Hyperekplexia: A Frequent Near Miss in Infants and Young Children.

Hyperekplexia, an underdiagnosed motor paroxysm of infancy, mimics epilepsy closely. It is hallmarked by episodic and excessive startle response, brief episodes of intense, generalized hypertonia, or stiffness in response to unexpected auditory and/or tactile stimuli right from birth. Though a seemingly benign entity with an excellent prognosis, hyperekplexia has been occasionally associated with recurrent apneas, feeding difficulties, and sudden infant death syndrome (SIDS). We describe three unrelated children with hyperekplexia (two SLC6A5; one GLRA1). All three children had the onset of motor paroxysms from the neonatal period and were initially labeled as drug-resistant epilepsy leading to a variable diagnostic delay, the longest being 2.5 years. An excellent response to oral clonazepam with a good neurodevelopmental outcome was observed. The lack of habituation on the nose-tapping test is a simple clinical clue to the diagnosis. Early differentiation from epilepsy minimizes treatment cost, allays caregiver anxiety, and empowers them with abortive measures.

Rescue of two trafficking-defective variants of the neuronal glycine transporter GlyT2 associated to hyperekplexia.

Hyperekplexia is a rare sensorimotor syndrome characterized by pathological startle reflex in response to unexpected trivial stimuli for which there is no specific treatment. Neonates suffer from hypertonia and are at high risk of sudden death due to apnea episodes. Mutations in the human SLC6A5 gene encoding the neuronal glycine transporter GlyT2 may disrupt the inhibitory glycinergic neurotransmission and cause a presynaptic form of the disease. The phenotype of missense mutations giving rise to protein misfolding but maintaining residual activity could be rescued by facilitating folding or intracellular trafficking. In this report, we characterized the trafficking properties of two mutants associated with hyperekplexia (A277T and Y707C, rat numbering). Transporter molecules were partially retained in the endoplasmic reticulum showing increased interaction with the endoplasmic reticulum chaperone calnexin. One transporter variant had export difficulties and increased ubiquitination levels, suggestive of enhanced endoplasmic reticulum-associated degradation. However, the two mutant transporters were amenable to correction by calnexin overexpression. Within the search for compounds capable of rescuing mutant phenotypes, we found that the arachidonic acid derivative N-arachidonoyl glycine can rescue the trafficking defects of the two variants in heterologous cells and rat brain cortical neurons. N-arachidonoyl glycine improves the endoplasmic reticulum output by reducing the interaction transporter/calnexin, increasing membrane expression and improving transport activity in a comparable way as the well-established chemical chaperone 4-phenyl-butyrate. This work identifies N-arachidonoyl glycine as a promising compound with potential for hyperekplexia therapy.

Approach to exaggerated startle reflex: a case of hyperekplexia minor.

A broad set of conditions may present with an exaggerated startle reflex in clinics. This, combined with the overall rarity of these disorders, may pose diagnostic uncertainty in the mind of the treating physician. Herein, we report a case of a patient who presented to us with the complaint of exaggerated startle reflex and outline a simple approach towards characterisation of these disorders.

Weird Laughing in Hyperekplexia: A new phenotype associated with a novel mutation in the GLRA1 gene?

Hyperekplexia (HPX) or startle disease is a rare hereditary neurological disorder characterized by generalized stiffness, excessive startle reflex to unexpected stimuli and a short period of generalized stiffness following the startle response, and can be complicated by umbilical or inguinal hernia, developmental delay and apnea spell. HPX is caused mainly by mutations in the GLRA1 gene, and has a good response to clonazepam. In this short communication we describe an 11-year-old girl with excessive startle reflex, weird laughing and developmental delay since early infancy. She also suffered from infantile spasms and generalized tonic-clonic seizures, and became seizure-free with antiepileptic drugs treatment. However, the weird laughing was still present during the treatment. Her mother also appeared excessive startle reflex during early infancy. A novel mutation in GLRA1 was detected in the girl and her mother. Consequently, she was diagnosed with HPX, and clonazepam was added. The weird laughing was dramatic improved, which hasn't been reported in HPX. This is the first report of weird laughing in a hyperekplexia patient carrying a novel GLRA1 mutation, and expanded the phenotype spectrum of HPX.

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.

[Myoclonus as a movement disorder]. / Myoklonien als Bewegungsstörung.

Myoclonus is often a diagnostic and therapeutic challenge due to its broad phenomenological variability and limited therapeutic options. This article gives a short survey and characterizes in detail two common types of myoclonus, cortical myoclonus and reticular reflex myoclonus. Clinical testing and electrophysiological investigations provide relevant local diagnostic indications for the generating structure(s). Such indications would influence not only the strategies of neuroimaging and laboratory investigations aimed at clarifying the underlying cause but also the selection of drugs to suppress myoclonus.