Genetik der idiopathischen Epilepsien

Idiopathic epilepsies are primarily genetic in origin and represent about 40% of all epilepsies. Mutations of genes encoding ion channels play a crucial role in the pathogenesis of monogenic forms of idiopathic epilepsies. Molecular genetic approaches are still at an early stage of development for elucidating the molecular mechanisms of the epileptogenesis of common epilepsies with genetically complex predisposition. Only a comprehensive identification of the most important susceptibility genes will allow assessment of reliable individual risk profiles and development of preventive therapy strategies.     

Identification of a novel idiopathic epilepsy locus in Belgian Shepherd dogs

Epilepsy is the most common neurological disorder in dogs, with an incidence ranging from 0.5% to up to 20% in particular breeds. Canine epilepsy can be etiologically defined as idiopathic or symptomatic. Epileptic seizures may be classified as focal with or without secondary generalization, or as primary generalized. Nine genes have been identified for symptomatic (storage diseases) and one for idiopathic epilepsy in different breeds. However, the genetic background of common canine epilepsies remains unknown. We have studied the clinical and genetic background of epilepsy in Belgian Shepherds. We collected 159 cases and 148 controls and confirmed the presence of epilepsy through epilepsy questionnaires and clinical examinations. The MRI was normal while interictal EEG revealed abnormalities and variable foci in the clinically examined affected dogs. A genome-wide association study using Affymetrix 50K SNP arrays in 40 cases and 44 controls mapped the epilepsy locus on CFA37, which was replicated in an independent cohort (81 cases and 88 controls; combined p = 9.70×10⁻¹⁰, OR = 3.3). Fine mapping study defined a ∼1 Mb region including 12 genes of which none are known epilepsy genes or encode ion channels. Exonic sequencing was performed for two candidate genes, KLF7 and ADAM23. No variation was found in KLF7 but a highly-associated non-synonymous variant, G1203A (R387H) was present in the ADAM23 gene (p = 3.7×10⁻⁸, OR = 3.9 for homozygosity). Homozygosity for a two-SNP haplotype within the ADAM23 gene conferred the highest risk for epilepsy (p = 6.28×10⁻¹¹, OR = 7.4). ADAM23 interacts with known epilepsy proteins LGI1 and LGI2. However, our data suggests that the ADAM23 variant is a polymorphism and we have initiated a targeted re-sequencing study across the locus to identify the causative mutation. It would establish the affected breed as a novel therapeutic model, help to develop a DNA test for breeding purposes and introduce a novel candidate gene for human idiopathic epilepsies.     

The genetics of idiopathic generalized epilepsy: implications for the understanding of its aetiology

Epilepsy is one of the most common neurological disorders. Both inherited and acquired factors contribute to its multifactorial pathogenesis. A genetic predisposition plays a major role in the aetiology of the common idiopathic generalized epilepsies. Susceptibility genes for two syndromes of idiopathic generalized epilepsies, the benign familial neonatal convulsions and juvenile myoclonic epilepsy, have been assigned to the chromosomal regions 20q13 (EBN1), 8q24 (EBN2) and 6p21 (EJM1). Positional cloning of the mutations causing these traits will help to elucidate the molecular pathways of epileptogenesis and will imply a classification on a neurobiological basis. Insights into the underlying impairment of neuronal excitability should provide new concepts for the development of rational treatment strategies.     

The genetic and molecular basis of epilepsy

In the past decade, studies of large families in which epilepsy has been inherited in an autosomal dominant fashion have revealed several mutated genes, most of which encode ion channel subunits. Despite these exciting findings, only a few families with similar phenotypes have mutations in these known genes. More frustrating has been the genetic research into idiopathic epilepsies with complex inheritance. Although these forms are more common than those with Mendelian inheritance, their unknown mode of inheritance, phenotypic heterogeneity and the uncertainty of the genetic overlap among syndrome subtypes have hampered gene mapping. New techniques of molecular analysis could help the dissection of genes for epilepsies with complex inheritance. Hopefully, in the near future, successful genetic studies will make possible the discovery of new and more-targeted anti-epileptic drugs.     

Ionenkanalerkrankungen des Gehirns – monogene Epilepsien

Epilepsy is one of the most common neurological disorders and is characterized by recurrent, unprovoked epileptic seizures. Seizures are generated by spontaneous, synchronous neuronal discharges which induce disturbances of perception or behaviour. About one third of all epilepsies are primarily caused by genetic factors. These so-called idiopathic epilepsies occur without observable structural alterations in the brain. Mutations in genes encoding neuronal ion channels play a central role in the etiology of such epilepsies. In this review, mutations in ion channel genes associated with idiopathic epilepsies and their functional consequences are described. The underlying pathomechanisms and consequences for treatment are discussed.     

Mapping genetic modifiers of survival in a mouse model of Dravet syndrome

Epilepsy is a common neurological disorder affecting approximately 1% of the population. Mutations in voltage‐gated sodium channels are responsible for several monogenic epilepsy syndromes. More than 800 mutations in the voltage‐gated sodium channel SCN1A have been reported in patients with generalized epilepsy with febrile seizures plus and Dravet syndrome. Heterozygous loss‐of‐function mutations in SCN1A result in Dravet syndrome, a severe infant‐onset epileptic encephalopathy characterized by intractable seizures, developmental delays and increased mortality. A common feature of monogenic epilepsies is variable expressivity among individuals with the same mutation, suggesting that genetic modifiers may influence clinical severity. Mice with heterozygous deletion of Scn1a (Scn1a^+/?) model a number of Dravet syndrome features, including spontaneous seizures and premature lethality. Phenotype severity in Scn1a^+/? mice is strongly dependent on strain background. On the 129S6/SvEvTac strain Scn1a^+/? mice exhibit no overt phenotype, whereas on the (C57BL/6J × 129S6/SvEvTac)F1 strain Scn1a^+/? mice exhibit spontaneous seizures and early lethality. To systematically identify loci that influence premature lethality in Scn1a^+/? mice, we performed genome scans on reciprocal backcrosses. Quantitative trait locus mapping revealed modifier loci on mouse chromosomes 5, 7, 8 and 11. RNA‐seq analysis of strain‐dependent gene expression, regulation and coding sequence variation provided a list of potential functional candidate genes at each locus. Identification of modifier genes that influence survival in Scn1a^+/? mice will improve our understanding of the pathophysiology of Dravet syndrome and may suggest novel therapeutic strategies for improved treatment of human patients.     

Genetik der Parkinson-Krankheit

In addition to the nine well-defined monogenic forms of Parkinson’s disease, there are numerous known genetic risk and protective variants that modulate the risk of Parkinson’s disease. Among the monogenic forms, three (PARK1/PARK4, PARK8, PARK17) follow an autosomal dominant mode of inheritance, whereas six are recessively inherited (PARK2, PARK6, PARK7, PARK9, PARK14, PARK15). Six forms have clinical characteristics very similar to those of idiopathic Parkinson’s disease (PARK1/PARK4, PARK2, PARK6, PARK7, PARK8, PARK17). Among the latter forms, late-onset PARK8 with mutations in the LRRK2 gene and early-onset PARK2 caused by mutations in the Parkin gene are by far the most common. Both the monogenic and the idiopathic forms of Parkinson’s disease share common pathophysiological mechanisms involving oxidative modification, impaired protein degradation and mitochondrial dysfunction. Therefore, monogenic forms of Parkinson’s disease can serve as human model diseases for the idiopathic forms.     

A polygenic heterogeneity model for common epilepsies with complex genetics

Approximately 40% of epilepsy has a complex genetic basis with an unknown number of susceptibility genes. The effect of each susceptibility gene acting alone is insufficient to account for seizure phenotypes, but certain numbers or combinations of variations in susceptibility genes are predicted to raise the level of neuronal hyperexcitability above a seizure threshold for a given individual in a given environment. Identities of susceptibility genes are beginning to be determined, initially by translation of knowledge gained from gene discovery in the monogenic epilepsies. This entrée into idiopathic epilepsies with complex genetics has led to the experimental validation of susceptibility variants in the first few susceptibility genes. The genetic architecture so far emerging from these results is consistent with what we have designated as a polygenic heterogeneity model for the epilepsies with complex genetics.     

Mutational Consequences of Aberrant Ion Channels in Neurological Disorders

Neurological channelopathies are attributed to aberrant ion channels affecting CNS, PNS, cardiac, and skeletal muscles. To maintain the homeostasis of excitable tissues, functional ion channels are necessary to rely electrical signals, whereas any malfunctioning serves as an intrinsic factor to develop neurological channelopathies. Molecular basis of these disease is studied based on genetic and biophysical approaches, e.g., loci positional cloning, whereas pathogenesis and bio-behavioral analysis revealed the dependency on genetic mutations and inter-current triggering factors. Although electrophysiological studies revealed the possible mechanisms of diseases, analytical study of ion channels remained unsettled and therefore underlying mechanism in channelopathies is necessary for better clinical application. Herein, we demonstrated (i) structural and functional role of various ion channels (Na⁺, K⁺, Ca²⁺,Cl^?), (ii) pathophysiology involved in the onset of their associated channelopathies, and (iii) comparative sequence and phylogenetic analysis of diversified sodium, potassium, calcium, and chloride ion channel subtypes.     

Drosophila as a Model Organism for Investigating Molecular and Cellular Etiologies Underlying Complex Neurological Disorders in Humans

The fruit fly Drosophila has been utilized as a powerful biological system to address fundamental questions concerning neurological disorders in humans, since the related basic molecular components and signal transduction pathways in humans are mostly conserved in Drosophila. In addition, Drosophila offers great experimental advantages in genetics, behavioral analysis and cell and molecular biology. Pathogenesis and etiologies underlying several monogenic neurological disorders including familial Parkinson disease, Alzheimer's disease, or ataxia have been faithfully replicated in Drosophila system when causative mutations of those disorders were transgenically introduced or loss of function mutations of endogenous homologues were made. However, more than 90% of reported cases of neurological disorders are complex forms whose inheritance patterns do not follow a monogenic inheritance. Nevertheless, complex disorders are more often observed among the families or relatives of affected patients, strongly suggesting that they are most likely to be caused by interaction of multiple genetic mutations or combinations of genetic and environmental risk factors. Complex neurological disorders are include sporadic forms of Parkinson disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dystonia, epilepsy, and mental retardation, etc. Our understanding of the genetic defects and environmental risk factors involved in the onset and progression of complex neurological disorders are, however, still rudimentary. Thus identifying unknown factors involved in the onset and progression of complex neurological disorders in humans is one of the major challenges in medical sciences.     

Genetic association analysis of KCNQ3 and juvenile myoclonic epilepsy in a South Indian population

Juvenile myoclonic epilepsy (JME) is a common subtype of idiopathic generalized epilepsy that shows a complex pattern of inheritance. We have tested the association between JME phenotype and an intragenic marker in KCNQ3 by using the transmission disequilibrium test in 119 probands and their parents. Mutations in KCNQ3 are known to cause benign familial neonatal convulsions and are involved in the physiologically important M current in neurons. Our results provide suggestive evidence of allelic association between JME and KCNQ3 (P-value=0.008) and raise an interesting possibility of a genetic contribution to JME, viz., of a gene that causes a monogenic form of human epilepsy.     

Cytoplasmic inheritance in green algae: patterns,mechanisms and relation to sex type

Cytological and genetic investigations of two major groups of green algae, chlorophyte and streptophyte green algae, show a predominance of uniparental inheritance of the plastid and mitochondrial genomes in most species. However, in some crosses of isogamous species of Ulva compressa, these genomes are transmitted from mt⁺, mt⁻, and both parents. In species with uniparental organelle inheritance, various mechanisms can eliminate organelles and their DNA during male gametogenesis or after fertilization. Concerning plastid inheritance, two major mechanisms are widespread in green algae: (1) digestion of plastid DNA during male gametogenesis, during fertilization, or after fertilization; and (2) disintegration or fusion of the plastid in the zygote. The first mechanism also eliminates the mitochondrial DNA in anisogamous and oogamous species. These mechanisms would ensure the predominantly uniparental inheritance of organelle genomes in green algae. To trace the evolutionary history of cytoplasmic inheritance in green algae, the relations between uniparental inheritance and sex type were considered in isogamous, anisogamous, and oogamous species using sex-specific features that might be nearly universal among Chlorophyta.     

Pathogenetic mechanisms in hereditary dysfunctions of complex I of the respiratory chain in neurological diseases

This paper covers genetic and biochemical aspects of mitochondrial bioenergetics dysfunction in hereditary neurological disorders associated with complex I defects. Three types of hereditary complex I dysfunction are dealt with: (i) homozygous mutations in the nuclear genes NDUFS1 and NDUFS4 of complex I, associated with mitochondrial encephalopathy; (ii) a recessive hereditary epileptic neurological disorder associated with enhanced proteolytic degradation of complex I; (iii) homoplasmic mutations in the ND5 and ND6 mitochondrial genes of the complex, cohexistent with mutation in the nuclear PINK1 gene in familial Parkinsonism. The genetic and biochemical data examined highlight different mechanisms by which mitochondrial bioenergetics is altered in these hereditary defects of complex I. This knowledge, besides clarifying molecular aspects of the pathogenesis of hereditary diseases, can also provide hints for understanding the involvement of complex I in sporadic neurological disorders and aging, as well as for developing therapeutical strategies.     

Molecular mechanisms of potassium and sodium uptake in plants

Potassium (K⁺) is an essential nutrient and the most abundant cation in plants, whereas the closely related ion sodium (Na⁺) is toxic to most plants at high millimolar concentrations. K⁺ deficiency and Na⁺ toxicity are both major constraints to crop production worldwide. K⁺ counteracts Na⁺ stress, while Na⁺, in turn, can to a certain degree alleviate K⁺ deficiency. Elucidation of the molecular mechanisms of K⁺ and Na⁺ transport is pivotal to the understanding – and eventually engineering – of plant K⁺ nutrition and Na⁺ sensitivity. Here we provide an overview on plant K⁺ transporters with particular emphasis on root K⁺ and Na⁺ uptake. Plant K⁺-permeable cation transporters comprise seven families: Shaker-type K⁺ channels, `two-pore' K⁺ channels, cyclic-nucleotide-gated channels, putative K⁺/H⁺ antiporters, KUP/HAK/KT transporters, HKT transporters, and LCT1. Candidate genes for Na⁺ transport are the KUP/HAK/KTs, HKTs, CNGCs, and LCT1. Expression in heterologous systems, localization in plants, and genetic disruption in plants will provide insight into the roles of transporter genes in K⁺ nutrition and Na⁺ toxicity.     

Genetic basis in epilepsies caused by malformations of cortical development and in those with structurally normal brain

Epilepsy is the most common neurological disorder affecting young people. The etiologies are multiple and most cases are sporadic. However, some rare families with Mendelian inheritance have provided evidence of genes’ important role in epilepsy. Two important but apparently different groups of disorders have been extensively studied: epilepsies associated with malformations of cortical development (MCDs) and epilepsies associated with a structurally normal brain (or with minimal abnormalities only). This review is focused on clinical and molecular aspects of focal cortical dysplasia, polymicrogyria, periventricular nodular heterotopia, subcortical band heterotopia, lissencephaly and schizencephaly as examples of MCDs. Juvenile myoclonic epilepsy, childhood absence epilepsy, some familial forms of focal epilepsy and epilepsies associated with febrile seizures are discussed as examples of epileptic conditions in (apparently) structurally normal brains.     

Genetic and phenotypic analysis of seizure susceptibility in PL/J mice

Epilepsy is one of the most common but genetically complex neurological disorders in humans. Identifying animal models that recapitulate human epilepsies is important for pharmacological studies of anticonvulsants, dissection of molecular and biochemical pathogenesis of epilepsy, and discovery of epilepsy susceptibility genes. We discovered that the PL/J inbred mouse strain is susceptible to handling- and rhythmic tossing–induced seizure. The tonic–clonic and generalized seizures observed after induction were accompanied by abnormal EEGs, similar to seizures observed in EL and SWXL-4 mice. PL/J mice also had an extremely low threshold to electroconvulsive seizures compared to other strains and showed variable sensitivity to pentylenetetrazole-induced seizures. Gross neurostructural abnormalities were not found in PL/J mice. Crosses with the seizure-resistant C57BL/6 J strain revealed semidominant inheritance of the rhythmic tossing seizure trait with low penetrance. F2 progeny indicated that the genetic inheritance of seizure susceptibility in PL/J is non-Mendelian. We crossed DBA/2 J mice, which are resistant to rhythmic tossing seizure but susceptible to audiogenic seizures, to PL/J. We found that seizure penetrance in (DBA/2 J × PL/J)F1 mice was similar to the penetrance in (C57BL/6 J × PL/J)F1 mice but the severity and frequency of seizure were higher in (DBA/2 J × PL/J)F1 mice. The PL/J strain serves as an interesting new model for studying the genetics, neurobiology, and pharmacology of epilepsy.     

The structures of the human neuronal nicotinic acetylcholine receptor β2- and α3-subunit genes (CHRNB2 and CHRNA3)

The α4-subunit gene (CHRNA4) of the neuronal nicotinic acetylcholine receptor (nAChR) subunit family has recently been identified in two families as the gene responsible for autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), a rare monogenic idiopathic epilepsy. As a result of this finding, other subunits of the neuronal nAChR gene family are being considered as candidate genes for ADNFLE in families not linked to CHRNA4 and for other idiopathic epilepsies. α4-subunitsoften assemble together with β2-subunits (gene symbol CHRNB2) to build heteromeric nAChRs. The gene encoding another abundant AChR subunit, the α3-subunit gene (CHRNA3), is present with those encoding two other subunits, CHRNB4 and CHRNA5, in a gene cluster whose functional role is still unclear. Here we provide the information on the genomic structures of both the CHRNB2 and the CHRNA3 genes that is necessary for comprehensive mutational analyses, and we refine the genomic assignment of CHRNB2 on chromosome 1. Received: 5 August 1998 / Accepted: 13 October 1998     

Mutation analyses in pedigrees and sporadic cases of ethnic Han Chinese Kallmann syndrome patients

Kallmann syndrome, a form of idiopathic hypogonadotropic hypogonadism, is characterized by developmental abnormalities of the reproductive system and abnormal olfaction. Despite association of certain genes with idiopathic hypogonadotropic hypogonadism, the genetic inheritance and expression are complex and incompletely known. In the present study, seven Kallmann syndrome pedigrees in an ethnic Han Chinese population were screened for genetic mutations. The exons and intron–exon boundaries of 19 idiopathic hypogonadotropic hypogonadism (idiopathic hypogonadotropic hypogonadism)-related genes in seven Chinese Kallmann syndrome pedigrees were sequenced. Detected mutations were also tested in 70 sporadic Kallmann syndrome cases and 200 Chinese healthy controls. In pedigrees 1, 2, and 7, the secondary sex characteristics were poorly developed and the patients’ sense of smell was severely or completely lost. We detected a genetic mutation in five of the seven pedigrees: homozygous KAL1 p.R191ter (pedigree 1); homozygous KAL1 p.C13ter (pedigree 2; a novel mutation); heterozygous FGFR1 p.R250W (pedigree 3); and homozygous PROKR2 p.Y113H (pedigrees 4 and 5). No genetic change of the assayed genes was detected in pedigrees 6 and 7. Among the 70 sporadic cases, we detected one homozygous and one heterozygous PROKR2 p.Y113H mutation. This mutation was also detected heterozygously in 2/200 normal controls and its pathogenicity is likely questionable. The genetics and genotype–phenotype relationships in Kallmann syndrome are complicated. Classical monogenic inheritance does not explain the full range of genetic inheritance of Kallmann syndrome patients. Because of stochastic nature of genetic mutations, exome analyses of Kallmann syndrome patients may provide novel insights.     

Canine epilepsy genetics

There has been much interest in utilizing the dog as a genetic model for common human diseases. Both dogs and humans suffer from naturally occurring epilepsies that share many clinical characteristics. Investigations of inherited human epilepsies have led to the discovery of several mutated genes involved in this disease; however, the vast majority of human epilepsies remain unexplained. Mouse models of epilepsy exist, including single-gene spontaneous and knockout models, but, similar to humans, other, polygenic models have been more difficult to discern. This appears to also be the case in canine epilepsy genetics. There are two forms of canine epilepsies for which gene mutations have been described to date: the progressive myoclonic epilepsies (PMEs) and idiopathic epilepsy (IE). Gene discovery in the PMEs has been more successful, with eight known genes; six of these are orthologous to corresponding human disorders, while two are novel genes that can now be used as candidates for human studies. Only one IE gene has been described in dogs, an LGI2 mutation in Lagotto Romagnolos with a focal, juvenile remitting epilepsy. This gene is also a novel candidate for human remitting childhood epilepsy studies. The majority of studies of dog breeds with IE, however, have either failed to identify any genes or loci of interest, or, as in complex mouse and human IEs, have identified multiple QTLs. There is still tremendous promise in the ongoing canine epilepsy studies, but if canine IEs prove to be as genetically complex as human and murine IEs, then deciphering the bases of these canine epilepsies will continue to be challenging.     

Morbus Parkinson

Monogenic Parkinson’s disease (PD), i.?e. parkinsonism caused by mutations in single genes, represents ~5% of all PD cases. Over the past 20 years, three autosomal dominantly (SNCA, LRRK2, VPS35) and three autosomal recessively (Parkin, PINK1, DJ-1) inherited causal PD genes have been identified and validated. Although pathogenic changes in SNCA are very rare, begin early, and may be associated with the development of dementia, pathogenic variants in LRRK2-linked PD are most common among monogenic PS and patients are clinically indistinguishable from those with idiopathic PD. In patients with onset before the age of 40 years, pathogenic variants in the Parkin and PINK1 genes should be suspected, and in patients with a positive family history, genetic counseling should be carried out. Recently, dynamic developments in the area of Parkinson’s genetics have led to new therapeutic approaches and the first gene-specific therapies have entered the early testing phase. Besides the established monogenic PD genes, candidate genes have been identified, but not yet conclusively validated. In addition to established monogenic PD, as yet unvalidated Parkinson’s candidate genes and well-characterized genetic risk exist at this time. As monogenic PD represents a “model disease” for idiopathic PD too, further progress toward more personalized medicine may be expected for both monogenic and idiopathic PD.