Benefits of vagus nerve stimulation on psychomotor functions in patients with severe drug-resistant epilepsy.

PURPOSE: Patients with severe drug-resistant epilepsy (DRE) experience psychomotor disorders. Our study aimed to assess the psychomotor outcomes after vagus nerve stimulation (VNS) in this population. METHODS: We prospectively evaluated psychomotor function in 17 adult patients with severe DRE who were referred for VNS. Psychomotor functions were examined, in the preoperative period and at 18 months post-surgery, by a psychomotor therapist using a full set of the following specific tests: the Rey-Osterrieth complex figure (ROCF) test, the Zazzo's cancelation task (ZCT), the Piaget-Head test and the paired images test. RESULTS: At 18 months post-VNS surgery, the Piaget-head scores increased by 3 points (p = 0.008) compared to baseline. Performances were also improved for ROCF test both in copy (+2.4 points, p = 0.001) and recall (+2.0 points, p = 0.008) tasks and for the paired images test (accuracy index: +28.6 %, p = 0.03). Regarding the ZCT findings, the efficiency index increased in both single (+16 %, p = 0.005) and dual (+17.1 %, p < 0.001) tasks. QoL improved in 88.2 % of patients. CONCLUSIONS: Patients with severe DRE treated with VNS experienced improved performance in terms of global psychomotor functions. Perceptual organization, visuospatial memory, laterality awareness, sustained attention, concentration, visual scanning, and inhibition were significantly improved.

A new neurodevelopmental disorder linked to heterozygous variants in UNC79.

PURPOSE: The "NALCN channelosome" is an ion channel complex that consists of multiple proteins, including NALCN, UNC79, UNC80, and FAM155A. Only a small number of individuals with a neurodevelopmental syndrome have been reported with disease causing variants in NALCN and UNC80. However, no pathogenic UNC79 variants have been reported, and in vivo function of UNC79 in humans is largely unknown. METHODS: We used international gene-matching efforts to identify patients harboring ultrarare heterozygous loss-of-function UNC79 variants and no other putative responsible genes. We used genetic manipulations in Drosophila and mice to test potential causal relationships between UNC79 variants and the pathology. RESULTS: We found 6 unrelated and affected patients with UNC79 variants. Five patients presented with overlapping neurodevelopmental features, including mild to moderate intellectual disability and a mild developmental delay, whereas a single patient reportedly had normal cognitive and motor development but was diagnosed with epilepsy and autistic features. All displayed behavioral issues and 4 patients had epilepsy. Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a heterozygous loss-of-function variant have a developmental delay in body weight compared with wild type. In addition, they have impaired ability in learning and memory. CONCLUSION: Our results demonstrate that heterozygous loss-of-function UNC79 variants are associated with neurologic pathologies.

A review of the natural history of Sturge-Weber syndrome through adulthood.

BACKGROUND: Sturge-Weber syndrome (SWS) is a neurocutaneous disorder caused by a somatic mutation in the GNAQ gene, leading to capillary venous malformations with neurological, ocular, and cutaneous abnormalities. Descriptions of adult and elderly patients with SWS are scarce compared to those of neonates or children. METHODS: We reviewed clinical, neuro-radiological and electroencephalographical findings of adult patients diagnosed with SWS, treated in our tertiary center for rare epilepsies. RESULTS: Ten adult patients were identified with a median age of 48 years at inclusion. All patients had seizures, with features of temporal lobe involvement for five patients. One patient presented typical drug-resistant mesial temporal seizures with ipsilateral hippocampal sclerosis and leptomeningeal enhancement, and was treated surgically. Other patients presented typical neurological and brain imaging features found in SWS. One patient without visible leptomeningeal angioma or brain calcifications presented neurological symptoms (tonic-clonic generalized seizures) for the first time at the age of 56. Two of the oldest patients in our cohort with supratentorial leptomeningeal angioma displayed contralateral cerebellar atrophy, consistent with crossed cerebellar diaschisis. Over 70 years of follow-up data were available for one patient whose epilepsy started at the age of 6 months, offering a vast overview of the course of SWS, in particular the onset of dementia and contralateral micro-bleeds in relation to the leptomeningeal angioma. CONCLUSION: The long follow-up of our cohort allows for a description of the course of SWS and a characterization of uncommon neurological features in adult and elderly patients.

SCN1A-related epilepsy with recessive inheritance: Two further families.

BACKGROUND: Variants in SCN1A gene, encoding the voltage-gated sodium channel Nav1.1, are associated with distinct epilepsy syndromes ranging from the relatively benign genetic epilepsy with febrile seizures plus (GEFS+) to Dravet syndrome, a severe developmental and epileptic encephalopathy (DEE). Most SCN1A pathogenic variants are heterozygous changes inherited in a dominant or de novo inheritance and many cause a loss-of-function of one allele. To date, recessive inheritance has been suggested in only two families with affected children harboring homozygous SCN1A missense variants while their heterozygous parents were asymptomatic. The aim of this report is to describe two additional families in which affected individuals have biallelic SCN1A variants possibly explaining their phenotype. METHODS AND RESULTS: We report two novel homozygous SCN1A missense variants in two patients from related parents. Both patients had fever-sensitive epilepsy beginning in the first months of life, followed by afebrile seizures, without severe cognitive impairment. Parents were asymptomatic. Next generation sequencing excluded a pathogenic variant in other genes involved in DEE. Estimation of pathogenicity scores by in-silico tools suggests that the impact of these SCN1A variants is less damaging than that of dominant pathogenic variants. CONCLUSION: This study provides additional evidence that homozygous variants in SCN1A can cause GEFS+. This recessive inheritance would imply that hypomorphic variants may not necessarily cause epilepsy at the heterozygous state but may decrease the seizure threshold when combined.

Outpatient vagus nerve stimulation surgery in patients with drug-resistant epilepsy with severe intellectual disability.

PURPOSE: Vagus nerve stimulation (VNS) implantation is increasingly proposed in outpatient procedure. Some epilepsy syndromes are associated with severe neurodevelopmental disabilities (intellectual disability, autism) and often motor or sensory handicaps, making ambulatory surgery more complex. METHODS: We prospectively assessed the feasibility and safety of outpatient VNS implantation in 26 adult patients with drug-resistant epilepsy with severe intellectual disability between December 2017 and October 2020. RESULTS: The male-to-female ratio was 0.9 and the mean age on surgery day was 23.1 years. Seventeen patients (65.4%) suffered from epileptic encephalopathy, 7 (26.9%) from cryptogenic or genetic generalized epilepsy, and 2 (7.7%) from severe multifocal epilepsy. Postoperatively, all patients were discharged the day of surgery. No patient was admitted to a hospital or have consulted within one month due to postoperative complications. There was no surgery-related complication during patients' follow-up. CONCLUSION: Our study highlights the safety and feasibility of VNS surgery in an outpatient setting for patients with severe intellectual disability. We report detailed protocol and preoperative checklist to optimize outpatient VNS surgery in these not able-bodied patients. Severe disabilities or epilepsy-associated handicaps should not be an exclusion criterion when considering ambulatory VNS implantation.

Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype.

Alternating hemiplegia of childhood is a rare disorder caused by de novo mutations in the ATP1A3 gene, expressed in neurons and cardiomyocytes. As affected individuals may survive into adulthood, we use the term 'alternating hemiplegia'. The disorder is characterized by early-onset, recurrent, often alternating, hemiplegic episodes; seizures and non-paroxysmal neurological features also occur. Dysautonomia may occur during hemiplegia or in isolation. Premature mortality can occur in this patient group and is not fully explained. Preventable cardiorespiratory arrest from underlying cardiac dysrhythmia may be a cause. We analysed ECG recordings of 52 patients with alternating hemiplegia from nine countries: all had whole-exome, whole-genome, or direct Sanger sequencing of ATP1A3. Data on autonomic dysfunction, cardiac symptoms, medication, and family history of cardiac disease or sudden death were collected. All had 12-lead electrocardiogram recordings available for cardiac axis, cardiac interval, repolarization pattern, and J-point analysis. Where available, historical and prolonged single-lead electrocardiogram recordings during electrocardiogram-videotelemetry were analysed. Half the cohort (26/52) had resting 12-lead electrocardiogram abnormalities: 25/26 had repolarization (T wave) abnormalities. These abnormalities were significantly more common in people with alternating hemiplegia than in an age-matched disease control group of 52 people with epilepsy. The average corrected QT interval was significantly shorter in people with alternating hemiplegia than in the disease control group. J wave or J-point changes were seen in six people with alternating hemiplegia. Over half the affected cohort (28/52) had intraventricular conduction delay, or incomplete right bundle branch block, a much higher proportion than in the normal population or disease control cohort (P = 0.0164). Abnormalities in alternating hemiplegia were more common in those ≥16 years old, compared with those <16 (P = 0.0095), even with a specific mutation (p.D801N; P = 0.045). Dynamic, beat-to-beat or electrocardiogram-to-electrocardiogram, changes were noted, suggesting the prevalence of abnormalities was underestimated. Electrocardiogram changes occurred independently of seizures or plegic episodes. Electrocardiogram abnormalities are common in alternating hemiplegia, have characteristics reflecting those of inherited cardiac channelopathies and most likely amount to impaired repolarization reserve. The dynamic electrocardiogram and neurological features point to periodic systemic decompensation in ATP1A3-expressing organs. Cardiac dysfunction may account for some of the unexplained premature mortality of alternating hemiplegia. Systematic cardiac investigation is warranted in alternating hemiplegia of childhood, as cardiac arrhythmic morbidity and mortality are potentially preventable.

Acute behavioral crises in psychiatric inpatients with autism spectrum disorder (ASD): recognition of concomitant medical or non-ASD psychiatric conditions predicts enhanced improvement.

During adolescence, some individuals with autism spectrum disorder (ASD) engage in severe challenging behaviors, such as aggression, self-injury, disruption, agitation and tantrums. We aimed to assess risk factors associated with very acute behavioral crises in adolescents with ASD admitted to a dedicated neurobehavioral unit. We included retrospectively in 2008 and 2009 29 adolescents and young adults with ASD hospitalized for severe challenging behaviors and proposed a guideline (Perisse et al., 2010) that we applied prospectively for 29 patients recruited for the same indications between 2010 and 2012. In total, 58 patients were admitted (n=70 hospitalizations, mean age=15.66 (±4.07) years, 76% male). We systematically collected data describing socio-demographic characteristics, clinical variables (severity, presence of language, cognitive level), comorbid organic conditions, etiologic diagnosis of the episode, and treatments. We explored predictors of Global Assessment Functioning Scale (GAFS) score and duration of hospitalization at discharge. All but 2 patients exhibited severe autistic symptoms and intellectual disability (ID), and two-thirds had no functional verbal language. During the inpatient stay (mean=84.3 (±94.9) days), patients doubled on average their GAFS scores (mean=17.66 (±9.05) at admission vs. mean=31.4 (±9.48) at discharge). Most common etiologies for acute behavioral crises were organic causes [n=20 (28%), including epilepsy: n=10 (14%) and painful medical conditions: n=10 (14%)], environmental causes [n=17 (25%) including lack of treatment: n=11 (16%) and adjustment disorder: n=6 (9%)], and non-ASD psychiatric condition [n=33 (48%) including catatonia: n=5 (7%), major depressive episode: n=6 (9%), bipolar disorder: n=4 (6%), schizophrenia: n=6 (9%), other/unknown diagnosis: n=12 (17%)]. We found no influence of age, gender, socio-economic status, migration, level of ID, or history of seizure on improvement of GAFS score at discharge. Severity of autism at admission was the only negative predictor (p<.001). Painful medical conditions (p=.04), non-ASD psychiatric diagnoses (p=.001), prior usage of specialized ASD care programs (p=.004), functional language (p=.007), as well as a higher number of challenging behaviors upon admission (p=.001) were associated with higher GAFS scores at discharge. Clinical severity at admission, based on the number of challenging behaviors (r=.35, p=.003) and GAFS score (r=-.32, p=.008) was correlated with a longer inpatient stay. Longer hospitalization was however correlated (r=.27, p=.03) with higher GAFS score at discharge even after adjustment for confounding factors. Challenging behaviors among adolescents with ASD may stem from diverse risk factors, including environmental problems, comorbid acute psychiatric conditions, or somatic illness such as epilepsy or acute pain. The management of these behavioral challenges requires a unified, multidisciplinary approach.

A diagnostic flow chart for POLG-related diseases based on signs sensitivity and specificity.

OBJECTIVE: Diseases due to mutations of POLG gene, encoding the mitochondrial DNA polymerase, are reputed to have very diverse clinical presentations and have been proposed to cause up to 25% adult mitochondrial diseases. Our objective was the evaluation of the specificity and sensitivity of the signs encountered with POLG mutations. DESIGN: Forty-four patients out of 154 with sequenced POLG gene had mutations affecting either one (POLG(+/-) group) or two POLG alleles (POLG(+/+) group). Phenotyping included clinical signs, electroneuromyography and brain imaging while mitochondrial investigations encompassed muscle histochemistry, respiratory chain assays and search for multiple mitochondrial deletions. The specificity and sensitivity of the signs associated with POLG mutations were analysed by comparison between POLG(+/+) and patients without POLG mutation. RESULTS: High sensitivity but low specificity was observed with single signs such as axonal sensory neuropathy, cerebellar syndrome, movement disorders and weakness involving ocular, pharyngeal, axial and/or limb muscles. Specificity was increased with combination of previous signs plus psychiatric symptoms, cognitive impairment and epilepsy. High specificity and sensitivity was only obtained with sensory neuronopathy associated with one of the following signs: weakness of ocular, pharyngeal, axial and/or limb muscles. Mitochondrial investigations did not suffice for diagnosis. The widespread neuromuscular signs were often present since disease onset and were the rule above 50 years of age leading to a very low probability of POLG mutations in patients with less than three signs and absent sensory neuropathy. CONCLUSIONS: Phenotypes associated with POLG mutations follow a reproducible pattern, which allows establishing a diagnostic flow chart.

Does epilepsy in multiplex autism pedigrees define a different subgroup in terms of clinical characteristics and genetic risk?

BACKGROUND: Autism spectrum disorders (ASD) and epilepsy frequently occur together. Prevalence rates are variable, and have been attributed to age, gender, comorbidity, subtype of pervasive developmental disorder (PDD) and risk factors. Recent studies have suggested disparate clinical and genetic settings depending on simplex or multiplex autism. The aim of this study was to assess: 1) the prevalence of epilepsy in multiplex autism and its association with genetic and non-genetic risk factors of major effect, intellectual disability and gender; and 2) whether autism and epilepsy cosegregate within multiplex autism families. METHODS: We extracted from the Autism Genetic Resource Exchange (AGRE) database (n = 3,818 children from 1,264 families) all families with relevant medical data (n = 664 children from 290 families). The sample included 478 children with ASD and 186 siblings without ASD. We analyzed the following variables: seizures, genetic and non-genetic risk factors, gender, and cognitive functioning as assessed by Raven's Colored Progressive Matrices (RCPM) and Vineland Adaptive Behavior Scales (VABS). RESULTS: The prevalence of epilepsy was 12.8% in cases with ASD and 2.2% in siblings without ASD (P <10-5). With each RCPM or VABS measure, the risk of epilepsy in multiplex autism was significantly associated with intellectual disability, but not with gender. Identified risk factors (genetic or non-genetic) of autism tended to be significantly associated with epilepsy (P = 0.052). When children with prematurity, pre- or perinatal insult, or cerebral palsy were excluded, a genetic risk factor was reported for 6/59 (10.2%) of children with epilepsy and 12/395 (3.0%) of children without epilepsy (P = 0.002). Finally, using a permutation test, there was significant evidence that the epilepsy phenotype co-segregated within families (P <10-4). CONCLUSIONS: Epilepsy in multiplex autism may define a different subgroup in terms of clinical characteristics and genetic risk.

Outcome of pediatric epilepsies in adulthood.

A good understanding of the long-term outcome of epileptic disorders that have begun in infancy or childhood allows the practitioner to choose the best medical management and to adjust it throughout the life of the patient. The identification of risk factors of poor outcome is crucial, the issue being to prevent or minimize their impacts by appropriate interventions. However, knowledge on the natural course and long-term outcome of pediatric epilepsies is fragmentary for a lot of them for reasons that the authors discuss in this chapter. After reviewing general considerations on outcome for the epilepsies persisting throughout life, the authors will discuss the present state of knowledge on specific aspects concerning some pediatric epilepsy syndromes. These disorders have been chosen because they are representative of the wide range of potential outcomes that can be observed in adults.

STXBP1-related encephalopathy presenting as infantile spasms and generalized tremor in three patients.

PURPOSE: Dominant mutations in the STXBP1 gene are a recently identified cause of infantile epileptic encephalopathy without metabolic and structural brain anomalies. To date, 25 patients with heterozygous mutation or deletion of STXBP1 have been reported. A diagnosis of early infantile epileptic encephalopathy with suppression-burst (Ohtahara syndrome) was made in most of them, with infantile spasms and nonsyndromic infantile epileptic encephalopathy being the diagnosis in other patients. Although the phenotypic spectrum of STXBP1-related encephalopathy is emerging with evidence suggesting the relatively frequent involvement of this gene in infantile epileptic encephalopathies, accurate clinical descriptions of patients are still necessary to delineate this entity. METHODS: The sequence of the STXPB1 gene was analyzed in 29 patients with early onset syndromic or nonsyndromic infantile epileptic encephalopathy without brain magnetic resonance imaging (MRI) anomalies and with normal chromosomal and metabolic checkup. Another patient with a complex phenotype was analyzed by comparative genomic hybridization (CGH) array. KEY FINDINGS: From the studied series, 2 of 29 patients were found to carry a de novo heterozygous mutation in STXBP1. One patient carried the recurrent p.Arg406His mutation and the other an insertion of 10 bases leading to a premature termination codon. CGH array experiment detected a deletion of 3-3.5 Mbp in the third patient with infantile epileptic encephalopathy and nail malformations. All three had infantile spasms associated with partial seizures that responded to antiepileptic drug therapy. Intellectual abilities were severely impaired in all of them. Generalized tremor was the main neurologic striking feature in the three patients, with one of them further displaying unilateral akinetic-hypertonic syndrome. SIGNIFICANCE: Mutations in STXBP1 are relatively frequent in patients with infantile epileptic encephalopathies. STXBP1-related encephalopathy may present as drug-responsive infantile spasms with focal/lateralized discharges. Generalized tremor appearing after the first year of life may be a clue to the diagnosis in some patients.

Lafora progressive myoclonus epilepsy: NHLRC1 mutations affect glycogen metabolism.

Lafora disease is a fatal autosomal recessive form of progressive myoclonus epilepsy. Patients manifest myoclonus and tonic-clonic seizures, visual hallucinations, intellectual, and progressive neurologic deterioration beginning in adolescence. The two genes known to be involved in Lafora disease are EPM2A and NHLRC1 (EPM2B). The EPM2A gene encodes laforin, a dual-specificity protein phosphatase, and the NHLRC1 gene encodes malin, an E3-ubiquitin ligase. The two proteins interact with each other and, as a complex, are thought to regulate glycogen synthesis. Here, we report three Lafora families with two novel pathogenic mutations (C46Y and L261P) and two recurrent mutations (P69A and D146N) in NHLRC1. Investigation of their functional consequences in cultured mammalian cells revealed that malin(C46Y), malin(P69A), malin(D146N), and malin(L261P) mutants failed to downregulate the level of R5/PTG, a regulatory subunit of protein phosphatase 1 involved in glycogen synthesis. Abnormal accumulation of intracellular glycogen was observed with all malin mutants, reminiscent of the polyglucosan inclusions (Lafora bodies) present in patients with Lafora disease.

A French experience of type 3 Gaucher disease: Phenotypic diversity and neurological outcome of 10 patients.

OBJECTIVE: To describe the clinical presentation of 10 patients with type 3 Gaucher disease and the clinical evolution of nine of them following specific therapy regimes. METHODS: The follow-up of these 10 patients was between 2 and 15 years. The clinical history was provided by each patient's general practitioner and a final clinical evaluation was made by two different physicians including a neurologist. One patient received no treatment, eight received enzyme replacement therapy (ERT) and one received ERT combined with substrate reduction therapy (SRT, miglustat). RESULTS: The clinical presentations were heterogeneous and most phenotypes reported for type 3 Gaucher disease were represented. The neurological involvement stabilized or improved in six patients under ERT with a follow-up of 2-15 years. Four of them showed isolated oculomotor signs only that improved or remained unchanged during the follow-up. Of two patients with progressive myoclonic epilepsy, the outcome was clearly unfavorable in one receiving ERT and disputable for the other receiving ERT+SRT. An unfavorable neurological outcome was observed in another patient in whom the ERT dose had been reduced before clinical decline. CONCLUSION: The stabilization of the clinical course in most patients is noteworthy. Though further evidence is needed from a larger series in order to draw any definite conclusions, our data suggest that ERT may be effective in preventing the evolution of neurological disturbances associated with type 3 Gaucher disease in some patients. However, the clinical course of the two patients with progressive myoclonic epilepsy was not influenced by ERT, as previously reported. In accordance with that reported in the literature, data from our series suggest that the outcome of patients undergoing ERT depends on the type of clinical involvement, treatment onset and dose. Genotype may also be an important factor, with p.L444P/p.L444P possibly indicating a better outcome.

Mutations and deletions in PCDH19 account for various familial or isolated epilepsies in females.

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.

Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome.

BACKGROUND Mutations in SCN1A can cause genetic epilepsy with febrile seizures plus (GEFS+, inherited missense mutations) or Dravet syndrome (DS, de novo mutations of all types). Although the mutational spectra are distinct, these disorders share major features and 10% of DS patients have an inherited SCN1A mutation. OBJECTIVES AND PATIENTS 19 selected families with at least one DS patient were studied to describe the mechanisms accounting for inherited SCN1A mutations in DS. The mutation identified in the DS probands was searched in available parents and relatives and quantified in the blood cells of the transmitting parent using quantitative allele specific assays. RESULTS Mosaicism in the blood cells of the transmitting parent was demonstrated in 12 cases and suspected in another case. The proportion of mutated allele in the blood varied from 0.04-85%. In the six remaining families, six novel missense mutations were associated with autosomal dominant variable GEFS+ phenotypes including DS as the more severe clinical picture. CONCLUSION The results indicate that mosaicism is found in at least 7% of families with DS. In the remaining cases (6/19, 32%), the patients were part of multiplex GEFS+ families and seemed to represent the extreme end of the GEFS+ clinical spectrum. In this latter case, additional genetic or environmental factors likely modulate the severity of the expression of the mutation.

Familial form of typical childhood absence epilepsy in a consanguineous context.

Causative genes for childhood absence epilepsy (CAE) are unknown partly because families are small or phenotypically heterogeneous. In five consanguineous Tunisian families with at least two sibs with CAE, 14 patients fulfilled the diagnostic criteria for CAE (Epilepsia 1989; 30:389-399). Linkage analyses or direct sequencing excluded CACNG2, CACNA1A, CACNB4, and CACNA2D2, orthologs of genes responsible for autosomal recessive (AR) absence seizures in mice. These families will help identify (a) gene(s) responsible for CAE.

Risk factors of acute behavioral regression in psychiatrically hospitalized adolescents with autism.

AIM: During adolescence, some individuals with autism engage in severe disruptive behaviors, such as violence, agitation, tantrums, or self-injurious behaviors. We aimed to assess risk factors associated with very acute states and regression in adolescents with autism in an inpatient population. METHOD: Between 2001 and 2005, we reviewed the charts of all adolescents with autism (N=29, mean age=14.8 years, 79% male) hospitalized for severe disruptive behaviors in a psychiatric intensive care unit. We systematically collected data describing socio-demographic characteristics, clinical variables (severity, presence of language, cognitive level), associated organic conditions, etiologic diagnosis of the episode, and treatments. RESULTS: All patients exhibited severe autistic symptoms and intellectual disability, and two-thirds had no functional verbal language. Fifteen subjects exhibited epilepsy, including three cases in which epilepsy was unknown before the acute episode. For six (21%) of the subjects, uncontrolled seizures were considered the main cause of the disruptive behaviors. Other suspected risk factors associated with disruptive behavior disorders included adjustment disorder (N=7), lack of adequate therapeutic or educational management (N=6), depression (N=2), catatonia (N=2), and painful comorbid organic conditions (N=3). CONCLUSION: Disruptive behaviors among adolescents with autism may stem from diverse risk factors, including environmental problems, comorbid acute psychiatric conditions, or somatic diseases such as epilepsy. The management of these behavioral changes requires a multidisciplinary functional approach.

Two novel CLCN2 mutations accelerating chloride channel deactivation are associated with idiopathic generalized epilepsy.

Heterozygous mutations in the CLCN2 gene encoding the voltage-gated chloride channel CLC2 have been identified in patients with idiopathic generalized epilepsy (IGE). Yet the involvement of CLCN2 in epilepsy remains controversial. To investigate the involvement of CLCN2 in another independent sample, we screened 52 unrelated patients from IGE families and 23 patients with Doose syndrome for mutations in CLCN2. No mutations were found in patients with Doose syndrome. In three unrelated IGE families, we identified two novel missense mutations, p.Arg235Gln and p.Arg577Gln, which were absent in large ethnically-matched control populations, and one novel p.Arg644Cys variant, which was also found in five Indian controls. Functional characterization of mutant channels using heterologous expression in mammalian cells and whole-cell patch-clamp recordings revealed faster deactivation kinetics as the major phenotype of both missense mutations. This finding predicts a loss of function that may contribute to intracellular chloride accumulation or neuronal hyperexcitability. However, the incomplete segregation of the mutations among affected members and the transmission by unaffected parents suggests that these CLCN2 mutations alone are not sufficient to induce epilepsy. They may instead represent susceptibility factors among other so far undetected genetic alterations in the respective families.