Romina Combi

Autosomal dominant nocturnal frontal lobe epilepsy - A critical overview

Abstract.Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an idiopathic epilepsy, with a spectrum of clinical manifestations, ranging from brief, stereotyped, sudden arousals to more complex dystonic–dyskinetic seizures. Video–polysomnography allows a correct differential diagnosis. There is no difference between sporadic nocturnal frontal lobe epilepsy (NFLE) and ADNFLE in the clinical and neurophysiological findings. ADNFLE is the first idiopathic epilepsy for which a genetic basis has been identified. Mutations have been found in two genes (CHRNA4 and CHRNB2) coding for neuronal nicotinic receptor subunits (α4 and β2, respectively). Contrasting data have been reported on the effect of these mutations on the functionality of the receptor.Moreover, the incomplete data on the neuronal network/s in which this receptor is involved, make difficult the understanding of the genotype–phenotype correlation. This is an overview on the clinical and genetic aspects of ADNFLE including a discussion of some open questions on the role of the neuronal nicotinic receptor subunit mutations in the pathogenesis of this form of epilepsy.

A rescuable folding defective Nav1.1 (SCN1A) sodium channel mutant causes GEFS+: Common mechanism in Nav1.1 related epilepsies?

Mutations of voltage‐gated Na+ channels are the most common known cause of genetically determined epilepsy; Nav1.1 (SCN1A) is the most frequent target. They can cause both mild and severe forms, also in patients harboring the same mutation. We have recently characterized in a family with extreme phenotypes the first epileptogenic folding‐defective Na+ channel mutant (Nav1.1‐M1841T), whose loss of function is attenuated by interactions with associated proteins and drugs. We hypothesized that in vivo variability of the interactions may modulate the functional effect and thus the phenotype (Rusconi et al., 2007). Here we characterize another Nav1.1 folding‐defective mutant (Nav1.1‐R1916G) that, however, has been identified in a GEFS+ family with relatively mild phenotypes. This novel mutant shows a number of specific characteristics, but, similarly to Nav1.1‐M1841T, it can be rescued by interactions with associated proteins and drugs. Thus, loss of function caused by folding defects that can be attenuated by molecular interactions may be a common pathogenic mechanism for Nav1.1 epileptogenic mutants. Folding defects can be present also in families showing only mild phenotypes in which, however, severe phenotypes could emerge within a permissive genetic background.

Maternal polymorphisms for methyltetrahydrofolate reductase and methionine synthetase reductase and risk of children with Down syndrome

OBJECTIVE The purpose of this research was to study factors that are involved in centromeric hypomethylation in the pathogenesis of Down syndrome (DS). STUDY DESIGN This was a case-control study to evaluate the association between methyltetrahydrofolate reductase (MTHFR) C677T and methionine synthetase-reductase (MTRR) A66G polymorphisms and the risk of DS; we compared mothers in Italy who had children with DS and matched control subjects. RESULTS Seventy-four cases of DS caused by an error in maternal meiosis were compared with 184 matched control subjects. The frequencies of the MTHFR C677T polymorphism were similar between the 2 groups. As regards the MTRR A66G polymorphism, the presence of the mutated G allele either in the heterozygous or homozygous form was significantly more common among mothers of children with DS than among control subjects (odds ratio, 2.21; 95% CI, 1.11-4.40). CONCLUSION In a population with a high prevalence of the mutated T allele, maternal MTRR A66G, but not MTHFR, polymorphisms are associated with Down syndrome.

Frontal lobe epilepsy and mutations of the corticotropin-releasing hormone gene

Nocturnal frontal lobe epilepsy up to now has been considered a channelopathy caused by mutations in the α4 and β2 subunits of the neuronal nicotinic acetylcholine receptor. However, these mutations account for only a minority of patients, and the existence of at least a new locus for the disease has been demonstrated. In one Italian nocturnal frontal lobe epilepsy family, we identified two new putative loci on chromosomes 3 and 8, where several candidate genes are mapped. In particular, on chromosome 8, corticotropin‐releasing hormone gene (CRH) appears to be a good candidate. We therefore searched for CRH mutations in the proband. The study allowed the identification of a nucleotide variation in the promoter that was subsequently detected in all affected and obligate carrier members of the same family, in two sporadic cases, in all affected members of an additional compliant family, and in the proband of a noncompliant family. Moreover, a different mutation in the promoter was detected in a familial case. In vitro experiments showed altered levels of gene expression. CRH alterations could explain several autosomal dominant nocturnal frontal lobe epilepsy clinical features. Ann Neurol 2006

Nocturnal frontal lobe epilepsy

Nocturnal frontal lobe epilepsy (NFLE) is a syndrome of heterogeneous etiology, characterized by the occurrence of sleep-related seizures with different complexity and duration. Genetic, lesional, and cryptogenetic NFLE forms have been described. NFLE is generally considered a benign clinical entity, although severe, drug-resistant forms do exist. A significant proportion of sleep-related complex motor seizures, hardly distinguishable from NFLE, originate outside the frontal lobe. Moreover, the distinction of NFLE from the non-rapid eye movement arousal parasomnias may be challenging. A correct diagnosis of NFLE should be based on a diagnostic approach that includes the anamnestic, video–polysomnographic, morphological, and genetic aspects. Studies on the relationships between genes, arousal regulatory mechanisms, and epileptogenesis, using both clinical and experimental models of NFLE might provide key insights in the interrelationship between sleep and epilepsy.

Potassium Channels and Human Epileptic Phenotypes: An Updated Overview

Potassium (K+) channels are expressed in almost every cells and are ubiquitous in neuronal and glial cell membranes. These channels have been implicated in different disorders, in particular in epilepsy. K+ channel diversity depends on the presence in the human genome of a large number of genes either encoding pore-forming or accessory subunits. More than 80 genes encoding the K+ channels were cloned and they represent the largest group of ion channels regulating the electrical activity of cells in different tissues, including the brain. It is therefore not surprising that mutations in these genes lead to K+ channels dysfunctions linked to inherited epilepsy in humans and non-human model animals. This article reviews genetic and molecular progresses in exploring the pathogenesis of different human epilepsies, with special emphasis on the role of K+ channels in monogenic forms.

Exclusion of linkage of nine neuronal nicotinic acetylcholine receptor subunit genes expressed in brain in autosomal dominant nocturnal frontal lobe epilepsy in four unrelated families

Abstract Members of the ligand-gated neuronal nicotinic acetylcholine receptor (nAChR) gene family (CHRNA4 and CHRNB2, coding for the α4 and β2 subunits, respectively) are involved in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). However, ADNFLE is genetically heterogeneous and mutations in CHRNA4 and CHRNB2 account for only a minority of ADNFLE cases. Additional nAChR subunits expressed in the brain are candidates for this epilepsy. The involvement of all genes coding for brain-expressed nAChR subunits, with known chromosome localization (CHRNB2, 1q21; CHRNA2, 8p21; CHRNA6, CHRNB3, 8p11.2; CHRNA7, 15q14; CHRNA5/A3/B4, 15q24 and CHRNA4, 20q13.2) was investigated in four unrelated ADNFLE Italian families for at least three generations. Families were selected on the basis of anamnestic and videopolysomnographic analyses. Individuals were typed for polymorphic markers located in the above mentioned chromosome regions. Linkage and mutation analyses were performed. In none of the families was linkage between ADNFLE and the analysed chromosome regions detected. These findings support the hypothesis that genes different from those coding for α2-7 and β2-4 neuronal nAChR subunits could be responsible for ADNFLE.

Two new putative susceptibility loci for ADNFLE

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) has been up to now considered a simple Mendelian trait caused by mutations in neuronal nicotinic acetylcholine receptor (nAChR) subunit genes. We previously demonstrated that in a three-generation Italian family the disease was unlinked to all known ADNFLE loci as well as to all known brain-expressed nAChR subunits. The genome-wide linkage analysis here presented performed on this family points to the existence of two new putative ADNFLE loci on chromosomes 3p22-p24 and 8q11.2-q21.1. These findings, together with several ADNFLE characteristics, suggest that this epilepsy could be, at least in the above family, a complex disorder. In particular, we propose and discuss the hypothesis of a digenic transmission of the disease.

The Synergistic Relationship between Alzheimer's Disease and Sleep Disorders: An Update.

Sleep disorders are frequently reported in Alzheimers disease (AD), with a significant impact on patients and caregivers and a major risk factor for early institutionalization. Although changes in sleep organization are a hallmark of the normal aging processes, sleep macro- and micro-architectural alterations are more evident in patients affected by AD. Degeneration of neural pathways regulating sleep-wake patterns and sleep architecture may contribute to sleep alterations. In return, several recent studies suggested that common sleep disorders may precede clinical symptoms of dementia and represent risk factors for cognitive decline, through impairment of sleep-dependent memory consolidation processes. Thus, a close relationship between sleep disorders and AD has been largely hypothesized. Here, sleep alterations in AD and its pre-dementia stage, mild cognitive impairment, and their complex interactions are reviewed.

Clinical and genetic familial study of a large cohort of Italian children with idiopathic epilepsy

Epilepsies are characterized by genetic heterogeneity and by the possible coexistence of different phenotypes in one family. Moreover, in different epilepsies, mutations in the same gene have been reported. We aimed to collect data in a large Italian cohort of 81 families with children affected by partial or generalized epilepsies and to evaluate the prevalence of several ion channel mutations. In particular, a clinical and genetic survey was performed and DNA regions known to be associated with several epilepsies were analysed by sequencing. We observed genetic complexity in all phenotype groups: any epileptic type may be transmitted as either autosomal dominant or recessive. No significant phenotype identity among generations and no differences among genders could be observed. Two missense mutations in SCN1A were identified in two GEFS+ probands confirming the importance of this channel for this epilepsy. Moreover, a previously unreported CLCN2 mutation was detected in a proband showing CAE. In conclusion, even in this highly heterogeneous cohort, the complexity of the epileptic condition was highlighted and mutations in the analysed candidate region of ion channel genes appear to explain only a minority of cases.