirabella, Di Giovanni, Silvestri, Tonali, & Servidei,
2000), and metachromatic leukodystrophy (MLD) (Taylor
et al., 2014) (Table 3). ALSP is the most common adult‐
onset leukoencephalopathy caused by autosomal dominant mutations in the colony‐stimulating factor receptor 1
(CSF1R) gene. Mutations in the CSF1R gene occur in the
tyrosine kinase domain of the CSF1R, which is primarily
expressed in the microglia in the CNS, and result in microglial dysfunction in ALSP. X‐ALD is caused by mutations in
the ABCD1 gene encoding the adrenoleukodystrophy protein (ALDP). X‐ALD is an X‐linked disorder that results
from a deficient very‐long‐chain fatty acid transport protein on the surface of the peroxisome. The adult‐onset form
accounts for 5% of all X‐ALD patients. Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal
disorder owing to ARSA gene mutations resulting in deficiency of the enzyme arylsulfatase A (ASA). The adult
form accounts for approximately 20% of all MLD cases.
ALSP has a relatively late onset, typically occurring in the
fifth decade, as opposed to AARS2, for which the disease
onset tends to occur in the third decade of life. Men and
women with adult‐onset X‐ALD may remain asymptomatic
into the fourth and sixth decade of life, respectively. The
age of MLD's onset can be up to 70 years. The course after
deterioration onset of ALSP and AARS2 is rapid; however, disease progression of X‐ALD and MLD is generally
slower, with death occurring after decades. Cognitive and
motor symptoms are the most common symptoms overall in all four leukoencephalopathies. Patients with ALSP
and AARS2 typically present with cognitive impairment
and gait problems first, then develop spasticity and ataxia.
Adult‐onset cerebral ALD usually presents with psychiatric
features followed by cognitive impairment, ataxia, movement disorders, and peripheral neuropathy. Adrenal insufficiency is also frequently associated with the condition.
The initial symptoms of MLD are often psychiatric and are

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followed by motor symptoms, including spastic paraparesis and cerebellar ataxia, then intellectual and cognitive
decline. MLD patients often experience other symptoms
late in life, including optic nerve atrophy and peripheral
neuropathy. All female patients with AARS2 mutation presented with ovarioleukodystrophy and ovarian failure, a
feature not seen in other leukoencephalopathies.
Brain MRI of all these leukoencephalopathies show confluent patterns of white matter lesions (van der Knaap, Breiter,
Naidu, Hart, & Valk, 1999; Schiffmann & van der Knaap,
2009) (Table 4). However, the predominant pattern is different. In AARS2‐related leukoencephalopathy and ALSP, white
matter changes are typically seen in the frontal and parietal
periventricular region, whereas white matter abnormalities
are usually seen in occipital regions in X‐ALD and frontal
regions in MLD. Corpus callosum involvement is present in
all diseases. Cerebral and cerebellar atrophy are prominent in
ALSP and MLD and are disproportionately mild in AARS2.
Spinal cord atrophy may develop in X‐ALD. The distribution
of white matter lesions is symmetric in AARS2 and MLD
and asymmetric in ALD and ALSP. Each leukoencephalopathy has a unique pattern of MRI‐abnormalities. ALSP occasionally shows calcifications in the frontal periventricular
white matter. In cerebral ALD, contrast enhancement at the
periphery of the white matter lesions is characteristic. The
subcortical U‐fibers are typically spared in MLD. AARS2‐related leukoencephalopathy is associated with white matter
rarefaction, which suppresses on a FLAIR image, a feature
not seen in other leukoencephalopathies.
The pathogenesis of AARS2‐related encephalopathy is not
clear yet. Here, for the first time we reported a typical RRF
identified by muscle biopsy in a patient with AARS2‐related
leukoencephalopathy, which suggests that AARS2‐related
leukoencephalopathy might be a new variant of mitochondrial encephalomyopathy. Mitochondrial encephalomyopathy is a heterogeneous group of disorders with various
biochemical defects in the respiratory chain (McFarland,
Taylor, & Turnbull, 2010; Shoubridge, 1998). Mutation of
AARS2, which is also a kind of mtARS mutation (Diodato,
Ghezzi, & Tiranti, 2014), may affect mitochondrial protein
synthesis and functioning of the respiratory chain, and thus
might cause a disorder of energy metabolism. Mitochondrial
encephalomyopathy can lead to a wide range of nervous system and muscle disorders (Moulinier, Ripp, Castillo, Poch,
& Sissler, 2017). The diagnostic workup routinely includes
skeletal muscle biopsies and genetic studies (Bernier et al.,
2002; Bourgeois & Tarnopolsky, 2004). Isolated cytochrome
c oxidase (COX) deficiency and typical RRF could be shown
in the skeletal muscle biopsy of mitochondrial encephalomyopathy (Holt, Harding, & Morgan‐Hughes, 1988; Shy, 1964).
COX is a multimeric inner mitochondrial membrane enzyme
formed by subunits encoded by nuclear or mitochondrial genomes. The RRF is the histological hallmark of abnormal

TANG et al.

mitochondria proliferation in muscle fibers. Identification
of any RRF in an individual aged <30 years is indicative of
mitochondrial disease and can be regarded as a diagnostic
indicator of myopathy. All of these findings strongly suggest
that AARS2‐related leukoencephalopathy is a new variant of
mitochondrial encephalomyopathy.
Genetic analysis demonstrated that the mutations in all 20
cases followed autosomal recessive inheritance, and 19 patients were compound heterozygotes for AARS2 mutations.
To date, AARS2 mutations have been reported among patients
with infantile mitochondrial hypertrophic cardiomyopathy
with early fatal outcomes, and patients with late‐onset leukoencephalopathy. Therefore, the question arises as to why
AARS2 mutations cause two very different subtypes with
distinct systemic involvement. Euro et al. (Euro et al., 2015)
have provided an elegant explanation for this phenomenon.
In addition to the aminoacylation domain and the C‐terminal
domain (Guo et al., 2009), AARS2 also has an editing domain
that can deacylate mischarged amino acids. None of the missense mutations identified in patients with adult‐onset leukoencephalopathy were in the editing domain, whereas at least
one c.1774C>T mutation in the editing domain was present in
patients with infantile‐onset cardiomyopathy (Scheper et al.,
2007). The difference in the location of AARS2 missense mutations leads to different aminoacylation activity, such that
cardiomyopathy results from a severe decrease in aminoacylation activity, and leukoencephalopathy results from only a
moderate decrease. The location of the mutations in P20 (the
present case) is consistent with this hypothesis.

5

|

CONCLUSIONS

In conclusion, we report an AARS2‐related leukoencephalopathy case with typical RRF for the first time. On the basis
of reviewing all known cases, the following findings are
strongly indicative of AARS2‐related leukoencephalopathy:
late‐onset and rapidly progressing encephalopathy; progressive cognitive decline; cerebellar ataxia; white matter signal
abnormalities in the frontal and parietal periventricular regions, posterior part of the corpus callosum and symmetrically along the corticospinal tract; and amenorrhea secondary
to ovarian failure among affected women. In the presence of
these symptoms, the diagnosis should be confirmed by genetic analysis. Finally, on the basis of the combination of
encephalopathy, increased plasma lactate level, isolated cytochrome c oxidase deficiency and typical RRF in muscle
biopsy, we propose that AARS2‐related leukoencephalopathy is a new variant of mitochondrial encephalomyopathy.
Currently, there are no treatment options for AARS2 leukoencephalopathy. The good response to intravenous coenzyme
complex in our patient will shed light on future treatment
development.

  

TANG et al.

ACKNOWLEDGMENTS
The authors have declared that no conflicts of interest exist.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the
institutional and/or national research committee and with the
1964 Helsinki declaration and its later amendments or comparable ethical standards.
CONFLICT OF INTEREST
None declared.
ORCID
Qi Qin

https://orcid.org/0000-0002-3019-2061

R E F E R E NC E S
Bernier, F. P., Boneh, A., Dennett, X., Chow, C. W., Cleary, M. A., &
Thorburn, D. R. (2002). Diagnostic criteria for respiratory chain disorders in adults and children. Neurology, 59(9), 1406–1411. https://
doi.org/10.1212/01.WNL.0000033795.17156.00
Bourgeois, J. M., & Tarnopolsky, M. A. (2004). Pathology of skeletal
muscle in mitochondrial disorders. Mitochondrion, 4(5–6), 441–
452. https://doi.org/10.1016/j.mito.2004.07.036
Calvo, S. E., Compton, A. G., Hershman, S. G., Lim, S. C., Lieber, D.
S., Tucker, E. J., & Mootha, V. K. (2012). Molecular diagnosis of infantile mitochondrial disease with targeted next‐generation sequencing. Science Translational Medicine, 4(118), 118ra110. https://doi.
org/10.1126/scitranslmed.3003310
Dallabona, C., Diodato, D., Kevelam, S. H., Haack, T. B., Wong, L. J.,
Salomons, G. S., … van der Knaap, M. S. (2014). Novel (ovario)
leukodystrophy related to AARS2 mutations. Neurology, 82(23),
2063–2071. https://doi.org/10.1212/WNL.0000000000000497
Diodato, D., Ghezzi, D., & Tiranti, V. (2014). The mitochondrial aminoacyl tRNA synthetases: Genes and syndromes. Int J Cell Biol, 2014,
787956. https://doi.org/10.1155/2014/787956
Dong, Q., Long, L., Chang, Y.‐Y., Lin, Y.‐J., Liu, M., & Lu, Z.‐Q.
(2018). An adolescence‐onset male leukoencephalopathy with remarkable cerebellar atrophy and novel compound heterozygous
AARS2 gene mutations: A case report. Journal of Human Genetics,
63(7), 841–846. https://doi.org/10.1038/s10038-018-0446-7
Euro, L., Konovalova, S., Asin‐Cayuela, J., Tulinius, M., Griffin, H.,
Horvath, R., … Tyynismaa, H. (2015). Structural modeling of tissue‐specific mitochondrial alanyl‐tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation. Front Genet, 6,
21. https://doi.org/10.3389/fgene.2015.00021
Gotz, A., Tyynismaa, H., Euro, L., Ellonen, P., Hyotylainen, T., Ojala,
T., … Suomalainen, A. (2011). Exome sequencing identifies mitochondrial alanyl‐tRNA synthetase mutations in infantile mitochondrial cardiomyopathy. American Journal of Human Genetics, 88(5),
635–642. https://doi.org/10.1016/j.ajhg.2011.04.006
Guo, M., Chong, Y. E., Beebe, K., Shapiro, R., Yang, X. L., & Schimmel,
P. (2009). The C‐Ala domain brings together editing and aminoacylation functions on one tRNA. Science, 325(5941), 744–747. https://
doi.org/10.1126/science.1174343

| 11 of 12

Hamatani, M., Jingami, N., Tsurusaki, Y., Shimada, S., Shimojima, K.,
Asada‐Utsugi, M., … Yamamoto, T. (2016). The first Japanese case
of leukodystrophy with ovarian failure arising from novel compound
heterozygous AARS2 mutations. Journal of Human Genetics,
61(10), 899–902. https://doi.org/10.1038/jhg.2016.64
Holt, I. J., Harding, A. E., & Morgan‐Hughes, J. A. (1988). Deletions
of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature, 331(6158), 717–719. https://doi.
org/10.1038/331717a0
Kaye, E. M., & Moser, H. (2004). Where has all the white matter gone?
Unraveling the mysteries of leukoencephalopathies Neurology,
62(9), 1464–1465. https://doi.org/10.1212/WNL.62.9.1464
Lakshmanan, R., Adams, M. E., Lynch, D. S., Kinsella, J. A., Phadke,
R., Schott, J. M., … Davagnanam, I. (2017). Redefining the phenotype of ALSP and AARS2 mutation‐related leukodystrophy. Neurol
Genet, 3(2), e135. https://doi.org/10.1212/NXG.0000000000000135
Lee, J. M., Yang, H. J., Kwon, J. H., Kim, W. J., Kim, S. Y., Lee, E. M.,
… Jeon, B. (2017). Two Korean siblings with recently described ovarioleukodystrophy related toAARS2mutations. European Journal of
Neurology, 24(4), e21–e22. https://doi.org/10.1111/ene.13245
Lynch, D. S., Brandão, Rodrigues, de Paiva, A., Zhang, W. J., Bugiardini,
E., Freua, F., Tavares Lucato, L., … Houlden, H. (2017). Clinical
and genetic characterization of leukoencephalopathies in adults.
Brain, 140(5), 1204–1211. https://doi.org/10.1093/brain/awx045
Lynch, D. S., Zhang, W. J., Lakshmanan, R., Kinsella, J. A., Uzun,
G. A., Karbay, M., … Houlden, H. (2016). Analysis of mutations
in AARS2 in a series of CSF1R‐negative patients with adult‐
onset leukoencephalopathy with axonal spheroids and pigmented
glia. JAMA Neurology, 73(12), 1433. https://doi.org/10.1001/
jamaneurol.2016.2229
McFarland, R., Taylor, R. W., & Turnbull, D. M. (2010). A neurological
perspective on mitochondrial disease. The Lancet Neurology, 9(8),
829–840. https://doi.org/10.1016/S1474-4422(10)70116-2
Mirabella, M., Di Giovanni, S., Silvestri, G., Tonali, P., & Servidei, S.
(2000). Apoptosis in mitochondrial encephalomyopathies with mitochondrial DNA mutations: A potential pathogenic mechanism.
Brain, 123(Pt 1), 93–104. https://doi.org/10.1093/brain/123.1.
93
Moulinier, L., Ripp, R., Castillo, G., Poch, O., & Sissler, M. (2017).
MiSynPat: An integrated knowledge base linking clinical, genetic,
and structural data for disease‐causing mutations in human mitochondrial aminoacyl‐tRNA synthetases. Human Mutation, 38(10),
1316–1324. https://doi.org/10.1002/humu.23277
Peragallo, J. H., Keller, S., van der Knaap, M. S., Soares, B. P., &
Shankar, S. P. (2018). Retinopathy and optic atrophy: Expanding
the phenotypic spectrum of pathogenic variants in the AARS2 gene.
Ophthalmic Genetics, 39(1), 99–102. https://doi.org/10.1080/13816
810.2017.1350723
Renaud, D. L. (2012). Inherited leukoencephalopathies. Seminars in
Neurology, 32(1), 3–8. https://doi.org/10.1055/s-0032-1306380
Scheper, G. C., van der Klok, T., van Andel, R. J., van Berkel, C. G.,
Sissler, M., Smet, J., … van der Knaap, M. S. (2007). Mitochondrial
aspartyl‐tRNA synthetase deficiency causes leukoencephalopathy
with brain stem and spinal cord involvement and lactate elevation.
Nature Genetics, 39(4), 534–539. https://doi.org/10.1038/ng2013
Schiffmann, R., & van der Knaap, M. S. (2009). Invited article:
An MRI‐based approach to the diagnosis of white matter disorders. Neurology, 72(8), 750–759. https://doi.org/10.1212/01.
wnl.0000343049.00540.c8

12 of 12

|   

Shoubridge, E. A. (1998). Mitochondrial encephalomyopathies. Current
Opinion in Neurology, 11(5), 491–496. https://doi.org/10.1097/
00019052-199810000-00012
Shy, G. M. (1964). The value of the muscle biopsy (a Review of 2300
Confirmed Cases). Revista de Neuro‐Psiquiatría, 27, 238–245.
Szpisjak, L., Zsindely, N., Engelhardt, J. I., Vecsei, L., Kovacs, G. G.,
& Klivenyi, P. (2017). Novel AARS2 gene mutation producing
leukodystrophy: A case report. Journal of Human Genetics, 62(2),
329–333. https://doi.org/10.1038/jhg.2016.126
Taglia, I., Di Donato, I., Bianchi, S., Cerase, A., Monti, L., Marconi,
R., … Dotti, M. T. (2018). AARS2‐related ovarioleukodystrophy: Clinical and neuroimaging features of three new cases.
Acta Neurologica Scandinavica, 138(4), 278–283. https://doi.
org/10.1111/ane.12954
Taylor, R. W., Pyle, A., Griffin, H., Blakely, E. L., Duff, J., He, L., &
Chinnery, P. F. (2014). Use of whole‐exome sequencing to determine

TANG et al.

the genetic basis of multiple mitochondrial respiratory chain complex deficiencies. JAMA, 312(1), 68–77. https://doi.org/10.1001/
jama.2014.7184
van der Knaap, M. S., Breiter, S. N., Naidu, S., Hart, A. A., & Valk,
J. (1999). Defining and categorizing leukoencephalopathies of unknown origin: MR imaging approach. Radiology, 213(1), 121–133.
https://doi.org/10.1148/radiology.213.1.r99se01121

How to cite this article: Tang Y, Qin Q, Xing Y, Guo
D, Di L, Jia J. AARS2 leukoencephalopathy: a new
variant of mitochondrial encephalomyopathy. Mol
Genet Genomic Med. 2019;7:e582. https://doi.org/10.
1002/mgg3.582