INTRODUCTION
Early Infantile Epileptic Encephalopathies (EIEE) are a group of
diseases with onset appearing within the first year of life, where
epileptiform abnormalities interfere with brain development and thus are
believed to contribute to the progressive disturbance in cerebral
function (Berg and Cross, 2010). In contrast, in the recently defined
Developmental and Epileptic Encephalopathies (DEE), developmental
impairment is recognized to occur as a direct consequence of the genetic
mutation, in addition to the potential deleterious effect of epileptic
activity on brain development (Scheffer et al., 2017).
With the transition of next-generation sequencing to genetic diagnostics
the pace of DEE gene discovery has accelerated (Hebbar and Mefford,
2020) with over 100 currently known genetic etiologies (Brunklaus et
al., 2020). Most of the genes involved in these conditions encode
proteins related with one of six fundamental processes: ion transport;
cell growth and differentiation; regulation of synaptic processes;
transport and metabolism of small molecules within and between cells;
and regulation of gene transcription and translation (Symonds and
McTague, 2020).
Cholinergic signalling has been associated with the maintenance of
cortical network excitability balance (Drever et al., 2011). To date,
only mutations in the nicotinic acetylcholine receptor have been
reported as disease-causing in genetic epilepsies (Steinlein et al.,
1995). However, mutations affecting PLCB1 , encoding phospholipase
C isoform β1, which is placed downstream on the muscarinic cholinergic
signalling pathway, have been associated with an EIEE phenotype (Kurian
et al., 2010) and so are mutations in the subunits of the
CHRM1-regulated Kv7 channels (Jentsch, 2000).
In the present work we identify a patient with a point mutation inCHRM1 , providing novel insight into the molecular mechanisms
underlying DEE and further implicate defects in the cholinergic pathway
in severe infantile epilepsies.