Expanded phenotype of AARS1-related white matter disease.
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Helman Guy, Mendes Marisa I, Nicita Francesco, Darbelli Lama, Sherbini Omar, Moore Travis, Derksen Alexa, Amy Pizzino, Carrozzo Rosalba, Torraco Alessandra, Catteruccia Michela, Aiello Chiara, Goffrini Paola, Figuccia Sonia, Smith Desiree E C, Hadzsiev Kinga, Hahn Andreas, Biskup Saskia, Brösse Ines, Kotzaeridou Urania, Gauck Darja, Grebe Theresa A, Elmslie Frances, Stals Karen, Gupta Rajat, Bertini Enrico, Thiffault Isabelle, Taft Ryan J, Schiffmann Raphael, Brandl Ulrich, Haack Tobias B, Salomons Gajja S, Simons Cas, Bernard Geneviève, van der Knaap Marjo S, Vanderver Adeline, Husain Ralf A
Аннотация
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.