GLRB – Hereditary Hyperekplexia

Hereditary hyperekplexia is a rare neurogenetic disorder characterized by exaggerated startle responses, hypertonia, and neonatal apnea due to disruption of glycinergic inhibitory neurotransmission. The GLRB gene encodes the β‐subunit of the glycine receptor, essential for receptor assembly and synaptic localization. Pathogenic variants in GLRB have been linked to autosomal recessive hyperekplexia and expand the diagnostic gene panel for startle disease. Cosegregation and functional predictions support a loss‐of‐function mechanism.

Genetic Evidence

Autosomal recessive inheritance is established by homozygous GLRB mutations in consanguineous pedigrees. A large family of nine affected individuals harbored a homozygous missense variant c.596T>G (p.Met199Arg) segregating with disease ([PMID:21391991]) and two unrelated neonates from separate consanguineous families presented with homozygous truncating variant c.1414C>T (p.Arg472Ter) ([PMID:40337415]). In total, 11 probands across two independent consanguineous lineages illustrate fair replication in multiple families.

Segregation analysis in the nine‐member pedigree shows eight additional affected relatives homozygous for c.596T>G, consistent with recessive inheritance and full penetrance at early ages. No heterozygous carriers displayed overt clinical features, supporting a loss‐of‐function mechanism.

Variant spectrum includes one conserved methionine‐to‐arginine substitution (p.Met199Arg) and a premature termination codon (p.Arg472Ter). Both variants disrupt highly conserved domains of the GlyR β‐subunit and are absent from population databases, indicating pathogenicity and founder effects in consanguineous populations.

Functional Evidence

In silico modelling predicts that p.Met199Arg perturbs the transmembrane interface and glycine binding, reducing receptor conductance and synaptic clustering ([PMID:21391991]). While no direct electrophysiological assays were performed for these specific variants, similar GLRB truncating alleles in startle disease have demonstrated complete loss of glycine‐evoked currents.

Clinical Correlation & Spectrum

Affected individuals uniformly exhibit exaggerated startle response (HP:0002267), hypertonia, and neonatal stiffness, with seven of nine family members demonstrating esotropia (HP:0000565) and a minority showing atypical behavior (HP:0000708). Early diagnosis allows prompt initiation of clonazepam therapy to prevent apnea and reduce SIDS risk.

No conflicting reports dispute the GLRB–hyperekplexia association. The genetic and phenotypic concordance across independent families, coupled with functional predictions, meet criteria for a strong gene–disease relationship.

Key Take-home: Biallelic pathogenic variants in GLRB cause autosomal recessive hyperekplexia by loss of glycine receptor β‐subunit function, supporting inclusion of GLRB in diagnostic panels for startle syndromes.

References

• Clinical Genetics • 2012 • Novel mutation in GLRB in a large family with hereditary hyperekplexia. PMID:21391991
• Annals of Medicine and Surgery • 2025 • A novel GLRB mutation in neonatal hyperekplexia with divergent EEG findings: a case series. PMID:40337415

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