Excessive Startle with Novel GLRA1 Mutations in 4 Chinese Patients and a Literature Review of GLRA1-Related Hyperekplexia

Abstract

Background and Purpose Hyperekplexia (HPX), a rare neurogenetic disorder, is classically characterized by neonatal hypertonia, exaggerated startle response provoked by the sudden external stimuli and followed by a shortly general stiffness. Glycine receptor alpha 1 (GLRA1) is the major pathogenic gene of the disease. We described the clinical manifestations of genetically confirmed HPX patients and made a literature review of GLRA1-related HPX to improve the early recognition and prompt the management of the disorder.Methods Extensive clinical evaluations were analyzed in 4 Chinese HPX patients from two unrelated families. Next generation sequencing was conducted in the probands. Sanger sequence and segregation analysis were applied to confirm the findings.Results All four patients including 3 males and 1 female presented with excessive startle reflex, a cautious gait and recurrent falls. Moreover, startle episodes were dramatically improved with the treatment of clonazepam in all cases. Exome sequencing revealed 2 homozygous GLRA1 mutations in the patients. The mutation c.1286T>A p.I429N has been previously reported, while c.754delC p.L252* is novel.Conclusions HPX is a treatable disease, and clonazepam is the drug of choice. By studying and reviewing the disorder, we summarized the phenotype, expanded the genotype spectrum, and discussed the possible pathogenic mechanisms to enhance the understanding and recognition of the disease. Early awareness of the disease is crucial to the prompt and proper administration, as well as the genetic counseling.

Reduced Serum Levels of Soluble Interleukin-15 Receptor α in Schizophrenia and Its Relationship to the Excited Phenotype

“…In addition, the IL-15Rα KO mice also displayed a higher startle reflex, which manifested as the increased startle amplitude than wild type in this study. The reduced GABA or glycine transmissions, or the increased glutamate transmission might contribute to excessive startle response, also suggesting that IL-15Rα was associated with increased excitability (63)(64)(65)(66). These data promoted the viewpoint that the reduced IL-15Rα not only resulted in schizophrenia, but also contributed to the excitatory phenotype in schizophrenia.…”

Startle Disease: New Molecular Insights into an Old Neurological Disorder

“…3A–C, Table 2). Among them, D70N/R316X in a compound heterozygous form and I401N as a single mutation or in a compound heterozygous form with L224X have not been functionally characterized (Zhan and others 2020; Zhang and others 2020).…”