Biallelic PI4KA Mutations Disrupt B-Cell Metabolism and Cause B-Cell Lymphopenia and Hypogammaglobulinemia.

PURPOSE: PI4KA-related disorder is a highly clinically variable condition characterized by neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus) and gastrointestinal (inflammatory bowel disease and multiple intestinal atresia) manifestations. Although features consistent with immunodeficiency (autoimmunity/autoinflammation and recurrent infections) have been reported in a subset of patients, the burden of B-cell deficiency and hypogammaglobulinemia has not been extensively investigated. We sought to describe the clinical presentation and manifestations of patients with PI4KA-related disorder and to investigate the metabolic consequences of biallelic PI4KA variants in B cells. METHODS: Clinical data from patients with PI4KA variants were obtained. Multi-omics analyses combining transcriptome, proteome, lipidome and metabolome analyses in conjunction with functional assays were performed in EBV-transformed B cells. RESULTS: Clinical and laboratory data of 13 patients were collected. Recurrent infections (7/13), autoimmune/autoinflammatory manifestations (5/13), B-cell deficiency (8/13) and hypogammaglobulinemia (8/13) were frequently observed. Patients' B cells frequently showed increased transitional and decreased switched memory B-cell subsets. Pathway analyses based on differentially expressed transcripts and proteins confirmed the central role of PI4KA in B cell differentiation with altered B-cell receptor (BCR) complex and signalling. By altering lipids production and tricarboxylic acid cycle regulation, and causing increased endoplasmic reticulum stress, biallelic PI4KA mutations disrupt B cell metabolism inducing mitochondrial dysfunction. As a result, B cells show hyperactive PI3K/mTOR pathway, increased autophagy and deranged cytoskeleton organization. CONCLUSION: By altering lipid metabolism and TCA cycle, impairing mitochondrial activity, hyperactivating mTOR pathway and increasing autophagy, PI4KA-related disorder causes a syndromic inborn error of immunity presenting with B-cell deficiency and hypogammaglobulinemia.

Loss of seryl-tRNA synthetase (SARS1) causes complex spastic paraplegia and cellular senescence.

BACKGROUND: Aminoacyl-tRNA synthetases (ARS) are key enzymes catalysing the first reactions in protein synthesis, with increasingly recognised pleiotropic roles in tumourgenesis, angiogenesis, immune response and lifespan. Germline mutations in several ARS genes have been associated with both recessive and dominant neurological diseases. Recently, patients affected with microcephaly, intellectual disability and ataxia harbouring biallelic variants in the seryl-tRNA synthetase encoded by seryl-tRNA synthetase 1 (SARS1) were reported. METHODS: We used exome sequencing to identify the causal variant in a patient affected by complex spastic paraplegia with ataxia, intellectual disability, developmental delay and seizures, but without microcephaly. Complementation and serylation assays using patient's fibroblasts and an Saccharomyces cerevisiae model were performed to examine this variant's pathogenicity. RESULTS: A de novo splice site deletion in SARS1 was identified in our patient, resulting in a 5-amino acid in-frame insertion near its active site. Complementation assays in S. cerevisiae and serylation assays in both yeast strains and patient fibroblasts proved a loss-of-function, dominant negative effect. Fibroblasts showed an abnormal cell shape, arrested division and increased beta-galactosidase staining along with a senescence-associated secretory phenotype (raised interleukin-6, p21, p16 and p53 levels). CONCLUSION: We refine the phenotypic spectrum and modes of inheritance of a newly described, ultrarare neurodevelopmental disorder, while unveiling the role of SARS1 as a regulator of cell growth, division and senescence.

Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment.

VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif. Affected individuals carrying de novo non-synonymous variants involving the C-terminal region presented a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. Reconstituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mechanisms. The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key roles of this gene in human brain development and function.

Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.

Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath.

Clinical experience with brivaracetam in a series of 46 children.

OBJECTIVES: The primary objective of the study was to analyze the efficacy of brivaracetam (BRV) in pediatric patients 12 months after starting treatment. The secondary objective was to establish safety 3, 6, and 12 months after starting treatment. MATERIALS AND METHOD: This was an observational and retrospective study. Data were collected from the electronic medical record. Inclusion criteria were as follows: patients under 18 years of age, diagnosis of focal or generalized epilepsy, treatment as an added therapy, initiation of treatment with BRV between June and September 2017, and at least one unprovoked seizure in the year prior to the start of treatment. RESULTS: Forty-six patients were included. The response rate was 65%, including 30% seizure-free patients. The rate of adverse effects was 43.5%, resulting in withdrawal in 16 patients (34.7%). The most common adverse effects were drowsiness (17.3%) and irritability (17.3%). CONCLUSIONS: Brivaracetam is effective in very diverse childhood epilepsies, including some that present with primarily generalized seizures. Given the characteristics of the population studied, we have not been able to confirm a better tolerability of BRV compared with levetiracetam (LEV).

Health-related quality of life and the burden of prolonged seizures in noninstitutionalized children with epilepsy.

OBJECTIVE: This study aimed to provide information on the burden of illness and health-related quality of life (HRQoL) in children with epilepsy who experience prolonged acute convulsive seizures (PACS) in the community setting, and to investigate factors that may predict poor HRQoL in this population. METHODS: Noninstitutionalized children (aged 3-16 years) who had experienced at least one PACS within the past year and had currently prescribed PACS rescue medication were enrolled in a cross-sectional study in Germany, Italy, Spain, and the United Kingdom (Practices in Emergency and Rescue medication For Epilepsy managed with Community-administered Therapy 3 [PERFECT-3]). Clinicians, parents/guardians, and patients completed web-based questionnaires regarding clinical characteristics, PACS frequency, and day-to-day impairment. Patients' HRQoL was rated by clinicians, parents/guardians, and patients themselves using the 5-dimension EuroQol questionnaire (EQ-5D) and summarized as a utility score. Potential predictors of poor HRQoL were tested in individual univariate generalized linear models and a global multivariable model. RESULTS: Enrolled children (N = 286) had experienced 1-400 PACS (median: 4) in the past year. Clinicians reported that 216/281 patients (76.9%) had learning disabilities of varying severity. Mean EQ-5D utility scores rated by clinicians (n = 279), parents (n = 277), and patients (n = 85) were 0.52 (standard deviation: 0.41), 0.51 (0.39), and 0.74 (0.29), respectively. Increasing PACS frequency, increasing severity of learning disability, and specialist school attendance were significantly associated with decreasing EQ-5D utility score. In the multivariable model, having learning disabilities was the best predictor of poor HRQoL. SIGNIFICANCE: Health-related quality of life was very poor in many children with epilepsy whose PACS were managed with rescue medication in the community, with learning disability being the most powerful predictor of patients' HRQoL. Mean EQ-5D utility scores were lower (worse) than published values for many other chronic disorders, indicating that optimal treatment should involve helping children and their families to manage learning disabilities and day-to-day impairments, in addition to preventing seizures.

Homomeric Kv7.2 current suppression is a common feature in KCNQ2 epileptic encephalopathy.

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.

Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum.

Epileptic encephalopathies are genetically heterogeneous severe disorders in which epileptic activity contributes to neurological deterioration. We studied two unrelated children presenting with a distinctive early-onset epileptic encephalopathy characterized by refractory epilepsy and absent developmental milestones, as well as thick and short corpus callosum and persistent cavum septum pellucidum on brain MRI. Using whole-exome sequencing, we identified biallelic mutations in seizure threshold 2 (SZT2) in both affected children. The causative mutations include a homozygous nonsense mutation and a nonsense mutation together with an exonic splice-site mutation in a compound-heterozygous state. The latter mutation leads to exon skipping and premature termination of translation, as shown by RT-PCR in blood RNA of the affected boy. Thus, all three mutations are predicted to result in nonsense-mediated mRNA decay and/or premature protein truncation and thereby loss of SZT2 function. Although the molecular role of the peroxisomal protein SZT2 in neuronal excitability and brain development remains to be defined, Szt2 has been shown to influence seizure threshold and epileptogenesis in mice, consistent with our findings in humans. We conclude that mutations in SZT2 cause a severe type of autosomal-recessive infantile encephalopathy with intractable seizures and distinct neuroradiological anomalies.

Herpes simplex virus encephalitis is a trigger of brain autoimmunity.

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.

Thirteen new patients with guanidinoacetate methyltransferase deficiency and functional characterization of nineteen novel missense variants in the GAMT gene.

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.

Early-onset eyelid stereotypies are a frequent and distinctive feature in Dravet syndrome.

Dravet syndrome (DS) is a severe infantile-onset epilepsy syndrome featuring drug resistant epilepsy, global developmental delay and intellectual disability. In addition to ataxia and progressive crouch gait, Parkinsonism has recently been reported as characteristic in young adults with DS. We describe 5 patients out of a series of 23 patients with DS who present between 12 and 24 months of age with repetitive episodes of eyelid closure, sometimes as fast as eye blinking or flickering. Consistent lack of any EEG correlate in serial video-EEG ruled out an epileptic origin. We propose that this movement disorder, namely 'eyelid stereotypies', might be an early motor trait of SCN1A-associated DS.

The medical management of the epilepsies in children: conceptual and practical considerations.

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.

Effect of rescue medication on seizure duration in non-institutionalized children with epilepsy.

OBJECTIVES: Characterize the real-world management of and outcomes for children with epilepsy receiving rescue medication for prolonged acute convulsive seizures (PACS) in the community. METHODS: PERFECT-3 (Practices in Emergency and Rescue medication For Epilepsy managed with Community-administered Therapy 3) was a European, retrospective observational study. Eligible patients were non-institutionalized children with epilepsy aged 3-16 years who had experienced ≥1 PACS in the past year and had ≥1 currently prescribed PACS rescue medication. Investigators provided clinical assessments and parents/guardians completed questionnaires. Statistical tests were post hoc; p values are descriptive. RESULTS: At enrollment (N = 286), most patients had prescriptions for diazepam (69.2%) and/or midazolam (55.9%); some had two (26.6%) or three (2.4%) prescribed rescue medications. Most patients experienced PACS despite regular anti-epilepsy medication. According to parents, the average duration of their child's seizures without rescue medication was <5 min in 35.7% of patients, 5-<20 min in 42.6%, and ≥20 min in 21.7% (n = 258); with rescue medication seizure duration was <5 min in 69.4% of patients, 5-<20 min in 25.6%, and ≥20 min in 5.0%. Rescue medication use was significantly associated with average seizures lasting <5 min (χ2 = 58.8; p < 0.0001). At the time of their most recent PACS, 58.5-67.8% of children reportedly received rescue medication within 5 min of seizure onset, and 85.4-94.1% within 10 min. CONCLUSION: This study provides the first real-world data that rescue medications administered in the community reduce the duration of PACS in children with epilepsy. Study limitations including potential recall bias are acknowledged.

Treatment outcome of twenty-two patients with guanidinoacetate methyltransferase deficiency: An international retrospective cohort study.

PURPOSE: Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder caused by pathogenic variants in GAMT. Brain creatine depletion and guanidinoacetate accumulation cause developmental delay, seizures and movement disorder. Treatment consists of creatine, ornithine and arginine-restricted diet. We initiated an international treatment registry using Research Electronic Data Capture (REDCap) software to evaluate treatment outcome. METHODS: Physicians completed an online REDCap questionnaire. Clinical severity score applied pre-treatment and on treatment. RESULTS: There were 22 patients. All had developmental delay, 18 had seizures and 8 had movement disorder. Based on the clinical severity score, 5 patients had a severe, 14 patients had a moderate and 3 patients had a mild phenotype. All patients had pathogenic variants in GAMT. The phenotype ranged from mild to moderate in patients with the most common c.327G > A variant. The phenotype ranged from mild to severe in patients with truncating variants. All patients were on creatine, 18 patients were on ornithine and 15 patients were on arginine- or protein-restricted diet. Clinical severity score improved in 13 patients on treatment. Developmental delay improved in five patients. One patient achieved normal development. Eleven patients became seizure free. Movement disorder resolved in four patients. CONCLUSION: In our small patient cohort, there seems to be no phenotype-genotype correlation. Creatine and ornithine and/or arginine- or protein-restricted diet were the most useful treatment to improve phenotype.

Outcome of paediatric convulsive status epilepticus: a systematic review.

We did a systematic review on the outcome of paediatric convulsive status epilepticus (CSE) and investigated the role of biological and non-biological variables in reported outcomes. The methodological quality of the 63 studies that met our inclusion criteria was assessed. Study design, type of study, and length of follow-up influenced the outcome. The studies with highest methodological quality are associated with better outcome: short-term mortality between 2.7% and 5.2% and morbidity other than epilepsy less than 15%. The incidence of subsequent epilepsy is not increased after cryptogenic CSE. Causal factor is the main determinant of outcome and the effect of age or duration is difficult to separate from the underlying cause. The risk of sequelae in unprovoked and febrile CSE is low. There is some evidence that CSE, especially febrile CSE, might cause hippocampal injury, although its role in the development of mesial temporal sclerosis is unknown.

Levetiracetam and Valproate Retention Rate in Juvenile Myoclonic Epilepsy.

BACKGROUND: Valproic acid (VPA) is an effective treatment in juvenile myoclonic epilepsy (JME), but concerns on its use during pregnancy are remarkable. Levetiracetam (LEV) is approved as second-line therapy, and used as monotherapy in clinical practice. Our objective was to analyze the outcome of LEV and VPA in JME. MATERIALS AND METHODS: We analyzed patients with JME attending our epilepsy unit between 2010 and 2014, including all patients treated with LEV and/or VPA at some point of the disease course. The primary end point was drug retention rate in monotherapy after the final analysis. RESULTS: We identified 58 patients (62% women). All had myoclonic seizures, 86% had generalized tonic-clonic seizures (GTCS) before the diagnosis, and 9% also had absences. All had generalized spike and wave on the interictal electroencephalogram, and 86% of them also had generalized polyspike and wave discharges. In total, LEV monotherapy was maintained in 15 (65%) of 23 patients, and VPA was maintained in 37 (74%) of 50 patients (P = 0.062). In women younger than 35 years, LEV had a similar retention rate with VPA (P = 0.939). More VPA patients achieved seizure freedom during follow-up (P < 0.01), whereas LEV patients showed a trend toward higher myoclonic freedom (0.085). CONCLUSIONS: Levetiracetam showed lower retention rate than VPA, primarily due to poorer seizure control during long-term follow-up. More LEV patients achieved myoclonic seizure freedom than VPA patients. In women younger than 35 years, LEV and VPA had comparable retention rate; therefore, LEV could be a good option for women with JME with prominent myoclonic seizures.

Error innat del metabolisme diagnosticat després d'encefalopatia hiperamonièmica induïda per valproat / Error innato del metabolismo diagnosticado tras encefalopatía hiperamoniémica inducida por valproato / Inborn error of metabolism diagnosed after valproate -induced hyperammonemic encephalopathy

Introducció: L’àcid valproic és un fàrmac antiepilèptic utilitzat àmpliament, tant per tractar l’epilèpsia com en patologia psiquiàtrica o migranya. Tot i que els seus efectessecundaris més freqüents són lleus i coneguts, determinatspacients poden presentar reaccions idiosincràtiques menysconegudes i potencialment greus. Cas clínic: Pacient de 10 anys amb antecedent d’epilèpsia,en el moment actual sense tractament. En el context denova crisi i administració d’àcid valproic, presenta un quadre d’instauració gradual caracteritzat per somnolència,vòmits i alteració conductual amb agressivitat verbal i física. Davant la sospita de reacció adversa farmacològica,se sol·liciten nivells plasmàtics de valproat (normals), nivells d’amoni (elevats) i funció hepàtica i renal (normals). L’electroencefalograma evidencia un alentiment generalitzat compatible amb encefalopatia. L’estudi metabòlic ensang i orina identifica alteracions compatibles amb un trastorn de la β-oxidació dels àcids grassos de cadena mitjana. L’estat clínic del pacient millora al cap de 48 hores del’ingrés amb la retirada del fàrmac, dieta absoluta ambseroterapia i administració de carnitina i àcid carglúmic. Comentaris: Per la seva simptomatologia inespecífica,l’encefalopatia per àcid valproic es pot confondre amb altres patologies, per la qual cosa és important tenir un elevat índex de sospita i fer estudis bioquímics complerts,tant per confirmar el diagnòstic com per excloure altresmalalties de base.(AU)

Introducción: El ácido valproico es un antiepiléptico muy empleadopara el tratamiento de distintas formas de epilepsia, además depara patología psiquiátrica o migraña. Aunque sus efectos adversos son en su mayoría leves y bien conocidos, algunos pacientespueden presentar reacciones idiosincráticas menos conocidas ypotencialmente graves. Caso clínico: Paciente de 10 años, con antecedentes de epilepsia,actualmente sin tratamiento. Tras una nueva crisis y en tratamiento con ácido valproico, presenta un cuadro de instauración radual con somnolencia, vómitos y alteración conductual conagresividad verbal y física. Ante la sospecha de una reacción farmacológica adversa, se solicitan niveles plasmáticos de valproato(normales), niveles de amonio (elevados) y función hepatorrenal(normal). El electroencefalograma evidencia un enlentecimientogeneralizado compatible con encefalopatía. El estudio metabólicoen sangre y orina identifica alteraciones compatibles con un defecto en la β-oxidación de los ácidos grasos de cadena media. Elestado clínico del paciente mejoró a las 48 horas del ingreso conla retirada del fármaco, dieta absoluta y sueroterapia, administración de carnitina endovenosa y ácido carglúmico.Comentarios: Por su sintomatología inespecífica, la encefalopatíapor ácido valproico puede confundirse con otras entidades, por loque es importante tener un alto índice de sospecha y realizar estudios bioquímicos completos tanto para la confirmación del diagnóstico como para excluir otras enfermedades de base.(AU)

Introduction: Valproic acid is an antiepileptic drug that is commonly used not only to treat epilepsy, but also for several psychiatric conditions and migraine. Most of its side effects are mild andwell known. However, some patients may present less knownidiosyncratic, potentially life-threatening side effects. Case report: A 10-year-old boy with history of epilepsy, currently offtreatment, presented with a new seizure. After treatment with valproic acid was initiated, the patient progressively developed altered consciousness with drowsiness, vomiting and physical andverbal aggressiveness. Valproate plasma levels and liver and renalfunction were withing normal limits, but ammonia levels were elevated. An electroencephalogram showed diffuse slow wave activity,suggestive of encephalopathy. Metabolic studies, in blood andurine, identified alterations on β-oxidation of medium chain fattyacid pathways. The patient’s clinical condition improved within 48hours after discontinuation of valproic acid, fasting, and administration of intravenous fluids, carglumic acid and carnitine. Comments: Because of its unspecific symptoms, hyperammonemicencephalopathy induced by valproate can be confused with otherillnesses. For this reason, it is important to have a high level ofsuspicion and perform a comprehensive laboratory evaluation toconfirm the diagnosis and rule out other conditions.(AU)

Clinical and genetic analysis in alternating hemiplegia of childhood: ten new patients from Southern Europe.

Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder featuring attacks of hemiplegia and other paroxysmal and non-paroxysmal manifestations leading to progressive neurological impairment. De novo mutations in ATP1A3 have been identified in up to 80% of patients. AHC is also associated with rare mutations in other genes involved in episodic neurological disorders. We sought to find mutations in ATP1A3, CACNA1A, ATP1A2, SCN1A and SLC2A1 in a cohort of ten unrelated patients from Spain and Greece. All patients fulfilled AHC diagnostic criteria. All five genes were amplified by PCR and Sanger sequenced. Copy number variation (CNV) analysis of SLC2A1 and CACNA1A was performed using two different approaches. We identified three previously described heterozygous missense ATP1A3 mutations (p.Asp801Asn, p.Glu815Lys and p.Gly947Arg) in five patients. No disease-causing mutations were found in the remaining genes. All mutations occurred de novo; carriers presented on average earlier than non-carriers. Intellectual disability was more severe with the p.Glu815Lys variant. A p.Gly947Arg carrier harbored a maternally-inherited CACNA1A p.Ala454Thr variant. Of note, three of our patients exhibited remarkable clinical responses to the ketogenic diet. We confirmed ATP1A3 mutations in half of our patients. Further AHC genetic studies will need to investigate large rearrangements in ATP1A3 or consider greater genetic heterogeneity than previously suspected.

[Cost-effectiveness of buccal midazolam in the treatment of prolonged convulsive seizures in the outpatient setting in Spain]. / Coste-efectividad de una solucion bucal de midazolam en el tratamiento de las crisis convulsivas prolongadas en el entorno ambulatorio en España.

INTRODUCTION: To be able to treat prolonged epileptic crises practical, safe and effective rescue medication is needed. Today, the standard treatment in community healthcare is rectal diazepam. The introduction of a buccal solution of midazolam opens up a new perspective in their treatment. AIMS: To evaluate the cost-effectiveness of buccal midazolam with respect to rectal diazepam for children diagnosed with epilepsy who present prolonged convulsive seizures in the community setting in Spain. MATERIALS AND METHODS: The study produces a model of its cost-effectiveness from the perspective of the Spanish National Health System (SNS), with the outcomes presented in terms of cost-quality adjusted life years. Data were collected from different sources, including estimations regarding the clinical effectiveness from a clinical trial, from a Delphi panel in Spain and from a national survey carried out on parents of children with epilepsy in order to determine the current practices. RESULTS: Treatment with buccal midazolam produces a saving in costs in comparison to rectal diazepam. The amount saved by the Spanish SNS comes to 5,484 euros per patient per year. Treatment with buccal midazolam offers an improved health-related quality of life. This, together with the savings in costs, means that there is a dominance of buccal midazolam over rectal diazepam in all the settings that have been examined. CONCLUSIONS: The results obtained with the model show that buccal midazolam is more cost-effective than rectal diazepam due to a reduction in the need to call out ambulances and for stays in hospital, as well as an improved health-related quality of life.

TITLE: Coste-efectividad de una solucion bucal de midazolam en el tratamiento de las crisis convulsivas prolongadas en el entorno ambulatorio en España.Introduccion. El tratamiento de las crisis epilepticas prolongadas requiere disponer de una medicacion de rescate comoda, segura y efectiva. Actualmente, el tratamiento estandar en la comunidad es el diacepam rectal. La introduccion de una solucion bucal de midazolam abre una perspectiva nueva en el tratamiento. Objetivo. Evaluar el coste-efectividad del midazolam bucal respecto al diacepam rectal para los niños con un diagnostico de epilepsia que presentan crisis convulsivas prolongadas en la comunidad en España. Materiales y metodos. Modelo coste-efectividad desde la perspectiva del Sistema Nacional de Salud (SNS) español, con resultados presentados en terminos de costes y años de vida ajustados por calidad. Los datos se obtuvieron de varias fuentes, incluidas las estimaciones de efectividad clinica de un ensayo clinico, de un panel Delphi en España y de una encuesta nacional a padres de niños con epilepsia para determinar las practicas actuales. Resultados. El tratamiento con midazolam bucal produce un ahorro de costes en comparacion con el diacepam rectal. El ahorro para el SNS español es de 5.484 euros por paciente al año. El tratamiento con midazolam bucal ofrece una mejora en la calidad de vida relacionada con la salud. Esto, unido al ahorro de costes, hace que el midazolam bucal sea dominante frente al diacepam rectal en todos los escenarios examinados. Conclusion. Los resultados del modelo muestran que el midazolam bucal es mas coste-efectivo que el diacepam rectal debido a una reduccion en la necesidad de llamadas a la ambulancia y estancias en el hospital, asi como a una mejora en la calidad de vida relacionada con la salud.