AARS1 was first reported in relation to an autosomal dominant form of leukoencephalopathy in 2019 in a single large Swedish family (Sundal et al., PMID: 31775912). The family was originally described in a 1984 publication as hereditary diffuse leukoencephalopathy with spheroids (Axelsson et al, PMID: 6595937) with follow-up described in a 2012 publication (Sundal et al, PMID: 22098561). Affected family members experienced variable onset (8–60 years, median: 36) of frontal lobe symptoms that progressed to encephalopathy with pyramidal, extrapyramidal, and optic tract involvement, along with ataxia, gait issues, dystonia, and vision loss; median survival was <10 years. Postmortem findings included white matter liquefaction, gliosis, axonal spheroids, and myelin loss. There were 10 clinically affected individuals in the family, two of whom underwent exome sequencing that identified a heterozygous missense variant, c.455G > T p.(Cys152Phe) in AARS1 (Sundal et al., PMID: 31775912). An additional 3 affected individuals were obligate heterozygotes, and the remaining 7 were not tested. Twenty-one unaffected relatives were tested for segregation purposes, none of whom were found to harbor the variant. No additional (unrelated) cases have been reported.
Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms, inheritance pattern, and phenotypic variability from other disease entities associated with AARS1 variants. Therefore, the following disease entities were split and curated separately: autosomal recessive AARS1-related leukoencephalopathy (Definitive) and autosomal dominant Charcot-Marie Tooth type 2N (Definitive).
A single missense variant has been reported in 2 related individuals in 1 publication in association with autosomal dominant AARS1-related leukoencephalopathy (PMID: 31775912). Functional data was available but did not provide additional information regarding variant pathogenicity. The mechanism of pathogenicity is unknown. Experimental evidence supporting or refuting the gene-disease association was not identified. In summary, there is limited evidence supporting the relationship between AARS1 and autosomal dominant AARS1-related leukoencephalopathy.
This classification was approved by the Leukodystrophy and Leukoencephalopathy Working Group GCEP on March 19, 2025 [SOP Version 11].
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