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Expanded phenotype of AARS1-related white matter disease



Recent reports of individuals with cytoplasmic transfer RNA (tRNA) synthetase-related disorders have identified cases with phenotypic variability from the index presentations. We sought to assess phenotypic variability in individuals with AARS1-related disease.


A cross-sectional survey was performed on individuals with biallelic variants in AARS1. Clinical data, neuroimaging, and genetic testing results were reviewed. Alanyl tRNA synthetase (AlaRS) activity was measured in available fibroblasts.


We identified 11 affected individuals. Two phenotypic presentations emerged, one with early infantile–onset disease resembling the index cases of AARS1-related epileptic encephalopathy with deficient myelination (n = 7). The second (n = 4) was a later-onset disorder, where disease onset occurred after the first year of life and was characterized on neuroimaging by a progressive posterior predominant leukoencephalopathy evolving to include the frontal white matter. AlaRS activity was significantly reduced in five affected individuals with both early infantile–onset and late-onset phenotypes.


We suggest that variants in AARS1 result in a broader clinical spectrum than previously appreciated. The predominant form results in early infantile–onset disease with epileptic encephalopathy and deficient myelination. However, a subgroup of affected individuals manifests with late-onset disease and similarly rapid progressive clinical decline. Longitudinal imaging and clinical follow-up will be valuable in understanding factors affecting disease progression and outcome.

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Fig. 1: Magnetic resonance image (MRI) findings in individuals with recessive AARS1-related disease.
Fig. 2: Calcium deposits in AARS1-related disorder.
Fig. 3: Variants identified in this cohort and aminoacylation studies of affected individuals.

Data availability

De-identified data are available upon request by contacting the Leukodystrophy Center at Children’s Hospital of Philadelphia at


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We thank the patients and their families. G.H. was supported by the Ochsner MD-PhD scholarship and a MCRI PhD Top-Up Scholarship. The participation of G.H. and C.S. is in part financed by the Australian National Health and Medical Research Council (NHMRC 1068278). The research conducted at the Murdoch Children’s Research Institute was supported by the Victorian Government’s Operational Infrastructure Support Program. This work was supported by the Italian Ministry of Health, grant RF-2016-02361241 (to E.B. and P.G.). T.B.H. was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)–Projektnummer (418081722). This study was partly supported by a grant from the Canadian Institutes of Health Research to G.B. (CIHR; 201610PJT-377869). G.B. has received the CIHR New Investigator Salary Award (2017-2022).

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Authors and Affiliations



G.H., A.V., R.A.H. were responsible for conceptualization and supervision of the project. G.H. wrote the first draft and performed data curation, investigation, determined the methodology and performed formal analysis. M.I.M., F.N., L.D., O.S., T.M., A.D., A.P., R.C., A.T., M.C., C.A., P.G., S.F., D.E.C.S., K.H., A.H., S.B., I.B., U.K., D.G., T.A.G., F.E., K.S., R.G., E.B., I.T., R.J.T., R.S., U.B., T.B.H., G.S.S., C.S., G.B., and M.S.v.d.K. performed formal analysis and investigation. A.P., I.B., D.G., T.A.G., F.E., K.S., I.T., R.J.T., T.B.H., and C.S. performed variant curation. R.C., E.B., R.J.T., G.B., M.S.v.d.K., and A.V. performed funding acquisition. All authors reviewed and approved the manuscript prior to submission.

Corresponding authors

Correspondence to Adeline Vanderver or Ralf A. Husain.

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Ethics Declaration

Patients and their families were collected prospectively in the Myelin Disorders Bioregistry. Project (MDBP) with approval from the institutional review board at Children’s Hospital of Philadelphia (IRB Approval #IRB 14-011236). Written informed consent for collection of clinical information, neuroimaging, and genetic information was obtained for each study participant.

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The authors declare no competing interests.

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Supplemental Text:A supplemental text with results regarding validation of variants identified in I-1 and I-4 is provided.

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Helman, G., Mendes, M.I., Nicita, F. et al. Expanded phenotype of AARS1-related white matter disease. Genet Med 23, 2352–2359 (2021).

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