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

Chiara Klöckner, J. Pedro Fernández-Murray, Mahtab Tavasoli, Heinrich Sticht, Gisela Stoltenburg-Didinger, Leila Motlagh Scholle, Somayeh Bakhtiari, Michael C. Kruer, Hossein Darvish, Saghar Ghasemi Firouzabadi, Alex Pagnozzi, Anju Shukla, Katta Mohan Girisha, Dhanya Lakshmi Narayanan, Parneet Kaur, Reza Maroofian, Maha S. Zaki, Mahmoud M. Noureldeen, Andreas Merkenschlager, Janina Gburek-AugustatElisa Cali, Selina Banu, Kamrun Nahar, Stephanie Efthymiou, Henry Houlden, Rami Abou Jamra, Jason Williams, Christopher R. McMaster, Konrad Platzer

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


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.

Original languageEnglish
Pages (from-to)1916-1923
Number of pages8
Issue number6
Publication statusPublished - 01-06-2022

All Science Journal Classification (ASJC) codes

  • Medicine(all)


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