Musculoskeletal Features without Ataxia Associated with a Novel de novo Mutation in KCNA1 Impairing the Voltage Sensitivity of Kv1.1 Channel

The KCNA1 gene encodes the subunit of the voltage-gated Kv1.1 potassium channel that critically regulates neuronal excitability in the central and peripheral nervous systems. Mutations in KCNA1 have been classically associated with episodic ataxia type 1 (EA1), a movement disorder triggered by physical and emotional stress. Additional features variably reported in recent years include epilepsy, myokymia, migraine, paroxysmal dyskinesia, hyperthermia, hypomagnesemia, and cataplexy. Interestingly, a few individuals with neuromyotonia, either isolated or associated with skeletal deformities, have been reported carrying variants in the S2–S3 transmembrane segments of Kv1.1 channels in the absence of any other symptoms. Here, we have identified by whole-exome sequencing a novel de novo variant, T268K, in KCNA1 in a boy displaying recurrent episodes of neuromyotonia, muscle hypertrophy, and skeletal deformities. Through functional analysis in heterologous cells and structural modeling, we show that the mutation, located at the extracellular end of the S3 helix, causes deleterious effects, disrupting Kv1.1 function by altering the voltage dependence of activation and kinetics of deactivation, likely due to abnormal interactions with the voltage sensor in the S4 segment. Our study supports previous evidence suggesting that specific residues within the S2 and S3 segments of Kv1.1 result in a distinctive phenotype with predominant musculoskeletal presentation

Alterations in the α2 δ ligand, thrombospondin-1, in a rat model of spontaneous absence epilepsy and in patients with idiopathic/genetic generalized epilepsies

Objectives Thrombospondins, which are known to interact with the α2δ subunit of voltage-sensitive calcium channels to stimulate the formation of excitatory synapses, have recently been implicated in the process of epileptogenesis. No studies have been so far performed on thrombospondins in models of absence epilepsy. We examined whether expression of the gene encoding for thrombospondin-1 was altered in the brain of WAG/Rij rats, which model absence epilepsy in humans. In addition, we examined the frequency of genetic variants of THBS1 in a large cohort of children affected by idiopathic/genetic generalized epilepsies (IGE/GGEs). Methods We measured the transcripts of thrombospondin-1 and α2δ subunit, and protein levels of α2δ, Rab3A, and the vesicular glutamate transporter, VGLUT1, in the somatosensory cortex and ventrobasal thalamus of presymptomatic and symptomatic WAG/Rij rats and in two control strains by real-time polymerase chain reaction (PCR) and immunoblotting. We examined the genetic variants of THBS1 and CACNA2D1 in two independent cohorts of patients affected by IGE/GGE recruited through the Genetic Commission of the Italian League Against Epilepsy (LICE) and the EuroEPINOMICS-CoGIE Consortium. Results Thrombospondin-1 messenger RNA (mRNA) levels were largely reduced in the ventrobasal thalamus of both presymptomatic and symptomatic WAG/Rij rats, whereas levels in the somatosensory cortex were unchanged. VGLUT1 protein levels were also reduced in the ventrobasal thalamus of WAG/Rij rats. Genetic variants of THBS1 were significantly more frequent in patients affected by IGE/GGE than in nonepileptic controls, whereas the frequency of CACNA2D1 was unchanged. Significance These findings suggest that thrombospondin-1 may have a role in the pathogenesis of IGE/GGEs

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice

Next-generation sequencing for genetic diagnosis of epileptic encephalopathies in infancy

Next-generation sequencing for genetic diagnosis of epileptic encephalopathies in infanc

Todd Paralysis in Rolandic Epilepsy

Investigators from University of Gaziantep, Turkey described the clinical and EEG findings of patients with benign epilepsy of childhood with centrotemporal spikes (BECTS) experiencing postictal Todd paralysis

Management of genetic epilepsies: From empirical treatment to precision medicine

Despite the over 20 antiepileptic drugs (AEDs) now licensed for epilepsy treatment, seizures can be effectively controlled in about 3c70% of patients. Thus, epilepsy treatment is still challenging in about one third of patients and this may lead to a severe medically, physically, and socially disabling condition. However, there is clear evidence of heterogeneity of response to existing AEDs and a significant unmet need for effective intervention. A number of studies have shown that polymorphisms may influence the poor or inadequate therapeutic response as well as the occurrence of adverse effects. In addition, the new frontier of genomic technologies, including chromosome microarrays and next-generation sequencing, improved our understanding of the genetic architecture of epilepsies. Recent findings in some genetic epilepsy syndromes provide insights into mechanisms of epileptogenesis, unrevealing the role of a number of genes with different functions, such as ion channels, proteins associated to the vesical synaptic cycle or involved in energy metabolism. The rapid progress of high-throughput genomic sequencing and corresponding analysis tools in molecular diagnosis are revolutionizing the practice and it is a fact that for some monogenic epilepsies the molecular confirmation may influence the choice of the treatment. Moreover, the novel genetic methods, that are able to analyze all known genes at a reasonable price, are of paramount importance to discover novel therapeutic avenues and individualized (or precision) medicine

De novo 12q22.q23.3 duplication associated with temporal lobe epilepsy

Purpose Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy and may be associated with acquired central nervous system lesions or could be genetic. Various susceptibility genes and environmental factors are believed to be involved in the aetiology of TLE, which is considered to be a heterogeneous, polygenic, and complex disorder. Rare point mutations in LGI1, DEPDC5, and RELN as well as some copy number variations (CNVs) have been reported in families with TLE patients. Methods We perform a genetic analysis by Array-CGH in a patient with dysmorphic features and temporal lobe epilepsy. Results We report a de novo duplication of the long arm of chromosome 12. Conclusion We confirm that 12q22-q23.3 is a candidate locus for familial temporal lobe epilepsy with febrile seizures and highlight the role of chromosomal rearrangements in patients with epilepsy and intellectual disability

Current and promising therapeutic options for Dravet syndrome

Introduction: Dravet Syndrome (DS) is a developmental and epileptic encephalopathy carrying high-level psychobehavioral burdens. Although the disease has been known for almost 4 decades, and despite significant progress in the understanding of its physiopathology and natural course, the pharmacological treatment leaves patients and caregivers with significant unmet needs. This review provides a summary of the current and promising therapeutic options for DS Areas covered: PubMed and ClinicalTrials.gov were screened using ‘Dravet Syndrome’ OR ‘DS,’ AND ‘pharmacotherapy,’ AND ‘treatments.’ Randomized clinical trials, structured reviews, and meta-analyses were selected for in-human application of well-known anti-seizure medications; while in-vivo experiments on models of DS were selected to evaluate the potential of new therapeutic strategies. Expert opinion: The search for new pharmacological treatment options is led by the need for care and defeat of the natural course of the disease, an aspect still largely neglected by the available therapeutic strategies. Yet, the last 6 years have led to a climate of increased interest and availability of clinical trials. Particularly, gene therapy could hopefully prevent DS evolution by directly relieving the specific genetic defect, although the possibility of off-target editing, and the uneasy administration route have still largely prevented its use

Precision medicine in early-onset epilepsy: the KCNQ2 paradigm

The identification of the genetic causes and the underlying pathogenic mechanisms in early-onset epilepsies has proved to be essential in improving the efficacy of therapeutic decisions and the overall patient management, especially in the era of precision medicine. We report an infant presenting with a cluster of focal motor seizures with autonomic manifestations at day 3 of life. Electroencephalograms showed multifocal epileptic abnormalities and a burst-suppression pattern. Neurological examination showed poor visual fixation and hypotonia. Neuroimaging was normal. Seizures remitted with phenytoin and were well-controlled after the switch to oral carbamazepine. In the hypothesis of a genetic etiology, next-generation sequencing panel for epileptic encephalopathies was performed and identified a de novo missense mutation in KCNQ2: c.1742G>A; p.(Arg581Gln) (NM_172107.2). This case report highlights the importance of the early recognition of the electroclinical phenotype and the detection of the underlying genetic cause in the implementation of “tailored” therapies in early-onset genetic epilepsies

Electroencephalographic findings in ATRX syndrome: A new case series and review of literature

Alpha-thalassemia X-linked intellectual disability syndrome (ATRX) is a rare genetic condition caused by mutations in the ATRX gene characterized by distinctive dysmorphic features, alpha thalassemia, mild-to-profound intellectual disability, and epilepsy, reported in nearly 30% of the patients. To date, different types of seizures are reported in patients with ATRX syndrome including either clonic, tonic, myoclonic seizures or myoclonic absences. However, an accurate analysis of electroencephalographic features is lacking in literature. We report on the epileptic and electroencephalographic phenotype of seven unpublished patients with ATRX syndrome, highlighting the presence of a peculiar EEG pattern characterized by diffuse background slowing with superimposed low voltage fast activity. Likewise, we also review the available literature on this topic