Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly

Kloeckner C, Murray JPF, Tavasoli M, Sticht H, Stoltenburg-Didinger G, Scholle LM, Bakhtiari S, Kruer MC, Darvish H, Firouzabadi SG, Pagnozzi A, Shukla A, Girisha KM, Narayanan DL, Kaur P, Maroofian R, Zaki MS, Noureldeen MM, Merkenschlager A, Gburek-Augustat J, Cali E, Banu S, Nahar K, Efthymiou S, Houlden H, Abou Jamra R, Williams J, Mcmaster CR, Platzer K (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Brain Oxford University Press

DOI: 10.1093/brain/awac074

Abstract

The Kennedy pathways catalyse the de novo synthesis of phosphatidylcholine and phosphatidylethanolamine, the most abundant components of eukaryotic cell membranes. In recent years, these pathways have moved into clinical focus because four of ten genes involved have been associated with a range of autosomal recessive rare diseases such as a neurodevelopmental disorder with muscular dystrophy (CHKB), bone abnormalities and cone-rod dystrophy (PCYT1A) and spastic paraplegia (PCYT2, SELENOI). We identified six individuals from five families with bi-allelic variants in CHKA presenting with severe global developmental delay, epilepsy, movement disorders and microcephaly. Using structural molecular modelling and functional testing of the variants in a cell-based Saccharomyces cerevisiae model, we determined that these variants reduce the enzymatic activity of CHKA and confer a significant impairment of the first enzymatic step of the Kennedy pathway. In summary, we present CHKA as a novel autosomal recessive gene for a neurodevelopmental disorder with epilepsy and microcephaly.

Authors with CRIS profile

Heinrich Sticht Professur für Bioinformatik

Involved external institutions

Universität Leipzig DE Germany (DE) Dalhousie University CA Canada (CA) Universitätsklinikum Leipzig DE Germany (DE) Dhaka Shishu (Children) Hospital BD Bangladesh (BD) Charité - Universitätsmedizin Berlin DE Germany (DE) Martin-Luther-Universität Halle-Wittenberg (MLU) DE Germany (DE) Phoenix Children's Hospital US United States (USA) (US) Golestan University IR Iran, Islamic Republic of (IR) University of Social Welfare and Rehabilitation Sciences IR Iran, Islamic Republic of (IR) Commonwealth Scientific and Industrial Research Organisation (CSIRO) AU Australia (AU) Manipal University IN India (IN) University College London (UCL) GB United Kingdom (GB) Beni-Suef University / جامعة بني سويف EG Egypt (EG) National Research Centre (NRC) / المركز القومي للبحوث EG Egypt (EG)

How to cite

APA:

Kloeckner, C., Murray, J.P.F., Tavasoli, M., Sticht, H., Stoltenburg-Didinger, G., Scholle, L.M.,... Platzer, K. (2022). Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly. Brain. https://dx.doi.org/10.1093/brain/awac074

MLA:

Kloeckner, Chiara, et al. "Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly." Brain (2022).

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