PubMed Health⌕ Search

Biomedical subjects

S F Berkovic

Publications and source records attributed to S F Berkovic.

At least 109 records · Page 6Linked to original sources
PubMed1998

Epilepsies in twins: genetics of the major epilepsy syndromes.

We studied twins to examine the genetics of epilepsy syndromes. We ascertained 358 twin pairs in whom one or both reported seizures. After evaluation, 253 of 358 (71%) had seizure disorders and 105 pairs were false positives. Among the monozygous (MZ) pairs, more were concordant for seizures (48 of 108; casewise concordance = 0.62 +/- 0.05) than among the dizygous (DZ) pairs (14 of 145; casewise concordance = 0.18 +/- 0.04). In 94% of concordant MZ pairs, and 71% of concordant DZ pairs, both twins had the same major epilepsy syndrome. When analyzed according to major epilepsy syndrome, the casewise concordances for generalized epilepsies (MZ = 0.82; DZ = 0.26), both idiopathic (MZ = 0.76; DZ = 0.33) and symptomatic (MZ = 0.83; DZ = 0), were greater than those for partial epilepsies (MZ = 0.36; DZ = 0.05), with intermediate values seen for febrile seizures (MZ = 0.58; DZ = 0.14) and unclassified epilepsies (MZ = 0.53; DZ = 0.18). We conclude that genetic factors are particularly important in the generalized epilepsies but also play a role in the partial epilepsies. The high frequency of concordant MZ pairs with the same major syndrome strongly suggests there are syndrome-specific genetic determinants rather than a broad genetic predisposition to seizures.

Analysis of Variance↗
PubMed1998

Familial partial epilepsy with variable foci: a new partial epilepsy syndrome with suggestion of linkage to chromosome 2.

Familial partial epilepsy with variable foci (FPEVF) joins the recently recognized group of inherited partial epilepsies. We describe an Australian family with 10 individuals with partial seizures over four generations. Detailed electroclinical studies were performed on all affected and 17 clinically unaffected family members. The striking finding was that the clinical features of the seizures and interictal electroencephalographic foci differed among family members and included frontal, temporal, occipital, and centroparietal seizures. Mean age of seizure onset was 13 years (range, 0.75-43 years). Two individuals without seizures had epileptiform abnormalities on electroencephalographic studies. Penetrance of seizures was 62%. A genome-wide search failed to demonstrate definitive linkage, but a suggestion of linkage was found on chromosome 2q with a LOD score of 2.74 at recombination fraction of zero with the marker D2S133. FPEVF differs from the other inherited partial epilepsies where partial seizures in different family members are clinically similar. The inherited nature of this new syndrome may be overlooked because of relatively low penetrance and because of the variability in age at onset and electroclinical features between affected family members.

Adult↗
PubMed1998

Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia.

Long-range, directed migration is particularly dramatic in the cerebral cortex, where postmitotic neurons generated deep in the brain migrate to form layers with distinct form and function. In the X-linked dominant human disorder periventricular heterotopia (PH), many neurons fail to migrate and persist as nodules lining the ventricular surface. Females with PH present with epilepsy and other signs, including patent ductus arteriosus and coagulopathy, while hemizygous males die embryonically. We have identified the PH gene as filamin 1 (FLN1), which encodes an actin-cross-linking phosphoprotein that transduces ligand-receptor binding into actin reorganization, and which is required for locomotion of many cell types. FLN1 shows previously unrecognized, high-level expression in the developing cortex, is required for neuronal migration to the cortex, and is essential for embryogenesis.

Abnormalities, Multiple↗
PubMed1998

Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B.

Febrile seizures affect approximately 3% of all children under six years of age and are by far the most common seizure disorder. A small proportion of children with febrile seizures later develop ongoing epilepsy with afebrile seizures. Segregation analysis suggests the majority of cases have complex inheritance but rare families show apparent autosomal dominant inheritance. Two putative loci have been mapped (FEB1 and FEB2), but specific genes have not yet been identified. We recently described a clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS+), in which many family members have seizures with fever that may persist beyond six years of age or be associated with afebrile generalized seizures. We now report linkage, in another large GEFS+ family, to chromosome region 19q13.1 and identification of a mutation in the voltage-gated sodium (Na+)-channel beta1 subunit gene (SCN1B). The mutation changes a conserved cysteine residue disrupting a putative disulfide bridge which normally maintains an extracellular immunoglobulin-like fold. Co-expression of the mutant beta1 subunit with a brain Na+-channel alpha subunit in Xenopus laevis oocytes demonstrates that the mutation interferes with the ability of the subunit to modulate channel-gating kinetics consistent with a loss-of-function allele. This observation develops the theme that idiopathic epilepsies are a family of channelopathies and raises the possibility of involvement of other Na+-channel subunit genes in febrile seizures and generalized epilepsies with complex inheritance patterns.

Amino Acid Sequence↗
PubMed1998

Properties of neuronal nicotinic acetylcholine receptor mutants from humans suffering from autosomal dominant nocturnal frontal lobe epilepsy.

1. Physiological and pharmacological properties of the human neuronal alpha4beta2 nicotinic AChR and mutants found in patients suffering from autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) were studied. 2. Investigations of nicotinic AChRs reconstituted in Xenopus oocytes with the control or mutated alpha4 subunits revealed that both mutation S248F as well as the Leucine insertion (776ins3) result in major but different changes in the physiological and pharmacological properties of the receptors. 3. Mutation S248F causes a decrease in apparent affinity to ACh of about 7 fold. In addition, this receptor already desensitizes during exposure to agonist concentration 3000 times lower than the control. 4. 776ins3 provokes a 10 fold increase of apparent ACh affinity, an increase in the IC50 caused by prolonged ACh exposures and a slowing down of the response decay. 5. At saturating ACh concentration cells expressing the S248F mutant display average currents that are about five times smaller than control. 6. When measured at very low concentration, agonist sensitivities of the control and mutated receptors to ACh, nicotine and epibatidine exhibit differences that match those observed for higher agonist concentrations. 7. Mutation 776ins3 increases the apparent efficacy to cytisine. 8. Data presented herein suggest that mutation S248F mainly affects the desensitization properties of the receptor while the leucine insertion (776ins3) increases the probability of transition to the active state. Although these mutations differentially affect the receptor properties they both result in reduced permeability to calcium and enhanced desensitization sensitivity that might account for the ADNFLE phenotype.

Animals↗
PubMed1998

Twins with different temporal lobe malformations: schizencephaly and arachnoid cyst.

The etiology and relationships between different forms of malformations of cortical development are poorly understood. Schizencephaly is generally regarded as unrelated to arachnoid cysts. As part of a systematic study of epilepsy in twins we observed a monozygotic twin pair discordant for temporal lobe epilepsy where the twin with epilepsy had unilateral temporal schizencephaly and periventricular heterotopia. The twin without epilepsy had an arachnoid cyst in the same temporal lobe. Although an incidental association is possible, this observation, together with occasional reports of schizencephaly and arachnoid cysts within one individual, suggests a shared pathogenic mechanism. Schizencephaly can be caused by both genetic and acquired factors. We propose that our observations in this twin pair are best explained by a genetic factor present in both twins, with an additional environmental insult resulting in schizencephaly in only one of the pair.

Adult↗
PubMed1998

Autosomal dominant nocturnal frontal-lobe epilepsy: genetic heterogeneity and evidence for a second locus at 15q24.

Autosomal dominant nocturnal frontal-lobe epilepsy (ADNFLE) is a recently identified partial epilepsy in which two different mutations have been described in the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA4). An additional seven families are presented in which ADNFLE is unlinked to the CHRNA4 region on chromosome 20q13.2. Seven additional sporadic cases showed no evidence of defective CHRNA4. One of the families showed evidence of linkage to 15q24, close to the CHRNA3/CHRNA5/CHRNB4 cluster (maximum LOD score of 3.01 with D15S152). Recombination between ADNFLE and CHRNA4, linkage to 15q24 in one family, and exclusion from 15q24 and 20q13.2 in others demonstrate genetic heterogeneity with at least three different genes for ADNFLE. The CHRNA4 gene and the two known CHRNA4 mutations are responsible for only a minority of ADNFLE. Although the ADNFLE phenotype is clinically homogeneous, there appear to be a variety of molecular defects responsible for this disorder, which will provide a challenge to the understanding of the basic mechanism of epileptogenesis.

Chromosome Mapping↗
PubMed1998

Febrile seizures: genetics and relationship to other epilepsy syndromes.

The relationship between febrile seizures and epilepsy has long been debated. We argue that there is some specificity to the types of epilepsy that follow febrile seizures, rather than febrile seizures being a nonspecific marker of a lowered seizure threshold. The relationship between febrile seizures and later epilepsy is frequently genetic. Recent clinical and molecular genetic studies suggest that there are a number of syndrome-specific genes for febrile seizures.

Child↗
PubMed1998

Hemicranial volume deficits in patients with temporal lobe epilepsy with and without hippocampal sclerosis.

PURPOSE: In patients with refractory temporal lobe epilepsy, studies have suggested volume deficits measured by MRI of brain structures outside the epileptogenic hippocampus. Hippocampal sclerosis (HS) is a frequent, but not obligate, finding in such patients. The present study examines the influence of the presence of HS on quantitative magnetic resonance imaging (MRI) measurements. METHODS: We analyzed 47 patients and 30 controls by quantitative MRI, including intracranial volume (ICV), hemicranial volume, hippocampal volume (HCV), and T2 relaxometry. MRI results were compared with histological findings in the resected temporal lobe. RESULTS: Histology documented HS in 35 patients (HS group) and other findings in 12 patients (no-HS group). In both groups, the hemicranial volume ipsilateral to the epileptogenic focus was significantly smaller than on the contralateral side (p < 0.004). The HCV on both sides was smaller in the HS group compared with patients without HS (p < or = 0.004). Unilateral hippocampal atrophy and increased T2 value were found in 71% of patients with HS, and bilaterally normal HCV and T2 value were found in 67% of patients without HS. CONCLUSIONS: The smaller hemicranial volume on the focus side, irrespective of the presence or absence of HS suggests a different pathogenic mechanism for the additional hemicranial volume deficit, compared to HS itself. The contralateral HCV deficit depends on the presence of HS, indicating a pathogenic connection between damage to both hippocampi.

Adult↗
PubMed1998

Double-blind, placebo-controlled, crossover study of lamotrigine in treatment-resistant generalised epilepsy.

PURPOSE: Lamotrigine (LTG) is recognised as effective add-on therapy for focal epilepsies, but this is the first double-blind, placebo-controlled, crossover study in treatment-resistant generalised epilepsy. METHODS: The study consisted of 2 x 8-week treatment periods followed by a 4-week washout period. Patients received doses of either 75 or 150 mg daily, depending on their concomitant antiepileptic drugs (AEDs). Long-term continuation was offered at the end of the study with open-label LTG. RESULTS: Five centres in Australia recruited 26 patients who were having absence, myoclonic, or generalized tonic-clonic seizures or a combination of these. Twenty-two patients completed the study. There was a significant reduction in frequency of both tonic-clonic and absence seizure types with LTG. A 350% decrease in seizures was observed for tonic-clonic seizures in 50% of cases and for absence seizures in 33% of evaluable cases. Rash was the only adverse effect causing discontinuation. Twenty-three of 26 opted for open-label LTG, with 20 still receiving LTG for a mean of 26 months. In these 20, 80% had > or =50% seizure reduction and five (25%) were seizure free. CONCLUSIONS: This study shows that LTG is effective add-on therapy in patients with refractory generalised epilepsies. Statistically significant reduction in seizures in both absence and tonic-clonic seizure types was seen even with low doses of LTG.

Adolescent↗
PubMed1998

Aggravation of generalized epilepsies.

Generalized epilepsies are treatable with a number of antiepileptic drugs (AEDs) that are effective in different seizure types and epilepsy syndromes. The mechanisms of action of these AEDs are incompletely understood but include inhibition of low-threshold calcium currents and of voltage-gated sodium channels and facilitation of GABA(A) receptor currents. The mechanisms of aggravation are also unknown but could include elevation of brain GABA, blockade of voltage-gated sodium channels, and idiosyncratic toxicity reactions. Anecdotal reports suggest that aggravation of generalized epilepsy can occur with virtually all AEDs. The best-documented examples are aggravation of absences by carbamazepine and aggravation of symptomatic generalized epilepsies by vigabatrin. Therefore, the physician must be constantly aware of the problem of aggravation of seizures by AEDs. With careful diagnosis of the epileptic syndrome and an awareness of the problem, aggravation of seizures can be minimized.

Acute Disease↗
PubMed1998

Second impact syndrome.

Diffuse cerebral swelling with delayed catastrophic deterioration, a known complication of brain trauma, has been postulated to occur after repeated concussive brain injury in sports--the "second impact syndrome" (SIS). Certain current concussion management guidelines are contingent upon this assumption. We established criteria for definite, probable, and possible SIS and analyzed all published cases. A total of 17 cases were identified in which the reports described the cases as being consistent with SIS. Of these, only five probable cases of SIS were found based on our diagnostic criteria. We also studied the accuracy of recalled episodes of minor concussion in football players by their teammates because the diagnosis of SIS is usually based on such accounts. We found overreporting of recalled episodes of concussion in teammates when compared with self reports and videotape analysis. Based on case reports, the claim that SIS is a risk factor for diffuse cerebral swelling is not established. Prevention strategies for sports-related cerebral swelling are difficult to implement in the absence of established risk factors.

Athletic Injuries↗
PubMed1998

Hippocampal sclerosis studied in identical twins.

OBJECTIVE: To test both the genetic and acquired hypotheses for the etiology of hippocampal sclerosis (HS) by studying with optimized and quantitative MRI three monozygous (MZ) twin pairs in which the index twin had temporal lobe epilepsy and HS. BACKGROUND: There is conflicting evidence in the literature regarding whether HS is genetic or acquired prenatally, perinatally, or as a consequence of prolonged childhood seizures. METHODS: We compared three MZ pairs with 30 age-matched control subjects who had no history of a neurologic disorder; we also used the twins as matched samples to assess subtle differences between the affected and the unaffected twins. RESULTS: All of the affected twins had prolonged seizures with fever in early childhood, which stood out as the unique factor common to all affected twins and was absent in all the unaffected twins. HS was present in all affected twins but was absent in the unaffected twin on visual, volumetric, and T2 relaxometry criteria. Comparison of the affected twin with the co-twin revealed that intracranial volume ipsilateral to the HS was relatively small in two of three affected twins. CONCLUSIONS: The absence of HS in the unaffected twin is strong evidence against a genetic hypothesis for HS. Neither perinatal problems nor birth order were factors in determining the presence of HS. This twin study supports the notion of HS as an acquired lesion secondary to prolonged seizures in early childhood and suggests that regional abnormalities of intracranial volume are associated with HS.

Adult↗
PubMed1998

Concussive convulsions. Incidence in sport and treatment recommendations.

Concussive convulsions (CC) are nonepileptic phenomena which are an immediate sequelae of concussive brain injury. Although uncommon, occurring with an approximate incidence of 1 case per 70 concussions, these episodes are often confused with post-traumatic epilepsy which may occur with more severe structural brain injury. The pathophysiological mechanism of CC remains speculative, but may involve a transient traumatic functional decerebration with loss of cortical inhibition and release of brainstem activity. The phenomenology of the CC is somewhat akin to convulsive syncope, with an initial tonic phase occurring within 2 seconds of impact, followed by a clonic or myoclonic phase which may last several minutes. Lateralising features are common during the convulsions. There is no evidence of structural or permanent brain injury on clinical assessment, neuropsychological testing or neuroimaging studies. Long term outcome is universally good with no evidence of long term epilepsy and athletes are usually able to return to sport within 2 weeks. The correct management of these episodes centres on the appropriate management of the associated concussive injury and the exclusion of other cerebral injury by medical assessment. The CC requires no specific management beyond immediate onfield first aid measures such as protection of the airway. Antiepileptic therapy is not indicated and prolonged absence from sport is unwarranted. These episodes, although dramatic, are relatively straightforward to manage and all team physicians and those involved in athlete care need to be aware of this condition.

Adult↗
PubMed1997

Developmental genetics of deleted mtDNA in mitochondrial oculomyopathy.

Heteroplasmic populations of mtDNA, consisting of normal mtDNA and mtDNA with large deletions, are found in the skeletal muscle and other tissues of certain patients with mitochondrial respiratory chain deficiencies, particularly in those with the CPEO (chronic progressive external ophthalmoplegia) phenotype. To study the developmental genetics of this mitochondrial disorder, the distribution of the deleted mtDNA in a wide range of tissues of different embryonic origins (total 34 samples from 27 tissues obtained at autopsy) was investigated in a patient with the CPEO syndrome. Three species of partially deleted mtDNA were observed, with deletions of 2.3 kb, 5.0 kb and 6.4 kb. Their tissue distribution suggests that the mtDNA deletions have occurred very early during embryonic development, prior to the differentiation events that lead to the formation of the three primary embryonic germ layers, and that the partially deleted mtDNA species were segregated during development mainly to the skeletal muscle and to tissues of the central nervous system.

Base Sequence↗
PubMed1997

Retrospective study of concussive convulsions in elite Australian rules and rugby league footballers: phenomenology, aetiology, and outcome.

OBJECTIVES: To study the ictal phenomenology, aetiology, and outcome of convulsions occurring within seconds of impact in violent collision sport. DESIGN: Retrospective identification of convulsions associated with concussive brain injury from case records from medical officers of football clubs over a 15 year period. SUBJECTS: Elite Australian rules and rugby league footballers. MAIN OUTCOME MEASURES: Neuroimaging studies, electroencephalography, neuropsychological test data, and statistics on performance in matches to determine presence of structural or functional brain injury. Clinical follow up and electroencephalography for evidence of epilepsy. RESULTS: Twenty two cases of concussive convulsions were identified with four events documented on television videotape. Convulsions began within 2 seconds of impact and comprised an initial period of tonic stiffening followed by myoclonic jerks of all limbs lasting up to 150 seconds. Some asymmetry in the convulsive manifestations was common, and recovery of consciousness was rapid. No structural or permanent brain injury was present on clinical assessment, neuropsychological testing, or neuroimaging studies. All players returned to elite competition within two weeks of the incident. Epilepsy did not develop in any player over a mean (range) follow up of 3.5 (1-13) years. CONCLUSIONS: These concussive or impact convulsions are probably a non-epileptic phenomenon, somewhat akin to convulsive syncope. The mechanism may be a transient traumatic functional decerebration. In concussive convulsions the outcome is universally good, antiepileptic treatment is not indicated, and prolonged absence from sport is unwarranted.

Adult↗