S F Berkovic

University of Melbourne, Melbourne, Victoria, Australia

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Publications (220)1533.47 Total impact

  • 07/2015; 1(2):e17-e17. DOI:10.1212/NXG.0000000000000016
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    ABSTRACT: Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2 variation is over-represented in cases overall (P = 2�17 � 10�5). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3�50 � 10�4). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity. CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into human cortical excitability.
    Brain 05/2015; DOI:10.1093/brain/awv052 · 9.20 Impact Factor
  • Human Molecular Genetics 11/2014; 23(22):6069-6080. DOI:10.1093/hmg/ddu306 · 6.39 Impact Factor
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    ABSTRACT: Background: Although there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the optimal techniques to detect somatic mosaicism have not been systematically evaluated. Methods: Using a customized panel of known and candidate genes associated with brain malformations, we applied targeted high-coverage sequencing (depth, ≥200×) to leukocyte-derived DNA samples from 158 persons with brain malformations, including the double-cortex syndrome (subcortical band heterotopia, 30 persons), polymicrogyria with megalencephaly (20), periventricular nodular heterotopia (61), and pachygyria (47). We validated candidate mutations with the use of Sanger sequencing and, for variants present at unequal read depths, subcloning followed by colony sequencing. Results: Validated, causal mutations were found in 27 persons (17%; range, 10 to 30% for each phenotype). Mutations were somatic in 8 of the 27 (30%), predominantly in persons with the double-cortex syndrome (in whom we found mutations in DCX and LIS1), persons with periventricular nodular heterotopia (FLNA), and persons with pachygyria (TUBB2B). Of the somatic mutations we detected, 5 (63%) were undetectable with the use of traditional Sanger sequencing but were validated through subcloning and subsequent sequencing of the subcloned DNA. We found potentially causal mutations in the candidate genes DYNC1H1, KIF5C, and other kinesin genes in persons with pachygyria. Conclusions: Targeted sequencing was found to be useful for detecting somatic mutations in patients with brain malformations. High-coverage sequencing panels provide an important complement to whole-exome and whole-genome sequencing in the evaluation of somatic mutations in neuropsychiatric disease. (Funded by the National Institute of Neurological Disorders and Stroke and others.).
    New England Journal of Medicine 08/2014; 371(8):733-43. DOI:10.1056/NEJMoa1314432 · 55.87 Impact Factor
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    ABSTRACT: Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 x 10-9, odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.
    Brain 10/2013; 136(10). DOI:10.1093/brain/awt233 · 9.20 Impact Factor
  • L. Tsai · M. Schwake · M.A. Corbett · J. Gecz · S. Berkovic · P. B. Shieh
    Neuromuscular Disorders 10/2013; 23(9-10):748. DOI:10.1016/j.nmd.2013.06.404 · 2.64 Impact Factor
  • D Lee · M J Desmond · S A Fraser · M Katerelos · K Gleich · S F Berkovic · D A Power
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    ABSTRACT: Background/aims: Renin processing and storage is believed to occur in lysosome-like structures in the afferent arteriole. SCARB2/Limp-2 is a transmembrane lysosomal protein responsible for the intracellular trafficking of β-glucocerebrosidase. This study aimed to confirm the expression of SCARB2/Limp-2 in renin secretory granules, and explore its role in renin processing and secretion. Methods: Co-localisation studies of (pro)renin with lysosomal membrane proteins, SCARB2/Limp-2, LAMP-1 and LAMP-2, were performed in mouse and human kidney sections. Intrarenal expression and secretion of (pro)renin in wild-type (WT) and Limp-2(-/-) mice were compared with and without stimulation. Results: SCARB2/Limp-2, LAMP-1 and LAMP-2 co-localised with (pro)- renin in mouse and human kidney. Plasma renin concentration was increased in Limp-2(-/-) mice when compared to WT littermates. No change in (pro)renin expression, however, was observed in Limp-2(-/-) mouse kidney cortex by immunofluorescence microscopy, Western blotting, quantitative RT-PCR or the ultrastructural appearance of renin secretory granules. Acute stimulation of renin release by isoprenaline or hydralazine was similar in WT and Limp-2(-/-) mice. Following chronic salt restriction, however, immunofluorescence microscopy showed less (pro)renin expressed in Limp-2(-/-) compared with WT mouse kidneys, and there was significantly less prorenin but not renin by Western blotting in Limp-2(-/-) mouse kidney cortex, despite no difference in circulating renin levels. Conclusion: Renin secretory granules possess integral lysosomal proteins, confirming that they are indeed modified lysosomes. Limp-2 deficiency leads to a minor increase in circulating renin. Limp-2, however, is not required for acute or chronic stimulation of renin release.
    Nephron Experimental Nephrology 04/2013; 122(3-4):103-113. DOI:10.1159/000350737 · 2.56 Impact Factor
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    ABSTRACT: BACKGROUND AND PURPOSE:Bilateral posterior PNH is a distinctive complex malformation with imaging features distinguishing it from classic bilateral PNH associated with FLNA mutations. The purpose of this study was to define the imaging features of posterior bilateral periventricular nodular heterotopia and to determine whether associated brain malformations suggest specific subcategories.MATERIALS AND METHODS:We identified a cohort of 50 patients (31 females; mean age, 13 years) with bilateral posterior PNH and systematically reviewed and documented associated MR imaging abnormalities. Patients were negative for mutations of FLNA.RESULTS:Nodules were often noncontiguous (n = 28) and asymmetric (n = 31). All except 1 patient showed associated developmental brain abnormalities involving a spectrum of posterior structures. A range of posterior fossa abnormalities affected the cerebellum, including cerebellar malformations and posterior fossa cysts (n = 38). Corpus callosum abnormalities (n = 40) ranged from mild dysplasia to agenesis. Posterior white matter volume was decreased (n = 22), and colpocephaly was frequent (n = 26). Most (n = 40) had associated cortical abnormalities ranging from minor to major (polymicrogyria), typically located in the cortex overlying the PNH. Abnormal Sylvian fissure morphology was common (n = 27), and hippocampal abnormalities were frequent (n = 37). Four family cases were identified-2 with concordant malformation patterns and 2 with discordant malformation patterns.CONCLUSIONS:The associations of bilateral posterior PNH encompass a range of abnormalities involving brain structures inferior to the Sylvian fissures. We were unable to identify specific subgroups and therefore conceptualize bilateral posterior PNH as a continuum of infrasylvian malformations involving the posterior cerebral and hindbrain structures.
    American Journal of Neuroradiology 01/2013; 34(2). DOI:10.3174/ajnr.A3427 · 3.59 Impact Factor
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    ABSTRACT: Studies of absence seizures (AS) using EEG with fMRI (EEG-fMRI) show a consistent network with prominent thalamic activation and a variety of cortical changes. Despite evidence suggesting a role of frontal cortex in seizure generation, group studies have not detected consistent AS-related changes in this region. We hypothesized that only a subgroup may show frontal cortical activation. We studied 13 subjects with AS during EEG-fMRI to classify the different individual patterns of frontal cortical activation associated with AS. Based upon visual inspection of surface-rendered activation maps we identified 2 subgroups that could be distinguished by the activation in the dorsolateral prefrontal cortex (DLPFC). One group of patients (n = 7) showed a primarily positive signal change (DLPFC-POS), whereas the other group (n = 6) showed a primarily negative signal change (DLFPC-NEG). When the DLPFC-POS group was compared to the DLPFC-NEG group, time-course analysis revealed a larger positive blood oxygenation level-dependent deflection following onset of the AS in cortical and subcortical areas beyond the DLPFC. This suggests a basic biological difference between these groups. These observations suggest that there may be at least 2 mechanisms underpinning AS in individuals with absence epilepsy. This may have phenotypic and genetic implications for understanding epilepsy syndromes.
    Neurology 04/2012; 78(15):1157-65. DOI:10.1212/WNL.0b013e31824f801d · 8.29 Impact Factor
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    ABSTRACT: To determine the genetic etiology of the severe early infantile onset syndrome of malignant migrating partial seizures of infancy (MPSI). Fifteen unrelated children with MPSI were screened for mutations in genes associated with infantile epileptic encephalopathies: SCN1A, CDKL5, STXBP1, PCDH19, and POLG. Microarray studies were performed to identify copy number variations. One patient had a de novo SCN1A missense mutation p.R862G that affects the voltage sensor segment of SCN1A. A second patient had a de novo 11.06 Mb deletion of chromosome 2q24.2q31.1 encompassing more than 40 genes that included SCN1A. Screening of CDKL5 (13/15 patients), STXBP1 (13/15), PCDH19 (9/11 females), and the 3 common European mutations of POLG (11/15) was negative. Pathogenic copy number variations were not detected in 11/12 cases. Epilepsies associated with SCN1A mutations range in severity from febrile seizures to severe epileptic encephalopathies including Dravet syndrome and severe infantile multifocal epilepsy. MPSI is now the most severe SCN1A phenotype described to date. While not a common cause of MPSI, SCN1A screening should now be considered in patients with this devastating epileptic encephalopathy.
    Neurology 07/2011; 77(4):380-3. DOI:10.1212/WNL.0b013e318227046d · 8.29 Impact Factor
  • Clinical Neurophysiology 06/2011; 122. DOI:10.1016/S1388-2457(11)60220-4 · 3.10 Impact Factor
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    ABSTRACT: Deficiency of the intrinsic lysosomal protein human scavenger receptor class B, member 2 (SCARB2; Limp-2 in mice) causes collapsing focal and segmental glomerular sclerosis (FSGS) and myoclonic epilepsy in humans, but patients with no apparent kidney damage have recently been described. We now demonstrate that these patients can develop tubular proteinuria. To determine the mechanism, mice deficient in Limp-2, the murine homolog of SCARB2, were studied. Most low-molecular-weight proteins filtered by the glomerulus are removed in the proximal convoluted tubule (PCT) by megalin/cubilin-dependent receptor-mediated endocytosis. Expression of megalin and cubilin was unchanged in Limp-2(-/-) mice, however, and the initial uptake of injected Alexa Fluor 555-conjugated bovine serum albumin (Alexa-BSA) was similar to wild-type mice, indicating that megalin/cubilin-dependent, receptor-mediated endocytosis was unaffected. There was a defect in proteolysis of reabsorbed proteins in the Limp-2(-/-) mice, demonstrated by the persistence of Alexa-BSA in the PCT compared with controls. This was associated with the failure of the lysosomal protease cathepsin B to colocalize with Alexa-BSA and endogenous retinol-binding protein in kidneys from Limp-2(-/-) mice. The data suggest that tubular proteinuria in Limp-2(-/-) mice is due to failure of endosomes containing reabsorbed proteins to fuse with lysosomes in the proximal tubule of the kidney. Failure of proteolysis is a novel mechanism for tubular proteinuria.
    AJP Renal Physiology 03/2011; 300(6):F1437-47. DOI:10.1152/ajprenal.00015.2011 · 3.25 Impact Factor
  • JC Mulley · RH Wallace · P Izzillo · AM MacIntosh · SF Berkovic
  • RH Wallace · IE Scheffer · S Barnett · SF Berkovic · GR Sutherland
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    ABSTRACT: Zusammenfassung Die Klassifikations- und Terminologiekommission der Internationalen Liga gegen Epilepsie (International League Against Epilepsy, ILAE) hat die Konzepte und Terminologie sowie die Vorgehensweise zur Klassifikation von epileptischen Anfällen und Epilepsieformen revidiert. „Generalisiert“ und „fokal“ werden neu definiert für Anfälle, die entweder in einem bilateral verteilten Netzwerk auftreten und sich dort rasch ausbreiten (generalisiert) oder aber in einem auf eine Großhemisphäre beschränkten Netzwerk auftreten und dabei eng umschrieben oder weiter ausgebreitet sein können (fokal). Die Klassifikation generalisierter Anfälle wird vereinfacht. Aufgrund des Fehlens einer natürlichen Klassifikation fokaler Anfälle sollten diese entsprechend ihrer Manifestationen beschrieben werden (z. B. dyskognitiv oder fokal-motorisch). Die Konzepte „generalisiert“ und „fokal“ beziehen sich nicht auf elektroklinische Syndrome. „Genetisch“, „strukturell-metabolisch“ und „unbekannt“ stellen modifizierte ätiologische Konzepte dar und ersetzen „idiopathisch“, „symptomatisch“ und „kryptogen“. Nicht alle Epilepsieformen sind als elektroklinische Syndrome erkenntlich. Die Einteilung der Epilepsieformen erfolgt zunächst aufgrund der Spezifität: elektroklinische Syndrome, nichtsyndromatische Epilepsien mit strukturell-metabolischen Ursachen und Epilepsien unbekannter Ursache. Je nach Verwendungszweck kann innerhalb dieser Gruppen eine flexible weitere Unterteilung erfolgen. Natürliche Klassen (z. B. spezifische zugrunde liegende Ursache, Manifestationsalter, assoziierte Anfallsform) oder pragmatische Gruppenbildungen [z. B. epileptische Enzephalopathien, selbstlimitierende (früher: benigne) elektroklinische Syndrome] können als Grundlage für die Organisation unseres Wissens bezüglich anerkannter Epilepsieformen dienen und die Erkennung neuer Formen erleichtern.
    Zeitschrift für Epileptologie 11/2010; 23(4). DOI:10.1007/s10309-010-0127-9
  • R. A. Badawy · R. A. Macdonell · S. F. Berkovic · G. D. Jackson
    Clinical Neurophysiology 10/2010; 121. DOI:10.1016/S1388-2457(10)60811-5 · 3.10 Impact Factor
  • R. A. Badawy · R. A. Macdonell · S. F. Berkovic · G. D. Jackson
    Clinical Neurophysiology 10/2010; 121. DOI:10.1016/S1388-2457(10)60812-7 · 3.10 Impact Factor
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    ABSTRACT: We used EEG-fMRI to study epileptiform activity in a cohort of untreated children with typical absence seizures (AS). Our aim was to identify cortical and subcortical regions involved in spike and wave events and to explore the timing of activity in these regions. Eleven children with AS confirmed on video-EEG underwent EEG-fMRI. An event-related analysis of epileptiform activity was performed. Regions of interest (ROIs), identified in the event-related analysis, were used to study the time course of the blood oxygen level-dependent (BOLD) signal prior to and immediately following events of interest in these ROIs. Group analysis confirmed positive BOLD in the thalamus and negative BOLD in the lateral and mesial parietal lobe, caudate nuclei, and additionally the brainstem reticular formation. The event-related time course differed between the thalamus, the parietal cortex, and the pons and caudate nuclei. In the subcortical structures, BOLD signal change occurred at, or immediately after, electrographic onset. Importantly, in the parietal cortex, but not in other cortical regions, there was a subtle BOLD signal increase for 10 seconds prior to the onset of epileptiform activity. In children with typical AS, we have confirmed a core network of structures involved in generalized epileptiform activity that includes the reticular structures of the brainstem. Furthermore, we have identified changes in parietal BOLD signal which precede the onset of epileptiform activity, suggesting the parietal cortex has a role in the initiation of epileptiform activity.
    Neurology 09/2010; 75(10):904-11. DOI:10.1212/WNL.0b013e3181f11c06 · 8.29 Impact Factor

Publication Stats

11k Citations
1,533.47 Total Impact Points


  • 1993–2014
    • University of Melbourne
      • Department of Medicine
      Melbourne, Victoria, Australia
  • 2011
    • Baker IDI Heart and Diabetes Institute
      Melbourne, Victoria, Australia
  • 2010
    • Hiroshima University
      • Department of Neurosurgery
      Hirosima, Hiroshima, Japan
  • 1983–2009
    • Austin Health
      • Department of Neurology
      Melbourne, Victoria, Australia
  • 1994–2007
    • The Royal Children's Hospital
      • Department of Neurology
      Melbourne, Victoria, Australia
  • 1996–2004
    • Women`s and Children`s Hospital
      Tarndarnya, South Australia, Australia
  • 2002
    • Sendai National College of Technology
      Sendai, Kagoshima, Japan
  • 1987–2000
    • McGill University
      • Department of Neurology and Neurosurgery
      Montréal, Quebec, Canada
  • 1998
    • University of Bonn
      • Institute of Human Genetics
      Bonn, North Rhine-Westphalia, Germany
  • 1995
    • Royal Melbourne Hospital
      Melbourne, Victoria, Australia