A novel disease-causing variant associated with a milder phenotype of AARS2-related leukodystrophy — A case report
Background and objectives: Adult-onset leukodystrophies are a rare group of neurological disorders characterized by progressive degeneration of the cerebral white matter. One of these diseases is caused by biallelic pathogenic variants in the AARS2 gene. We describe a patient with late-onset AARS2-r...
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| Language: | English |
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Elsevier
2024-12-01
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| Series: | Molecular Genetics and Metabolism Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214426924001101 |
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| author | Joana Fernandes João Moura João Tarrio Jorge Oliveira Ana Lopes João Parente Freixo Gonçalo Videira |
| author_facet | Joana Fernandes João Moura João Tarrio Jorge Oliveira Ana Lopes João Parente Freixo Gonçalo Videira |
| author_sort | Joana Fernandes |
| collection | DOAJ |
| description | Background and objectives: Adult-onset leukodystrophies are a rare group of neurological disorders characterized by progressive degeneration of the cerebral white matter. One of these diseases is caused by biallelic pathogenic variants in the AARS2 gene. We describe a patient with late-onset AARS2-related leukoencephalopathy, a milder phenotype and a novel disease-causing variant. Methods: The patient was characterized during routine clinical practice. Results: A 40-year-old male was evaluated for chronic headaches. Six years before, he was hospitalized for a major depression with psychotic features. The first neurological examination was normal, except for a slow downbeat nystagmus. Brain MRI revealed significant hyperintensities in T2 and T2-FLAIR bilaterally in the frontal lobes, with periventricular and corpus callosum involvement, and without restricted diffusion. A multigene panel for leukodystrophies based on whole-exome sequencing identified two heterozygous variants in the AARS2 gene: one previously reported in the literature, already classified as pathogenic, NM_020745.4:c.595C > T (p.(Arg199Cys)), and one novel variant c.730G > A (p.(Val244Ile)), later reclassified as likely pathogenic. Nine years have passed since the first symptoms without clear clinical progression. Discussion: This case underlines that adult-onset leukodystrophy caused by variants in AARS2 may have a wide range of phenotypes and patterns of progression. The new variant c.730G > A (p.(Val244Ile)) herein described may induce a milder clinical picture and a less severe radiological pattern. Practical implications: Adult-onset leukoencephalopathies may present with milder clinical signs than what is generally perceived, and novel disease-causing variants are being identified. |
| format | Article |
| id | doaj-art-cd362a06e5ad41a985835ef96c6e351a |
| institution | OA Journals |
| issn | 2214-4269 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Genetics and Metabolism Reports |
| spelling | doaj-art-cd362a06e5ad41a985835ef96c6e351a2025-08-20T01:58:23ZengElsevierMolecular Genetics and Metabolism Reports2214-42692024-12-014110115710.1016/j.ymgmr.2024.101157A novel disease-causing variant associated with a milder phenotype of AARS2-related leukodystrophy — A case reportJoana Fernandes0João Moura1João Tarrio2Jorge Oliveira3Ana Lopes4João Parente Freixo5Gonçalo Videira6Neurology Department, Unidade Local de Saúde de Santo António, Porto, Portugal; Corresponding author.Neurology Department, Unidade Local de Saúde de Santo António, Porto, PortugalNeuroradiology Department, Unidade Local de Saúde de Santo António, Porto, Portugal; Neuroradiology Department, Hospital Central do Funchal – Dr. Nélio Mendonça, Madeira, PortugalCentro de Genética Preditiva e Preventiva (CGPP), Instituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, PortugalCentro de Genética Preditiva e Preventiva (CGPP), Instituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, PortugalCentro de Genética Preditiva e Preventiva (CGPP), Instituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, PortugalNeurophysiology Department, Unidade Local de Saúde de Santo António, Porto, PortugalBackground and objectives: Adult-onset leukodystrophies are a rare group of neurological disorders characterized by progressive degeneration of the cerebral white matter. One of these diseases is caused by biallelic pathogenic variants in the AARS2 gene. We describe a patient with late-onset AARS2-related leukoencephalopathy, a milder phenotype and a novel disease-causing variant. Methods: The patient was characterized during routine clinical practice. Results: A 40-year-old male was evaluated for chronic headaches. Six years before, he was hospitalized for a major depression with psychotic features. The first neurological examination was normal, except for a slow downbeat nystagmus. Brain MRI revealed significant hyperintensities in T2 and T2-FLAIR bilaterally in the frontal lobes, with periventricular and corpus callosum involvement, and without restricted diffusion. A multigene panel for leukodystrophies based on whole-exome sequencing identified two heterozygous variants in the AARS2 gene: one previously reported in the literature, already classified as pathogenic, NM_020745.4:c.595C > T (p.(Arg199Cys)), and one novel variant c.730G > A (p.(Val244Ile)), later reclassified as likely pathogenic. Nine years have passed since the first symptoms without clear clinical progression. Discussion: This case underlines that adult-onset leukodystrophy caused by variants in AARS2 may have a wide range of phenotypes and patterns of progression. The new variant c.730G > A (p.(Val244Ile)) herein described may induce a milder clinical picture and a less severe radiological pattern. Practical implications: Adult-onset leukoencephalopathies may present with milder clinical signs than what is generally perceived, and novel disease-causing variants are being identified.http://www.sciencedirect.com/science/article/pii/S2214426924001101 |
| spellingShingle | Joana Fernandes João Moura João Tarrio Jorge Oliveira Ana Lopes João Parente Freixo Gonçalo Videira A novel disease-causing variant associated with a milder phenotype of AARS2-related leukodystrophy — A case report Molecular Genetics and Metabolism Reports |
| title | A novel disease-causing variant associated with a milder phenotype of AARS2-related leukodystrophy — A case report |
| title_full | A novel disease-causing variant associated with a milder phenotype of AARS2-related leukodystrophy — A case report |
| title_fullStr | A novel disease-causing variant associated with a milder phenotype of AARS2-related leukodystrophy — A case report |
| title_full_unstemmed | A novel disease-causing variant associated with a milder phenotype of AARS2-related leukodystrophy — A case report |
| title_short | A novel disease-causing variant associated with a milder phenotype of AARS2-related leukodystrophy — A case report |
| title_sort | novel disease causing variant associated with a milder phenotype of aars2 related leukodystrophy a case report |
| url | http://www.sciencedirect.com/science/article/pii/S2214426924001101 |
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