Expanded phenotype of AARS1-related white matter disease.

December 01, 2021

Helman G1 2, Mendes MI3, Nicita F4, Darbelli L5 6 7 8, Sherbini O9, Moore T5 6, Derksen A5 6, Pizzino A9, Carrozzo R4, Torraco A4, Catteruccia M4, Aiello C4, Goffrini P10, Figuccia S10, Smith DEC3, Hadzsiev K11, Hahn A12, Biskup S13, Brösse I14, Kotzaeridou U14, Gauck D15, Grebe TA16, Elmslie F17, Stals K18, Gupta R19, Bertini E4, Thiffault I20 21 22, Taft RJ23, Schiffmann R24, Brandl U25, Haack TB15, Salomons GS3, Simons C1 2, Bernard G5 6 7 8, van der Knaap MS26 27, Vanderver A28 29, Husain RA30


Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.