Nathalie Villeneuve

Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes

N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian brain. Two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits each form highly Ca2+-permeable cation channels which are blocked by extracellular Mg2+ in a voltage-dependent manner. Either GRIN2B or GRIN2A, encoding the NMDA receptor subunits NR2B and NR2A, was found to be disrupted by chromosome translocation breakpoints in individuals with mental retardation and/or epilepsy. Sequencing of GRIN2B in 468 individuals with mental retardation revealed four de novo mutations: a frameshift, a missense and two splice-site mutations. In another cohort of 127 individuals with idiopathic epilepsy and/or mental retardation, we discovered a GRIN2A nonsense mutation in a three-generation family. In a girl with early-onset epileptic encephalopathy, we identified the de novo GRIN2A mutation c.1845C>A predicting the amino acid substitution p.N615K. Analysis of NR1-NR2AN615K (NR2A subunit with the p.N615K alteration) receptor currents revealed a loss of the Mg2+ block and a decrease in Ca2+ permeability. Our findings suggest that disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes depending on which NR2 subunit of NMDA receptors is affected.

Gamma Knife Surgery for Epilepsy Related to Hypothalamic Hamartomas

OBJECTIVEDrug-resistant epilepsy associated with hypothalamic hamartomas (HHs) can be cured by microsurgical resection of the lesions. Morbidity and mortality rates for microsurgery in this area are significant. Gamma knife surgery (GKS) is less invasive and seems to be well adapted for this indication. METHODSTo evaluate the safety and efficacy of GKS to treat this uncommon pathological condition, we organized a multicenter retrospective study. Ten patients were treated in seven different centers. The follow-up periods were more than 12 months for eight patients, with a median follow-up period of 28 months (mean, 35 mo; range, 12–71 mo). All patients had severe drug-resistant epilepsy, including frequent gelastic and generalized tonic or tonicoclonic attacks. The median age was 13.5 years (range, 1–32 yr; mean, 14 yr) at the time of GKS. Three patients experienced precocious puberty. All patients had sessile HHs. The median marginal dose was 15.25 Gy (range, 12–20 Gy). Two patients were treated two times (at 19 and 49 mo) because of insufficient efficacy. RESULTSAll patients exhibited improvement. Four patients were seizure-free, one experienced rare nocturnal seizures, one experienced some rare partial seizures but no more generalized attacks, and two exhibited only improvement, with reductions in the frequency of seizures but persistence of some rare generalized seizures. Two patients, now seizure-free, were considered to exhibit insufficient improvement after the first GKS procedure and were treated a second time. A clear correlation between efficacy and dose was observed in this series. The marginal dose was more than 17 Gy for all patients in the successful group and less than 13 Gy for all patients in the “improved” group. No side effects were reported, except for poikilothermia in one patient. Behavior was clearly improved for two patients (with only slight improvements in their epilepsy). Complete coverage of the HHs did not seem to be mandatory, because the dosimetry spared a significant part of the lesions for two patients in the successful group. CONCLUSIONWe report the first series demonstrating that GKS can be a safe and effective treatment for epilepsy related to HHs. We advocate marginal doses greater than or equal to 17 Gy and partial dose-planning when necessary, for avoidance of critical surrounding structures.

Epilepsy related to hypothalamic hamartomas: surgical management with special reference to gamma knife surgery

ObjectiveA large spectrum of surgical techniques can be proposed to young patients presenting with hypothalamic hamartomas (HH) associated with severe epilepsy. The aim of this report is to point on some clinical and anatomical parameters supposed to influence the choice of the surgical approach and to emphasize the specific role of radiosurgery.Materials and methodsWe reviewed both our experience and the recent literature based on a Pubmed search. Lateral pterional, midline frontal through the lamina terminalis, transcallosal interforniceal approaches, endoscopic treatment through the foramen of Monro, disconnecting surgery, radiofrequency ablation, brachytherapy and gamma knife surgery (GKS) were all considered. Mortality, morbidity, and efficacy of each of these techniques were compared. Specific limits, difficulties, and constraints were taken into account. Our experience of radiosurgery is based on a prospective trial which enrolled 60 patients with HH and associated severe epilepsy between October 1999 and December 2005.ResultsSeveral surgical techniques can lead to a real reversal of the epileptic encephalopathy. The main factors for the decision-making process are the age, the size of the lesion and its anatomical type (according to our original classification), the severity of the epilepsy, and the severity of the cognitive/psychiatric comorbidity. In our prospective trial (GKS), 27 patients have a follow-up superior to 3xa0years. Among those, 59.2% have an excellent result with a dramatic behavioral and cognitive improvement and are completely seizure-free (37%) or have only rare non-disabling seizures (22.2%). No permanent neurological complication has been observed so far; three patients have presented a transient poïkilothermia. GKS is clearly the safer approach for these difficult patients. Young patients with severe epilepsy and comorbidity must be operated on using a curative approach as early as possible. Very large type VI or mixed type with a large component above the floor of the third ventricle must be disconnected and then the upper remnant can be ideally treated by GKS (staged surgery). Type V (rarely epileptic) and IV are frequently operable by disconnection. Type I HH deeply embedded in the hypothalamus are operated on by GKS efficiently and safely. Type II HH can be operated on either endoscopically or transcallosally or by GKS depending on the parents’ choice and severity of epilepsy. In small type III HH, GKS is a safer procedure, due to the very close relationship to the fornix and mammillary bodies. In very large type III HH, transcallosal interforniceal approach is proposed but with significant risks especially concerning short-term memory. When the lesion is sufficiently small, GKS is globally offering the patient a rate of seizure cessation comparable to microsurgery with, however, a much lower risk (no neurological deficit reported till now).ConclusionOur first results indicate that GKS is as effective as microsurgical resection and very much safer. GKS also allows avoiding the vascular risk related to radiofrequency lesioning or stimulation. The disadvantage of radiosurgery is its delayed action. Longer follow-up is mandatory for a reliable evaluation of the role of GKS. The early effect on subclinical discharges turns out to play a major role in the dramatic improvement of sleep quality, behavior, and developmental learning acceleration at school.

Epileptic and nonepileptic features in patients with early onset epileptic encephalopathy and STXBP1 mutations

Purpose:u2002 STXBP1 (MUNC18‐1) mutations have been associated with various types of epilepsies, mostly beginning early in life. To refine the phenotype associated with STXBP1 aberrations in early onset epileptic syndromes, we studied this gene in a cohort of patients with early onset epileptic encephalopathy.

Novel Compound Heterozygous Mutations in TBC1D24 Cause Familial Malignant Migrating Partial Seizures of Infancy

Early‐onset epileptic encephalopathies (EOEEs) are a group of rare devastating epileptic syndromes of infancy characterized by severe drug‐resistant seizures and electroencephalographic abnormalities. The current study aims to determine the genetic etiology of a familial form of EOEE fulfilling the diagnosis criteria for malignant migrating partial seizures of infancy (MMPSI). We identified two inherited novel mutations in TBC1D24 in two affected siblings. Mutations severely impaired TBC1D24 expression and function, which is critical for maturation of neuronal circuits. The screening of TBC1D24 in an additional set of eight MMPSI patients was negative. TBC1D24 loss of function has been associated to idiopathic infantile myoclonic epilepsy, as well as to drug‐resistant early‐onset epilepsy with intellectual disability. Here, we describe a familial form of MMPSI due to mutation in TBC1D24, revealing a devastating epileptic phenotype associated with TBC1D24 dysfunction.

Absence Epilepsy with Onset before Age Three Years : A Heterogeneous and Often Severe Condition

Summary:u2003 Purpose: The classification of epilepsies and epileptic syndromes recognizes three syndromes with typical absences [TA, i.e., childhood and juvenile absence epilepsies (CAE and JAE), and epilepsy with myoclonic absences (EMA), none of which is characterized by onset in early childhood]. Although several other forms of absence epilepsies have been described recently, none concerns infants and very young children, and little is known about the nosology and prognosis of early‐onset absences.

Mutations in SLC13A5 Cause Autosomal-Recessive Epileptic Encephalopathy with Seizure Onset in the First Days of Life

Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of severe disorders characterized by seizures, abnormal interictal electro-encephalogram, psychomotor delay, and/or cognitive deterioration. We ascertained two multiplex families (including one consanguineous family) consistent with an autosomal-recessive inheritance pattern of EE. All seven affected individuals developed subclinical seizures as early as the first day of life, severe epileptic disease, and profound developmental delay with no facial dysmorphism. Given the similarity in clinical presentation in the two families, we hypothesized that the observed phenotype was due to mutations in the same gene, and we performed exome sequencing in three affected individuals. Analysis of rare variants in genes consistent with an autosomal-recessive mode of inheritance led to identification of mutations in SLC13A5, which encodes the cytoplasmic sodium-dependent citrate carrier, notably expressed in neurons. Disease association was confirmed by cosegregation analysis in additional family members. Screening of 68 additional unrelated individuals with early-onset epileptic encephalopathy for SLC13A5 mutations led to identification of one additional subject with compound heterozygous mutations of SLC13A5 and a similar clinical presentation as the index subjects. Mutations affected key residues for sodium binding, which is critical for citrate transport. These findings underline the value of careful clinical characterization for genetic investigations in highly heterogeneous conditions such as EE and further highlight the role of citrate metabolism in epilepsy.

Reading abilities and cognitive functions of children with epilepsy: Influence of epileptic syndrome

Children with epilepsy are at risk of developing learning disorders. To explore the influence of the epileptic syndrome on reading abilities, we have compared the neuropsychological profile of 12 children with benign idiopathic epilepsy with rolandic spikes, 10 with temporal lobe epilepsy and 12 with idiopathic generalized epilepsy. Children underwent a selection of standardised tests designed to assess: oral language, reading, short-term memory, attention and behavioural adjustment. Analysis of variance was adjusted according to age of onset of the epileptic syndrome, duration of the syndrome, and performance IQ for each group. Children with temporal lobe epilepsy (TLE) had significantly lower scores for reading speed and comprehension, but epileptic variables (the age of onset of epilepsy, duration and activity of epilepsy) had influenced academic performances. In the TLE group there was a clear effect of the topography of the epileptic foci (left-side TLE vs. right-side TLE) on reading profile. Furthermore, the effect of epileptic syndromes was found in phonological, semantic and verbal working memory deficits in the TLE group. To a lesser extent children with idiopathic generalized epilepsy (IGE) also exhibit cognitive deficit. The results of the present study lend support to epilepsy-specific patterns of neuropsychological dysfunction in children that should be considered to improve remediation of academic underachievement in these populations.

Inhibition of glutamate transporters results in a suppression-burst pattern and partial seizures in the newborn rat

Summary:u2002 Purpose: To determine the electrophysiological pattern and propose a clinical relevance of a deficient glutamate transport in the developing brain.

Similar early characteristics but variable neurological outcome of patients with a de novo mutation of KCNQ2

BackgroundEarly onset epileptic encephalopathies (EOEEs) are dramatic heterogeneous conditions in which aetiology, seizures and/or interictal EEG have a negative impact on neurological development. Several genes have been associated with EOEE and a molecular diagnosis workup is challenging since similar phenotypes are associated with mutations in different genes and since mutations in one given gene can be associated with very different phenotypes. Recently, de novo mutations in KCNQ2, have been found in about 10% of EOEE patients. Our objective was to confirm that KCNQ2 was an important gene to include in the diagnosis workup of EOEEs and to fully describe the clinical and EEG features of mutated patients.MethodsWe have screened KCNQ2 in a cohort of 71 patients with an EOEE, without any brain structural abnormality. To be included in the cohort, patient’s epilepsy should begin before three months of age and be associated with abnormal interictal EEG and neurological impairment. Brain MRI should not show any structural abnormality that could account for the epilepsy.ResultsOut of those 71 patients, 16 had a de novo mutation in KCNQ2 (23%). Interestingly, in the majority of the cases, the initial epileptic features of these patients were comparable to those previously described in the case of benign familial neonatal epilepsy (BFNE) also caused by KCNQ2 mutations. However, in contrast to BFNE, the interictal background EEG was altered and displayed multifocal spikes or a suppression-burst pattern. The ongoing epilepsy and development were highly variable but overall severe: 15/16 had obvious cognitive impairment, half of the patients became seizure-free, 5/16 could walk before the age of 3 and only 2/16 patient acquired the ability to speak.ConclusionThis study confirms that KCNQ2 is frequently mutated de novo in neonatal onset epileptic encephalopathy. We show here that despite a relatively stereotyped beginning of the condition, the neurological and epileptic evolution is variable.