Recurrent homozygous GLRB p.Arg472Ter variant in Palestinian hereditary hyperekplexia: a retrospective genotype–phenotype case series of nine children

Abstract

Hereditary hyperekplexia is a treatable neurogenetic disorder of impaired glycinergic inhibition that may present neonatally with exaggerated startle, generalized stiffness, and life-threatening tonic apneic spells. Data from Palestine remain limited. We aimed to describe the clinical spectrum, molecular findings, diagnostic course, neurodevelopmental outcome, and treatment response of children with genetically confirmed GLRB-related hyperekplexia in the West Bank. We conducted a retrospective descriptive case series of children evaluated in pediatric neurology clinics between 2015 and 2024. Medical records, electroencephalography, brain magnetic resonance imaging, final clinical genetic reports, medication history, complications, and follow-up data were reviewed. Molecular testing had been performed by targeted Sanger sequencing or whole exome sequencing. Data were summarized descriptively. Nine children from seven unrelated families were included: five males (55.6%) and four females (44.4%). All nine (100%) carried the homozygous GLRB c.1414 C > T (p.Arg472Ter) variant and presented from the first day of life with excessive startle, generalized stiffness, tonic apneic spells, and a positive nose tap test. Consanguinity was documented in eight (88.9%), family history in four (44.4%), and a previous alternative diagnosis in five (55.6%), including epilepsy in four (44.4%). EEG was normal in all eight tested patients, and brain MRI was normal in all five imaged patients. Among the eight survivors, seven (87.5%) had a documented developmental concern. Clonazepam was used in all nine patients; tonic apneic spells disappeared or improved in seven (77.8%). This series documents a consistent neonatal phenotype and repeated identification of the same GLRB variant across unrelated Palestinian families, with variable developmental and treatment outcomes. Because population-based ascertainment and haplotype analysis were not performed, the findings should not be interpreted as evidence of population frequency or a founder effect. Early clinical recognition, genetic confirmation, individualized clonazepam management, and structured developmental follow-up are important.