Expanded phenotype of AARS1-related white matter disease

Response to Leidi et al

“…First, our report was intended to present a greater spectrum of disease presentations associated with AARS1 variants and not to provide two restrictive subgroups of a disease (severe early infantile vs older onset milder presentations). 2 Thus, we agree with Leidi et al 1 that additional subjects might have intermediate neurologic severity presentation and, furthermore, other organ involvement. For example, we had referred to the case report of Marten et al 3 of an affected patient with bi-allelic AARS1 variants and decreased enzymatic activity that showed early infantile onset with microcephaly, white matter signal hyperintensities, and developmental delay with improvement over time and, in addition, recurrent liver failure triggered by febrile illness, as seen in other cytosolic aminoacylation disorders (deficiencies of FARS1, IARS1, LARS1, MARS1, QARS1, and YARS1).…”

“…As stated by the authors, the decrease in AARS1 activity is milder in this individual than in other published cases with AARS1 variants. [2][3][4] No normative data exist on this enzyme activity, as might be available in more common disorders. In particular, no data exist on the range of enzyme activities that might be expected in heterozygous subjects or if an individual carries one pathogenic variant but a second variant of uncertain significance.…”

Correspondence on “Expanded phenotype of AARS1-related white matter disease” by Helman et al

“…It is of note that the residual enzyme activity was higher than that reported in patients so far, suggesting a possible correlation between clinical severity and enzyme activity impairment. However, this hypothesis does not seem to be supported by the data from the large series published by Helman et al 1 Further studies will be needed to better understand the pathophysiological basis of the wide phenotypic variability of this and other aminoacyl-tRNA synthetase-related disorders.…”

“…We read with great interest the study by Helman et al, 1 which describes a series of 11 individuals with AARS1related disease. The authors identify 2 main presentations in accordance with age at disease onset and neuroimaging findings.…”

“…Alessia Leidi 1 Roberto Previtali 1 Cecilia Parazzini 2,3 Federico Raviglione 4 Stephana Carelli 1,5 Marisa I. Mendes 6 Gajja S. Salomons 6 Maria Iascone 7 Davide Tonduti 3,8,*…”