Journal of neurology · 2026
The clinical, radiological and genetic spectrum AARS2-related leukoencephalopathy: a case series of 15 patients and review of the literature.
СтатьяМногоцентровое исследованиеСистематический обзорНазвание и аннотация: Перевод в очереди
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Wade Charles, de Paiva Anderson Rodrigues Brandão, Nóbrega Paulo Ribeiro, de Freitas Ferreira Ana C Andorinho, Borges Ana C Martins, Pinto Lecio Figueira, Brandão Paula, Saffi Pedro Maia Nobre Rocha, Vasconcellos Luiz Felipe, Rangel Deborah Moreira, Matos Paula Camila A A P, Pessoa André Luiz Santos, Embiruçu Emília K, Cabral Katiane Sayão Souza, Kok Fernando, Chowdhury Rumana, Roberts Jessica, Chataway Jeremy, Barkhof Frederik, Hayton Tom, Adams Matthew E, Lynch David S
Аннотация
BACKGROUND: AARS2-related leukoencephalopathy is a rare autosomal recessive leukodystrophy with overlapping clinical and radiological features with CSF1R-related disease but distinct genetic and phenotypic characteristics. Since its description in 2014, fewer than 60 cases have been reported.
METHODS: We conducted a multicentre retrospective case series of individuals with genetically confirmed AARS2-related leukoencephalopathy, integrating clinical, radiological, and molecular data from 15 newly identified patients. Neuroimaging was reviewed by experienced neuroradiologists, and variants were classified using ACMG criteria. A systematic literature review identified 56 additional cases.
RESULTS: Across 71 individuals, mean age at onset was 27.3 years (range 0-57), with balanced sex distribution. Psychiatric and cognitive symptoms predominated early, affecting 70% and 86% of patients. Pyramidal signs (82%), gait disturbance (80%), and extrapyramidal motor features (45%) were common, whilst seizures occurred in 10%. Premature ovarian failure was reported in 82% of females. Sixteen individuals (22.5%) had childhood onset. Neuroimaging showed confluent frontoparietal white matter abnormalities, corpus callosum thinning, and multifocal diffusion abnormalities. Seventy-two unique AARS2 variants were identified, including seven novel variants. Missense variants predominated. Notably, variants previously linked only to infantile cardiomyopathy, including p.Arg592Trp, were observed.
CONCLUSIONS: AARS2-related leukoencephalopathy is clinically and genetically heterogeneous with characteristic imaging and broad onset. Recognition of defining features is essential for diagnosis, and genomic testing should be prioritised. This study provides the most comprehensive characterisation to date and suggests genotype-phenotype separation between cardiomyopathy- and leukodystrophy-associated variants may not be absolute.
METHODS: We conducted a multicentre retrospective case series of individuals with genetically confirmed AARS2-related leukoencephalopathy, integrating clinical, radiological, and molecular data from 15 newly identified patients. Neuroimaging was reviewed by experienced neuroradiologists, and variants were classified using ACMG criteria. A systematic literature review identified 56 additional cases.
RESULTS: Across 71 individuals, mean age at onset was 27.3 years (range 0-57), with balanced sex distribution. Psychiatric and cognitive symptoms predominated early, affecting 70% and 86% of patients. Pyramidal signs (82%), gait disturbance (80%), and extrapyramidal motor features (45%) were common, whilst seizures occurred in 10%. Premature ovarian failure was reported in 82% of females. Sixteen individuals (22.5%) had childhood onset. Neuroimaging showed confluent frontoparietal white matter abnormalities, corpus callosum thinning, and multifocal diffusion abnormalities. Seventy-two unique AARS2 variants were identified, including seven novel variants. Missense variants predominated. Notably, variants previously linked only to infantile cardiomyopathy, including p.Arg592Trp, were observed.
CONCLUSIONS: AARS2-related leukoencephalopathy is clinically and genetically heterogeneous with characteristic imaging and broad onset. Recognition of defining features is essential for diagnosis, and genomic testing should be prioritised. This study provides the most comprehensive characterisation to date and suggests genotype-phenotype separation between cardiomyopathy- and leukodystrophy-associated variants may not be absolute.