Jocelyn F. Bautista

De novo mutations in epileptic encephalopathies

Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox–Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10−3). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10−10 and P = 7.8 × 10−12, respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10−8), as has been reported previously for autism spectrum disorders.

Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder

The large conductance calcium-sensitive potassium (BK) channel is widely expressed in many organs and tissues, but its in vivo physiological functions have not been fully defined. Here we report a genetic locus associated with a human syndrome of coexistent generalized epilepsy and paroxysmal dyskinesia on chromosome 10q22 and show that a mutation of the α subunit of the BK channel causes this syndrome. The mutant BK channel had a markedly greater macroscopic current. Single-channel recordings showed an increase in open-channel probability due to a three- to fivefold increase in Ca2+ sensitivity. We propose that enhancement of BK channels in vivo leads to increased excitability by inducing rapid repolarization of action potentials, resulting in generalized epilepsy and paroxysmal dyskinesia by allowing neurons to fire at a faster rate. These results identify a gene that is mutated in generalized epilepsy and paroxysmal dyskinesia and have implications for the pathogenesis of human epilepsy, the neurophysiology of paroxysmal movement disorders and the role of BK channels in neurological disease.

Efficacy and Tolerability of the New Antiepileptic Drugs, II: Treatment of Refractory Epilepsy. Report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society

Summary:  Purpose: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs [AEDs; gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), and zonisamide (ZNS), reviewed in the order in which these agents received approval by the U.S. Food and Drug Administration] in the treatment of children and adults with newly diagnosed partial and generalized epilepsies.

Focal cortical dysplasia and intractable epilepsy in adults: clinical, EEG, imaging, and surgical features.

PURPOSE The clinical features of focal cortical dysplasia (FCD) in adults are poorly understood. The purpose of this report is to describe the clinical, electrographic, and neuroimaging characteristics of adults with FCD undergoing surgical resection for intractable epilepsy. METHODS Case series of 55 patients, aged 17-57 years, with a histopathological diagnosis of FCD. Medical history, neurological examination, non-invasive video-EEG, neuroimaging, and surgical outcome data were analyzed retrospectively. RESULTS There were 36 patients with temporal, 19 with extra-temporal lobe resections. Mean age at surgery was 29 years. Mean age at epilepsy onset was 10 years. Dual pathology was seen in 56% of patients, with 68% of these having hippocampal sclerosis (HS). Epilepsy risk factors included febrile seizures (16%), head trauma (16%), CNS infections (11%), and perinatal stroke (4%). Interictal EEG showed regional epileptiform activity in 89% of patients. Only 24% were diagnosed with FCD pre-operatively. Of those with dual pathology, only 6% were suspected of having FCD pre-operatively. Of those patients with >12 months follow-up, surgical outcomes were as follows: 65% seizure-free, 19% significant improvement, 16% without significant improvement. CONCLUSIONS In this series of adult patients with intractable epilepsy and FCD, a significant number have other seizure risk factors, normal neurological examinations and neuroimaging, and regional EEG findings. Dual pathology was common in patients with FCD. FCD should be considered as an etiology of epilepsy even in patients whose evaluation suggests other mechanisms.

Ultra-rare genetic variation in common epilepsies: a case-control sequencing study

BACKGROUND Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies. METHODS We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies. FINDINGS We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2·3, 95% CI 1·7-3·2, p=9·1 × 10-8; familial non-acquired focal epilepsy 3·6, 2·7-4·9, p=1·1 × 10-17). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5·8 × 10-8) that were lower than expected from a random sampling of genes. INTERPRETATION We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future. FUNDING National Institute of Neurological Disorders and Stroke (NINDS), and Epilepsy Research UK.

Copy number variant analysis from exome data in 349 patients with epileptic encephalopathy

Infantile spasms (IS) and Lennox–Gastaut syndrome (LGS) are epileptic encephalopathies characterized by early onset, intractable seizures, and poor developmental outcomes. De novo sequence mutations and copy number variants (CNVs) are causative in a subset of cases. We used exome sequence data in 349 trios with IS or LGS to identify putative de novo CNVs. We confirm 18 de novo CNVs in 17 patients (4.8%), 10 of which are likely pathogenic, giving a firm genetic diagnosis for 2.9% of patients. Confirmation of exome‐predicted CNVs by array‐based methods is still required due to false‐positive rates of prediction algorithms. Our exome‐based results are consistent with recent array‐based studies in similar cohorts and highlight novel candidate genes for IS and LGS. Ann Neurol 2015;78:323–328

Focal malformations of cortical development

Malformations of cortical development (MCDs) represent a heterogeneous group of disorders characterized by abnormal cortical and glial proliferation, neuronal migration, and cortical organization. Advances in neuroimaging have allowed for the growing recognition of a variety of developmental lesions associated with focal seizures. MCDs were present in 68% of infants and in 26% of children and adolescents with medically refractory epilepsy in recent surgical series.1,2⇓ In 1971, Taylor and Falconer3 described distinctive histopathologic findings in lobectomy specimens from 10 patients with epilepsy. Although the tissue appeared normal on gross examination, microscopically, cortical lamination was disrupted and large, and bizarre neurons were scattered randomly throughout the cortex and white matter. Large, distorted, round cells with clear, multiple nuclei and opalescent cytoplasm, known as balloon cells, were found in the deeper cortical layers and subjacent white matter. These histopathologic findings are referred to as focal cortical dysplasia–Taylor type (FCD-T). Although these pathologic changes were reminiscent of tuberous sclerosis (TS), no patients exhibited clinical or radiologic features of that disorder. FCD now is known to encompass a spectrum of pathologic changes from mild cortical disruption to more severe patterns of cortical dyslamination with large bizarre neurons, balloon cells, and astrocytosis.4 Tassi et al.5 recently differentiated FCD into three histopathologic subgroups and found notable differences in terms of their clinical, EEG, and imaging characteristics. In patients with FDC-T, seizure frequency was higher (nearly 100 seizures per month), and the epileptogenic zone was primarily extratemporal compared with patients with architectural dysplasia characterized by abnormal cortical lamination and ectopic neurons in white matter that were located primarily in the temporal lobe and associated with lower seizure frequency (average daily frequency >1).5 Those with cytoarchitectural dysplasia characterized by altered cortical lamination and giant neurofilament-enriched neurons had a seizure frequency exceeding that of …

Addressing genetic heterogeneity in complex disease: finding seizure genes in systemic lupus erythematosus.

Complex genetic disease is inherently difficult to study due to an imperfect relationship between genotype and phenotype. One important reason for this imperfect relationship is genetic heterogeneity, the occurrence of different genetic factors underlying the same clinical syndrome. One method of addressing genetic heterogeneity is covariate‐based linkage analysis, which allows the use of additional phenotypic features to define genetically distinct subsets of patients. Systemic lupus erythematosus (SLE) is one example of a complex genetic disease affecting multiple organ systems including the central nervous system. We report here the use of covariate‐based linkage analysis to detect a potential genetic locus on chromosome 15 influencing the development of seizures in individuals with SLE. The use of covariates increases the power to detect linkage in the presence of genetic heterogeneity.

Linkage analysis of alcoholism-related electrophysiological phenotypes: genome scans with microsatellites compared to single-nucleotide polymorphisms.

P300 amplitude is an electrophysiological quantitative trait that is correlated with both alcoholism and smoking status. Using the Collaborative Study on the Genetics of Alcoholism data, we performed model-free linkage analysis to investigate the relationship between alcoholism, P300 amplitude, and habitual smoking. We also analyzed the effect of parent-of-origin on alcoholism, and utilized both microsatellites (MS) markers and single-nucleotide polymorphisms (SNPs). We found significant evidence of linkage for alcoholism to chromosome 10; inclusion of P300 amplitude as a covariate provided additional evidence of linkage to chromosome 12. This same region on chromosome 12 showed some evidence for a parent-of-origin effect. We found evidence of linkage for the P300 phenotype to chromosome 7 in non-smokers, and to chromosome 17 in alcoholics. The effects of alcoholism and habitual smoking on P300 amplitude appear to have separate genetic determinants. Overall, there were few differences between MS and SNP genome scans. The use of covariates and parent-of-origin effects allowed detection of linkage not seen otherwise.

Temporal lobe neoplasm and seizures: how deep does the story go?

[March 2008-Cleveland Case Report]. There is a well-described association between the occurrence of developmental tumors and the presence of cortical dysplasia in the neighboring brain tissue. The main surgical approaches in the treatment of medically refractory epilepsy related to such developmental tumors include a lesionectomy versus a tailored cortical resection, often guided by an invasive evaluation. This case report describes the surgical management of a 26-year-old female with olfactory auras evolving into automotor seizures and convulsions, occurring in the context of a right temporo-parietal developmental lesion. It illustrates the pros and cons of various surgical approaches, and discusses some pathophysiological aspects of developmental tumors, dysplasia and epilepsy. [Published with video sequences].