Objective
The leading cause of epilepsy‐related premature mortality is sudden unexpected death in epilepsy (SUDEP). The cause of SUDEP remains unknown. To search for genetic risk factors in SUDEP ...cases, we performed an exome‐based analysis of rare variants.
Methods
Demographic and clinical information of 61 SUDEP cases were collected. Exome sequencing and rare variant collapsing analysis with 2,936 control exomes were performed to test for genes enriched with damaging variants. Additionally, cardiac arrhythmia, respiratory control, and epilepsy genes were screened for variants with frequency of <0.1% and predicted to be pathogenic with multiple in silico tools.
Results
The 61 SUDEP cases were categorized as definite SUDEP (n = 54), probable SUDEP (n = 5), and definite SUDEP plus (n = 2). We identified de novo mutations, previously reported pathogenic mutations, or candidate pathogenic variants in 28 of 61 (46%) cases. Four SUDEP cases (7%) had mutations in common genes responsible for the cardiac arrhythmia disease, long QT syndrome (LQTS). Nine cases (15%) had candidate pathogenic variants in dominant cardiac arrhythmia genes. Fifteen cases (25%) had mutations or candidate pathogenic variants in dominant epilepsy genes. No gene reached genome‐wide significance with rare variant collapsing analysis; however, DEPDC5 (p = 0.00015) and KCNH2 (p = 0.0037) were among the top 30 genes, genome‐wide.
Interpretation
A sizeable proportion of SUDEP cases have clinically relevant mutations in cardiac arrhythmia and epilepsy genes. In cases with an LQTS gene mutation, SUDEP may occur as a result of a predictable and preventable cause. Understanding the genetic basis of SUDEP may inform cascade testing of at‐risk family members. Ann Neurol 2016;79:522–534
We performed genomic mapping of a family with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and intellectual and psychiatric problems, identifying a disease-associated region on ...chromosome 9q34.3. Whole-exome sequencing identified a mutation in KCNT1, encoding a sodium-gated potassium channel subunit. KCNT1 mutations were identified in two additional families and a sporadic case with severe ADNFLE and psychiatric features. These findings implicate the sodium-gated potassium channel complex in ADNFLE and, more broadly, in the pathogenesis of focal epilepsies.
Objective:
We examined whether glucose transporter 1 (GLUT1) deficiency causes common idiopathic generalized epilepsies (IGEs).
Methods:
The IGEs are common, heritable epilepsies that usually follow ...complex inheritance; currently little is known about their genetic architecture. Previously considered rare, GLUT1 deficiency, due to mutations in SLC2A1, leads to failure of glucose transport across the blood–brain barrier and inadequate glucose for brain metabolism. GLUT1 deficiency was first associated with an encephalopathy and more recently found in rare dominant families with epilepsy and paroxysmal exertional dyskinesia (PED). Five hundred four probands with IGEs and 470 controls underwent SLC2A1 sequencing. Glucose transport was assayed following expression of SLC2A1 variants in Xenopus oocytes. All available relatives were phenotyped, and SLC2A1 was sequenced.
Results:
Functionally validated mutations in SLC2A1 were present in 7 of 504 (1.4%) probands and 0 of 470 controls. PED, undiagnosed prior to study, occurred in 1 proband and 3 of 13 relatives with mutations. The IGEs in probands and relatives were indistinguishable from typical IGE. Three cases (0.6%) had mutations of large functional effect and showed autosomal dominant inheritance or were de novo. Four (0.8%) cases had a subtle functional effect; 2 showed possible dominant inheritance, and 2 did not. These alleles leading to subtle functional impairment may contribute to complex, polygenic inheritance of IGE.
Interpretation:
SLC2A1 mutations contribute to approximately 1% of IGE both as a dominant gene and as a susceptibility allele in complex inheritance. Diagnosis of GLUT1 deficiency has important treatment (ketogenic diet) and genetic counseling implications. The mechanism of restricted glucose delivery differs from the current focus on IGEs as ion channel disorders. ANN NEUROL 2012;72:807–815
Hepatitis C Virus (HCV) is a common cause of chronic liver disease and its ensuing complications. In the last years, there has been a revolution of the treatment for patients with HCV regarding ...efficacy, simplicity, safety and duration of treatment. The role of the family physician is vital in all steps of care: screening, diagnosis, linkage to treatment, treatment and follow-up.
This review aims to summarise the family physician and the important updated recommendations for diagnosis and treatment of patients with chronic HCV.
The updated recommendations were reviewed and summarised in a short and simple review.
Patients with any risk factor for HCV should first be screened for HCV antibodies. In the case of positive antibodies, reflex testing for RNA polymerase chain reaction (PCR) should be done without waiting for genotype. For patients with positive PCR, fibrosis assessment should be conducted using laboratory panels (Fibrosis-4 index (FIB-4) or aspartate aminotransferase to platelet ratio index (APRI)); if advanced fibrosis is suspected, additional non-invasive fibrosis assessment is needed, such as fibrotest or liver elastography. Naïve non-cirrhotic or compensated cirrhosis (Child-Pugh-Score A) could be treated with pangenotypic drugs, Glecaprevir/pibrentasvir (Maviret) for eight weeks, or Sofosbuvir/velpatasvir (Epclusa) for 12 weeks.
Patients without advanced fibrosis and comorbidities can be treated by the educated family physician. However, patients with comorbidities, cirrhosis or coinfection (HIV, Hepatitis B Virus (HBV)) should be referred to the liver clinic. In case of screening patients with risk factors or likelihood of dormant HCV, health organisations should provide the appropriate resources, logistics, finances and workforce.
Mutations or structural genomic alterations of the X-chromosomal gene
ARHGEF9
have been described in male and female patients with intellectual disability. Hyperekplexia and epilepsy were observed to ...a variable degree, but incompletely described. Here, we expand the phenotypic spectrum of
ARHGEF9
by describing a large Ethiopian-Jewish family with epilepsy and intellectual disability. The four affected male siblings, their unaffected parents and two unaffected female siblings were recruited and phenotyped. Parametric linkage analysis was performed using SNP microarrays. Variants from exome sequencing in two affected individuals were confirmed by Sanger sequencing. All affected male siblings had febrile seizures from age 2–3 years and intellectual disability. Three developed afebrile seizures between age 7–17 years. Three showed focal seizure semiology. None had hyperekplexia. A novel
ARHGEF9
variant (c.967G>A, p.G323R, NM_015185.2) was hemizygous in all affected male siblings and heterozygous in the mother. This family reveals that the phenotypic spectrum of
ARHGEF9
is broader than commonly assumed and includes febrile seizures and focal epilepsy with intellectual disability in the absence of hyperekplexia or other clinically distinguishing features. Our findings suggest that pathogenic variants in
ARHGEF9
may be more common than previously assumed in patients with intellectual disability and mild epilepsy.
Objective
Copy number variants (CNVs) contribute to genetic risk and genetic etiology of both rare and common epilepsies. Whereas many studies have explored the role of CNVs in sporadic or severe ...cases, fewer have been done in familial generalized and focal epilepsies.
Methods
We analyzed exome sequence data from 267 multiplex families and 859 first‐degree relative pairs with a diagnosis of genetic generalized epilepsies or nonacquired focal epilepsies to predict CNVs. Validation and segregation studies were performed using an orthogonal method when possible.
Results
We identified CNVs likely to contribute to epilepsy risk or etiology in the probands of 43 of 1116 (3.9%) families, including known recurrent CNVs (16p13.11 deletion, 15q13.3 deletion, 15q11.2 deletion, 16p11.2 duplication, 1q21.1 duplication, and 5‐Mb duplication of 15q11q13). We also identified CNVs affecting monogenic epilepsy genes, including four families with CNVs disrupting the DEPDC5 gene, and a de novo deletion of HNRNPU in one affected individual from a multiplex family. Several large CNVs (>500 kb) of uncertain clinical significance were identified, including a deletion in 18q, a large duplication encompassing the SCN1A gene, and a 15q13.3 duplication (BP4‐BP5).
Significance
The overall CNV landscape in common familial epilepsies is similar to that of sporadic epilepsies, with large recurrent deletions at 15q11, 15q13, and 16p13 contributing in 2.5%–3% of families. CNVs that interrupt known epilepsy genes and rare, large CNVs were also identified. Multiple etiologies were found in a subset of families, emphasizing the importance of genetic testing for multiple affected family members. Rare CNVs found in a single proband remain difficult to interpret and require larger cohorts to confirm their potential role in disease. Overall, our work indicates that CNVs contribute to the complex genetic architecture of familial generalized and focal epilepsies, supporting the role for clinical testing in affected individuals.
Epilepsy is a chronic non-infectious disease of the brain, characterized primarily by recurrent unprovoked seizures, defined as an episode of disturbance of motor, sensory, autonomic, or mental ...functions resulting from excessive neuronal discharge. Despite the advances in the treatment achieved with the use of antiepileptic drugs and other non-pharmacological therapies, about 30% of patients suffer from uncontrolled seizures. This review summarizes the currently available methods of gene and cell therapy for epilepsy and discusses the development of these approaches. Currently, gene therapy for epilepsy is predominantly adeno-associated virus (AAV)-mediated delivery of genes encoding neuro-modulatory peptides, neurotrophic factors, enzymes, and potassium channels. Cell therapy for epilepsy is represented by the transplantation of several types of cells such as mesenchymal stem cells (MSCs), bone marrow mononuclear cells, neural stem cells, and MSC-derived exosomes. Another approach is encapsulated cell biodelivery, which is the transplantation of genetically modified cells placed in capsules and secreting various therapeutic agents. The use of gene and cell therapy approaches can significantly improve the condition of patient with epilepsy. Therefore, preclinical, and clinical studies have been actively conducted in recent years to prove the benefits and safety of these strategies.
Summary
Synaptic proteins are critical to neuronal function in the brain, and their deficiency can lead to seizures and cognitive impairments. CNKSR2 (connector enhancer of KSR2) is a synaptic ...protein involved in Ras signaling‐mediated neuronal proliferation, migration and differentiation. Mutations in the X‐linked gene CNKSR2 have been described in patients with seizures and neurodevelopmental deficits, especially those affecting language. In this study, we sequenced 112 patients with phenotypes within the epilepsy‐aphasia spectrum (EAS) to determine the frequency of CNKSR2 mutation within this complex set of disorders. We detected a novel nonsense mutation (c.2314 C>T; p.Arg712*) in one Ashkenazi Jewish family, the male proband of which had a severe epileptic encephalopathy with continuous spike‐waves in sleep (ECSWS). His affected brother also had ECSWS with better outcome, whereas the sister had childhood epilepsy with centrotemporal spikes. This mutation segregated in the three affected siblings in an X‐linked manner, inherited from their mother who had febrile seizures. Although the frequency of point mutation is low, CNKSR2 sequencing should be considered in families with suspected X‐linked EAS because of the specific genetic counseling implications.
We characterized an autosomal-recessive syndrome of focal epilepsy, dysarthria, and mild to moderate intellectual disability in a consanguineous Arab-Israeli family associated with subtle cortical ...thickening. We used multipoint linkage analysis to map the causative mutation to a 3.2 Mb interval within 16p13.3 with a LOD score of 3.86. The linked interval contained 160 genes, many of which were considered to be plausible candidates to harbor the disease-causing mutation. To interrogate the interval in an efficient and unbiased manner, we used targeted sequence enrichment and massively parallel sequencing. By prioritizing unique variants that affected protein translation, a pathogenic mutation was identified in TBC1D24 (p.F251L), a gene of unknown function. It is a member of a large gene family encoding TBC domain proteins with predicted function as Rab GTPase activators. We show that TBC1D24 is expressed early in mouse brain and that TBC1D24 protein is a potent modulator of primary axonal arborization and specification in neuronal cells, consistent with the phenotypic abnormality described.
Summary
Objective: We aimed to determine the type, frequency, and size of microchromosomal copy number variations (CNVs) affecting the neuronal sodium channel α 1 subunit gene (SCN1A) in Dravet ...syndrome (DS), other epileptic encephalopathies, and generalized epilepsy with febrile seizures plus (GEFS+).
Methods: Multiplex ligation‐dependent probe amplification (MLPA) was applied to detect SCN1A CNVs among 289 cases (126 DS, 97 GEFS+, and 66 with other phenotypes). CNVs extending beyond SCN1A were further characterized by comparative genome hybridization (array CGH).
Results: Novel SCN1A CNVs were found in 12.5% of DS patients where sequence‐based mutations had been excluded. We identified the first partial SCN1A duplications in two siblings with typical DS and in a patient with early‐onset symptomatic generalized epilepsy. In addition, a patient with DS had a partial SCN1A amplification of 5–6 copies. The remaining CNVs abnormalities were four partial and nine whole SCN1A deletions involving contiguous genes. Two CNVs (a partial SCN1A deletion and a duplication) were inherited from a parent, in whom there was mosaicism. Array CGH showed intragenic deletions of 90 kb and larger, with the largest of 9.3 Mb deleting 49 contiguous genes and extending beyond SCN1A.
Discussion: Duplication and amplification involving SCN1A are now added to molecular mechanisms of DS patients. Our findings showed that 12.5% of DS patients who are mutation negative have MLPA‐detected SCN1A CNVs with an overall frequency of about 2–3%. MLPA is the established second‐line testing strategy to reliably detect all CNVs of SCN1A from the megabase range down to one exon. Large CNVs extending outside SCN1A and involving contiguous genes can be precisely characterized by array CGH.