RESUMEN
Glycinergic neurotransmission is a major inhibitory influence in the CNS and its disruption triggers a paediatric and adult startle disorder, hyperekplexia. The postsynaptic α(1)-subunit (GLRA1) of the inhibitory glycine receptor (GlyR) and the cognate presynaptic glycine transporter (SLC6A5/GlyT2) are well-established genes of effect in hyperekplexia. Nevertheless, 52% of cases (117 from 232) remain gene negative and unexplained. Ligand-gated heteropentameric GlyRs form chloride ion channels that contain the α(1) and ß-subunits (GLRB) in a 2α(1):3ß configuration and they form the predominant population of GlyRs in the postnatal and adult human brain, brainstem and spinal cord. We screened GLRB through 117 GLRA1- and SLC6A5-negative hyperekplexia patients using a multiplex-polymerase chain reaction and Sanger sequencing approach. The screening identified recessive and dominant GLRB variants in 12 unrelated hyperekplexia probands. This primarily yielded homozygous null mutations, with nonsense (n = 3), small indel (n = 1), a large 95 kb deletion (n = 1), frameshifts (n = 1) and one recurrent splicing variant found in four cases. A further three cases were found with two homozygous and one dominant GLRB missense mutations. We provide strong evidence for the pathogenicity of GLRB mutations using splicing assays, deletion mapping, cell-surface biotinylation, expression studies and molecular modelling. This study describes the definitive assignment of GLRB as the third major gene for hyperekplexia and impacts on the genetic stratification and biological causation of this neonatal/paediatric disorder. Driven principally by consanguineous homozygosity of GLRB mutations, the study reveals long-term additive phenotypic outcomes for affected cases such as severe apnoea attacks, learning difficulties and developmental delay.
Asunto(s)
Epilepsia/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Hipertonía Muscular/genética , Receptores de Glicina/genética , Reflejo Anormal/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Niño , Preescolar , Epilepsia/fisiopatología , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/fisiopatología , Predisposición Genética a la Enfermedad , Proteínas de Transporte de Glicina en la Membrana Plasmática/genética , Proteínas de Transporte de Glicina en la Membrana Plasmática/metabolismo , Homocigoto , Humanos , Masculino , Datos de Secuencia Molecular , Hipertonía Muscular/fisiopatología , Mutación , Linaje , Conformación Proteica , Sitios de Empalme de ARN/genética , Receptores de Glicina/química , Receptores de Glicina/metabolismo , Relación Estructura-ActividadRESUMEN
OBJECTIVE: To determine the origin and dynamic characteristics of the generalised hyper-synchronous spike and wave (SW) discharges in childhood absence epilepsy (CAE). METHODS: We applied nonlinear methods, the error reduction ratio (ERR) causality test and cross-frequency analysis, with a nonlinear autoregressive exogenous (NARX) model, to electroencephalograms (EEGs) from CAE, selected with stringent electro-clinical criteria (17 cases, 42 absences). We analysed the pre-ictal and ictal strength of association between homologous and heterologous EEG derivations and estimated the direction of synchronisation and corresponding time lags. RESULTS: A frontal/fronto-central onset of the absences is detected in 13 of the 17 cases with the highest ictal strength of association between homologous frontal followed by centro-temporal and fronto-central areas. Delays consistently in excess of 4â¯ms occur at the very onset between these regions, swiftly followed by the emergence of "isochronous" (0-2â¯ms) synchronisation but dynamic time lag changes occur during SW discharges. CONCLUSIONS: In absences an initial cortico-cortical spread leads to dynamic lag changes to include periods of isochronous interhemispheric synchronisation, which we hypothesize is mediated by the thalamus. SIGNIFICANCE: Absences from CAE show ictal epileptic network dynamics remarkably similar to those observed in WAG/Rij rats which guided the formulation of the cortical focus theory.
Asunto(s)
Corteza Cerebral/fisiopatología , Electroencefalografía/métodos , Epilepsia Tipo Ausencia/fisiopatología , Cuero Cabelludo/fisiopatología , Niño , Preescolar , Femenino , Humanos , Masculino , Dinámicas no LinealesRESUMEN
The authors report a case of hyperekplexia presenting in the neonatal period resistant to clonazepam that responded subsequently to levetiracetam. Hyperekplexia is often misdiagnosed as epilepsy and can be difficult to manage with a particular concern over neonatal apnea and an increased risk of sudden infant death syndrome. The mainstay of therapy to date has been with clonazepam. The authors describe the salient features of their case, clinical diagnosis, and issues pertaining to management. The authors believe this is the first reported case of the use of levetiracetam for effectively treating hyperekplexia within the neonatal and infant period.