Molecular mechanisms of GlyT2 mutations in startle disease

Hyperekplexia or startle disease affects newborn children and is characterised by an exaggerated startle response and hypertonia in response to acoustic or tactile stimuli. Although rare, this orphan disorder can have serious consequences, including sudden infant death. Fortunately, startle disease can be readily treated using benzodiazepines such as clonazepam, which potentiate inhibitory GABA_A receptor function. A simple intervention called the Vigevano manoeuvre (flexing of the head and limbs towards the trunk) also dissipates and counteracts the effects of acute hypertonia. The primary cause of startle disease is defective inhibitory glycinergic transmission due to mutations in the glycine receptor (GlyR) alpha1 subunit gene (GLRA1). However, rarely, mutations have also been discovered in the genes encoding the GlyR beta subunit (GLRB) and the presynaptic glycine transporter GlyT2 (SLC6A5). I report the characterisation of twenty additional SLC6A5 mutations that revealing new pathogenic mechanisms resulting in loss of GlyT2 function. I also report new clinical characteristics of individuals with GlyT2 mutations that have significant implications for neonatal intervention and patient care. Lastly, I will also provide an update on GlyT2 mutations found in Belgian Blue cattle and Irish Wolfhounds, revealing how rapid genotyping tests can have significant economic and animal welfare impacts.