Samuel F Berkovic

Publications of Samuel F Berkovic

• Rare protein sequence variation in SV2A gene does not affect response to levetiracetam.

  Authors: Leanne M Dibbens, Bree L Hodgson, Katherine L Helbig, Karen L Oliver, John C Mulley, Samuel F Berkovic, Ingrid E Scheffer

  Epilepsy research. 04/2012;

  Levetiracetam, a broad spectrum antiepileptic drug, binds to membrane protein SV2A. The protein coding region of SV2A was sequenced in 158 patients with focal or generalized epilepsies divided intoLevetiracetam, a broad spectrum antiepileptic drug, binds to membrane protein SV2A. The protein coding region of SV2A was sequenced in 158 patients with focal or generalized epilepsies divided into three groups based on their response to levetiracetam: responders (>75% decrease), exacerbators (50% increase) and non-responders. Nonsynonymous coding variation within SV2A was extremely rare, suggesting that rare variation is not likely to account for the individual differences in response to levetiracetam.

• Familial adult myoclonic epilepsy: recognition of mild phenotypes and refinement of the 2q locus.

  Authors: Douglas E Crompton, Lynette G Sadleir, Catherine J Bromhead, Melanie Bahlo, Susannah T Bellows, Todor Arsov, Rosemary Harty, Kate M Lawrence, John W Dunne, Samuel F Berkovic, Ingrid E Scheffer

  Archives of neurology. 04/2012; 69(4):474-81.

  Familial adult myoclonic epilepsy (FAME) is an autosomal dominant syndrome characterized by a core triad of cortical tremor, multifocal myoclonus, and generalized tonic-clonic seizures. To expand theFamilial adult myoclonic epilepsy (FAME) is an autosomal dominant syndrome characterized by a core triad of cortical tremor, multifocal myoclonus, and generalized tonic-clonic seizures. To expand the phenotypic spectrum of FAME, to highlight diagnostic pointers to this underrecognized disorder, and to refine the FAME2 genetic locus. Observational family study. The study was coordinated in a tertiary academic hospital, with data acquired in diverse primary, secondary, and tertiary care settings. Consenting members of a single large family. A 6-generation FAME kindred of European descent was ascertained in New Zealand and Australia. Affected family members (N = 55) had fine hand tremor, with onset typically in adolescence (median age, 15 years; age range, 4-60 years). Proximal myoclonus was present in 44 of 55 (80%), arising later than hand tremor (median age, 17 years; age range, 5-60 years). Generalized tonic-clonic seizures occurred in 8 of 55 (15%), with a median age at onset of 43.5 years (age range, 18-76 years). Neurophysiological testing confirmed features of cortical reflex myoclonus. Genetic mapping narrows the FAME2 (OMIM 607876) locus on chromosome 2 to a 13.3-megabase interval, harboring 99 known protein-coding genes. The most common FAME phenotype in this large family is mild postural hand tremor resembling essential tremor, combined with subtle proximal myoclonus. Generalized tonic-clonic seizures are uncommon and occur around sleep onset following severe generalized myoclonus.

• Long-term seizure outcome and risk factors for recurrence after extratemporal epilepsy surgery.

  Authors: Anne M McIntosh, Clare A Averill, Renate M Kalnins, L Anne Mitchell, Gavin C A Fabinyi, Graeme D Jackson, Samuel F Berkovic

  Epilepsia. 03/2012;

  Purpose:  We aimed to assess long-term seizure outcome and risk factors for seizure recurrence in a cohort of patients who have undergone extratemporal resection for management of refractoryPurpose:  We aimed to assess long-term seizure outcome and risk factors for seizure recurrence in a cohort of patients who have undergone extratemporal resection for management of refractory seizures. Methods:  Eighty-one patients underwent extratemporal resection at Austin Health, Melbourne, Australia (1991-2004). Seizure recurrence was any postoperative disabling seizure (complex partial seizure [CPS] ± secondary generalization). Multivariate Cox proportional hazards regression models examined potential preoperative and perioperative risk factors and the risk associated with early postoperative seizures (≤28 days postsurgery). The change between preoperative and postoperative seizure frequency was also measured. Key Findings:  Median follow-up was 10.3 years (range 1-17.7). The probabilities of freedom from disabling seizures (on or off antiepileptic medication) were 40.7% (95% confidence interval [CI] 30-51) at 1 month, 23.5% (95% CI 15-33) at 1 year, and 14.7% (95% CI 8-23) at 5 years postoperative. Reduction of disabling seizures to at least 20% of preoperative frequency was attained by 57% of patients at 5 postoperative years. Of the preoperative/perioperative factors, focal cortical dysplasia (FCD) type 1 (hazard ratio [HR] 1.90, 95% CI 1.08-3.34, p = 0.025) and incomplete resection (HR 1.71, 95% CI 1.06-2.76, p = 0.028) were independent recurrence risks. After surgery, an early postoperative seizure was the only factor associated with higher risk (HR 4.28 [2.42-7.57], p = 0.00). Significance:  Distinction between subtypes of focal cortical dysplasia, which can be made using magnetic resonance imaging (MRI) criteria, may be useful for preoperative prognostication. Early seizures after surgery are not benign and may be markers of factors that contribute to seizure recurrence. Most patients achieve substantial reduction in seizure frequency. Further study of the significance of this reduction in terms of surgical "success" or otherwise is required.

• Progressive Gait Deterioration in Adolescents With Dravet Syndrome.

  Authors: Jill M Rodda, Ingrid E Scheffer, Jacinta M McMahon, Samuel F Berkovic, H Kerr Graham

  Archives of neurology. 03/2012;

  OBJECTIVE: To characterize changes in gait by age in patients with Dravet syndrome. DESIGN: Prospective, cross-sectional study. SETTING: Tertiary children's hospital. Patients Twenty-six subjectsOBJECTIVE: To characterize changes in gait by age in patients with Dravet syndrome. DESIGN: Prospective, cross-sectional study. SETTING: Tertiary children's hospital. Patients Twenty-six subjects with Dravet syndrome, aged 2 to 34 years. Twenty-three patients had mutations of the sodium channel α1 subunit gene, SCN1A. INTERVENTIONS: Assessment via video gait analysis, physical examination of the lower limbs, use of the Functional Mobility Scale, and radiographs of the pelvis and feet. MAIN OUTCOME MEASURES: Classification of the sagittal gait pattern and foot posture, assessment of muscle extensibility and joint range, and rating of functional mobility. RESULTS: Children aged 0 to 5 years had a normal or near-normal gait, whereas 5 of 10 children aged 6 to 12 years and 8 of 9 children aged 13 years or older had crouch gait. Physical examination showed that with increasing age, passive knee extension (P = .008) and hip extension (P = .003) decreased, external tibial torsion (P = .007) and pes planovalgus (P = .05) increased, and increased hip internal rotation did not show age-related change (P = .27). The Functional Mobility Scale showed universal independent walking over 5 and 50 m; however, adolescents showed wide variation in their ratings over 500 m, indicating mobility ranging from wheelchair use to independent walking (P = .02). CONCLUSIONS: Children with Dravet syndrome show progressive gait deterioration in the second decade of life, with crouch gait and skeletal malalignment comprising increased femoral neck anteversion, external tibial torsion, and pes valgus. These age-related changes have a significant impact on mobility and independence in the community setting.

• Febrile infection-related epilepsy syndrome is not caused by SCN1A mutations.

  Authors: Daniel Carranza Rojo, A Simon Harvey, Xenia Iona, Leanne M Dibbens, John A Damiano, Todor Arsov, Deepak Gill, Jeremy L Freeman, Richard J Leventer, Angela Vincent, Samuel F Berkovic, Jacinta M McMahon, Ingrid E Scheffer

  Epilepsy research. 02/2012;

  Two distinctive epileptic encephalopathies, febrile infection-related epilepsy syndrome (FIRES) and Dravet syndrome (DS), present with febrile status epilepticus in a normal child followed byTwo distinctive epileptic encephalopathies, febrile infection-related epilepsy syndrome (FIRES) and Dravet syndrome (DS), present with febrile status epilepticus in a normal child followed by refractory focal seizures and cognitive decline although there are differentiating features. Abnormalities of the sodium channel gene SCN1A are found in 75% of DS patients. We found no SCN1A mutations or copy number variants in 10 patients with FIRES. Other genetic etiologies deserve consideration.

• Significance of post-operative auras after temporal lobectomy: A surprising methodological trap.

  Authors: Daniel W Kinsella, Clare A Averill, Samuel F Berkovic, Anne M McIntosh

  Epilepsy & behavior : E&B. 02/2012; 23(3):348-52.

  We aimed to examine post-operative auras/simple partial seizures and the associated risk of seizure recurrence after temporal lobectomy. Included were 159 patients who underwent anterior temporalWe aimed to examine post-operative auras/simple partial seizures and the associated risk of seizure recurrence after temporal lobectomy. Included were 159 patients who underwent anterior temporal lobectomy (1995-2006) at Austin Health, Australia. Initial analyses used Cox regression. Post-hoc, exploratory analyses of aura and seizure patterns were undertaken. Initial analyses indicated that post-operative auras were not associated with subsequent disabling seizures (HR 0.65, 95%CI 0.4-1.1 p=0.08). However, post-hoc examination found data patterns that suggest that post-operative auras may have been under-reported when medical contact between these events was absent. These findings are relevant to current research, as similar methodology is commonly employed in post-operative outcome studies. Important implications include potential underestimation of seizure risk associated with auras. Carefully planned prospective studies are required to assess the risk associated with post-operative auras.

• Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies.

  Authors: Costin Leu, Carolien G F de Kovel, Federico Zara, Pasquale Striano, Marianna Pezzella, Angela Robbiano, Amedeo Bianchi, Francesca Bisulli, Antonietta Coppola, Anna Teresa Giallonardo [......] Nerses Bebek, Ugur Ozbek, Anne Hempelmann, Herbert Schulz, Franz Rüschendorf, Holger Trucks, Peter Nürnberg, Giuliano Avanzini, Bobby P C Koeleman, Thomas Sander

  Epilepsia. 02/2012; 53(2):308-18.

  Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display anGenetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type-related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively. Meta-analysis of three genome-wide linkage datasets was carried out in 379 GGE-multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type-related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE-multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families. For the entire set of 379 GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome-wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02). Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31.3 preferentially predispose to myoclonic seizures or absence seizures, respectively. Phenotype- genotype strategies applying narrow trait definitions in phenotypic homogeneous subgroups of families improve the prospects of disentangling the genetic basis of common familial GGE syndromes.

• Clinical genetic studies in benign childhood epilepsy with centrotemporal spikes.

  Authors: Danya F Vears, Meng-Han Tsai, Lynette G Sadleir, Bronwyn E Grinton, Leasha M Lillywhite, Patrick W Carney, A Simon Harvey, Samuel F Berkovic, Ingrid E Scheffer

  Epilepsia. 02/2012; 53(2):319-24.

  To accurately determine the frequency and nature of the family history of seizures in patients with benign childhood epilepsy with centrotemporal spikes (BECTS). Participants with BECTS wereTo accurately determine the frequency and nature of the family history of seizures in patients with benign childhood epilepsy with centrotemporal spikes (BECTS). Participants with BECTS were recruited from the electroencephalography (EEG) laboratories of three pediatric centers and by referral. Pedigrees were constructed for up to three degrees of relatedness for each proband. All available affected and unaffected individuals underwent phenotyping using a validated seizure questionnaire. The proportion of affected relatives according to degree of relatedness was calculated and phenotypic patterns were analyzed. Fifty-three probands with BECTS had a mean age of seizure onset at 7.8 years (range 2-12 years). Thirty-four (64%) of 53 patients were male. For 51 participants, pedigrees were available for three degrees of relatedness. Fifty-seven (2.7%) of 2,085 relatives had a history of seizures: Twenty-one (9.8%) of 214 first-degree, 15 (3%) of 494 second-degree, and 21 (1.5%) of 1,377 third-degree relatives. Febrile seizures were the most frequent phenotype, occurring in 26 of 57 affected relatives. There were 34 relatives with epilepsy: 6.5% (14 of 214) first-degree, 1.8% (9 of 494) second-degree, and 0.8% (11 of 1,377) third-degree relatives. Of 21 affected first-degree relatives: 8 of 21 had febrile seizures (FS), 4 had BECTS, 2 had epilepsy-aphasia spectrum disorder, one had temporal lobe epilepsy with hippocampal sclerosis, 2 had focal epilepsy of unknown cause, 2 had genetic generalized epilepsies, and 3 had miscellaneous. The frequency of epilepsies in relatives and the heterogeneous syndromes observed suggest that BECTS has a genetic component consistent with complex inheritance. Focal epilepsies are the most common seizure disorder observed in relatives, especially BECTS and epilepsy-aphasia spectrum disorder. Additional acquired or environmental factors are likely to be necessary for expression of the seizure disorder.

• Inter-session repeatability of cortical excitability measurements in patients with epilepsy.

  Authors: Radwa A B Badawy, Graeme D Jackson, Samuel F Berkovic, Richard A L Macdonell

  Epilepsy research. 02/2012; 98(2-3):182-6.

  Previous studies have evaluated the inter-session variability of motor thresholds (MT), short intracortical inhibition and intracortical facilitation using paired pulse transcranial magneticPrevious studies have evaluated the inter-session variability of motor thresholds (MT), short intracortical inhibition and intracortical facilitation using paired pulse transcranial magnetic stimulation (TMS) in normal individuals. Here we evaluate the reproducibility of a range of measures of cortical excitability in patients with epilepsy. Twenty-four drug naïve patients with newly diagnosed epilepsy (13 idiopathic generalised epilepsy [IGE], 11 focal epilepsy) and seventeen non-epilepsy controls were studied. Motor threshold (MT) at rest and recovery curves constructed using paired pulse stimulation at short (2-15 ms) and long (50-400 ms) interstimulus intervals (ISIs) were analysed on two separate occasions, 4-20 weeks apart. The Lin's concordance correlation coefficient test was used to measure agreement between the two sessions. Significant levels of agreement between the two sessions were observed at MT and all the ISIs measured. This was highest in non-epilepsy controls. Cortical excitability measures are repeatable over time in both patients with epilepsy and healthy controls. Increased motor cortex excitability is a stable feature in epilepsy without significant inter-session variability.

• PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome.

  Authors: Sarah E Heron, Bronwyn E Grinton, Sara Kivity, Zaid Afawi, Sameer M Zuberi, James N Hughes, Clair Pridmore, Bree L Hodgson, Xenia Iona, Lynette G Sadleir [......] Eric Haan, Amos D Korczyn, Alison E Gardner, Mark A Corbett, Jozef Gécz, Paul Q Thomas, John C Mulley, Samuel F Berkovic, Ingrid E Scheffer, Leanne M Dibbens

  American journal of human genetics. 01/2012; 90(1):152-60.

  Benign familial infantile epilepsy (BFIE) is a self-limited seizure disorder that occurs in infancy and has autosomal-dominant inheritance. We have identified heterozygous mutations in PRRT2, whichBenign familial infantile epilepsy (BFIE) is a self-limited seizure disorder that occurs in infancy and has autosomal-dominant inheritance. We have identified heterozygous mutations in PRRT2, which encodes proline-rich transmembrane protein 2, in 14 of 17 families (82%) affected by BFIE, indicating that PRRT2 mutations are the most frequent cause of this disorder. We also report PRRT2 mutations in five of six (83%) families affected by infantile convulsions and choreoathetosis (ICCA) syndrome, a familial syndrome in which infantile seizures and an adolescent-onset movement disorder, paroxysmal kinesigenic choreoathetosis (PKC), co-occur. These findings show that mutations in PRRT2 cause both epilepsy and a movement disorder. Furthermore, PRRT2 mutations elicit pleiotropy in terms of both age of expression (infancy versus later childhood) and anatomical substrate (cortex versus basal ganglia).

• KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy.

  Authors: Sarah Weckhuysen, Simone Mandelstam, Arvid Suls, Dominique Audenaert, Tine Deconinck, Lieve R F Claes, Liesbet Deprez, Katrien Smets, Dimitrina Hristova, Iglika Yordanova [......] Danièle Hasaerts, Filip Roelens, Lieven Lagae, Simone Yendle, Thorsten Stanley, Sarah E Heron, John C Mulley, Samuel F Berkovic, Ingrid E Scheffer, Peter de Jonghe

  Annals of neurology. 01/2012; 71(1):15-25.

  KCNQ2 and KCNQ3 mutations are known to be responsible for benign familial neonatal seizures (BFNS). A few reports on patients with a KCNQ2 mutation with a more severe outcome exist, but a definiteKCNQ2 and KCNQ3 mutations are known to be responsible for benign familial neonatal seizures (BFNS). A few reports on patients with a KCNQ2 mutation with a more severe outcome exist, but a definite relationship has not been established. In this study we investigated whether KCNQ2/3 mutations are a frequent cause of epileptic encephalopathies with an early onset and whether a recognizable phenotype exists. We analyzed 80 patients with unexplained neonatal or early-infantile seizures and associated psychomotor retardation for KCNQ2 and KCNQ3 mutations. Clinical and imaging data were reviewed in detail. We found 7 different heterozygous KCNQ2 mutations in 8 patients (8/80; 10%); 6 mutations arose de novo. One parent with a milder phenotype was mosaic for the mutation. No KCNQ3 mutations were found. The 8 patients had onset of intractable seizures in the first week of life with a prominent tonic component. Seizures generally resolved by age 3 years but the children had profound, or less frequently severe, intellectual disability with motor impairment. Electroencephalography (EEG) at onset showed a burst-suppression pattern or multifocal epileptiform activity. Early magnetic resonance imaging (MRI) of the brain showed characteristic hyperintensities in the basal ganglia and thalamus that later resolved. KCNQ2 mutations are found in a substantial proportion of patients with a neonatal epileptic encephalopathy with a potentially recognizable electroclinical and radiological phenotype. This suggests that KCNQ2 screening should be included in the diagnostic workup of refractory neonatal seizures of unknown origin.

• Long-term follow-up of febrile infection-related epilepsy syndrome.

  Authors: Katherine B Howell, Kamornwan Katanyuwong, Mark T Mackay, Catherine A Bailey, Ingrid E Scheffer, Jeremy L Freeman, Samuel F Berkovic, A Simon Harvey

  Epilepsia. 12/2011; 53(1):101-10.

  Febrile infection-related epilepsy syndrome (FIRES) is an increasingly recognized epileptic syndrome that presents with multifocal refractory status epilepticus in previously normal children andFebrile infection-related epilepsy syndrome (FIRES) is an increasingly recognized epileptic syndrome that presents with multifocal refractory status epilepticus in previously normal children and evolves into a chronic, refractory, focal epilepsy with associated cognitive and behavioral difficulties. Herein we describe the features of the chronic epilepsy and critically review evidence for the etiology of this syndrome. Seven patients with FIRES were studied. The duration of follow-up in six survivors was 5-17 years. Clinical, electroencephalography (EEG), neuroimaging, and other investigative findings during the acute and chronic phases were reviewed. These previously normal children presented with a febrile illness and status epilepticus that was refractory to antiepileptic medications in all children, to immunotherapies (including immunoglobulin, corticosteroids, plasma exchange, and rituximab) in four, and to acute vagus nerve stimulation in one. Markers of cerebral inflammation were few and response to antiepileptic and immunomodulatory therapies was poor. Evolution to chronic epilepsy occurred without a silent period. Seizure characteristics in the chronic phase were strikingly stereotyped and similar to the acute phase, with head and eye version, unilateral facial jerking, asymmetric tonic posturing, and unilateral limb jerking in all patients. Electrographic ictal onset was lateralized in all recorded seizures, unilateral in one patient, and independent bilateral in three. Seizures were refractory to multiple antiepileptic medications in all patients and partly responsive to chronic vagus nerve stimulation in two patients. Moderate to severe intellectual impairment was noted in four patients, and borderline intellectual abilities were noted in two. Magnetic resonance imaging (MRI) in the chronic phase was normal in three patients and showed mild diffuse cortical atrophy and/or mild hippocampal atrophy or sclerosis in three. The similar perirolandic and perisylvian features of acute and chronic seizures, the lack of a silent period, the absence of evidence of cerebral inflammation, and the poor response to immunotherapies suggest FIRES is best conceptualized as a chronic epilepsy with explosive onset, not a remote-symptomatic epilepsy with an acute inflammatory antecedent.

• Rare copy number variants are an important cause of epileptic encephalopathies.

  Authors: Heather C Mefford, Simone C Yendle, Cynthia Hsu, Joseph Cook, Eileen Geraghty, Jacinta M McMahon, Orvar Eeg-Olofsson, Lynette G Sadleir, Deepak Gill, Bruria Ben-Zeev, Tally Lerman-Sagie, Mark Mackay, Jeremy L Freeman, Eva Andermann, James T Pelakanos, Ian Andrews, Geoffrey Wallace, Evan E Eichler, Samuel F Berkovic, Ingrid E Scheffer

  Annals of neurology. 12/2011; 70(6):974-85.

  Rare copy number variants (CNVs)--deletions and duplications--have recently been established as important risk factors for both generalized and focal epilepsies. A systematic assessment of the roleRare copy number variants (CNVs)--deletions and duplications--have recently been established as important risk factors for both generalized and focal epilepsies. A systematic assessment of the role of CNVs in epileptic encephalopathies, the most devastating and often etiologically obscure group of epilepsies, has not been performed. We evaluated 315 patients with epileptic encephalopathies characterized by epilepsy and progressive cognitive impairment for rare CNVs using a high-density, exon-focused, whole-genome oligonucleotide array. We found that 25 of 315 (7.9%) of our patients carried rare CNVs that may contribute to their phenotype, with at least one-half being clearly or likely pathogenic. We identified 2 patients with overlapping deletions at 7q21 and 2 patients with identical duplications of 16p11.2. In our cohort, large deletions were enriched in affected individuals compared to controls, and 4 patients harbored 2 rare CNVs. We screened 2 novel candidate genes found within the rare CNVs in our cohort but found no mutations in our patients with epileptic encephalopathies. We highlight several additional novel candidate genes located in CNV regions. Our data highlight the significance of rare CNVs in the epileptic encephalopathies, and we suggest that CNV analysis should be considered in the genetic evaluation of these patients. Our findings also highlight novel candidate genes for further study.

• Clinical and neurophysiologic features of progressive myoclonus epilepsy without renal failure caused by SCARB2 mutations.

  Authors: Guido Rubboli, Silvana Franceschetti, Samuel F Berkovic, Laura Canafoglia, Antonio Gambardella, Leanne M Dibbens, Patrizia Riguzzi, Claudio Campieri, Adriana Magaudda, Carlo Alberto Tassinari, Roberto Michelucci

  Epilepsia. 11/2011; 52(12):2356-63.

  Mutations of the SCARB2 gene cause action myoclonus renal failure syndrome (AMRF), a rare condition that combines progressive myoclonus epilepsy (PME) with severe renal dysfunction. We describe theMutations of the SCARB2 gene cause action myoclonus renal failure syndrome (AMRF), a rare condition that combines progressive myoclonus epilepsy (PME) with severe renal dysfunction. We describe the clinical and neurophysiologic features of PME associated with SCARB2 mutations without renal impairment. Clinical and neurophysiologic investigations, including wakefulness and sleep electroencephalography (EEG), polygraphic recording (with jerk-locked back-averaging and analysis of the EEG-EMG (electromyography) relationship by coherence spectra and phase calculation), multimodal evoked potentials, and electromyography were performed on five Italian patients with SCARB2 mutations. The main clinical features were adolescent-young adulthood onset, progressive action myoclonus, ataxia, absence of cognitive deterioration and, in most cases, epilepsy. The severity of the epilepsy could vary from uncontrolled seizures and status epilepticus in patients with adolescent onset to absent or rare seizures in patients with adult onset. Relevant neurophysiologic findings were a pronounced photosensitivity and massive action myoclonus associated with rhythmic myoclonic jerks at a frequency of 12-20 Hz, clinically resembling a postural tremor. The cortical origin of rhythmic myoclonus was demonstrated mainly by coherence and phase analysis of EEG-EMG signals indicating a significant EEG-EMG coupling and a direct corticospinal transfer. Our patients with SCARB2 mutations showed the clinical and neurophysiologic phenotype of PME, in which epilepsy could be extremely severe, extending the spectrum reported in the typical AMRF syndrome. Patients with PME of unknown origin of adolescent or young adult onset, with these neurophysiologic features, should be tested for SCARB2 mutations, even in the absence of renal impairment.

• Investigation of the 15q13.3 CNV as a genetic modifier for familial epilepsies with variable phenotypes.

  Authors: John C Mulley, Ingrid E Scheffer, Tarishi Desai, Marta A Bayly, Bronwyn E Grinton, Danya F Vears, Samuel F Berkovic, Leanne M Dibbens

  Epilepsia. 07/2011; 52(10):e139-42.

  Incomplete penetrance and variable phenotypic expression are characteristic of a number of syndromes of familial epilepsy. The purpose of the present investigation is to determine if the 15q13.3 copyIncomplete penetrance and variable phenotypic expression are characteristic of a number of syndromes of familial epilepsy. The purpose of the present investigation is to determine if the 15q13.3 copy number deletion functions as a locus modifying the epilepsy phenotype caused by other known or presumed pathogenic mutations segregating in families with epilepsies. No 15q13.3 microdeletions were detected in 756 affected or definite obligate carrier individuals across 151 families selected on the basis of having multiple members affected with epilepsy and showing a range of seizure types. Therefore, the 15q13.3 microdeletion does not act as a genetic modifier in this cohort of families and is not responsible for any of the genetic heterogeneity hypothesized to account for failure to detect linkage in previous genome-wide scans in five of the larger families included in this study.

• A retrospective population-based study on seizures related to childhood vaccination.

  Authors: Sarah von Spiczak, Ingo Helbig, Ursula Drechsel-Baeuerle, Hiltrud Muhle, Andreas van Baalen, Marjan J van Kempen, Dick Lindhout, Ingrid E Scheffer, Samuel F Berkovic, Ulrich Stephani, Brigitte Keller-Stanislawski

  Epilepsia. 06/2011; 52(8):1506-12.

  Cases of severe childhood epilepsies in temporal association with vaccination have great impact on the acceptance of vaccination programs by parents and health care providers. However, little isCases of severe childhood epilepsies in temporal association with vaccination have great impact on the acceptance of vaccination programs by parents and health care providers. However, little is known about the type and frequency of seizures and epilepsy syndromes following vaccination. This study aims to describe the clinical features of children presenting with seizures after vaccination using a register-based cohort. We surveyed the national German database of adverse events following immunization (AEFI) for reported seizures and epilepsies in children aged 0-6 years. All cases reported in 2006-2008 were analyzed retrospectively; available clinical information was reevaluated and classified by seizure type and epilepsy syndrome. In total, 328 cases reported between 2006 and 2008 were included. Data supportive of seizures or epilepsy were present in 247 (75.3%) of 328 patients with a mean interval between the vaccination and the epileptic event of 24 h and 7.5 days for inactivated and attenuated vaccines, respectively. Fifty-one (15.5%) of 328 patients presented with syncope, hypotonic-hyporesponsive episodes, or other nonepileptic events. Information was insufficient for classification into epileptic versus nonepileptic events in 30 (11.3%) of 328 patients. For cases with confirmed seizures, febrile seizures were present in 121 (49%) of 247 cases, and 38 (15.4%) of 247 patients had single afebrile seizures. Status epilepticus was described in 21 (8.5%) of 247 patients. Thirty-one (12.6%) of 247 patients presented with various pediatric epilepsy syndromes. Severe childhood epilepsies (Dravet syndrome, West syndrome, Lennox-Gastaut syndrome, or Doose syndrome) were diagnosed in 29 (11.7%) of 247 patients, with the vaccination-associated event being the first documented seizure in 15 (51.7%) of 29 patients. Vaccination-associated seizures present in the setting of various epilepsy syndromes, including severe childhood epilepsies in >10% of cases. Early diagnosis of the corresponding epilepsy syndromes and confirmation of an underlying etiology is important for treatment decisions, genetic counseling, and public health evaluation of vaccine safety.

• Mutation of SCARB2 in a patient with progressive myoclonus epilepsy and demyelinating peripheral neuropathy.

  Authors: Leanne M Dibbens, Ioannis Karakis, Marta A Bayly, Daniel J Costello, Andrew J Cole, Samuel F Berkovic

  Archives of neurology. 06/2011; 68(6):812-3.

  To report the detection of mutations in the SCARB2 gene in a previously described patient with progressive myoclonus epilepsy (PME) and demyelinating peripheral neuropathy. Case report. EpilepsyTo report the detection of mutations in the SCARB2 gene in a previously described patient with progressive myoclonus epilepsy (PME) and demyelinating peripheral neuropathy. Case report. Epilepsy Genetics Research Laboratory and Epilepsy Service in a tertiary care center. A 27-year old male patient with PME with preserved intellect and peripheral neuropathy. We have solved a previously reported case of PME, preserved intellect, and demyelinating peripheral neuropathy. The patient is a compound heterozygote for 2 mutations in the SCARB2 gene, which has recently been found to be a cause of PME. Demyelinating neuropathy is a clinical clue to the presence of SCARB2 mutations in PME.

• A mutation in the Golgi Qb-SNARE gene GOSR2 causes progressive myoclonus epilepsy with early ataxia.

  Authors: Mark A Corbett, Michael Schwake, Melanie Bahlo, Leanne M Dibbens, Meng Lin, Luke C Gandolfo, Danya F Vears, John D O'Sullivan, Thomas Robertson, Marta A Bayly, Alison E Gardner, Annemarie M Vlaar, G Christoph Korenke, Bastiaan R Bloem, Irenaeus F de Coo, Judith M A Verhagen, Anna-Elina Lehesjoki, Jozef Gecz, Samuel F Berkovic

  American journal of human genetics. 05/2011; 88(5):657-63.

  The progressive myoclonus epilepsies (PMEs) are a group of predominantly recessive disorders that present with action myoclonus, tonic-clonic seizures, and progressive neurological decline. Many PMEsThe progressive myoclonus epilepsies (PMEs) are a group of predominantly recessive disorders that present with action myoclonus, tonic-clonic seizures, and progressive neurological decline. Many PMEs have similar clinical presentations yet are genetically heterogeneous, making accurate diagnosis difficult. A locus for PME was mapped in a consanguineous family with a single affected individual to chromosome 17q21. An identical-by-descent, homozygous mutation in GOSR2 (c.430G>T, p.Gly144Trp), a Golgi vesicle transport gene, was identified in this patient and in four apparently unrelated individuals. A comparison of the phenotypes in these patients defined a clinically distinct PME syndrome characterized by early-onset ataxia, action myoclonus by age 6, scoliosis, and mildly elevated serum creatine kinase. This p.Gly144Trp mutation is equivalent to a loss of function and results in failure of GOSR2 protein to localize to the cis-Golgi.

• Kufs disease, the major adult form of neuronal ceroid lipofuscinosis, caused by mutations in CLN6.

  Authors: Todor Arsov, Katherine R Smith, John Damiano, Silvana Franceschetti, Laura Canafoglia, Catherine J Bromhead, Eva Andermann, Danya F Vears, Patrick Cossette, Sulekha Rajagopalan [......] Michael Farrell, Umberto Aguglia, Andrea Zini, Stefano Meletti, Michela Morbin, Saul Mullen, Frederick Andermann, Sara E Mole, Melanie Bahlo, Samuel F Berkovic

  American journal of human genetics. 05/2011; 88(5):566-73.

  The molecular basis of Kufs disease is unknown, whereas a series of genes accounting for most of the childhood-onset forms of neuronal ceroid lipofuscinosis (NCL) have been identified. Diagnosis ofThe molecular basis of Kufs disease is unknown, whereas a series of genes accounting for most of the childhood-onset forms of neuronal ceroid lipofuscinosis (NCL) have been identified. Diagnosis of Kufs disease is difficult because the characteristic lipopigment is largely confined to neurons and can require a brain biopsy or autopsy for final diagnosis. We mapped four families with Kufs disease for whom there was good evidence of autosomal-recessive inheritance and found two peaks on chromosome 15. Three of the families were affected by Kufs type A disease and presented with progressive myoclonus epilepsy, and one was affected by type B (presenting with dementia and motor system dysfunction). Sequencing of a candidate gene in one peak shared by all four families identified no mutations, but sequencing of CLN6, found in the second peak and shared by only the three families affected by Kufs type A disease, revealed pathogenic mutations in all three families. We subsequently sequenced CLN6 in eight other families, three of which were affected by recessive Kufs type A disease. Mutations in both CLN6 alleles were found in the three type A cases and in one family affected by unclassified Kufs disease. Mutations in CLN6 are the major cause of recessive Kufs type A disease. The phenotypic differences between variant late-infantile NCL, previously found to be caused by CLN6, and Kufs type A disease are striking; there is a much later age at onset and lack of visual involvement in the latter. Sequencing of CLN6 will provide a simple diagnostic strategy in this disorder, in which definitive identification usually requires invasive biopsy.

• Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy.

  Authors: Saul A Mullen, Carla Marini, Arvid Suls, Davide Mei, Elvio Della Giustina, Daniela Buti, Todor Arsov, John Damiano, Kate Lawrence, Peter De Jonghe, Samuel F Berkovic, Ingrid E Scheffer, Renzo Guerrini

  Archives of neurology. 05/2011; 68(9):1152-5.

  To determine if a significant proportion of patients with myoclonic-astatic epilepsy (MAE) have glucose transporter 1 (GLUT1) deficiency. Genetic analysis. Ambulatory and hospitalizedTo determine if a significant proportion of patients with myoclonic-astatic epilepsy (MAE) have glucose transporter 1 (GLUT1) deficiency. Genetic analysis. Ambulatory and hospitalized care. Eighty-four unrelated probands with MAE were phenotyped and SLC2A1 was sequenced and analyzed by multiplex ligation-dependent probe amplification. Any identified mutations were then screened in controls. Any SLC2A1 mutations. Four of 84 probands with MAE had a mutation of SLC2A1 on sequencing. Multiplex ligation-dependent probe amplification analysis did not reveal any genomic rearrangements in 75 of the remaining cases; 5 could not be tested. Two patients with MAE with SLC2A1 mutations also developed paroxysmal exertional dyskinesia in childhood. Five percent of our patients with MAE had SLC2A1 mutations, suggesting that patients with MAE should be tested for GLUT1 deficiency. Diagnosis of GLUT1 deficiency is a strong indication for early use of the ketogenic diet, which may substantially improve outcome of this severe disorder.