Impaired glycinergic transmission in hyperekplexia: a model of parasomnia overlap disorder.

We report sleep phenotypes and polysomnographic findings in two siblings with a novel homozygous variant of the GLRA1 gene causing hereditary hyperekplexia (HH). Both sisters had startles during wakefulness and sleep, sleep terrors, and one had symptoms of REM sleep behavior disorder (RBD). Frequent startles were found in NREM sleep associated with NREM parasomnias in deep sleep. In REM sleep, both had motor behaviors and increased phasic/tonic muscle activities confirming RBD. Clonazepam improved startles, motor behaviors, and muscle activities in REM sleep. Impaired glycinergic transmission in human HH could be involved in the pathophysiology of RBD and NREM parasomnias.

Mutations affecting glycinergic neurotransmission in hyperekplexia increase pain sensitivity.

See Dickenson (doi:10.1093/brain/awx334) for a scientific commentary on this article.Inhibitory interneurons in the spinal cord use glycine and GABA for fast inhibitory neurotransmission. While there is abundant research on these inhibitory pain pathways in animal models, their relevance in humans remains unclear, largely due to the limited possibility to manipulate selectively these pathways in humans. Hyperekplexia is a rare human disease that is caused by loss-of-function mutations in genes encoding for glycine receptors and glycine transporters. In the present study, we tested whether hyperekplexia patients display altered pain perception or central pain modulation compared with healthy subjects. Seven patients with genetically and clinically confirmed hyperekplexia were compared to 14 healthy age- and sex-matched controls. The following quantitative sensory tests were performed: pressure pain detection threshold (primary outcome), ice water tolerance, single and repeated electrical pain detection thresholds, nociceptive withdrawal reflex threshold, and conditioned pain modulation. Statistical analysis was performed using linear mixed models. Hyperekplexia patients displayed lower pain thresholds than healthy controls for all of the quantitative sensory tests [mean (standard deviation)]: pressure pain detection threshold [273 (170) versus 475 (115) kPa, P = 0.003], ice water tolerance [49.2 (36.5) versus 85.7 (35.0) s, P = 0.015], electrical single pain detection threshold [5.42 (2.64) versus 7.47 (2.62) mA, P = 0.012], electrical repeated pain detection threshold [3.76 (1.41) versus 5.8 (1.73) mA, P = 0.003], and nociceptive withdrawal reflex [7.42 (3.63) versus 14.1 (6.9) mA, P = 0.015]. Conditioned pain modulation was significantly reduced in hyperekplexia [increase to baseline: 53.2 (63.7) versus 105 (57) kPa, P = 0.030]. Our data demonstrate increased pain sensitivity and impaired central pain modulation in hyperekplexia patients, supporting the importance of glycinergic neurotransmission for central pain modulation in humans.