Expanding the electro-clinical phenotype of CARS2associated neuroregression

Abstract

Highlights Pathogenic variants in cysteinyl-tRNA synthetase-2 ( CARS2 ) gene have recently been described to cause severe myoclonic epilepsy, neuroregression, progressive audio-visual impairment and movement disorder. We present an 11-year-old boy with neuroregression, dysfluent speech, aggressive behavior, tremors and ESES pattern on EEG Our case expands the existing electro-clinical phenotype of CARS2 associated neuroregression.

Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes

“…Strengthened burden was also found for potential novel genes -e.g., CARS2 (MIM: 612800) in DEEs and NCOA1 (MIM: 602691) in GGE, both with accumulating evidence from literature and case reports. [37][38][39][40][41][42][43] Analysis of CNV duplications did not show any individual genes close to exome-wide significance (Supplementary Data 10). Collectively, the joint burden analysis suggests at least partial convergence in the protein-truncating-effect caused by SNVs/indels and CNVs, and therefore, it may provide a strategy for improving the power of detecting rare, large-effect genetic risk factors for epilepsy.…”

Severe neonatal onset neuroregression with paroxysmal dystonia and apnoea: Expanding the phenotypic and genotypic spectrum of CARS2‐related mitochondrial disease

“…The c.655G>A substitution, previously characterized by both Hallman et al and Kapoor et al, 9,13 affects an amino acid that is highly conserved in vertebrates 9 and is responsible for a splicing defect that removes exon 6 and results in the deletion of 28-amino acids in a surface loop of the CARS2 ligase catalytic domain. This specific loop stabilizes the acceptor end hairpin by making contacts at its G1-C72 base pair and at the backbone of U73.…”

“…9 Interestingly, half of all reported individuals to date (four of eight) suffering from CARS2-related disease harbor at least one allele with this specific c.655G>A variant. 9,13 The novel variant c.1478T>C substitutes a phenylalanine with a serine at residue 493. This is the second reported variant affecting the CARS2 anticodon binding domain (Figure 1C).…”

“…The removal of these 28 amino acids is thus predicted to compromise acceptor hairpin stability and alter cysteine‐tRNA binding, substantially reducing aminoacylation activity 9 . Interestingly, half of all reported individuals to date (four of eight) suffering from CARS2 –related disease harbor at least one allele with this specific c.655G>A variant 9,13 …”

“…Eight unique CARS2 gene variants have been previously reported in seven distinct individuals. They have all presented with infantile or childhood-onset epileptic encephalopathy and developmental regression [9][10][11][12][13] (Table 1).…”