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Background <p><i>AARS2</i>-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.</p> Methods <p>We conducted a multicentre retrospective case series of individuals with genetically confirmed <i>AARS2</i>-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.</p> Results <p>Across 71 individuals, mean age at onset was 27.3&#xa0;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 <i>AARS2</i> variants were identified, including seven novel variants. Missense variants predominated. Notably, variants previously linked only to infantile cardiomyopathy, including p.Arg592Trp, were observed.</p> Conclusions <p><i>AARS2</i>-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.</p>

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The clinical, radiological and genetic spectrum AARS2-related leukoencephalopathy: a case series of 15 patients and review of the literature

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月26日

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  • Charles Wade,
  • Anderson Rodrigues Brandão de Paiva,
  • Paulo Ribeiro Nóbrega,
  • Ana C Andorinho de Freitas Ferreira,
  • Ana C Martins Borges,
  • Lecio Figueira Pinto,
  • Paula Brandão,
  • Pedro Maia Nobre Rocha Saffi,
  • Luiz Felipe Vasconcellos,
  • Deborah Moreira Rangel,
  • Paula Camila A. A. P. Matos,
  • André Luiz Santos Pessoa,
  • Emília K. Embiruçu,
  • Katiane Sayão Souza Cabral,
  • Fernando Kok,
  • Rumana Chowdhury,
  • Jessica Roberts,
  • Jeremy Chataway,
  • Frederik Barkhof,
  • Tom Hayton,
  • Matthew E. Adams,
  • David S. Lynch

摘要

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.