Objective: To describe novel mutations in a case of hyperekplexia, the patient’s clinical presentation and possible pathophysiological mechanism.

Background: Hyperekplexia is a rare neurological disorder presenting with neonatal hypertonia and exaggerated startle responses with variable incidence of apnea, intellectual disability and speech delay. Mutations in five genes, mostly involved in glycine transport and receptor function have been identified in patients with hyperekplexia (GLRA1, GLRB, SLC6A5, GPHN and ARHGEF9). Our patient has a severe phenotype. Cumulative effect of multiple mutations in two proteins involved in glycinergic neuro-transmission may contribute to pronounced disease severity.

Methods: The patient is a fourteen year old African American male who presented with recurrent apneic episodes in infancy through late childhood, persistent startle and head retraction reflex and mild intellectual disability. Targeted Sanger sequencing of GLRA1 gene and whole exome sequencing were obtained in a clinical sequencing lab.

Results: Compound heterozygous GLRA1 missense variants were identified; maternally inherited c.139G>A and paternally inherited c.284A>C. Additionally, a single maternally inherited missense SLC6A5 variant of uncertain significance (VUS) was identified at c.2171 G>C (p.C724S).

Conclusions: We report hyperekplexia associated with novel compound heterozygous GLRA1 (glycine receptor subunit α) mutations and heterozygous SLC6A5 (presynaptic glycine transporter) VUS. Both GLRA1 mutations result in non-conservative amino acid substitutions likely to impact protein structure. The c139G>A change affects a nucleotide residue conserved across multiple species and the c284A>C alteration impacts a residue conserved across mammals. The SLC6A5 variant results in a non-conservative amino acid substitution likely to impact protein structure, and impacts a nucleotide residue conserved across multiple species. We hypothesize that the GLRA1 variants, affecting glycine receptor function, are likely pathogenic. In addition, we propose that the SLC6A5 variant, affecting glycine transporter, though not pathogenic on its own, may lead in a cumulative fashion to a more severe phenotype. Our patient displays both pronounced learning disability as well as apnea into late childhood, both features less common in GLRA1 associated hyperekplexia suggesting that the SLC6A5 variant may modify the phenotype.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/hyperekplexia-secondary-to-cumulative-novel-glycine-pathway-mutations/