Two Korean siblings with recently described ovarioleukodystrophy related to <i>AARS2</i> mutations

Lee, J. M.; Yang, Hui-Jun; Kwon, Jee‐Hyun; Kim, W. J.; Kim, S. Y.; Lee, E. M.; Park, J. Y.; Weon, Young Cheol; Park, S. H.; Gwon, Bareum; Ryu, Jae-Chan; Lee, Sang Kun; Kim, Han Joon; Jeon, Beomseok

doi:10.1111/ene.13245

Cited by 19 publications

(14 citation statements)

References 8 publications

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“…AARS2 mutations were first identified in infantile mitochondrial cardiomyopathy in 2011 (Gotz et al, ), and later found to cause two different phenotypic disorders: severe infantile cardiomyopathy and adult‐onset leukodystrophy (Dallabona et al, ). Strikingly, no cardiopathy is present in adult‐onset leukodystrophy as suggested in our patient and 15 other reported cases (Table ) (Dallabona et al, ; Hamatani et al, ; Lee et al, ; Lynch et al, ; Szpisjak et al, ). 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, ).…”

Section: Discussionsupporting

confidence: 81%

“…The probability for this case to occur is rather small given that his biological parents are non‐consanguineous. The mutation was previously reported in a pair of Korean brother‐sister twin, despite having compound heterozygous mutations additionally bearing a nonsense mutation site, c. 963C>A (p. Y321*) (Lee et al, ). Due to the small number of reported cases, it is difficult to correlate these mutations with specific clinical phenotypes.…”

Section: Discussionmentioning

confidence: 87%

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

et al. 2019

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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.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 87%

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

et al. 2019

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“…In subsequent studies, researchers from Japan and South Korea reported white Abbreviations: AARS2, Alanyl-tRNA synthetase 2; MELAS, Mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes; MNGIE, Mitochondrial neurogastrointestinal encephalopathy; ARS2, Arseniteresistance protein 2; DARS2, Mitochondrial aspartyl-tRNA synthetase; LBSL, Leukodystrophy with brain stem and spinal cord involvement and lactate elevation; OMIM, Online Mendelian Inheritance in Man; OXPHOS, Oxidativephosphorylation; AARS2-L, Alanyl-transfer RNA synthetase 2 mutation-related leukodystrophy; ALD, Adrenoleukodystrophy; ALSP, Adult-onset leukodystrophy with axonal spheroids and pigmented glia; VWM, Vanishing white matter disease; CADASIL, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukodystrophy; RRF, Ragged-red fiber; MGT, Modified Gomori trichrome; COX, Cytochrome oxidase; SDH, Succinic dehydrogenase; HE, Hematoxylin-eosin; DWI, Diffusion-weighted imaging; MRA, MR angiography; SWI, Susceptibility weighted imaging; RBF, Ragged blue fiber. matter disease caused by different AARS2 mutations in Asian patients (18,19). At present, a total of 15 sporadic AARS2 mutation-related leukodystrophy patients (including eight females and seven males) have been reported around the world.…”

Section: Introductionmentioning

confidence: 99%

Novel Alanyl-tRNA Synthetase 2 Pathogenic Variants in Leukodystrophies

Wang

Tang

et al. 2019

Front. Neurol.

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The white matter disease spectrum is associated with many genetic diseases, including AARS2, CADASIL, ALD, and others. In this study, to determine the novel alanyl-tRNA synthetase 2 mutation implicated in white matter disease, several families with an autosomal recessive inheritance pattern of white matter disease were analyzed by whole-exome sequencing. Variants were prioritized according to their rarity and pathogenic variants in genes already known to be associated with leukodystrophies and were confirmed by Sanger sequencing using standard protocols. We identified 5 rare variants (c.452T>C chr6:44279256 p.M151T, c.1871G>A chr6:44272054 p.W624X, c.802A>G chr6:44278128 p.M268V, c.1703-1704del chr6:-44272430-44272431 p.Q568fs, and c.179C>A chr6-44280882 p.P60H) with varying expression in 4 independent Chinese families with leukodystrophy. These single nucleotide variants (SNVs), or deletion mutations, each induced a frameshift, causing a missense mutation in alanyl-tRNA synthetase 2. These findings suggested that all mutations might contribute to the development of leukodystrophy in the examined family members. Combined with previous findings, our data confirmed that the novel mutations are located in leukodystrophy-related risk genes. We also summarized all the alanyl-tRNA synthetase 2 mutations related to the onset of leukodystrophies in adults.

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“…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., ; Dong et al., ; Hamatani et al., ; Lee et al., ; Peragallo et al., ; Szpisjak et al., ; Taglia et al., ). 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.…”

Section: Literature Reviewmentioning

confidence: 99%

“…Leukoencephalopathy due to AARS2 mutations is a syndrome with progressive cerebral white matter degeneration (Kaye & Moser, ). Since first identified in 2014, only 19 AARS2 ‐related leukoencephalopathy cases have been reported in English literature until now (Dallabona et al., ; Dong et al., ; Hamatani et al., ; Lee et al., ; Peragallo, Keller, van der Knaap, Soares, & Shankar, ; Szpisjak et al., ; Taglia et al., ). Owing to the low number of known cases, most clinicians have limited knowledge about the clinical presentation and neuroimaging features of AARS2 ‐related leukoencephalopathy.…”

Section: Introductionmentioning

confidence: 99%

AARS2 leukoencephalopathy: A new variant of mitochondrial encephalomyopathy

Tang

Qin

Xing

et al. 2019

Molec Gen & Gen Med

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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.

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Two Korean siblings with recently described ovarioleukodystrophy related to AARS2 mutations

Cited by 19 publications

References 8 publications

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

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

Novel Alanyl-tRNA Synthetase 2 Pathogenic Variants in Leukodystrophies

AARS2 leukoencephalopathy: A new variant of mitochondrial encephalomyopathy

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