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|Year : 2019 | Volume
| Issue : 3 | Page : 871-872
Adult-onset leukodystrophy with homozygous AARS2 mutation located in the aminoacylation domain
Gunes A Uzun
Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Millet Cad Capa 34390, Istanbul, Turkey
|Date of Web Publication||23-Jul-2019|
Dr. Gunes A Uzun
Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Millet Cad Capa 34390, Istanbul
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Uzun GA. Adult-onset leukodystrophy with homozygous AARS2 mutation located in the aminoacylation domain. Neurol India 2019;67:871-2
Leukodystrophies are a hereditary progressive group of disorders characterized by acquired myelin loss or destruction. It has recently been made clear that mitochondrial alanyl-transfer RNA synthetase 2 (AARS2) gene mutations lead to mitochondrial alanyl-tRNA synthetase (mtAlaRS) dysfunction, which, in return, causes early-onset cardiomyopathy (Online Mendelian Inheritance in Man [OMIM]: 614096) and leukodystrophy, accompanied by ovarian failure in female cases (OMIM: 615889)., This report describes a patient who presented with spastic paraparesis and had adult-onset leukodystrophy induced by a novel AARS2 mutation.
The patient is a 22-year-old male with a 2-year history of mild dysphagia, dysarthria, spasms in both legs, and clumsiness while walking. The patient was born to consanguineous parents. Neurologic examination revealed spastic paraparesis accompanied by pyramidal and pseudobulbar findings. Within the last 6 months, he had developed mild frontal executive dysfunctions while performing daily activities. Cranial magnetic resonance imaging (MRI) revealed heterogeneous white matter lesions that were hyperintense on T2 and fluid-attenuated inversion recovery sequences. The U fibers were not involved and there was no contrast enhancement [Figure 1]. Laboratory test results were within normal limits. Whole exome analysis revealed a novel homozygous mutation, c.130G>C; p.A44P, in the AARS2 (NM_020745) gene.
|Figure 1: Cranial magnetic resonance imaging (MRI) revealed heterogeneous white matter lesions in the bilateral periventricular regions which affected the corpus callosum, and which were hyperintense on T2 and FLAIR sequences. The U fibres were not involved and there was no contrast enhancement|
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AARS2 gene mutation has recently been detected in some cases with lactic acidosis, infantile cardiomyopathy with a fatal course, and brain and muscular involvement. Dallabona et al., and Lynch et al., have detected AARS2 mutation in some adult-onset leukodystrophy cases that did not have cardiomyopathy but had one or more of the following findings: depression, behavioral changes, hemiparesis, spastic paraparesis, rapidly progressive cognitive decline, ataxia, and dystonia. These cases did not have have any diseases other than leukodystrophy, but the females had ovarian failure, in whom leukodystrophy had developed with cognitive decline and progressed to spastic paraparesis and ataxia.,
Cranial MRI findings of this case were in support of the clinical data as the corpus callosum and frontopontine fibers were involved. The clinicoradiologic findings of the patient were similar to some cases reported in the literature that were detected to have AARS2 mutation.,, mtAlaRS, which is encoded in the DNA, comprises different subdomains that affect aminoacylation activity [Figure 2]. In our case, alanine/proline substitution at position 44 of the protein was located in the aminoacylation subdomain of mtAlaRS [Figure 2]. The changes in the subdomain are considered to be associated with the late-onset leukodystrophy phenotype. Genetic testing could not be done in other family members.
|Figure 2: Schematic demonstration of mtAlaRS protein and significant changes taking place on it. Editing domain missense mutation leads to the development of early-onset cardiomyopathy phenotype by causing a major decrease in the protein function (OMIM: 614096). Aminoacylation and c-terminal domain missense mutations, on the other hand, cause a minor decrease in the protein function (OMIM: 615889) and are associated with a leukodystrophy phenotype|
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In conclusion, special attention should be paid to the radiologic findings of the cases with late-onset leukodystrophy in which biochemical and metabolic screening tests give unremarkable results. AARS2 gene mutation should then be considered in the differential diagnosis. Definition of further phenotypes will help in developing the clinical algorithms for adulthood leukodystrophies.
The authors thank the patient and his family members for their collaboration.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]