[Show abstract][Hide abstract] ABSTRACT: We report a consanguineous family with 2 affected individuals whose clinical symptoms closely resembled MERRF (myoclonus epilepsy with ragged red fibers) syndrome including severe myoclonic epilepsy, progressive spastic tetraparesis, progressive impairment of vision and hearing, as well as progressive cognitive decline.
[Show abstract][Hide abstract] ABSTRACT: Background: The epilepsies are a clinically heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identification of risk loci associated with epilepsy, probably because of relatively small sample sizes and insufficient power. We aimed to identify risk loci through meta-analyses of genome-wide association studies for all epilepsy and the two largest clinical subtypes (genetic generalised epilepsy and focal epilepsy).
Methods: We combined genome-wide association data from 12 cohorts of individuals with epilepsy and controls from population-based datasets. Controls were ethnically matched with cases. We phenotyped individuals with epilepsy into categories of genetic generalised epilepsy, focal epilepsy, or unclassified epilepsy. After standardised filtering for quality control and imputation to account for different genotyping platforms across sites, investigators at each site conducted a linear mixed-model association analysis for each dataset. Combining summary statistics, we conducted fixed-effects meta-analyses of all epilepsy, focal epilepsy, and genetic generalised epilepsy. We set the genome-wide significance threshold at p<1·66 × 10–8.
Findings: We included 8696 cases and 26 157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8·71 × 10–10), implicating SCN1A, and at 4p15.1 (p=5·44 × 10–9), harbouring PCDH7, which encodes a protocadherin molecule not previously implicated in epilepsy. For the cohort of genetic generalised epilepsy, we noted a single signal at 2p16.1 (p=9·99 × 10–9), implicating VRK2 or FANCL. No single nucleotide polymorphism achieved genome-wide significance for focal epilepsy.
Interpretation: This meta-analysis describes a new locus not previously implicated in epilepsy and provides further evidence about the genetic architecture of these disorders, with the ultimate aim of assisting in disease classification and prognosis. The data suggest that specific loci can act pleiotropically raising risk for epilepsy broadly, or can have effects limited to a specific epilepsy subtype. Future genetic analyses might benefit from both lumping (ie, grouping of epilepsy types together) or splitting (ie, analysis of specific clinical subtypes).
The Lancet Neurology 07/2014; · 23.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Known disease mechanisms in mitochondrial DNA (mtDNA) maintenance disorders alter either the mitochondrial replication machinery (POLG, POLG2 and C10orf2) or the biosynthesis pathways of deoxyribonucleoside 5'-triphosphates for mtDNA synthesis. However, in many of these disorders, the underlying genetic defect has yet to be discovered. Here, we identify homozygous nonsense and missense mutations in the orphan gene C20orf72 in three families with a mitochondrial syndrome characterized by external ophthalmoplegia, emaciation and respiratory failure. Muscle biopsies showed mtDNA depletion and multiple mtDNA deletions. C20orf72, hereafter MGME1 (mitochondrial genome maintenance exonuclease 1), encodes a mitochondrial RecB-type exonuclease belonging to the PD-(D/E)XK nuclease superfamily. We show that MGME1 cleaves single-stranded DNA and processes DNA flap substrates. Fibroblasts from affected individuals do not repopulate after chemically induced mtDNA depletion. They also accumulate intermediates of stalled replication and show increased levels of 7S DNA, as do MGME1-depleted cells. Thus, we show that MGME1-mediated mtDNA processing is essential for mitochondrial genome maintenance.
[Show abstract][Hide abstract] ABSTRACT: Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 x 10-9, odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.
[Show abstract][Hide abstract] ABSTRACT: Disorders of mitochondrial DNA (mtDNA) maintenance have emerged as an important cause of human genetic disease, but demonstrating the functional consequences of de novo mutations remains a major challenge. We studied the rate of depletion and repopulation of mtDNA in human fibroblasts exposed to ethidium bromide in patients with heterozygous POLG mutations, POLG2 and TK2 mutations. Ethidium bromide induced mtDNA depletion occurred at the same rate in human fibroblasts from patients and healthy controls. By contrast, the restoration of mtDNA levels was markedly delayed in fibroblasts from patients with compound heterozygous POLG mutations. Specific POLG2 and TK2 mutations did not delay mtDNA repopulation rates. These observations are consistent with the hypothesis that mutations in POLG impair mtDNA repopulation within intact cells, and provide a potential method of demonstrating the functional consequences of putative pathogenic alleles causing a defect of mtDNA synthesis.
Biochimica et Biophysica Acta 03/2011; 1812(3):321-5. · 4.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have analyzed the complete mitochondrial genomes of 22 Pan paniscus (bonobo, pygmy chimpanzee) individuals to assess the detailed mitochondrial DNA (mtDNA) phylogeny of this close relative of Homo sapiens.
We identified three major clades among bonobos that separated approximately 540,000 years ago, as suggested by Bayesian analysis. Incidentally, we discovered that the current reference sequence for bonobo likely is a hybrid of the mitochondrial genomes of two distant individuals. When comparing spectra of polymorphic mtDNA sites in bonobos and humans, we observed two major differences: (i) Of all 31 bonobo mtDNA homoplasies, i.e. nucleotide changes that occurred independently on separate branches of the phylogenetic tree, 13 were not homoplasic in humans. This indicates that at least a part of the unstable sites of the mitochondrial genome is species-specific and difficult to be explained on the basis of a mutational hotspot concept. (ii) A comparison of the ratios of non-synonymous to synonymous changes (dN/dS) among polymorphic positions in bonobos and in 4902 Homo sapiens mitochondrial genomes revealed a remarkable difference in the strength of purifying selection in the mitochondrial genes of the F0F1-ATPase complex. While in bonobos this complex showed a similar low value as complexes I and IV, human haplogroups displayed 2.2 to 7.6 times increased dN/dS ratios when compared to bonobos.
Some variants of mitochondrially encoded subunits of the ATPase complex in humans very likely decrease the efficiency of energy conversion leading to production of extra heat. Thus, we hypothesize that the species-specific release of evolutionary constraints for the mitochondrial genes of the proton-translocating ATPase is a consequence of altered heat homeostasis in modern humans.
[Show abstract][Hide abstract] ABSTRACT: Idiopathic generalized epilepsies account for 30% of all epilepsies. Despite a predominant genetic aetiology, the genetic factors predisposing to idiopathic generalized epilepsies remain elusive. Studies of structural genomic variations have revealed a significant excess of recurrent microdeletions at 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 in various neuropsychiatric disorders including autism, intellectual disability and schizophrenia. Microdeletions at 15q13.3 have recently been shown to constitute a strong genetic risk factor for common idiopathic generalized epilepsy syndromes, implicating that other recurrent microdeletions may also be involved in epileptogenesis. This study aimed to investigate the impact of five microdeletions at the genomic hotspot regions 1q21.1, 15q11.2, 16p11.2, 16p13.11 and 22q11.2 on the genetic risk to common idiopathic generalized epilepsy syndromes. The candidate microdeletions were assessed by high-density single nucleotide polymorphism arrays in 1234 patients with idiopathic generalized epilepsy from North-western Europe and 3022 controls from the German population. Microdeletions were validated by quantitative polymerase chain reaction and their breakpoints refined by array comparative genomic hybridization. In total, 22 patients with idiopathic generalized epilepsy (1.8%) carried one of the five novel microdeletions compared with nine controls (0.3%) (odds ratio = 6.1; 95% confidence interval 2.8-13.2; chi(2) = 26.7; 1 degree of freedom; P = 2.4 x 10(-7)). Microdeletions were observed at 1q21.1 [Idiopathic generalized epilepsy (IGE)/control: 1/1], 15q11.2 (IGE/control: 12/6), 16p11.2 IGE/control: 1/0, 16p13.11 (IGE/control: 6/2) and 22q11.2 (IGE/control: 2/0). Significant associations with IGEs were found for the microdeletions at 15q11.2 (odds ratio = 4.9; 95% confidence interval 1.8-13.2; P = 4.2 x 10(-4)) and 16p13.11 (odds ratio = 7.4; 95% confidence interval 1.3-74.7; P = 0.009). Including nine patients with idiopathic generalized epilepsy in this cohort with known 15q13.3 microdeletions (IGE/control: 9/0), parental transmission could be examined in 14 families. While 10 microdeletions were inherited (seven maternal and three paternal transmissions), four microdeletions occurred de novo at 15q13.3 (n = 1), 16p13.11 (n = 2) and 22q11.2 (n = 1). Eight of the transmitting parents were clinically unaffected, suggesting that the microdeletion itself is not sufficient to cause the epilepsy phenotype. Although the microdeletions investigated are individually rare (<1%) in patients with idiopathic generalized epilepsy, they collectively seem to account for a significant fraction of the genetic variance in common idiopathic generalized epilepsy syndromes. The present results indicate an involvement of microdeletions at 15q11.2 and 16p13.11 in epileptogenesis and strengthen the evidence that recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 confer a pleiotropic susceptibility effect to a broad range of neuropsychiatric disorders.
[Show abstract][Hide abstract] ABSTRACT: Idiopathic generalized epilepsy (IGE) is an inherited neurological disorder affecting about 0.4% of the world's population. Mutations in ten genes causing distinct forms of idiopathic epilepsy have been identified so far, but the genetic basis of many IGE subtypes is still unknown. Here we report a gene associated with the four most common IGE subtypes: childhood and juvenile absence epilepsy (CAE and JAE), juvenile myoclonic epilepsy (JME), and epilepsy with grand mal seizures on awakening (EGMA; ref. 8). We identified three different heterozygous mutations in the chloride-channel gene CLCN2 in three unrelated families with IGE. These mutations result in (i) a premature stop codon (M200fsX231), (ii) an atypical splicing (del74-117) and (iii) a single amino-acid substitution (G715E). All mutations produce functional alterations that provide distinct explanations for their pathogenic phenotypes. M200fsX231 and del74-117 cause a loss of function of ClC-2 channels and are expected to lower the transmembrane chloride gradient essential for GABAergic inhibition. G715E alters voltage-dependent gating, which may cause membrane depolarization and hyperexcitability.
[Show abstract][Hide abstract] ABSTRACT: Missense mutations in the GABRG2 gene, which encodes the gamma 2 subunit of central nervous gamma-aminobutyric acid (GABA)(A) receptors, have recently been described in 2 families with idiopathic epilepsy. In one of these families, the affected individuals predominantly exhibited childhood absence epilepsy and febrile convulsions.
To assess the role of GABRG2 in the genetic predisposition to idiopathic absence epilepsies.
The GABRG2 gene was screened by single-strand conformation analysis for mutations. Furthermore, a population-based association study assessing a common exon 5 polymorphism (C588T) was carried out.
The sample was composed of 135 patients with idiopathic absence epilepsy and 154 unrelated and ethnically matched controls.
A point mutation (IVS6 + 2T-->G) leading to a splice-donor site mutation in intron 6 was found. The mutation, which is predicted to lead to a nonfunctional protein, cosegregates with the disease status in a family with childhood absence epilepsy and febrile convulsions. The association study did not find any significant differences in the allele and genotype frequencies of the common exon 5 polymorphism (C588T) between patients with idiopathic absence epilepsy and controls (P>.35).
Our study identified a splice-donor-site mutation that was probably causing a nonfunctional GABRG2 subunit. This mutation occurred in heterozygosity in the affected members of a single nuclear family, exhibiting a phenotypic spectrum of childhood absence epilepsy and febrile convulsions. The GABRG2 gene seems to confer a rare rather than a frequent major susceptibility effect to common idiopathic absence epilepsy syndromes.
[Show abstract][Hide abstract] ABSTRACT: We tested the hypothesis that genetic variation in the human sodium channel gene SCN2A confers liability to idiopathic generalized epilepsy (IGE). We performed a systematic search for mutations in 46 familial IGE cases and detected three novel polymorphisms, however, allele frequencies did not differ significantly between patients and controls. A rare mutation (R1918H) was identified in one patient but was absent in one further affected family member. Thus, our results do not suggest a major role of SCN2A in the etiology of IGE.
Epilepsy Research 01/2002; 47(3):243-6. · 2.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Idiopathic generalized epilepsy (IGE) comprises a heterogeneous group of disorders, in which a high genetic predisposition and a complex mode of inheritance have been suggested. Recent identification of ion channel gene mutations in Mendelian epileptic disorders suggests genetically driven neuronal hyperexcitability as one important factor in epileptogenesis. Mutations in two neuronal voltage-gated potassium channel genes (KCNQ2 and KCNQ3) have already been shown to cause epilepsy (BFNC), and we now tested the hypothesis that genetic variation in the KCNQ3 gene confers liability to common IGE subtypes. Length variation of two intragenic polymorphic markers (D8S558 and D8S1835) were therefore assessed in 71 nuclear families ascertained for an affected child. However, the transmission-disequilibrium-test did not show significant differences between the transmitted and non-transmitted parental alleles. Thus, our findings do not provide evidence that genetic variation in the KCNQ3 gene exerts a relevant effect in the etiology of common IGE subtypes.
[Show abstract][Hide abstract] ABSTRACT: Recent identification of ion channel gene mutations in Mendelian epilepsies suggests that genetically driven neuronal hyper-excitability plays an important role in epileptogenesis. In this study, we tested the hypothesis that genetic variation in the human SCN2B gene confers liability to common subtypes of idiopathic generalized epilepsies (IGE). A systematic search for mutations was performed in 92 IGE patients. We detected a novel single nucleotide polymorphism (SNP), however, allele frequencies did not differ between IGE patients and controls (χ2 = 0.19, df = 1, p = 0.744). Furthermore, a missense mutation in codon 209 (Asn209Pro) was identified in one patient, but was found to be absent in an affected sibling of the index patient. Thus, our results do not suggest a major role of the SCN2B gene in the etiology of common IGE subtypes.
[Show abstract][Hide abstract] ABSTRACT: Idiopathic generalized epilepsy (IGE) comprises a heterogeneous group of disorders, in which a high genetic predisposition and a complex mode of inheritance have been suggested. However, genes, which confer liability to common IGE subtypes including juvenile myoclonic epilepsy (JME) and childhood absence epilepsy (CAE) have not been identified so far. Here, we tested the hypothesis that genetic variation in the human homolog of the (ARC) contributes to the etiology of common IGE disorders. The gene has recently been mapped to chromosome 8q24.3, a region which spans previously identified major IGE susceptibility loci. A systematic search for mutations was performed in 143 patients with a known family history of IGE. However, no evidence for functional variants was found in the ARC coding sequence. Nevertheless, we detected a novel common C489T single nucleotide polymorphism, which provides a useful marker in genetic linkage and association studies. By performing a population- and family-based study we however failed to show significant association between this novel single nucleotide polymorphism and IGE, a finding, which most likely rules out that genetic variation in or close to the ARC gene confers liability to common IGE subtypes.
Molecular and Cellular Probes 08/2000; 14(4):255-60. · 1.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Monoaminergic neurotransmission plays an important role in the regulation of neuronal network excitability and seizure activity. Therapeutic inhibition of the mitochondrial enzyme monoamine oxidase A (MAO-A), which is involved in the degradation and inactivation of monoaminergic neurotransmitters, has been shown to confer a potent anticonvulsant effect. These and other findings suggest a possible role of the X-linked MAO-A gene in epileptogenesis. Therefore, our study was designed to test for an association between a novel MAO-A gene promoter polymorphism and common subtypes of idiopathic generalized epilepsy (IGE). The length of a 30-bp repetitive sequence approximately 1.2 kb upstream of the ATG initiation codon was assessed in 126 patients with juvenile myoclonic epilepsy (JME), 122 patients with idiopathic absence epilepsy (IAE), and 248 healthy controls of German descent. Both sexes were analyzed separately. Although we observed a trend towards a lower number of heterozygotes carrying the 3 and 4 copy alleles in female IAE patients (chi2 = 3.813, df = 1, P = 0.053), allele frequencies did not deviate significantly between patients and controls. Thus, our results do not provide evidence for a contribution of the functional MAO-A gene promoter polymorphism to the pathogenesis of common IGE subtypes.
Epilepsy Research 05/2000; 39(2):127-32. · 2.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Benign familial neonatal convulsions (BFNC) are one of the rare idiopathic epilepsies with autosomal dominant mode of inheritance. Two voltage-gated potassium channels, KCNQ2 on chromosome 20q13.3 and KCNQ3 on 8q24, have been recently identified as the genes responsible for BFNC. Here we describe a large family with BFNC in which we found a previously undescribed mutation in the KCNQ2 gene. A 1187(+2)T/G nucleotide exchange affects the conserved donor splice site motif in intron 9. This mutation can be predicted to give rise to aberrant splicing of the primary transcript. There was a wide range of clinical manifestations in this family. An unusual clinical feature is the occurrence of partial seizures in later life with corresponding focal neurological deficits.
[Show abstract][Hide abstract] ABSTRACT: Genetic factors play a major role in the etiology of idiopathic generalized epilepsy. However, in most syndromes, especially the common ones, multiple genetic factors seem to be involved. Mutations in K(+) channel genes have previously found to be associated with epilepsy both in humans and in mice. The weaver mice phenotype, characterized by ataxia, tremor, male infertility, and tonic-clonic seizures, is caused by a point mutation in the inwardly rectifier K(+) channel gene KCNJ6 (GIRK2). A knockout mouse model deprived of functional KCNJ6 protein is susceptible to spontaneous and provoked seizures without showing the histological signs of neuronal cell death found in the weaver mouse. Thus, the KCNJ6 gene seems to play an important role in seizure control. We therefore performed a mutation analysis of KCNJ6 and the related KCNJ3 gene in 38 patients with juvenile myoclonic epilepsy (JME). Two novel same-sense nucleotide exchanges were identified, but none of these changed the coding sequence. These results do not support a major role for the KCNJ6/KCNJ3 heteromeric receptor in the etiology of JME. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:8-11, 2000
American Journal of Medical Genetics 03/2000; 96(1):8-11.