Anne de Saint Martin

GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction

Epileptic encephalopathies are severe brain disorders with the epileptic component contributing to the worsening of cognitive and behavioral manifestations. Acquired epileptic aphasia (Landau-Kleffner syndrome, LKS) and continuous spike and waves during slow-wave sleep syndrome (CSWSS) represent rare and closely related childhood focal epileptic encephalopathies of unknown etiology. They show electroclinical overlap with rolandic epilepsy (the most frequent childhood focal epilepsy) and can be viewed as different clinical expressions of a single pathological entity situated at the crossroads of epileptic, speech, language, cognitive and behavioral disorders. Here we demonstrate that about 20% of cases of LKS, CSWSS and electroclinically atypical rolandic epilepsy often associated with speech impairment can have a genetic origin sustained by de novo or inherited mutations in the GRIN2A gene (encoding the N-methyl-D-aspartate (NMDA) glutamate receptor α2 subunit, GluN2A). The identification of GRIN2A as a major gene for these epileptic encephalopathies provides crucial insights into the underlying pathophysiology.

Antiepileptic effect of high-frequency stimulation of the subthalamic nucleus (corpus luysi) in a case of medically intractable epilepsy caused by focal dysplasia: a 30-month follow-up: technical case report.

OBJECTIVE AND IMPORTANCE Currently, some forms of epilepsy are resistant to both pharmacological and surgical interventions. As a result, there is a need for new therapeutic strategies. Because the nigral system modulates neuronal excitability in animal models of epilepsy, we considered therapeutic high-frequency stimulation of the subthalamic nucleus (STN). We were encouraged by the known relationship between the STN and the nigral system, as well as by our experience with high-frequency stimulation of the STN in Parkinsonian patients. CLINICAL PRESENTATION A 5-year-old girl with pharmacologically resistant, inoperable epilepsy caused by focal centroparietal dysplasia underwent implantation with a permanent electrode in the left STN and was chronically stimulated. To date, we have followed up this patient for 30 months postoperatively. TECHNIQUE High-frequency stimulation of the STN induced a significant voltage-dependent reduction (by 80%) in the number and severity of seizures. In addition, consistent improvement in both motor and cognitive functions was noted as a result of reduced postictal states. The effect was more prominent for seizures occurring in clusters (89% reduction) and during the day (88% reduction) than for those that occurred during sleep (53% reduction). CONCLUSION This is the first report of epilepsy control using chronic high-frequency stimulation of the STN. Preliminary observations in three other operated patients (at 2, 12, and 18 mo) confirm these data. We think that high-frequency stimulation of the STN may hold significant future potential as a treatment for epilepsy, similar to its established role in the treatment of Parkinson’s disease. This finding opens completely new experimental and therapeutic avenues for the treatment of surgically and medically intractable epilepsy.

Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link with autism.

Purpose:  The continuous spike and waves during slow‐wave sleep syndrome (CSWSS) and the Landau‐Kleffner (LKS) syndrome are two rare epileptic encephalopathies sharing common clinical features including seizures and regression. Both CSWSS and LKS can be associated with the electroencephalography pattern of electrical status epilepticus during slow‐wave sleep and are part of a clinical continuum that at its benign end also includes rolandic epilepsy (RE) with centrotemporal spikes. The CSWSS and LKS patients can also have behavioral manifestations that overlap the spectrum of autism disorders (ASD). An impairment of brain development and/or maturation with complex interplay between genetic predisposition and nongenetic factors has been suspected. A role for autoimmunity has been proposed but the pathophysiology of CSWSS and of LKS remains uncharacterized.

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.

A subset of genomic alterations detected in rolandic epilepsies contains candidate or known epilepsy genes including GRIN2A and PRRT2.

Rolandic epilepsies (REs) represent the most frequent epilepsy in childhood. Patients may experience cognitive, speech, language, reading, and behavioral issues. The genetic origin of REs has long been debated. The participation of rare copy number variations (CNVs) in the pathophysiology of various human epilepsies has been increasingly recognized. However, no systematic search for microdeletions or microduplications has been reported in RE so far.

Long-term outcome after cognitive and behavioral regression in nonlesional epilepsy with continuous spike-waves during slow-wave sleep.

Purpose:  To present the long‐term follow‐up of 10 adolescents and young adults with documented cognitive and behavioral regression as children due to nonlesional focal, mainly frontal, epilepsy with continuous spike‐waves during slow wave sleep (CSWS).

Epileptic patients with de novo STXBP1 mutations: Key clinical features based on 24 cases.

Mutations in the syntaxin binding protein 1 gene (STXBP1) have been associated mostly with early onset epileptic encephalopathies (EOEEs) and Ohtahara syndrome, with a mutation detection rate of approximately 10%, depending on the criteria of selection of patients. The aim of this study was to retrospectively describe clinical and electroencephalography (EEG) features associated with STXBP1‐related epilepsies to orient molecular screening.

Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive disorders with prenatal onset, characterized by hypoplasia of pons and cerebellum. Mutations in a small number of genes have been reported to cause PCH, and the vast majority of PCH cases are explained by mutations in TSEN54, which encodes a subunit of the tRNA splicing endonuclease complex. Here we report three families with homozygous truncating mutations in TBC1D23 who display moderate to severe intellectual disability and microcephaly. MRI data from available affected subjects revealed PCH, small normally proportioned cerebellum, and corpus callosum anomalies. Furthermore, through in utero electroporation, we show that downregulation of TBC1D23 affects cortical neuron positioning. TBC1D23 is a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins (TBC/RABGAPs). Members of this protein family negatively regulate RAB proteins and modulate the signaling between RABs and other small GTPases, some of which have a crucial role in the trafficking of intracellular vesicles and are involved in neurological disorders. Here, we demonstrate that dense core vesicles and lysosomal trafficking dynamics are affected in fibroblasts harboring TBC1D23 mutation. We propose that mutations in TBC1D23 are responsible for a form of PCH with small, normally proportioned cerebellum and should be screened in individuals with syndromic pontocereballar hypoplasia.

The onset of acute oxcarbazepine toxicity related to prescription of clarithromycin in a child with refractory epilepsy

In comparison with carbamazepine, oxcarbazepine (OXC) has fewer associated side-effects and a reduced number of reported drug–drug interactions. The only cases of serious toxicity have been documented after suicide attempts using multiple drugs [1], but OXC toxicity alone has never been noted to be the only cause of death [2]. The main drug–drug interactions reported (in particular with other antiepileptics such as carbamazepine, phenobarbital and sodium valproate) actually result in the lowering of plasma OXC concentrations [3, 4]. We report a case of severe OXC toxicity after starting clarithromycin in a patient with refractory epilepsy and discuss the mechanism of this potential interaction. We suggest that clarithromycin may inhibit the efflux proteins of the blood–brain barrier (BBB), which are thought to be overexpressed in drug-resistant patients [5]. This inhibition may result in increased cerebrospinal fluid (CSF) concentrations of OXC and explain the signs of toxicity observed. A 10-year-old boy with known refractory epilepsy presented to our department with symptoms suggestive of acute OXC toxicity. His past medical history included a diagnosis of epilepsy at the age of 18 months when he presented with generalized tonic clonic seizures and associated global developmental delay. There were no other significant illnesses or dysmorphism and he had been born at term without complications. The first child of nonconsanguineous North African parents, there was a family history of epilepsy in three paternal second cousins (one with developmental delay). Diagnostic investigations performed included normal brain magnetic resonance imaging and positron emission tomography scan, karyotyping, genetic screening for fragile X syndrome and a metabolic screen, all of which were unremarkable. His medications at the time of presentation included: OXC 540 mg am/510 mg nocte, lamotrigine 100 mg b.d., sodium valproate 100 mg am/300 mg and topiramate 100 mg b.d. Despite the treatment, between two and three epileptic fits were reported per month. A course of clarithromycin (250 mg b.d.) was started due to a mild respiratory tract infection 3 days after the onset of coryzal symptoms. An hour after he had taken the first dose, the parents noticed their son was unsteady on his feet (Figure 1) and had a brief episode where he appeared unresponsive. Twenty-four hours after starting the antibiotic, he was brought to our paediatric emergency department with an increase in symptoms including vomiting, drowsiness and dizzy spells. Clinical neurological examination revealed hyperkinesia, ataxia and nystagmus. At the time of presentation, the patient was already apyrexial with no respiratory signs other than mild coryzal symptoms. The rest of the clinical examination was unremarkable. On admission, blood tests were essentially normal, including: plasma electrolytes, liver enzymes, renal function and inflammatory markers (sodium 142 mmol l−1, potassium 3.5 mmol l−1, C-reactive protein 57 mg l−1). An initial electroencephalogram showed a decrease in paroxysmal activity. Plasma levels of sodium valproate were dosed as suboptimal (21.7 mg l−1, ref 50–100 mg l−1) and as an incidental finding, the patient was noted to be mildly hypocalcaemic (2.08 mg l−1, ref 2.20–2.80 mg l−1). Twelve hours after admission, the dose of OXC was reduced to 420 mg (80% of the original) and the clarithromycin was stopped. The other medications remained unchanged. After a further 12 h, the dose of OXC was increased back to 540 mg as the clinical symptoms were much improved. Following this increase, once again the patient developed drowsiness and ataxia. As a result, the OXC dose was halved for 24 h. No further symptoms were reported and the dose was then progressively increased back to the initial value over a period of 72 h. No further symptoms or seizures were reported during the rest of his hospital stay and the patient was discharged home after 5 days. Figure 1 Clinical symptoms vs. time since starting clarithromycin OXC is particularly recommended due to the minimal side-effects and drug interactions seen in comparison with carbamazepine. We report the first case of OXC toxicity likely to have been induced by a drug–drug interaction with clarithromycin (250 mg b.d.). After two doses of clarithromycin, the patient needed to be hospitalized as an emergency for suspected toxicity. Many of the symptoms observed in our patient are known to be linked to possible OXC toxicity, including drowsiness, dizziness, nausea, vomiting, hyperkinesia, ataxia and nystagmus. Once the clarithromycin was stopped, a clear improvement was seen (t1/2= 4 h). However, the early re-introduction of OXC (back to the initial dose after 12 h) resulted in a further similar episode. The dose was then halved and progressively increased over a period of 72 h with no further problems. This shows there is a latent period in the mechanism of interaction between clarithromycin and OXC. Furthermore, halving the OXC dose did not lead to any seizures in our patient. In the absence of treatment with clarithromycin, the patient had not previously developed any signs of OXC toxicity (despite being on the medication at the same dose for several months). To date, the only reported OXC interactions are due to modifications in liver metabolism. Ninety-five percent of OXC is metabolized to the active monohydroxy derivative (DMH) and 4% to the inactive dihydroxy derivative (DDH). Pisani et al. have shown that an increase in levels of the active metabolite and a decrease in the inactive form occur when OXC is administered in conjunction with viloxazine (an antidepressant) [6]. This inhibition of the conversion of the active DMH to the inactive DDH form has never been linked to any adverse clinical effects. Studies carried out to research possible interactions between macrolides (erythromycin) and OXC have not shown any interactions [7]. However, such studies were conducted in healthy volunteers with no prior drug resistance, and the results were based on potential changes in plasma concentrations of OXC and DMH. It has been shown that normal OXC or DMH serum levels do not exclude central nervous system (CNS) toxicity or the occurrence of serious neurological adverse effects [8]. The lack of correlation between serum OXC levels and neurological side-effects can be explained by the fact that serum levels do not give a reliable reflection of the actual levels in the CNS. Thus, passage across the BBB may be an important factor in the efficacy of OXC and DMH. Numerous studies have demonstrated the role played by efflux proteins present on the membranes of cells which make up the BBB [9]. Increased expression of efflux proteins such as the P-glycoproteins (multidrug resistance 1 and 2) and the Multidrug Resistance Proteins 1–9 has been observed in some drug-resistant patients, which could be responsible for a decreased concentration of OXC in the CSF, resulting in decreased clinical effects [4, 9–11]. Macrolides are known to be potent inhibitors of P-glycoprotein (50% decrease in activity). Therefore, we propose that the toxic side-effects observed in our patient after starting clarithromycin (whilst already on OXC) may be explained by an increase in brain OXC concentrations due to the inhibition of the active BBB efflux proteins. We recommend physicians consider adjusting the dose of OXC when using a macrolide in drug-resistant patients due to the potential risks of drug toxicity.

A Pediatric Case of Fisher-Bickerstaff Spectrum

Miller Fisher syndrome is classically described as an acute inflammatory polyneuropathy clinical variant, associating external ophthalmoplegia, ataxia and loss of tendon reflexes. Despite recent advances in the comprehension of this syndrome, with the description of anti-GQ1b anti-ganglioside antibodies associated with abnormal neuromuscular transmission in the serum of Miller Fisher syndrome patients, there is ongoing debate on the peripheral or central origin of the symptoms. Some authors argue that there is a brainstem and cerebellar involvement. Indeed, since description of the syndrome, numerous cases have been reported with electrophysiologic and imaging evidences of brainstem involvement in the syndrome. Described and discussed here is the case of a 4-year-old child with Miller Fisher syndrome and cerebral lesions evident on magnetic resonance imaging, suggesting a Fisher-Bickerstaff spectrum.