Peter Kinirons

Publications of Peter Kinirons

• Novel α1 and γ2 GABAA receptor subunit mutations in families with idiopathic generalized epilepsy.

  Authors: Pamela Lachance-Touchette, Patricia Brown, Caroline Meloche, Peter Kinirons, Line Lapointe, Hélène Lacasse, Anne Lortie, Lionel Carmant, Fiona Bedford, Derek Bowie, Patrick Cossette

  The European journal of neuroscience. 06/2011; 34(2):237-49.

  Epilepsy is a heterogeneous neurological disease affecting approximately 50 million people worldwide. Genetic factors play an important role in both the onset and severity of the condition, withEpilepsy is a heterogeneous neurological disease affecting approximately 50 million people worldwide. Genetic factors play an important role in both the onset and severity of the condition, with mutations in several ion-channel genes being implicated, including those encoding the GABA(A) receptor. Here, we evaluated the frequency of additional mutations in the GABA(A) receptor by direct sequencing of the complete open reading frame of the GABRA1 and GABRG2 genes from a cohort of French Canadian families with idiopathic generalized epilepsy (IGE). Using this approach, we have identified three novel mutations that were absent in over 400 control chromosomes. In GABRA1, two mutations were found, with the first being a 25-bp insertion that was associated with intron retention (i.e. K353delins18X) and the second corresponding to a single point mutation that replaced the aspartate 219 residue with an asparagine (i.e. D219N). Electrophysiological analysis revealed that K353delins18X and D219N altered GABA(A) receptor function by reducing the total surface expression of mature protein and/or by curtailing neurotransmitter effectiveness. Both defects would be expected to have a detrimental effect on inhibitory control of neuronal circuits. In contrast, the single point mutation identified in the GABRG2 gene, namely P83S, was indistinguishable from the wildtype subunit in terms of surface expression and functionality. This finding was all the more intriguing as the mutation exhibited a high degree of penetrance in three generations of one French Canadian family. Further experimentation will be required to understand how this mutation contributes to the occurrence of IGE in these individuals.

• Status epilepticus: a modern approach to management.

  Authors: Peter Kinirons, Colin P Doherty

  European journal of emergency medicine : official journal of the European Society for Emergency Medicine. 09/2008; 15(4):187-95.

  Status epilepticus (SE) is a common medical emergency. Two problems continue to militate against improved outcome in SE, namely, failure to recognize the wide spectrum of clinical presentation andStatus epilepticus (SE) is a common medical emergency. Two problems continue to militate against improved outcome in SE, namely, failure to recognize the wide spectrum of clinical presentation and failure to treat in an appropriately aggressive and timely manner. In this study, we aim to provide a clear understanding of the clinical presentation of SE, as well as providing an evidence-based review of the pathophysiological consequences of prolonged seizures, enabling the reader to adopt a rational approach to its management. We discuss current best practice for the management of SE as well as discussing alternative strategies, and briefly explore possible future therapeutic interventions.

• Phenotypic concordance in 70 families with IGE-implications for genetic studies of epilepsy.

  Authors: Peter Kinirons, Daniel Rabinowitz, Micheline Gravel, James Long, Melodie Winawer, Geneviève Sénéchal, Ruth Ottman, Patrick Cossette

  Epilepsy research. 09/2008;

  INTRODUCTION: A crucial issue in the genetic analysis of idiopathic generalized epilepsy (IGE) is deciding on the phenotypes that are likely to give the greatest power to detect predisposingINTRODUCTION: A crucial issue in the genetic analysis of idiopathic generalized epilepsy (IGE) is deciding on the phenotypes that are likely to give the greatest power to detect predisposing variants. A complex inheritance pattern and unclear nature of the genotype-phenotype correlation makes this task difficult. In the absence of much definitive genetic information to clarify this correlation, we inferred the putative effects of predisposing genes by studying the clustering of various phenotypic features, both clinical and electrophysiological, within families. METHODS: We examined the distribution of clinical features among relatives of a proband in 70 French-Canadian families with a minimum of two affected individuals with a clear diagnosis of IGE and then, using concordance analysis, identified the relative genetic influences on IGE syndrome, seizure type, age-at-onset, and EEG features. RESULTS: The mean number of affected individuals with IGE per family was three. One-third of relatives had the same syndrome as the proband. 16-22.5% of relatives of a proband with one of the absence syndromes had juvenile myoclonic epilepsy (JME). Conversely, 27% of relatives of probands with JME had an absence syndrome. 15% of relatives displayed the exact constellation of seizure types as the proband. Concordance analysis demonstrated greater clustering within families of IGE syndrome, seizure type, and age-at-onset than would be expected by chance. Significant concordance was not evident for EEG features. DISCUSSION: There was a large degree of clinical heterogeneity present within families. However we found evidence for clustering of a number of clinical features. Further refinement of the phenotypes used in genetic studies of complex IGE is necessary for progress to be made.

• Tolerability and dosing experience of intravenous levetiracetam in children and infants.

  Authors: Costas Michaelides, Ronald L Thibert, Michelle J Shapiro, Peter Kinirons, Tanya John, Dipti Manchharam, Elizabeth A Thiele

  Epilepsy research. 07/2008;

  OBJECTIVE: To evaluate the use and tolerability of intravenous (IV) levetiracetam (LEV) in a pediatric cohort under 14 years of age. METHODS: A retrospective analysis of the use of the IV formulationOBJECTIVE: To evaluate the use and tolerability of intravenous (IV) levetiracetam (LEV) in a pediatric cohort under 14 years of age. METHODS: A retrospective analysis of the use of the IV formulation of LEV was performed for the first 9 months that it was available in our institution. RESULTS: Overall, 118 infusions in 15 patients were performed during the period assessed. No adverse reactions were observed during the infusion phase of the IV formulation. Nine minor adverse reactions were observed during the rest of the hospitalization that were potentially related to the IV formulation. Three of these were decreases in the white cell counts, while the majority of the rest were behavioral adverse effects. The median starting dose in LEV naïve patients was 8.8mg/kg (range=5.0-50), with a median maintenance dose of 30.4mg/kg/day for all patients (range=5.0-92). The majority of these infusions (82/118) were in a subgroup of children under 4 years of age where the median maintenance dose was 28mg/kg/day. CONCLUSION: IV LEV was very well tolerated in this cohort of pediatric patients including a subgroup of children under the age of 4 years.

• A novel locus for idiopathic generalized epilepsy in French-Canadian families maps to 10p11.

  Authors: Peter Kinirons, Dominique J Verlaan, Marie-Pierre Dubé, Josée Poirier, Charles Deacon, Anne Lortie, Jean-François Clément, Richard Desbiens, Lionel Carmant, Cecile Cieuta-Walti, Michael Shevell, Guy A Rouleau, Patrick Cossette

  American journal of medical genetics. Part A. 04/2008; 146A(5):578-84.

  Idiopathic generalized epilepsy (IGE) has evidence of a strong genetic etiology. We conducted genomewide linkage analysis for genes responsible for familial IGE in French-Canadian pedigrees. TwentyIdiopathic generalized epilepsy (IGE) has evidence of a strong genetic etiology. We conducted genomewide linkage analysis for genes responsible for familial IGE in French-Canadian pedigrees. Twenty families segregating autosomal dominant epilepsy were collected. Four larger IGE families sufficiently powerful for independent linkage analysis were genome-scanned and follow-up fine mapping was performed over regions with LOD scores >3.0. The genotyping of 16 smaller families was carried out at significantly linked loci for supportive linkage analysis and haplotype comparisons. One of the four families provided a significant linkage result at marker D10S1426 on chromosome 10 (two-point LOD score = 3.05, theta = 0, multipoint LOD score = 3.18). Fine mapping revealed a segregating haplotype and key recombination breakpoints, suggesting a candidate gene interval of 6.5 Mb. Multipoint linkage analyses using the additional 16 families yielded a maximum LOD score under heterogeneity of 4.23 (alpha = 0.34) at this locus. Evaluation of recombination breakpoints in these families narrowed the candidate region to 1.7 Mb. Sequencing of the two known genes in this region, NRP1 and PARD3, was negative for mutation. Replication of linkage to this locus in other cohorts of IGE families is essential to characterize the underlying genetic mechanism for the disease.

• Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study.

  Authors: Gianpiero L Cavalleri, Michael E Weale, Kevin V Shianna, Rinki Singh, John M Lynch, Bronwyn Grinton, Cassandra Szoeke, Kevin Murphy, Peter Kinirons, Deirdre O'Rourke [......] Terence J O'Brien, Josemir W Sander, John S Duncan, Ingrid E Scheffer, Samuel F Berkovic, Nicholas W Wood, Colin P Doherty, Norman Delanty, Sanjay M Sisodiya, David B Goldstein

  Lancet neurology. 12/2007; 6(11):970-80.

  BACKGROUND: The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development andBACKGROUND: The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development and treatment of common forms of epilepsy. METHODS: We examined common variations across 279 prime candidate genes in 2717 case and 1118 control samples collected at four independent research centres (in the UK, Ireland, Finland, and Australia). Single nucleotide polymorphism (SNP) and combined set-association analyses were used to examine the contribution of genetic variation in the candidate genes to various forms of epilepsy. FINDINGS: We did not identify clear, indisputable common genetic risk factors that contribute to selected epilepsy subphenotypes across multiple populations. Nor did we identify risk factors for the general all-epilepsy phenotype. However, set-association analysis on the most significant p values, assessed under permutation, suggested the contribution of numerous SNPs to disease predisposition in an apparent population-specific manner. Variations in the genes KCNAB1, GABRR2, KCNMB4, SYN2, and ALDH5A1 were most notable. INTERPRETATION: The underlying genetic component to sporadic epilepsy is clearly complex. Results suggest that many SNPs contribute to disease predisposition in an apparently population-specific manner. However, subtle differences in phenotyping across cohorts, combined with a poor understanding of how the underlying genetic component to epilepsy aligns with current phenotypic classifications, might also account for apparent population-specific genetic risk factors. Variations across five genes warrant further study in independent cohorts to clarify the tentative association.

• A multicenter study of BRD2 as a risk factor for juvenile myoclonic epilepsy.

  Authors: Gianpiero L Cavalleri, Nicole M Walley, Nicole Soranzo, John Mulley, Colin P Doherty, Ashish Kapoor, Chantal Depondt, John M Lynch, Ingrid E Scheffer, Armin Heils [......] Peter Kinirons, Sonia Gandhi, Parthasarathy Satishchandra, Nicholas W Wood, Anuranjan Anand, Thomas Sander, Samuel F Berkovic, Norman Delanty, David B Goldstein, Sanjay M Sisodiya

  Epilepsia. 05/2007; 48(4):706-12.

  PURPOSE: Although complex idiopathic generalized epilepsies (IGEs) are recognized to have a significant genetic component, as yet there are no known common susceptibility variants. It has recentlyPURPOSE: Although complex idiopathic generalized epilepsies (IGEs) are recognized to have a significant genetic component, as yet there are no known common susceptibility variants. It has recently been suggested that variation in the BRD2 gene confers increased risk of juvenile myoclonic epilepsy (JME), which accounts for around a quarter of all IGE. Here we examine the association between the candidate causal SNP (the promoter variant rs3918149) and JME in five independent cohorts comprising in total 531 JME cases and 1,390 healthy controls. METHODS: The strongest candidate causal variant from the original report (rs3918149) was genotyped across all five cohorts. In an effort to identify novel candidate causal polymorphisms, previously unscreened regions of UTR were resequenced. RESULTS: We observed a significant effect in a small sample recruited in Britain (genotype p = 0.001, allele p = 0.001), a borderline significant effect in a sample recruited in Ireland and no association in larger samples of German, Australian, and Indian populations. There was no association with other common forms of epilepsy or any other clear candidate casual variants in or near the BRD2 region. CONCLUSIONS: The replication of an effect in the British cohort and suggestive evidence from that recruited in Ireland but lack of replication from the larger German, Australian, and Indian cohorts is surprising and difficult to explain. Further replication in carefully matched populations is required. Results presented here do not, however, support a strong effect for susceptibility to JME across populations of European descent.

• The controversial association of ABCB1 polymorphisms in refractory epilepsy: an analysis of multiple SNPs in an Irish population.

  Authors: Amre Shahwan, Kevin Murphy, Colin Doherty, Gianpiero L Cavalleri, Clare Muckian, Pat Dicker, Mary McCarthy, Peter Kinirons, David Goldstein, Norman Delanty

  Epilepsy research. 03/2007; 73(2):192-8.

  Controversy has surrounded the reported association of the single nucleotide polymorphism (SNP) C3435T of the ATP-binding cassette subfamily B member 1 (ABCB1, MDR1) gene, with refractory epilepsy.Controversy has surrounded the reported association of the single nucleotide polymorphism (SNP) C3435T of the ATP-binding cassette subfamily B member 1 (ABCB1, MDR1) gene, with refractory epilepsy. Here we examine this question by: (1) attempting to replicate the original association, (2) assessing the association of other variants in high linkage disequilibrium (LD) with C3435T, and (3) evaluating and comparing our findings with other published studies. We defined drug-responsiveness as seizure freedom or a 50% or more reduction in seizure frequency in the preceding year. Drug resistance was defined as a less than 50% reduction in seizure frequency in the preceding year. We used a combination of map-based (tagging SNPs) and direct sequence-based methods allowing a comprehensive assessment of variation across the associated interval. Genotypic data on 8 SNPs was collected on 440 patients, of whom 242 were drug-responsive and 198 were drug-resistant. We were unable to observe the original association of drug-resistant epilepsy with C3435T, nor any association with other functional variants at SNP or haplotype level in the ABCB1 gene. Evaluation of other attempted replication studies suggest that if the original C3435T association is indeed real, it would appear highly sensitive to the phenotype used. Alternatively, the discrepant results of this and other association attempts may be indicative of the original report of the CC genotype at C3435T in ABCB1 being a false positive finding. Variability in phenotypic descriptions in genetic association studies may partly explain the inconsistency of attempted replications.

• Examining the role of common genetic variation in the gamma2 subunit of the GABA(A) receptor in epilepsy using tagging SNPs.

  Authors: Peter Kinirons, Gianpiero L Cavalleri, Amre Shahwan, Nicholas W Wood, David B Goldstein, Sanjay M Sisodiya, Norman Delanty, Colin P Doherty

  Epilepsy research. 09/2006; 70(2-3):229-38.

  INTRODUCTION: Mutations in the gamma2 subunit gene of the GABA(A) receptor, GABRG2, have been shown to cause generalised epilepsy syndromes in rare familial cases. Here we set out to examine whetherINTRODUCTION: Mutations in the gamma2 subunit gene of the GABA(A) receptor, GABRG2, have been shown to cause generalised epilepsy syndromes in rare familial cases. Here we set out to examine whether common variation in GABRG2 predisposes to the development of common, complex forms of epilepsy in two large independent cohorts. METHODS: We have applied a tagging single nucleotide polymorphism (tSNP) technique allowing us to satisfactorily represent common variation in the gene. However, to ensure maximal representation of functional variation and in particular in cases of low minor allele frequency (MAF), we have identified and forced known functional variation as tagging SNPs. We examined the association between tagging SNPs and subtypes of epilepsy in two independent cohorts; the first consisted of 677 cases and 384 healthy controls, the second of 684 cases and 277 healthy controls. RESULTS: We failed to detect any variation that conferred an increased risk of disease development in both cohorts. DISCUSSION: Our results suggest that common variants of strong effect in GABRG2 do not appear to play a role in the development of common, complex forms of epilepsy. This report illustrates a number of important features of study design in genetic association studies, including the simultaneous use of map and sequence-based techniques and the necessity of replication before robust conclusions can be drawn from results.

• A pharmacogenetic exploration of vigabatrin-induced visual field constriction.

  Authors: Peter Kinirons, Gianpiero L Cavalleri, Rinki Singh, Amre Shahwan, James F Acheson, Nicholas W Wood, David B Goldstein, Sanjay M Sisodiya, Colin P Doherty, Norman Delanty

  Epilepsy research. 09/2006; 70(2-3):144-52.

  INTRODUCTION: Use of the antiepileptic drug (AED) vigabatrin is severely limited by irreversible visual field constriction, an adverse reaction to the drug reported in approximately 40% of patients.INTRODUCTION: Use of the antiepileptic drug (AED) vigabatrin is severely limited by irreversible visual field constriction, an adverse reaction to the drug reported in approximately 40% of patients. Given the evidence suggesting an idiosyncratic drug response, we set out to detect genetic variation of strong, clinically relevant effect that might guide clinicians in the safe, controlled prescribing of this otherwise usefuldrug. METHODS: Patients with a history of at least 1-year exposure to vigabatrin were enrolled at two independent referral centers. Using Goldmann perimetry, visual fields and the extent of constriction were calculated for each patient. We examined the correlation between the extent of vigabatrin induced visual field constriction and genetic variation across six candidate genes (SLC6A1, SLC6A13, SCL6A11, ABAT, GABRR1 and GABRR2). We availed of HapMap data and used a tagging SNP technique in an effort to efficiently capture all common variation within these genes. We attempted to replicate any positive associations before drawing conclusions from our results. RESULTS: The degree of visual field constriction correlated with three SNPs and one haplotype in a cohort of 73 patients. However we were unable to replicate these findings in a second independent cohort consisting of 58 patients, suggesting the initial results were possibly false positives, or variants of weak effect. CONCLUSION: Common variants of strong, clinically relevant effect do not appear to reside in the candidate genes studied here. This does not rule out the presence of genetic variants of weak effect in these genes, nor of variants of strong effect in other genes.

• Vigabatrin retinopathy in an Irish cohort: lack of correlation with dose.

  Authors: Peter Kinirons, Gianpiero L Cavalleri, Dierdre O'Rourke, Colin P Doherty, Irene Reid, Patricia Logan, Brenda Liggan, Norman Delanty

  Epilepsia. 03/2006; 47(2):311-7.

  PURPOSE: The anticonvulsant vigabatrin (VGB) causes irreversible visual-field constriction in 19-92% of patients. It is unclear whether this correlates with dosing, and the natural history of thePURPOSE: The anticonvulsant vigabatrin (VGB) causes irreversible visual-field constriction in 19-92% of patients. It is unclear whether this correlates with dosing, and the natural history of the retinopathy remains obscure. We conducted a retrospective analysis of patients receiving long-term VGB to examine whether toxicity is related to the daily dose, duration of therapy, or cumulative dose. METHODS: Information from 93 patients taking long-term, stable VGB therapy was analyzed. We recorded data on patient demographics, VGB dosing, and all visual-field assessments. We used the mean redial degrees (MRD) from the right eye to compare the amount of constriction with the dose of VGB. RESULTS: The mean number of assessments was two (range, 1-6). Of patients having more than one assessment (n = 65), the mean follow-up time was 2.4 years (range, 0.7-5.6 years); in 52.7%, visual-field constriction developed. Male and female patients were affected equally. We found no correlation between the average MRD and either the maximum dose of VGB taken, the duration of exposure, or the cumulative dose. The shortest exposure time to development of constriction was 1.1 years. All patients with normal fields on initial assessment continued to have normal fields on follow-up. Most patients who had evidence of constriction on initial assessment and remained taking VGB showed no progression on follow-up. One patient had a substantial recovery of vision after discontinuation of VGB. CONCLUSIONS: Development of visual constriction in patients receiving prolonged, standard doses of VGB does not depend on the daily dose, duration of exposure, or cumulative dose. Other contributing factors were not identified. Our data suggest that field defects may develop within the first few years of therapy and possibly remain stable thereafter.