Homozygous mutation in mitochondrial Cysteinyl-tRNA synthase gene (CARS2) presenting as movement disorder, developmental regression and epilepsy

Rao, T.S; Maw, A; Gradham, A

Homozygous mutation in mitochondrial Cysteinyl-tRNA synthase gene (CARS2) presenting as movement disorder, developmental regression and epilepsy

Authors

Rao, T.S

Maw, A

Gradham, A

Issue Date

2022

Type

Scientific Paper

Keywords

Research Subject Categories::MEDICINE::Dermatology and venerology,clinical genetics, internal medicine::Internal medicine::Paediatric medicine

Abstract

Homozygous mutation in mitochondrial Cysteinyl-tRNA synthase gene (CARS2) presenting as movement disorder, developmental regression and epilepsy TS RAO1, A MAW2, A GRADHAM3 1Luton and Dunstable University Hospital, Luton, UK; 2Addenbrookes Hospital, Cambridge, UK; 3Northwest Thames Regional Genetic service, London, UK Mitochondrial disorders are suspected in children with developmental regression with epilepsy. Newer genetic approaches with trio exome and whole genome sequencing are enabling clinicians detecting rarer genetic conditions in consanguineous population in UK. We present a rare case of CARS2 gene homozygous mutation. Case Report: A 6 year old male of Pakistani descent referred to hospital with worsening recurrent falls with onset at 4 years. Male was 1st born of consanguineous parents related as cousins, has uneventful pregnancy and birth. Initial development was normal except mild delay in motor milestones. Tremors and myoclonic jerks resulted in recurrent falls leading to injuries particularly when tired. At 6 years of age he presented with generalised tonic clonic seizures in sleep at monthly intervals and also reported absences. Clinical examination showed few café-au-lait patches, normal physical growth, truncal and peripheral tremor at rest and in action, cerebellar signs and nystagmus. Initial metabolic blood results including white cell enzymes, genetic array CGH and neuroimaging were normal. An awake interictal electroencephalogram showed multifocal epileptiform spike and slow waves bilaterally. A joint neurogenetic clinical review recognised progressive degenerative condition, hence a rapid trio-exome sequence analysis was ordered which revealed homozygous CARS2 splicing variant (NM_024537.4:c.655G>A). Both parents were identified as carriers. Epilepsy was managed with Levetiracetam resulting in remission of motor seizures. Multidisciplinary management and education support were put in place. Discussion and Conclusion: There are few reported cases of CARS2 related mitochondrial disorder in the medical literature. The presentation with developmental delay, epilepsy and movement disorder are consistent with previous cases but additionally we report neuroregression in our proband. The widespread availability of trio exome and whole genome sequencing will identify further affected individuals and increase the knowledge of this rare condition.

Citation

Rao, T. S., Maw, A., Gradham, A. (2022) Homozygous mutation in mitochondrial Cysteinyl-tRNA synthase gene (CARS2) presenting as movement disorder, developmental regression and epilepsy. Developmental Medicine and Child Neurology. 64(Suppl 1): 45. DOI: https://dx.doi.org/10.1111/dmcn.15123