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ABSTRACT: ClC-2 is a voltage-dependent chloride channel that activates slowly at voltages negative to the chloride reversal potential. Adenosine triphosphate (ATP) and other nucleotides have been shown to bind to carboxy-terminal cystathionine-ß-synthase (CBS) domains of ClC-2, but the functional consequences of binding are not sufficiently understood. We here studied the effect of nucleotides on channel gating using single-channel and whole-cell patch clamp recordings on transfected mammalian cells. ATP slowed down macroscopic activation and deactivation time courses in a dose-dependent manner. Removal of the complete carboxy-terminus abolishes the effect of ATP, suggesting that CBS domains are necessary for ATP regulation of ClC-2 gating. Single-channel recordings identified long-lasting closed states of ATP-bound channels as basis of this gating deceleration. ClC-2 channel dimers exhibit two largely independent protopores that are opened and closed individually as well as by a common gating process. A seven-state model of common gating with altered voltage dependencies of opening and closing transitions for ATP-bound states correctly describes the effects of ATP on macroscopic and microscopic ClC-2 currents. To test for a potential pathophysiological impact of ClC-2 regulation by ATP, we studied ClC-2 channels carrying naturally occurring sequence variants found in patients with idiopathic generalized epilepsy, G715E, R577Q, and R653T. All naturally occurring sequence variants accelerate common gating in the presence but not in the absence of ATP. We propose that ClC-2 uses ATP as a co-factor to slow down common gating for sufficient electrical stability of neurons under physiological conditions.
Pflügers Archiv - European Journal of Physiology 05/2013; · 4.46 Impact Factor
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ABSTRACT: BACKGROUND: Randomized controlled trials (RCTs) in refractory paediatric epilepsy usually involve the two main types of epilepsy shared by children and adults, focal epilepsy and Lennox-Gastaut syndrome (LGS). Most other epilepsy syndromes, specifically paediatric, are excluded from drug development. In order to identify among them the candidate(s) for dedicated RCTs with a new drug, the European Medicine Agency (EMA) recently recommended proceeding in two steps: (1) an exploratory (prospective-observational) trial (POT) including a large variety of paediatric epilepsy syndromes and (2) a subsequent RCT in each of those that disclose a signal for possible efficacy. OBJECTIVE: Our objective was to address the three following issues that have not been addressed by the EMA: (1) to determine a minimal threshold for this signal; (2) to establish a list of epilepsies to evaluate; and (3) to estimate the number of patients to include in such POTs. METHODS: We extensively reviewed the POTs (including various syndromes) and RCTs reported in paediatric patients with uncontrolled epilepsy using MEDLINE (from 1990 to 2011) and the Cochrane library. We determined the threshold as the lowest percentage of responders observed in a POT with a positive corresponding RCT. The syndromes that reached this threshold in a POT were those to evaluate in an RCT. The minimal number of patients to include for each syndrome for a POT with a new antiepileptic drug was estimated in order to reach at least this threshold of responders with a 95 % confidence interval. RESULTS: We found the minimal responder threshold to be 25 %. We identified eight epilepsy types/syndromes reaching this threshold and estimated for each of them the minimal sample needed: refractory focal epilepsy (n = 40), Lennox-Gastaut syndrome (n = 32), infantile spasms (n = 50), Dravet syndrome (n = 32), childhood absence epilepsy (n = 12), other symptomatic generalized epilepsy (n = 38), epileptic encephalopathy with continuous spikes and waves during sleep (n = 7) and epilepsy with myoclonic-astatic seizures (n = 4) [the two last samples may be underestimated due to the lack of RCTs in these conditions]. CONCLUSION: Among the eight epilepsy types/syndromes that we recommend to systematically include in exploratory trials using the POT procedure, we assume that, for the minimal sample given above, a responder threshold of 25 % will provide a reliable efficacy signal, to be confirmed by a dedicated RCT. This strategy should avoid missing new therapeutic possibilities for children with epilepsy and reduce the off-label use of drugs in paediatric neurology.
CNS Drugs 01/2013; · 4.80 Impact Factor
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ABSTRACT: One of the most exciting areas in epilepsy has been the explosion in our understanding of the genetics of the epilepsies over the last decade. Built on a long history of careful clinical genetic studies of the epilepsies, the relatively recent discovery of epilepsy genes has enabled insights into pathways causing seizure disorders. A variety of mutational mechanisms can cause epilepsy resulting from different, and sometimes surprising, molecular processes such as copy number variation within the genome. The majority of known epilepsy genes encode ion channel subunits leading many of the genetic epilepsies to be regarded as channelopathies. Understanding how dysfunction of a mutant protein leads to hyperexcitability is key to understanding the pathophysiology of this group of serious and common childhood disorders. The architecture of the common genetic epilepsies following complex inheritance, where multiple genes are involved, is also beginning to be unraveled. The clinical approach to understanding the genetics of the epilepsies has matured and requires a detailed family history of seizures together with delineation of the child's epilepsy syndrome. Recognition of specific genetic epilepsy syndromes enables optimal treatment and prognostic and genetic counseling.
Handbook of Clinical Neurology 01/2013; 111:567-78.
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La Revue du praticien 12/2012; 62(10):1388-9.
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Young Ok Kim,
Leanne Dibbens,
Carla Marini,
Arvid Suls,
Nicole Chemaly,
Davide Mei,
Jacinta M McMahon,
Xenia Iona,
Samuel F Berkovic,
Peter De Jonghe,
Renzo Guerrini, Rima Nabbout,
Ingrid E Scheffer
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ABSTRACT: A homozygous SCN1B mutation was previously identified in a patient with early onset epileptic encephalopathy (EOEE) described as Dravet syndrome (DS) despite a more severe phenotype than DS. We investigated whether SCN1B mutations are a common cause of DS. Patients with DS who did not have a SCN1A sequencing mutation or copy number variation were studied. Genomic DNA was Sanger sequenced for mutations in the 6 exons of SCN1B. In 54 patients with DS recruited from four centres, no SCN1B mutations were identified. SCN1B mutation is not a common cause of DS.
Epilepsy research 11/2012; · 2.48 Impact Factor
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Giulia Barcia,
Matthew R Fleming,
Aline Deligniere,
Valeswara-Rao Gazula,
Maile R Brown,
Maeva Langouet,
Haijun Chen,
Jack Kronengold,
Avinash Abhyankar,
Roberta Cilio,
Patrick Nitschke,
Anna Kaminska,
Nathalie Boddaert,
Jean-Laurent Casanova,
Isabelle Desguerre,
Arnold Munnich,
Olivier Dulac,
Leonard K Kaczmarek,
Laurence Colleaux, Rima Nabbout
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ABSTRACT: Malignant migrating partial seizures of infancy (MMPSI) is a rare epileptic encephalopathy of infancy that combines pharmacoresistant seizures with developmental delay. We performed exome sequencing in three probands with MMPSI and identified de novo gain-of-function mutations affecting the C-terminal domain of the KCNT1 potassium channel. We sequenced KCNT1 in 9 additional individuals with MMPSI and identified mutations in 4 of them, in total identifying mutations in 6 out of 12 unrelated affected individuals. Functional studies showed that the mutations led to constitutive activation of the channel, mimicking the effects of phosphorylation of the C-terminal domain by protein kinase C. In addition to regulating ion flux, KCNT1 has a non-conducting function, as its C terminus interacts with cytoplasmic proteins involved in developmental signaling pathways. These results provide a focus for future diagnostic approaches and research for this devastating condition.
Nature Genetics 10/2012; · 35.53 Impact Factor
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Epicure Consortium,
Eminet Consortium,
Michael Steffens,
Costin Leu,
Ann-Kathrin Ruppert,
Federico Zara,
Pasquale Striano,
Angela Robbiano,
Giuseppe Capovilla,
Paolo Tinuper, [......],
Herbert Schulz,
Franz Rüschendorf,
Markus Leber,
Steffen M Pauck,
Holger Trucks,
Mohammad R Toliat,
Peter Nürnberg,
Giuliano Avanzini,
Bobby P C Koeleman,
Thomas Sander
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ABSTRACT: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.
Human Molecular Genetics 09/2012; · 7.64 Impact Factor
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ABSTRACT: The efficacy of stiripentol (STP) in Dravet Syndrome (DS) was discovered first in an exploratory study in pediatric pharmacoresistant epilepsies. This efficacy signal, used as a proof of concept, led to - two independent multicenter randomized, double-blind, placebo-controlled trials in DS patients: STICLO-France and STICLO-Italy. In adjunction to valproate and clobazam, STP demonstrated marked efficacy and these trials became the basis for the registration of STP as an orphan drug for DS. Although STP had previously shown antiepileptic activity, since it inhibits cytochromes P450, the increased plasma levels of clobazam (CLB), norclobazam (NCLB), and NCLB/CLB ratio reported in STICLO studies brought into question the activity of STP per se. Recent pharmacological studies demonstrated that (i) STP is a direct allosteric modulator of the GABA receptors at a site distinct from benzodiazepines; (ii) STP and CLB/NCLB act independently at GABA(A) receptors; (iii) their combination increases the maximum response beyond that of either drug alone. All these effects are independent of considerations of changes in metabolism. Some responders in STICLO studies failed to display any increase of plasmatic concentrations of NCLB/CLB ratio as STP could not inhibit CYP2C19 because of its inhibition by progabide or due to an inactivating CYP polymorphism. The responder rate proved to be in the same range whether the NCLB/CLB ratio increased or not. These analyses confirmed that the effects of STP cannot result from a simple pharmacokinetic interaction. We propose that the success of STP should serve as a model for AED development in rare pediatric epileptic syndromes.
European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society 06/2012; 16 Suppl 1:S13-7. · 2.01 Impact Factor
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Nature Reviews Neurology 04/2012; 8(5):243-4. · 12.46 Impact Factor
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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
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ABSTRACT: 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 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.
Epilepsia 02/2012; 53(2):308-18. · 3.96 Impact Factor
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ABSTRACT: Genetically determined epilepsy with encephalopathy can develop early in life, often with prenatal onset, which makes diagnosis difficult. New molecular screening studies have identified causative mutations in patients with early-onset epilepsy with encephalopathy. What can we learn from the results of genetic screening in patients with this disorder?
Nature Reviews Neurology 01/2012; 8(3):129-30. · 12.46 Impact Factor
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ABSTRACT: To explore the correlations between treatment modalities and selected disease parameters with outcome in febrile infection-related epilepsy syndrome (FIRES), a catastrophic epileptic encephalopathy with a yet undefined etiology.
We conducted a retrospective multicenter study on children who had been included in eight studies published between November 2001 and July 2010. Additional data were retrieved from six of the eight participating centers.
The 77 enrolled patients presented with prolonged refractory status epilepticus. A preceding febrile infection had been reported in 96% of them. Treatment modalities included antiepileptic drugs (a median of six), intravenous immunoglobulin (IVIG, 30 patients), steroids (29 patients), burst-suppression coma (BSC, 46 patients), and other less conventional agents. There was no evidence of efficacy for those treatment modalities except for IVIG (two patients), a ketogenic diet (one patient), and a prolonged cycle of barbiturate anesthesia coma (one patient). Nine patients (11.7%) died during the acute phase of FIRES. Only 12 of the 68 surviving patients (18%) retained normal cognitive level, but most of them had learning disabilities. Sixty-three patients (93%) had refractory epilepsy at follow-up. Cognitive levels at follow-up were significantly associated with duration of BSC (p = 0.005) and younger age at FIRES onset (p = 0.02).
The outcome of FIRES is poor. No therapeutic agent was efficacious in shortening the acute phase, with the possible exception of a ketogenic diet. Treatment by inducing a prolonged BSC was associated with a worse cognitive outcome.
Epilepsia 08/2011; 52(11):1956-65. · 3.96 Impact Factor
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ABSTRACT: Purpose: To explore the correlations between treatment modalities and selected disease parameters with outcome in febrile infection–related epilepsy syndrome (FIRES), a catastrophic epileptic encephalopathy with a yet undefined etiology.Methods: We conducted a retrospective multicenter study on children who had been included in eight studies published between November 2001 and July 2010. Additional data were retrieved from six of the eight participating centers.Key Findings: The 77 enrolled patients presented with prolonged refractory status epilepticus. A preceding febrile infection had been reported in 96% of them. Treatment modalities included antiepileptic drugs (a median of six), intravenous immunoglobulin (IVIG, 30 patients), steroids (29 patients), burst-suppression coma (BSC, 46 patients), and other less conventional agents. There was no evidence of efficacy for those treatment modalities except for IVIG (two patients), a ketogenic diet (one patient), and a prolonged cycle of barbiturate anesthesia coma (one patient). Nine patients (11.7%) died during the acute phase of FIRES. Only 12 of the 68 surviving patients (18%) retained normal cognitive level, but most of them had learning disabilities. Sixty-three patients (93%) had refractory epilepsy at follow-up. Cognitive levels at follow-up were significantly associated with duration of BSC (p = 0.005) and younger age at FIRES onset (p = 0.02).Significance: The outcome of FIRES is poor. No therapeutic agent was efficacious in shortening the acute phase, with the possible exception of a ketogenic diet. Treatment by inducing a prolonged BSC was associated with a worse cognitive outcome.
Epilepsia 08/2011; 52(11):1956 - 1965. · 3.96 Impact Factor
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ABSTRACT: We aimed to test the efficacy of ketogenic diet (KD) in patients with Dravet syndrome (DS) not satisfactorily controlled by antiepileptic drugs (AEDs). We included prospectively 15 DS patients aged >3 years with partial response to AEDs including stiripentol. All patients had a seizure diary and clinical examination with Conners and Achenbach scales before KD, at 1 month following onset and every 3 months thereafter. At 1 month, 10 patients (66%) had a decrease of seizure frequency ≥75%. Efficacy was maintained in eight responders at 3 and 6 months and in six responders at 9 months. Five patients (33%) remained on KD over 12 months, and one was seizure-free. In addition to efficacy on seizure frequency, KD was beneficial on behavior disturbances including hyperactivity. This effect was reported in all responders and in a few nonresponders. KD might have a double effect, on seizure control and on hyperactivity and behavior disturbances in patients with DS.
Epilepsia 05/2011; 52(7):e54-7. · 3.96 Impact Factor
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ABSTRACT: Dravet syndrome (DS), otherwise known as severe myoclonic epilepsy of infancy (SMEI), is an epileptic encephalopathy presenting in the first year of life. DS has a genetic etiology: between 70% and 80% of patients carry sodium channel α1 subunit gene (SCN1A) abnormalities, and truncating mutations account for about 40% and have a significant correlation with an earlier age of seizures onset. The remaining SCN1A mutations comprise splice-site and missense mutations, most of which fall into the pore-forming region of the sodium channel. Mutations are randomly distributed across the SCN1A protein. Most mutations are de novo, but familial SCN1A mutations also occur. Somatic mosaic mutations have also been reported in some patients and might explain the phenotypical variability seen in some familial cases. SCN1A exons deletions or chromosomal rearrangements involving SCN1A and contiguous genes are also detectable in about 2-3% of patients. A small percentage of female patients with a DS-like phenotype might carry PCDH19 mutations. Rare mutations have been identified in the GABARG2 and SCN1B genes. The etiology of about 20% of DS patients remains unknown, and additional genes are likely to be implicated.
Epilepsia 04/2011; 52 Suppl 2:24-9. · 3.96 Impact Factor
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Neurology 03/2011; 76(13):1193-4; author reply 1194. · 8.31 Impact Factor
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ABSTRACT: To determine the range of topiramate (TPM) concentrations obtained in children under 4 with the recommended dosage regimen (3-9 mg/kg/day) and to compare them to adult target ranges.
The population pharmacokinetic model developed for TPM, with/without enzyme inducer antiepileptic drugs (EIAEDs) in children was used to determine dosage regimens providing AUC and trough concentrations (C(trough)s) within the adult ranges.
TPM pharmacokinetics was described by a one-compartment model. EIAEDs increased the apparent clearance (CL/F) and age and body weight increased the apparent distribution volume (Vd/F). Mean population estimates (% CV interindividual variability) were 0.608/1.15 L/h (13%) for CL/F without/with EIAEDs, 28.6L (0.2%) for Vd/F and 1.4h(-1) (124%) for the absorption rate constant. Mean AUC(0-12h) reached with a 2mg/kg/day dosing regimen was within described range. A 6-16 mg/kg/day dose depending on age allowed reaching target C(trough) range with the highest probability. Combined EIAEDs led to a 2- and 3-fold decrease in AUC and C(trough), respectively.
TPM dosage of 2/4 mg/kg/day (without/with EIEADs, respectively) provides the AUC reported in adults. In children under 4, alternative dosing regimen should be considered mainly when associated to EIAED to reach C(trough) comparable to adult values.
Epilepsy research 02/2011; 93(2-3):208-11. · 2.48 Impact Factor
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ABSTRACT: Fever-induced refractory epileptic encephalopathy in school-aged children (FIRES), and idiopathic hemiconvulsion-hemiplegia syndrome (IHHS) are both triggered by fever, although evidence for a causal microorganism or an autoimmune phenomenon is lacking. FIRES begins in school age with status epilepticus lasting several weeks, involves perisylvian areas including mesial temporal structures, and is followed by pharmacoresistant epilepsy with major cognitive deterioration. IHHS begins in infancy with unilateral clonic status epilepticus and is followed by hemiplegia with pharmacoresistant epilepsy. The aetiology of FIRES and IHHS remains unknown, although clinical features and experimental models point to a likely vicious cycle involving inflammation and seizure activity that depends on the stage of brain maturation. We therefore propose to group these conditions under the concept of acute encephalopathy with inflammation-mediated status epilepticus. In addition to preliminary but encouraging clinical observations, there are theoretical reasons to consider the ketogenic diet as an early means to control both seizures and inflammation.
The Lancet Neurology 01/2011; 10(1):99-108. · 23.46 Impact Factor
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Karine Poirier,
Yoann Saillour,
Nadia Bahi-Buisson,
Xavier H Jaglin,
Catherine Fallet-Bianco, Rima Nabbout,
Laetitia Castelnau-Ptakhine,
Agathe Roubertie,
Tania Attie-Bitach,
Isabelle Desguerre,
David Genevieve,
Christine Barnerias,
Boris Keren,
Nicolas Lebrun,
Nathalie Boddaert,
Féréchté Encha-Razavi,
Jamel Chelly
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ABSTRACT: Mutations in the TUBB3 gene, encoding β-tubulin isotype III, were recently shown to be associated with various neurological syndromes which all have in common the ocular motility disorder, congenital fibrosis of the extraocular muscle type 3 (CFEOM3). Surprisingly and in contrast to previously described TUBA1A and TUBB2B phenotypes, no evidence of dysfunctional neuronal migration and cortical organization was reported. In our study, we report the discovery of six novel missense mutations in the TUBB3 gene, including one fetal case and one homozygous variation, in nine patients that all share cortical disorganization, axonal abnormalities associated with pontocerebellar hypoplasia, but with no ocular motility defects, CFEOM3. These new findings demonstrate that the spectrum of TUBB3-related phenotype is broader than previously described and includes malformations of cortical development (MCD) associated with neuronal migration and differentiation defects, axonal guidance and tract organization impairment. Complementary functional studies revealed that the mutated βIII-tubulin causing the MCD phenotype results in a reduction of heterodimer formation, yet produce correctly formed microtubules (MTs) in mammalian cells. Further to this, we investigated the properties of the MT network in patients' fibroblasts and revealed that MCD mutations can alter the resistance of MTs to depolymerization. Interestingly, this finding contrasts with the increased MT stability observed in the case of CFEOM3-related mutations. These results led us to hypothesize that either MT dynamics or their interactions with various MT-interacting proteins could be differently affected by TUBB3 variations, thus resulting in distinct alteration of downstream processes and therefore explaining the phenotypic diversity of the TUBB3-related spectrum.
Human Molecular Genetics 11/2010; 19(22):4462-73. · 7.64 Impact Factor
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Christel Depienne,
Oriane Trouillard,
Delphine Bouteiller,
Isabelle Gourfinkel-An,
Karine Poirier,
François Rivier,
Patrick Berquin, Rima Nabbout,
Denys Chaigne,
Dominique Steschenko, [......],
Marie Bru,
Brigitte Gilbert-Dussardier,
Agathe Roubertie,
Anna Kaminska,
Sandra Whalen,
Cyril Mignot,
Stéphanie Baulac,
Gaetan Lesca,
Alexis Arzimanoglou,
Eric LeGuern
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ABSTRACT: Mutations in PCDH19, encoding protocadherin 19 on chromosome X, cause familial epilepsy and mental retardation limited to females or Dravet-like syndrome. Heterozygous females are affected while hemizygous males are spared, this unusual mode of inheritance being probably due to a mechanism called cellular interference. To extend the mutational and clinical spectra associated with PCDH19, we screened 150 unrelated patients (113 females) with febrile and afebrile seizures for mutations or rearrangements in the gene. Fifteen novel point mutations were identified in 15 female patients (6 sporadic and 9 familial cases). In addition, qPCR revealed two whole gene deletions and one partial deletion in 3 sporadic female patients. Clinical features were highly variable but included almost constantly a high sensitivity to fever and clusters of brief seizures. Interestingly, cognitive functions were normal in several family members of 2 families: the familial condition in family 1 was suggestive of Generalized Epilepsy with Febrile Seizures Plus (GEFS+) whereas all three affected females had partial cryptogenic epilepsy. These results show that mutations in PCDH19 are a relatively frequent cause of epilepsy in females and should be considered even in absence of family history and/or mental retardation.
Human Mutation 11/2010; 32(1):E1959-75. · 5.69 Impact Factor
