A homozygous mutation of alanyl‐transfer RNA synthetase 2 in a patient of adult‐onset leukodystrophy: A case report and literature review

Abstract Introduction Leukodystrophy is a group of hereditary leukoencephalopathies predominantly affecting the white matter. Multiple genes and mutations have been reported to be associated with this disorder. Identification of pathogenic genes can facilitate diagnosis of leukodystrophy and development of therapeutic strategies. Methods A case was presented with clinical examinations. Exome sequencing was applied to identify potential mutations. Sanger sequencing of blood DNA was applied to confirm the mutation and to examine additional members. Results We reported a Chinese male patient of adult‐onset leukodystrophy. Genetic examinations identified a homozygous mutation, c. 452T>C (p. M151T), in alanyl‐tRNA synthetase 2 (AARS2) in the patient. The disease was autosomal recessive as suggested by the genotypic analyses of his family members. We also reviewed phenotypic spectra of AARS2 mutation‐associated leukodystrophies from a total of 16 reported cases. Conclusions Our data provide further evidence that mutations of AARS2 are implicated in adult‐onset leukodystrophy.

The phenotypes are variable subjecting to interactions between genetic mutations and environmental exposure (Kaye & Moser, 2004). Mutations in GFAP, EIF2B1, ARSA, ABCD1, and MLC1 have been identified in leukodystrophies (Renaud, 2012). Discovery of additional pathogenic genes may facilitate diagnosis and treatment of leukodystrophies.
In this study, we reported a Chinese patient who was diagnosed as adult-onset leukodystrophy. We unveiled a unique homozygous mutation in alanyl-transfer RNA (tRNA) synthetase 2 (AARS2) (OMIM #612035) in this patient.

| C A S E PRE S ENTATI ON
The patient was a 44-year-old Chinese man who was born healthy and developed normally until the age of 40 when he felt difficult to walk straight. The patient displayed cognitive decline and behavioral abnormality when he first sought medical advices associated with this discomfort at the age of 43 at the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University.
Neurological examinations revealed bilateral cerebellar ataxia and generalized hyperreflexia. The Mini-Mental State Examination score of the patient was 12/30. His muscle bulk, tone, strength, and sensory function were normal. No abnormality in electrocardiogram and echocardiography was found. No endocrine disorder was detected.
The Laboratory parameters including plasma lactate, complete blood count, and cerebrospinal fluid protein content were normal. His parents are non-consanguineous. His grandparents, parents, and his elder brother did not show any neurological or psychiatric problems.
The T1-and T2-weighted image of brain magnetic resonance imaging (MRI) exhibited extensive symmetric periventricular white matter abnormalities with slight ventricular system enlargement and sulci widening. The midline structure remained unchanged (Figure 1a,b).
Multiple segments of high signal in the corpus callosum were de- The mutation was missense and localized in the exon 3 of AARS2 ( Figure 2d). There was no record of this mutation in dbSNP (https :// www.ncbi.nlm.nih.gov/SNP/). The mutation was "probably damaging" as predicted by PolyPhen-2 (http://genet ics.bwh.harva rd.edu/ pph2/) and ascribed to the category of "affected protein function" based on SIFT (http://sift.jcvi.org).
Donepezil at the dose of 5 mg/day was prescribed to the patient for a duration of 1 month. Regular exercise such as walking was suggested. No significant improvement in cognitive function was observed in his follow-up visits.

| D ISCUSS I ON
Leukoencephalopathy is a broad term that predominantly affects the white matter in association with multiple types of disorders, including infectious, inflammatory, vascular, and hereditary (Costello, Eichler, & Eichler, 2009;Vanderver et al., 2015). Leukodystrophy is generally referred to the hereditary type of leukoencephalopathy (Vanderver et al., 2015), and there is no effective treatment. In this study, we reported a unique case of adult-onset leukodystrophy with a homozygous mutation of c. 452T>C (p. M151T) in AARS2.
AARS2 encodes mitochondrial alanyl-tRNA synthetase, which is responsible for the aminoacylation between alanine and the tRNA during translation in the mitochondria. Deficiency in aminoacyl-tRNA synthetases is known to contribute to mitochondrial diseases in association with a wide spectrum of clinical phenotypes (Fuchs et al., 2018;Konovalova & Tyynismaa, 2013). The AARS2 protein contains an editing and an aminoacylation domain, and mutations site-specifically change its function in the catalysis of aminoacylation (Euro et al., 2015).
AARS2 mutations were first identified in infantile mitochondrial cardiomyopathy in 2011 (Gotz et al., 2011), and later found to cause two different phenotypic disorders: severe infantile cardiomyopathy and adult-onset leukodystrophy (Dallabona et al., 2014).
Strikingly, no cardiopathy is present in adult-onset leukodystrophy as suggested in our patient and 15 other reported cases (Table 1) (Dallabona et al., 2014;Hamatani et al., 2016;Lee et al., 2017;Lynch et al., 2016;Szpisjak et al., 2017). To date, all of the infantile cardiomyopathy exhibit a founder mutation, c. 1774C>T (p. R592W), which is located in the editing domain and severely compromises the aminoacylation activity of AARS2 (Euro et al., 2015). In comparison, mutations in adult-onset leukodystrophy include combinations of two missense mutations in the aminoacylation domain, a missense mutation in the aminoacylation domain with a truncating mutation, and other combinations. These mutations can be classified into three categories of activity impairment based on structural analyses, that is, loss of function, severely impaired, and moderate impaired (Euro et al., 2015). The extent of reduced aminoacylation activities may lead to differential phenotypes.

| CON CLUS ION
In summary, we herein report a Chinese male patient of adultonset leukodystrophy carrying a c. 452T>C (p. M151T) homozygous mutation in AARS2. It is autosomal recessive based on genotypic analyses of his family members. Our data provide further evidence that mutations of AARS2 are implicated in adultonset leukodystrophy. Bureau (Y20170071 and C20170003).

CO N FLI C T O F I NTE R E S T S
The authors declare that there is no potential conflict of interest.

E TH I C S A PPROVA L A N D CO N S E NT TO PA RTI CI PATE
The study was approved by the Ethics Committee of the Second

Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical
University. Written informed consents were obtained from the patient's next-of-kin older brother on behalf of the patient and all of the other subjects to participate in the study.

CO N S E NT FO R PU B LI C ATI O N
The Mini-Mental State Examination score of the patient was 12/30, indicating moderate-to-severe cognitive impairment. As such, written informed consents were obtained from the older brother on behalf of the patient, as well as all of the other participants for publication of this report.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no other data were created or analyzed in this study.