Hyperekplexia is a human neurological disorder characterized by an excessive startle response and is typically caused by missense and nonsense mutations in the gene encoding the inhibitory glycine receptor (GlyR) α1 subunit (GLRA1)1,2,3. Genetic heterogeneity has been confirmed in rare sporadic cases, with mutations affecting other postsynaptic glycinergic proteins including the GlyR β subunit (GLRB)4, gephyrin (GPHN)5 and RhoGEF collybistin (ARHGEF9)6. However, many individuals diagnosed with sporadic hyperekplexia do not carry mutations in these genes2,3,4,5,6,7. Here we show that missense, nonsense and frameshift mutations in SLC6A5 (ref. 8), encoding the presynaptic glycine transporter 2 (GlyT2), also cause hyperekplexia. Individuals with mutations in SLC6A5 present with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnea episodes. SLC6A5 mutations result in defective subcellular GlyT2 localization, decreased glycine uptake or both, with selected mutations affecting predicted glycine and Na+ binding sites.
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We thank E.A. Peeters and K. Braun for referrals of research participants. This work was supported by grants from the Medical Research Council (UK) to R.J.H. and T.G.S., from the Neurological Foundation for New Zealand and Auckland Medical Research Foundation to M.I.R. and from the Fédération pour la Recherche sur le Cerveau and the Association Française contre les Myopathies to S.S.
Patient 6 Video. When placed in water for his bath, he developed rapid quivering of his limbs, with a staccato grunting cry, followed by silence and intense stiffening in a semi-flexed posture. He became deeply cyanosed and had anoxic non-epileptic seizures in the form of spasms, together with forcible urination. Thereafter he had a grey moribund appearance. When an episode was induced with EEG and ECG leads attached, EMG “spikes” appeared on EEG channels overlying muscle and on the ECG channel, either as repetitive giant potentials in the “clonic” phase or as closely spaced giant muscle potentials in the “tonic” phase. Meanwhile the EEG became isoelectric, and the ECG showed junctional bradycardia, reflecting severe syncope.
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The astrocytic transporter SLC7A10 (Asc-1) mediates glycinergic inhibition of spinal cord motor neurons
Scientific Reports (2016)