Karl Martin Klein

15q13.3 microdeletions increase risk of idiopathic generalized epilepsy

We identified 15q13.3 microdeletions encompassing the CHRNA7 gene in 12 of 1,223 individuals with idiopathic generalized epilepsy (IGE), which were not detected in 3,699 controls (joint P = 5.32 × 10−8). Most deletion carriers showed common IGE syndromes without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia. Our results indicate that 15q13.3 microdeletions constitute the most prevalent risk factor for common epilepsies identified to date.

Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies

Idiopathic generalized epilepsies account for 30% of all epilepsies. Despite a predominant genetic aetiology, the genetic factors predisposing to idiopathic generalized epilepsies remain elusive. Studies of structural genomic variations have revealed a significant excess of recurrent microdeletions at 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 in various neuropsychiatric disorders including autism, intellectual disability and schizophrenia. Microdeletions at 15q13.3 have recently been shown to constitute a strong genetic risk factor for common idiopathic generalized epilepsy syndromes, implicating that other recurrent microdeletions may also be involved in epileptogenesis. This study aimed to investigate the impact of five microdeletions at the genomic hotspot regions 1q21.1, 15q11.2, 16p11.2, 16p13.11 and 22q11.2 on the genetic risk to common idiopathic generalized epilepsy syndromes. The candidate microdeletions were assessed by high-density single nucleotide polymorphism arrays in 1234 patients with idiopathic generalized epilepsy from North-western Europe and 3022 controls from the German population. Microdeletions were validated by quantitative polymerase chain reaction and their breakpoints refined by array comparative genomic hybridization. In total, 22 patients with idiopathic generalized epilepsy (1.8%) carried one of the five novel microdeletions compared with nine controls (0.3%) (odds ratio = 6.1; 95% confidence interval 2.8-13.2; chi(2) = 26.7; 1 degree of freedom; P = 2.4 x 10(-7)). Microdeletions were observed at 1q21.1 [Idiopathic generalized epilepsy (IGE)/control: 1/1], 15q11.2 (IGE/control: 12/6), 16p11.2 IGE/control: 1/0, 16p13.11 (IGE/control: 6/2) and 22q11.2 (IGE/control: 2/0). Significant associations with IGEs were found for the microdeletions at 15q11.2 (odds ratio = 4.9; 95% confidence interval 1.8-13.2; P = 4.2 x 10(-4)) and 16p13.11 (odds ratio = 7.4; 95% confidence interval 1.3-74.7; P = 0.009). Including nine patients with idiopathic generalized epilepsy in this cohort with known 15q13.3 microdeletions (IGE/control: 9/0), parental transmission could be examined in 14 families. While 10 microdeletions were inherited (seven maternal and three paternal transmissions), four microdeletions occurred de novo at 15q13.3 (n = 1), 16p13.11 (n = 2) and 22q11.2 (n = 1). Eight of the transmitting parents were clinically unaffected, suggesting that the microdeletion itself is not sufficient to cause the epilepsy phenotype. Although the microdeletions investigated are individually rare (<1%) in patients with idiopathic generalized epilepsy, they collectively seem to account for a significant fraction of the genetic variance in common idiopathic generalized epilepsy syndromes. The present results indicate an involvement of microdeletions at 15q11.2 and 16p13.11 in epileptogenesis and strengthen the evidence that recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 confer a pleiotropic susceptibility effect to a broad range of neuropsychiatric disorders.

Mutations in DEPDC5 cause familial focal epilepsy with variable foci

The majority of epilepsies are focal in origin, with seizures emanating from one brain region. Although focal epilepsies often arise from structural brain lesions, many affected individuals have normal brain imaging. The etiology is unknown in the majority of individuals, although genetic factors are increasingly recognized. Autosomal dominant familial focal epilepsy with variable foci (FFEVF) is notable because family members have seizures originating from different cortical regions. Using exome sequencing, we detected DEPDC5 mutations in two affected families. We subsequently identified mutations in five of six additional published large families with FFEVF. Study of families with focal epilepsy that were too small for conventional clinical diagnosis with FFEVF identified DEPDC5 mutations in approximately 12% of families (10/82). This high frequency establishes DEPDC5 mutations as a common cause of familial focal epilepsies. Shared homology with G protein signaling molecules and localization in human neurons suggest a role of DEPDC5 in neuronal signal transduction.

Burden Analysis of Rare Microdeletions Suggests a Strong Impact of Neurodevelopmental Genes in Genetic Generalised Epilepsies

Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.

Topiramate, nutrition and weight change: a prospective study

Purpose: To evaluate prospectively the relationship between appetite, food composition, nutritional habits and weight loss following administration of topiramate (TPM) and to identify predictors for TPM induced weight loss. Methods: 22 patients with epilepsy who were started on TPM were prospectively followed for 6 months and contacted again after a mean follow-up time of 37.1 months. Results: Body mass index (BMI) loss occurred in 59% of patients, with a mean weight loss of 9.5 kg after 6 months while receiving TPM without further weight loss at the long term follow-up. Weight loss was associated with reduction in appetite without affecting food composition. Predictors for BMI loss after 6 months were high initial BMI and body fat. After 3 weeks of treatment with TPM, the recorded parameters did not predict BMI loss but at 3 months, weight loss, reduction of appetite and amount of food intake were predictive for the amount of BMI loss after 6 months.

The LaLiMo Trial: lamotrigine compared with levetiracetam in the initial 26 weeks of monotherapy for focal and generalised epilepsy—an open-label, prospective, randomised controlled multicenter study

Background Of the newer antiepileptic drugs, lamotrigine (LTG) and levetiracetam (LEV) are popular first choice drugs for epilepsy. The authors compared these drugs with regard to their efficacy and tolerability in the initial monotherapy for epilepsy. Methods A randomised, open-label, controlled, parallel group, multicenter trial was conducted to test the superiority of the LEV arm over the LTG arm. The primary endpoint was the rate of seizure-free patients in the first 6 weeks (two-sided Fishers exact test, α=0.05, intent-to-treat set). Furthermore, efficacy, tolerability and quality of life were evaluated. The authors included 409 patients aged ≥12 years with newly diagnosed focal or generalised epilepsy defined by either two or more unprovoked seizures or one first seizure with high risk for recurrence. Patients were titrated to 2000 mg/day of LEV or 200 mg/day of LTG reached on day 22 or 71, respectively. Two dose adjustments by 500/50 mg were allowed. Results The proportions of seizure-free patients were 67.5% (LEV) versus 64.0% (LTG) 6 weeks after randomisation (p=0.47), and 45.2% (LEV) versus 47.8% (LTG) during the whole treatment period of 26 weeks. The HR (LEV vs LTG) for seizure-free time was 0.86 (95% CI, 0.61 to 1.22). Adverse events occurred in 74.5% (LEV) versus 70.6% (LTG) of the patients (p=0.38). Adverse events associated with study discontinuation occurred in 17/204 (LEV) versus 8/201 (LTG) patients (p=0.07). Conclusions There were no significant differences with regard to efficacy and tolerability of LEV and LTG in newly diagnosed focal and generalised epilepsy despite more rapid titration in the LEV arm. Clinical trial registration number ClinicalTrials.gov identifier NCT00242606.

Familial focal epilepsy with variable foci mapped to chromosome 22q12: Expansion of the phenotypic spectrum

We aimed to refine the phenotypic spectrum and map the causative gene in two families with familial focal epilepsy with variable foci (FFEVF). A new five‐generation Australian FFEVF family (A) underwent electroclinical phenotyping, and the original four‐generation Australian FFEVF family (B) (Ann Neurol, 44, 1998, 890) was re‐analyzed, including new affected individuals. Mapping studies examined segregation at the chromosome 22q12 FFEVF region. In family B, the original whole genome microsatellite data was reviewed. Five subjects in family A and 10 in family B had FFEVF with predominantly awake attacks and active EEG studies with a different phenotypic picture from other families. In family B, reanalysis excluded the tentative 2q locus reported. Both families mapped to chromosome 22q12. Our results confirm chromosome 22q12 as the solitary locus for FFEVF. Both families show a subtly different phenotype to other published families extending the clinical spectrum of FFEVF.

Phenotypic spectrum of GABRA1 From generalized epilepsies to severe epileptic encephalopathies

Objective: To delineate phenotypic heterogeneity, we describe the clinical features of a cohort of patients with GABRA1 gene mutations. Methods: Patients with GABRA1 mutations were ascertained through an international collaboration. Clinical, EEG, and genetic data were collected. Functional analysis of 4 selected mutations was performed using the Xenopus laevis oocyte expression system. Results: The study included 16 novel probands and 3 additional family members with a disease-causing mutation in the GABRA1 gene. The phenotypic spectrum varied from unspecified epilepsy (1), juvenile myoclonic epilepsy (2), photosensitive idiopathic generalized epilepsy (1), and generalized epilepsy with febrile seizures plus (1) to severe epileptic encephalopathies (11). In the epileptic encephalopathy group, the patients had seizures beginning between the first day of life and 15 months, with a mean of 7 months. Predominant seizure types in all patients were tonic-clonic in 9 participants (56%) and myoclonic seizures in 5 (31%). EEG showed a generalized photoparoxysmal response in 6 patients (37%). Four selected mutations studied functionally revealed a loss of function, without a clear genotype–phenotype correlation. Conclusions: GABRA1 mutations make a significant contribution to the genetic etiology of both benign and severe epilepsy syndromes. Myoclonic and tonic-clonic seizures with pathologic response to photic stimulation are common and shared features in both mild and severe phenotypes.

Sustained seizure remission on perampanel in progressive myoclonic epilepsy (Lafora disease).

Aim The aim of this report is to provide initial evidence that add-on treatment with perampanel might be highly effective in progressive myoclonic epilepsy such as Lafora disease. Case report We report on a 21-year-old woman suffering from persistent myoclonus and generalized tonic–clonic seizures for more than seven years. Additionally, ataxia, a disturbance in speech and gait, as well as a cognitive decline were rapidly progressing. Subsequently, the diagnosis of Lafora disease was confirmed by the identification of a novel homozygous missense mutation in exon 3 of the EPM2A gene (c.538C>G; p.L180V). Adjunctive therapy with perampanel was started in this patient with advanced Lafora disease and was titrated up to 8 mg/day. A sustained and reproducible remission of myoclonus and GTCS could be achieved for a follow-up of three months. After dosage reduction to 6 mg/day, seizures recurred; however, on increasing the daily dose to 10 mg, seizures stopped for another three months. The patient also regained her ability to walk with help and the aid of a walker. Conclusions Perampanel is a selective, noncompetitive antagonist of AMPA-type glutamate receptors and recently licensed as adjunctive therapy for the treatment of refractory focal onset seizures. There is evidence for its effectiveness in generalized epilepsies, and phase III studies for this indication are on the way. Our case illustrates the possibility that perampanel might be a valuable option for treatment in PME. Considering its impressive efficacy in this case, we suggest a prospective, multicenter study evaluating perampanel in PME.

Pregabalin-induced generalized myoclonic status epilepticus in patients with chronic pain

Pregabalin is often used for the treatment of chronic pain syndromes. We here describe two patients with chronic pain and pregabalin-induced myoclonic status epilepticus. Patients treated with pregabalin who experience sudden behavioral changes or mycloni should be investigated for this possible side effect, and pregabalin should be reduced or discontinued if myocloni or status epilepticus occurs.