In 5 prospectively diagnosed patients with relapsing post–herpes simplex encephalitis (HSE), N‐methyl‐D‐aspartate receptor (NMDAR) antibodies were identified. Antibody synthesis started 1 to 4 weeks ...after HSE, preceding the neurological relapse. Three of 5 patients improved postimmunotherapy, 1 spontaneously, and 1 has started to improve. Two additional patients with NMDAR antibodies, 9 with unknown neuronal surface antibodies, and 1 with NMDAR and unknown antibodies, were identified during retrospective assessment of 34 HSE patients; the frequency of autoantibodies increased over time (serum, p = 0.004; cerebrospinal fluid, p = 0.04). The 3 retrospectively identified NMDAR antibody–positive patients also had evidence of relapsing post‐HSE. Overall, these findings indicate that HSE triggers NMDAR antibodies and potentially other brain autoimmunity. Ann Neurol 2014;75:317–323
Summary
Objective
To gain insight into the mechanisms underlying KCNQ2 encephalopathy by examining the electrophysiologic properties of mutant Kv7.2 channels in different multimeric configurations.
...Methods
We analyzed the genotype‐phenotype relationship in 4 patients with KCNQ2 encephalopathy and performed electrophysiologic analysis of M‐currents mediated by homomeric Kv7.2 or heteromeric Kv7.2/Kv7.3 channels.
Results
Negligible or no current was recorded in cells expressing homomeric E130K, W270R, or G281R de novo mutants, and it was reduced by more than 90% for the L243F maternally inherited mutant. The E130K and G281R mutants presented a marked dominant‐negative behavior, whereas the current density was partially reduced (L243F) or not affected (W270R) when coexpressed with wild‐type Kv7.2 subunits. In contrast, the extent of Kv7.3 “rescue,” which yields negligible currents on its own, followed the sequence E130K > L243F > W270R, whereas no rescue was observed with the G281R mutant. No significant effects on current density were observed when subunits were expressed in a 0.5:0.5:1.0 (Kv7.2:mutant:Kv7.3) DNA ratio to mimic the genetic balance. There was an increase in sensitivity to phosphatidylinositol 4,5‐bisphosphate (PIP2) depletion for W270R/Kv7.3, but no substantial differences were observed when the mutated subunits were coexpressed with Kv7.2 or both Kv7.2 and Kv7.3.
Significance
There was a marked disparity of the impact of these mutations on Kv7.2 function, which varied on association with Kv7.2 or Kv7.3 subunits. Current density of homomeric channels was the most reliable property relating Kv7.2 function to encephalopathy, but other factors are required to explain the milder phenotype for some individuals carrying the maternally inherited L243F mutation. We hypothesize that the role of homomeric Kv7.2 channels for fine‐tuning neuronal connections during development is critical for the severity of the KCNQ2 encephalopathy.
There is ongoing debate regarding the most appropriate definition of status epilepticus. This depends upon the research question being asked. Based on the most widely used “30 min definition,” the ...incidence of childhood convulsive status epilepticus (CSE) in developed countries is approximately 20/100,000/year, but will vary depending, among others, on socioeconomic and ethnic characteristics of the population. Age is a main determinant of the epidemiology of CSE and, even within the pediatric population there are substantial differences between older and younger children in terms of incidence, etiology, and frequency of prior neurological abnormalities or prior seizures. Overall, incidence is highest during the first year of life, febrile CSE is the single most common cause, around 40% of children will have previous neurological abnormalities and less than 15% will have a prior history of epilepsy. Outcome is mainly a function of etiology. However, the causative role of CSE itself on mesial temporal sclerosis and subsequent epilepsy or the influence of age, duration, or treatment on outcome of CSE remains largely unknown. Future studies should aim at clarifying these issues and identifying specific ethnic, genetic, or socioeconomic factors associated with CSE to pinpoint potential targets for its primary and secondary prevention.
ABSTRACT
Guanidinoacetate methyltransferase deficiency (GAMT‐D) is an autosomal recessively inherited disorder of creatine biosynthesis. Creatine deficiency on cranial proton magnetic resonance ...spectroscopy, and elevated guanidinoacetate levels in body fluids are the biomarkers of GAMT‐D. In 74 patients, 50 different mutations in the GAMT gene have been identified with missense variants being the most common. Clinical and biochemical features of the patients with missense variants were obtained from their physicians using a questionnaire. In 20 patients, 17 missense variants, 25% had a severe, 55% a moderate, and 20% a mild phenotype. The effect of these variants on GAMT enzyme activity was overexpressed using primary GAMT‐D fibroblasts: 17 variants retained no significant activity and are therefore considered pathogenic. Two additional variants, c.22C>A (p.Pro8Thr) and c.79T>C (p.Tyr27His) (the latter detected in control cohorts) are in fact not pathogenic as these alleles restored GAMT enzyme activity, although both were predicted to be possibly damaging by in silico analysis. We report 13 new patients with GAMT‐D, six novel mutations and functional analysis of 19 missense variants, all being included in our public LOVD database. Our functional assay is important for the confirmation of the pathogenicity of identified missense variants in the GAMT gene.
We report 13 new patients with GAMT deficiency, six novel mutations in the GAMT gene and functional analysis of 19 missense variants by side‐directed mutagenesis (SDM). By software modelling, p.Pro8Thr and p.Tyr27His were predicted to be pathogenic, but functional analysis showed non‐pathogenicity and p.Arg208Pro predicted not to be pathogenic, but was pathogenic by functional analysis. These findings prove that functional characterization of missense variants in the GAMT gene is essential for the confirmation of the pathogenicity of the missense variants.
Summary Epilepsy in children encompasses several syndromes. The cardinal feature of these syndromes is a predisposition to epileptic seizures but each is associated with different prognoses. The ...goals of treatment will clearly differ between children who become seizure-free on antiepileptic drug (AED) treatment and those children with refractory epilepsy. Treatment should be tailored to the needs of the patient, with a comprehensive approach that addresses the common additional morbidities in children with epilepsy. In this Review, we present an overview of the medical management of epilepsy in children and discuss the dilemmas of everyday practice, such as selection of AED, assessment of outcome, monitoring of treatment, and the decision to withdraw medication when the child is free from seizures. Furthermore, we emphasise the need to establish rational goals for treatment, such as aiming for the best possible quality of life rather than freedom from seizures at all costs.
Highlights • We confirm the existence of a new epilepsy syndrome after HHV6-PALE in children. • It may present with epileptic encephalopathy featuring epileptic spasms. • Bilateral temporal lobe ...involvement may not be evident on MRI in the short-term. • Clinical manifestations are refractory to rituximab and other immunomodulating agents. • Further evidence arguing against an immune-mediated basis is provided.
AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following ...post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca
-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.
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