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Nicolaides–Baraitser syndrome (NCBRS), caused by a mutation in the SMARCA2 gene, which goes along with intellectual disability, congenital malformations, especially of face and limbs, and often difficult-to-treat epilepsy, is surveyed focusing on epilepsy and its treatment. Patients were recruited via "Network Therapy of Rare Epilepsies (NETRE)" and an international NCBRS parent support group. Inclusion criterion is NCBRS-defining SMARCA2 mutation. Clinical findings including epilepsy classification, anticonvulsive treatment, electroencephalogram (EEG) findings, and neurodevelopmental outcome were collected with an electronic questionnaire. Inclusion of 25 NCBRS patients with epilepsy in 23 of 25. Overall, 85% of the participants (17/20) reported generalized seizures, the semiology varied widely. EEG showed generalized epileptogenic abnormalities in 53% (9/17), cranial magnetic resonance imaging (cMRI) was mainly inconspicuous. The five most frequently used anticonvulsive drugs were valproic acid (VPA [12/20]), levetiracetam (LEV [12/20]), phenobarbital (PB [8/20]), topiramate (TPM [5/20]), and carbamazepine (CBZ [5/20]). LEV (9/12), PB (6/8), TPM (4/5), and VPA (9/12) reduced the seizures' frequency in more than 50%. Temporary freedom of seizures (>6 months) was reached with LEV (4/12), PB (3/8), TPM (1/5, only combined with PB and nitrazepam [NZP]), and VPA (4/12). Seizures aggravation was observed under lamotrigine (LTG [2/4]), LEV (1/12), PB (1/8), and VPA (1/12). Ketogenic diet (KD) and vagal nerve stimulation (VNS) reduced seizures' frequency in one of two each. This first worldwide retrospective analysis of anticonvulsive therapy in NCBRS helps to treat epilepsy in NCBRS that mostly shows only initial response to anticonvulsive therapy, especially with LEV and VPA, but very rarely shows complete freedom of seizures in this, rather genetic than structural epilepsy. [ABSTRACT FROM AUTHOR]

Nicolaides–Baraitser syndrome (NCBRS) is a rare disease caused by a mutation in the SMARCA2 gene. Clinical features include craniofacial dysmorphia and abnormalities of the limbs, as well as intellectual disorder and often epilepsy. Hepatotoxicity is a rare complication of the therapy with valproic acid (VPA) and a mutation of the polymerase γ (POLG) might lead to a higher sensitivity for liver hepatotoxicity. We present a patient with the coincidence of two rare diseases, the NCBRS and additionally a POLG1 mutation in combination with a liver hepatotoxicity. The co-occurrence in children for two different genetic diseases is discussed with the help of literature review. [ABSTRACT FROM AUTHOR]

Background SYNGAP1, which encodes a RAS-GTPase-activating protein, is located on the short arm of chromosome 6. Heterozygous SYNGAP1 gene mutations have been associated with autism spectrum disorders, delay of psychomotor development, acquired microcephaly, and several forms of idiopathic generalized epilepsy. Here, we report a patient with a new SYNGAP1 stop mutation, and compare the phenotype with published cases with SYNGAP1 mutations and epilepsy. Patient This 15-year-old nondysmorphic girl with intellectual disability developed drop attacks at the age of 2 years, later clonic and clonic-tonic as well as myoclonic seizures predominantly during sleep. The epilepsy was well-controlled by valproic acid (VPA) and later on with levetiracetam. Electroencephalogram (EEG) showed a complete EEG-normalization with eye opening as well as photosensitivity. Magnetic resonance imaging was normal. Genetic analysis revealed a de novo heterozygous stop mutation (c.348C > A, p.Y116*) in exon 4 of the SYNGAP1 gene. Discussion The main clinical features of our patient (i.e., intellectual disability and idiopathic epilepsy) are compatible with previous reports on patients with SYNGAP1 mutations. The unusual feature of complete EEG normalization with eye opening has not been reported yet for this genetic abnormality. Furthermore, our case provides further support for efficacy of VPA in patients with SYNGAP1 mutation-related epilepsy. [ABSTRACT FROM AUTHOR]

Antiepileptic treatment response has been suggested to be modulated by genetic polymorphisms of drug efflux transporters, in particular ABCB1. Recently, we found a significant association of ABCC2 -24C>T with nonresponse, primarily in the context of generalized epilepsy. Moreover, ABCC2 1249G>A was reported to alter transmembranal carbamazepine transport. Therefore, we aimed to confirm the association of ABCC2 variants with pharmacotherapy-resistance in Caucasians mainly affected by partial epilepsy.A total of 208 patients (114 male; age: 11.3±5.9 years) were genotyped for three putatively functionally relevant polymorphisms of ABCC2 (-24C>T, 1249G>A, 3972C>T). Genotype and haplotype frequencies were compared between responders and nonresponders to first-line antiepileptic treatment.Carriers of the ABCC2 1249G>A variant (417V>I) were more frequent among responders [odds ratio (OR)=2.68 (1.25-5.78); P=0.010]. This association remained significant after adjusting for age, sex and seizure type, [OR=2.88 (1.23-6.73); P=0.015]. The impact of 1249G>A was more pronounced among 64 patients receiving carbamazepine or oxcarbazepine (P=0.005), but nonsignificant in patients receiving other anticonvulsants. ABCC2 -24C>T and 3972C>T showed lack of association to therapy response. Haplotype analyses revealed that haplotype H2 containing solely the 1249A variant allele was more frequent in the responder group [OR=2.98 (1.38-6.44); P=0.004].These data argue for a greater probability of antiepileptic drug response among carriers of the ABCC2 1249A variant that is associated with reduced carbamazepine transport. Although we could not confirm an impact of ABCC2 -24C>T, these results suggest that ABCC2 genotype may also modulate the response to anticonvulsants besides the extensively studied ABCB1 (P-glycoprotein). [ABSTRACT FROM AUTHOR]

The goal of this pilot study was to evaluate the effect of a trigger point-specific physiotherapy on headache frequency, intensity, and duration in children with episodic or chronic tension-type headache. Patients were recruited from the special headache outpatient clinic. A total of 9 girls (mean age 13.1 years; range, 5-15 years) with the diagnosis of tension-type headache participated in the pilot study from May to September 2006 and received trigger point-specific physiotherapy twice a week by a trained physiotherapist. After an average number of 6.5 therapeutic sessions, the headache frequency had been reduced by 67.7%, intensity by 74.3%, and duration by 77.3%. No side effects were noted during the treatment. These preliminary findings suggest a role for active trigger points in children with tension-type headache. Trigger point-specific physiotherapy seems to be an effective therapy in these children. Further prospective and controlled studies in a larger cohort are warranted. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented commenting on pharmacoresistance to anticonvulsive drugs in patients with childhood-onset epilepsy.

Dravet syndrome is a severe developmental and epileptic encephalopathy mostly caused by heterozygous mutation of the SCN1A gene encoding the voltage-gated sodium channel α subunit Nav1.1. Multiple seizure types, cognitive deterioration, behavioral disturbances, ataxia, and sudden unexpected death associated with epilepsy are a hallmark of the disease. Recently approved antiseizure medications such as fenfluramine and cannabidiol have been shown to reduce seizure burden. However, patients with Dravet syndrome are still medically refractory in the majority of cases, and there is a high demand for new therapies aiming to improve behavioral and cognitive outcome. Drug-repurposing approaches for SCN1A -related Dravet syndrome are currently under investigation (i.e., lorcaserin, clemizole, and ataluren). New therapeutic concepts also arise from the field of precision medicine by upregulating functional SCN1A or by activating Nav1.1. These include antisense nucleotides directed against the nonproductive transcript of SCN1A with the poison exon 20N and against an inhibitory noncoding antisense RNA of SCN1A. Gene therapy approaches such as adeno-associated virus–based upregulation of SCN1A using a transcriptional activator (ETX101) or CRISPR/dCas technologies show promising results in preclinical studies. Although these new treatment concepts still need further clinical research, they offer great potential for precise and disease modifying treatment of Dravet syndrome. [ABSTRACT FROM AUTHOR]

We investigated the cognitive and behavioral profile of three distinct groups of epilepsies with a genetic background for intergroup differences: (1) idiopathic/genetic generalized epilepsies (IGE/GGE group); (2) idiopathic focal epilepsies (IFE group); and (3) epilepsies with proven or strongly suggested monogenic or structural/numeric chromosomal etiology (genetic epilepsies, GE group). Cognitive (total IQ and subcategories) and behavioral parameters (CBCL) were assessed at the tertiary epilepsy center of the University of Munich (Germany). We used ANOVA with post-hoc Bonferroni-correction to explore significant mean differences and Fisher's exact test for significant proportional differences of intelligence impairment and behavioral problems. 126 (56 IGE/GGE, 26 IFE, 44 GE) patients were available. Total IQ was 89.0 ± 15.9 (95% CI 84.5–93.4) for IGE/GGE, 94.8 ± 18.1 (95% CI 87.3–102.3) for IFE and 76.4 ± 22.4 (95% CI 67.6–85.3) for GE (p = 0.001). The same trend was significant for all but one IQ subcategory. The rate of patients with an intelligence impairment (total IQ < 70) was higher for GE (40%) than for IGE/GGE (14%) and for IFE (7%) patients (p = 0.033). There were no significant differences between groups for behavior scores and behavioral problems. This study shows that the current ILAE classification of epilepsies with genetic etiology creates a heterogeneous group of patients with respect to cognitive performance but not behavior. These findings may help in further delineating epilepsies as regards cognitive performance, notwithstanding their closely related etiological classification. [ABSTRACT FROM AUTHOR]

Background There are only few reports on patients with duplications of the short arm of chromosome 5, with little information about concomitant epilepsy. Patients We report on two patients with generalized epilepsies since age 2.5 years, in whom array comparative genomic hybridization revealed microduplications of different sizes in the short arm of chromosome 5. Both patients showed developmental delay, and magnetic resonance images were normal. The larger duplication in patient 1, who additionally exhibited dysmorphic features and photosensivity on electroencephalogram, occurred de novo, whereas the smaller duplication in patient 2 was paternally inherited. Discussion The overlapping duplicated region in band 5p13.1 comprises four genes (RICTOR, FYB, C9, and DAB2). Further investigation on patients with duplication 5p and epilepsy are needed to possibly identify a potential susceptibility locus for epilepsy at chromosome 5p13.1. [ABSTRACT FROM AUTHOR]

The article presents a study on the phenotypic spectrum of the Aicardi-Goutières syndrome (AGS), a congenital infection. It states that 26 patients were examined and their laboratory and clinical record were obtained for AGS clinical diagnostic criteria. The results show that among 20 AGS patients, 12 mutations were considered novel while high prevalence of features were revealed which are commonly diagnosed with systemic lupus erythematosus (SLE) patients.