Genotype-phenotype correlations in hyperekplexia: apnoeas, learning difficulties and speech delay

摘要: Congenital hyperekplexia is a rare, potentially treatable neuromotor disorder. Three major genes of effect are known, and all three affect glycinergic neurotransmission. Two encode for subunits the postsynaptic inhibitory glycine receptor, GLRA1 encoding α1 subunit GLRB β subunit. The third, SLC6A5, encodes cognate presynaptic transporter 2. Ninety-seven individuals had clinical diagnosis confirmed by genetic testing: 61 cases mutations in GLRA1, 24 SLC6A5 12 GLRB. Detailed retrospective analysis ascertained that gene-positive present neonatal period (occasionally prenatally) clonazepam treatment choice (95% found it to be efficacious). We confirm predominantly recessive condition but dominant seen (16%). no evidence ‘major’ or ‘minor’ forms on population basis. Thirty-five gene-negative were studied comparison, their cardinal feature was presentation after first month life (P < 0.001). In addition characteristic ‘stiffness, startles stumbles’ hyperekplexia, apnoea attacks (50 89) delayed development (47 92) frequently reported. Patients with significantly more likely have recurrent infantile apnoeas (RR1.9; P 0.005) than those mutations. developmental delay (RR1.5 0.01; RR1.9 0.03) mutations; 92% reported mild severe speech acquisition. Molecular modelling pathogenic demonstrates specific patterns protein disruption can used predict phenotype severity. acquisition particular, may represent failure neural networks subtle neurogenic migration defects absence release. recommend early testing symptomatic neonates possibly preconception counselling at risk mutations, because challenging phenotype.