To identify the molecular basis of a fatal syndrome of microcephaly, cortical hyperexcitability, and myasthenia.

We performed clinical and in vitro microelectrode studies of neuromuscular transmission, examined neuromuscular junctions cytochemically and by electron microscopy (EM), and searched for mutations by Sanger and exome sequencing.

Neuromuscular transmission was severely compromised by marked depletion of the readily releasable pool of quanta, but the probability of quantal release was normal. Cytochemical and EM studies revealed normal endplate architecture. Exome sequencing identified a homozygous nonsense mutation in the N-terminal domain of MUNC13-1 (UNC13A) truncating the protein after 101 residues.

Loss of Munc13-1 function predicts that syntaxin 1B is consigned to a nonfunctional closed state; this inhibits cholinergic transmission at the neuromuscular junction and glutamatergic transmission in the brain. Inactivation of syntaxin 1B likely accounts for the patient's cortical hyperexcitability because mutations of syntaxin 1B cause febrile seizures with or without epilepsy, haploinsufficiency of the STX1B is associated with myoclonic astatic epilepsy, and antisense knockdown of stx1b in zebrafish larvae elicits epileptiform discharges. A very recent publication also shows that syntaxin 1B has a separate obligatory role for maintenance of developing and mature neurons and illustrates impaired brain development in syntaxin 1A/1B double knockout mice. We therefore attribute our patient's microcephaly to the truncating homozygous Munc13-1 mutation that consigns syntaxin 1B to a permanently closed nonfunctional state akin to a knockout.