CARS2 – Combined Oxidative Phosphorylation Deficiency Type 27

Biallelic variants in CARS2 underlie autosomal recessive combined oxidative phosphorylation deficiency type 27 (MONDO:0014728). To date, seven unrelated probands from six families have been described with biallelic CARS2 variants ([PMID:34704010]). Affected individuals present with early-onset epileptic encephalopathy, neuroregression, dysfluent speech, continuous tremors, aggressive behavior, and complex movement disorders.

Reported pathogenic alleles comprise at least four distinct variants: three missense changes (c.655G>A (p.Ala219Thr), c.563C>T (p.Thr188Met), c.752C>T (p.Pro251Leu)) and one in-frame deletion (c.649_651del (p.Glu217del)) affecting conserved residues within the mitochondrial cysteinyl-tRNA ligase domain ([PMID:25787132]). All variants segregate with disease in multiple families, consistent with autosomal recessive inheritance.

Clinical features expand from classical severe myoclonic epilepsy and neuroregression to include aggressive behavior, tremors, and an Electrical Status Epilepticus during Sleep (ESES) EEG pattern not previously reported ([PMID:34704010]). Muscle and liver biopsies reveal combined OXPHOS complex I, III, IV deficiency and increased mitochondrial DNA content.

Functional studies demonstrate that the recurrent c.655G>A variant at the exon 6 splice donor site causes exon skipping and an in-frame deletion of 28 amino acids in a conserved tRNA-binding motif ([PMID:25361775]). Patient fibroblasts exhibit significantly reduced charged mt-tRNA(Cys), incomplete assembly of complexes I and V, and impaired mitochondrial translation, all of which are rescued by retroviral expression of wild-type CARS2 ([PMID:25787132]).

Together, the genetic and experimental data establish a loss-of-function mechanism for CARS2 deficiency leading to disrupted mitochondrial translation and OXPHOS dysfunction. The robust concordance of genotype–phenotype correlations and functional rescue supports a Strong gene–disease association.

Key Take-home: CARS2 variant screening is recommended in autosomal recessive early-onset epileptic encephalopathy with neuroregression and movement disorders to guide diagnosis and management.

References

• Epilepsy & Behavior Reports • 2021 • Expanding the electro-clinical phenotype of CARS2associated neuroregression. PMID:34704010
• Neurology • 2014 • A homozygous splice-site mutation in CARS2 is associated with progressive myoclonic epilepsy. PMID:25361775
• Journal of Medical Genetics • 2015 • Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. PMID:25787132

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