A novel SCN1A mutation in a cytoplasmic loop in intractable juvenile myoclonic epilepsy without febrile seizures

Generalised (genetic) epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with various phenotypes. The majority of individuals with GEFS+ have generalised seizure types, in addition to febrile seizures (FS) or febrile seizures plus (FS+), defined as either continued FS after 6 years of age or afebrile seizures following FS. A 27‐year‐old man with no history of FS/FS+ experienced intractable generalised convulsive seizures. The patient's father had a history of similar seizures during puberty and the patient's siblings had only FS. No individual in the family had both generalised seizures and FS/FS+, although GEFS+ might be considered to be present in the family. Analysis of SCN1A, a sodium channel gene, revealed a novel mutation (c.3250A>T [S1084C]) in the cytoplasmic loop 2 of SCN1A in both the patient and his father. Most previously reported SCN1A mutations in GEFS+ patients are located in the conserved homologous domains of SCN1A, whereas mutations in the cytoplasmic loops are very rare. SCN1A gene analysis is not commonly performed in subjects with generalised seizures without FS. SCN1A mutation may be a clinically‐useful genetic marker in order to distinguish GEFS+ patients from those with classic idiopathic generalised epilepsy, even if they present an atypical clinical picture.     

Predictors of neuropsychological impairment in seizure-free epilepsy patients

Persons with epilepsy are at increased risk of cognitive deficits as a result of various factors like etiology, structural brain lesions, seizure frequency, seizure type, age at onset of epilepsy, hereditary factors, psychosocial factors, and possible adverse effects of antiepileptic drugs (AEDs). Despite the fact that the majority of epilepsy patients are seizure-free, previous studies on the relationship between epilepsy-related variables and cognitive function have mainly been conducted on patients with persisting seizures. In this study 158 adults with epilepsy on AED monotherapy and without epileptic seizures for at least 2 years were investigated with a neuropsychological test battery in addition to a neurological examination, MRI and EEG. The major findings were that the group had education and employment status similar to the population mean and neuropsychological function in the normal range. In the patient group without idiopathic generalized epilepsy known cerebral etiology was found to be a highly significant predictor of neuropsychological deficit. For patients with idiopathic generalized epilepsy, early seizure debut at < or =18 years was a powerful predictor of neuropsychological impairment.     

Copy number variations in neurodevelopmental disorders

Common neurodevelopmental disorders (including autism, speech and language delay, schizophrenia, epilepsy and intellectual disability) have complex aetiology, which is predominantly genomic, but also environmental in origin. They share a paradox, in that high heritability is matched by lowered fecundity, placing them under negative genetic selection. This implicates variants of recent origin, such as de novo mutations or common, very low-risk polymorphisms that escape negative selection. High or moderate risk variants have been discovered by chromosome analysis, genome sequencing and copy number variant (CNV) detection, including a 3Mb deletion causing 22q11.2 deletion syndrome (Velo-Cardio-Facial Syndrome) that has penetrance of up to 50% for schizophrenia. More recently, rare, recurrent and often de novo pathogenic CNVs, including deletions at NRXN1, 1q21.2, 15q11.2 and 15q13.3, 16p11.2 and duplications at VIPR2 and 16p13.11, have also been discovered. These have several unique features that differentiate them from Mendelian disease mutations in that they have incomplete penetrance, with moderate-to-high odds ratios for risk, and show diagnostic pleiotropy, increasing risk across the neurodevelopmental disorder spectrum. Some are also syndromic, with characteristic features such as facial dysmorphology, and other specific risks such as aortic dissection or obesity, implying that they might be better classified as distinct diagnoses. The discovery of pathogenic CNVs provide new opportunities for translation leading to patent benefit, including improvements in clinical genetic diagnosis and genetic counselling, the possibility of clinician decision-making tools for risk prediction, and the identification of drug targets and implementation of personalised medicine using stratification by genotype.     

Dynamic functional network connectivity in idiopathic generalized epilepsy with generalized tonic–clonic seizure

Idiopathic generalized epilepsy (IGE) has been linked with disrupted intra‐network connectivity of multiple resting‐state networks (RSNs); however, whether impairment is present in inter‐network interactions between RSNs, remains largely unclear. Here, 50 patients with IGE characterized by generalized tonic–clonic seizures (GTCS) and 50 demographically matched healthy controls underwent resting‐state fMRI scans. A dynamic method was implemented to investigate functional network connectivity (FNC) in patients with IGE‐GTCS. Specifically, independent component analysis was first carried out to extract RSNs, and then sliding window correlation approach was employed to obtain dynamic FNC patterns. Finally, k‐mean clustering was performed to characterize six discrete functional connectivity states, and state analysis was conducted to explore the potential alterations in FNC and other dynamic metrics. Our results revealed that state‐specific FNC disruptions were observed in IGE‐GTCS and the majority of aberrant functional connectivity manifested itself in default mode network. In addition, temporal metrics derived from state transition vectors were altered in patients including the total number of transitions across states and the mean dwell time, the fraction of time spent and the number of subjects in specific FNC state. Furthermore, the alterations were significantly correlated with disease duration and seizure frequency. It was also found that dynamic FNC could distinguish patients with IGE‐GTCS from controls with an accuracy of 77.91% (P < 0.001). Taken together, this study not only provided novel insights into the pathophysiological mechanisms of IGE‐GTCS but also suggested that the dynamic FNC analysis was a promising avenue to deepen our understanding of this disease. Hum Brain Mapp 38:957–973, 2017. © 2016 Wiley Periodicals, Inc.     

Excitability of the human epileptic cortex after chronic valproate: a reappraisal

We explored the action of chronic valproic acid (VPA) on the human epileptic cortex by means of transcranial magnetic stimulation (TMS). TMS is an emerging biomarker for neurotropic drugs. We had 15 drug-naive patients with different epileptic syndromes. Interictally, we measured several TMS indexes of cortical excitability before commencing VPA and 3 months later. At that time, all patients were clinical responders to the drug, whose plasma levels were in the "therapeutic range". We then compared the two conditions, while 18 healthy subjects, of whom 12 were retested at a similar delay, acted as controls. In the pooled patients, the baseline resting motor threshold to TMS was similar to that of controls, but it increased significantly (P < 0.05) after VPA. Intracortical facilitation, another index of cortical excitability, was abnormally enhanced at baseline but decreased significantly after VPA (P < 0.05). On splitting patients according to their diagnosis, the threshold increase was significant (P < 0.05) among partial, but not generalized epilepsies. The reverse was true for changes in intracortical facilitation. TMS phenomena had no linear relation to VPA serum levels. Based on the known pharmacology of TMS effects, VPA reduced the intrinsic membrane excitability of motor cortical neurons, possibly through changes in Na+ channel activity. Then, VPA corrected a transmitter-mediated interneuronal hyper-excitability of the primary motor cortex. The former effect was best seen in partial, and the latter in generalized epilepsy patients.     

Epilepsy in offspring of whom both parents have idiopathic generalized epilepsy: biparental inheritance

BACKGROUND: Little is known about offspring of parents who both have idiopathic generalized epilepsy (IGE). This is of importance for understanding the complex genetic architecture of IGE.METHODS: Families in whom both parents had proven IGE were ascertained through a multiplex families database. Clinical information including EEG recordings and detailed pedigrees was obtained. RESULTS: In family I, the mother had juvenile myoclonic epilepsy (JME), and the father had IGE. One daughter had Lennox-Gastaut syndrome, and the other had unclassified epilepsy. In family II, the mother had JME, and the father had IGE. Two of three sons had an identical clinical picture of clinical picture of childhood absence epilepsy (CAE), but with fast polyspike-wave discharges on EEG. CONCLUSIONS: The clinical phenotype of affected offspring suggested that their epilepsy could be due to the combination of a putative "double dose" of genes from both sides of the family. In such families, as epilepsy genes could be inherited from both parents, a high risk of epilepsy in the offspring could be expected.     

Prognostic value of EEG asymmetries for development of drug-resistance in drug-naïve patients with genetic generalized epilepsies

ObjectivePrevious studies based solely on visual EEG analysis reported equivocal results regarding an association of pharmaco-resistance with EEG asymmetries in genetic generalized epilepsies (GGE). We addressed this issue by applying both visual and quantitative methods to the pretreatment EEG of GGE patients.MethodsSocio-demographic/disease characteristics and response to treatment/discontinuation trial for these patients were recorded at 6 months and at last follow up. The first EEG was retrospectively, blindly, and visually assessed for focal slowing, focal discharges and also quantitatively analyzed for amplitude or latency asymmetries of generalized discharges. Association between these variables and development of drug-resistance was evaluated.ResultsOut of 51 subjects, 40% had some type of EEG asymmetry by visual, 37% by quantitative and 54% by combined analysis. Drug-resistance was identified in 52% of patients after 6 months and in 24% at the end of the follow up period (∼4.2 years). 27% of patients underwent a discontinuation trial; 43% unsuccessfully. There was no association between baseline EEG asymmetries of any type and refractoriness to medical therapy, regardless of analytical method used.ConclusionsIn a carefully selected cohort of medication-naïve GGE patients, visual and quantitative asymmetries in the first EEG were not associated with the development of pharmaco-resistance.SignificanceThese findings do not provide support for utilization of EEG asymmetries as a prognostic tool in GGE.     

NIPA1 mutation in complex hereditary spastic paraplegia with epilepsy

Background and purpose: Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurodegenerative disorders characterized in the ‘pure’ phenotype by progressive spasticity and weakness of the lower limbs. In the ‘complex’ phenotype, additional neurologic symptoms or signs are found. Mutations in the NIPA1 gene have been reported to cause spastic paraplegia type 6 (SPG6) in 10 families. SPG6 is a rare form of autosomal dominantly inherited HSP associated with a pure phenotype; however, in one complex SPG6 family, idiopathic generalized epilepsy (IGE) has been described and in addition, recurrent microdeletions at 15q11.2 including NIPA1 have been identified in patients with IGE. The purpose was to identify NIPA1 mutations in patients with pure and complex HSP. Methods: Fifty‐two patients with HSP were screened for mutations in NIPA1. Results: One previously reported missense mutation c.316G>A, p.Gly106Arg, was identified in a complex HSP patient with spastic dysarthria, facial dystonia, atrophy of the small hand muscles, upper limb spasticity, and presumably IGE. The epilepsy co‐segregated with HSP in the family. Conclusion: NIPA1 mutations were rare in our population of patients with HSP, but can be found in patients with complex HSP. Epilepsy might be more common in SPG6 than in other forms of HSP because of a genetic risk factor closely linked to NIPA1.