Medicine (Austin & Northern Health) - Research Publications
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ItemGain-of-function HCN2 variants in genetic epilepsy(WILEY, 2018-02)Genetic generalized epilepsy (GGE) is a common epilepsy syndrome that encompasses seizure disorders characterized by spike-and-wave discharges (SWDs). Pacemaker hyperpolarization-activated cyclic nucleotide-gated channels (HCN) are considered integral to SWD genesis, making them an ideal gene candidate for GGE. We identified HCN2 missense variants from a large cohort of 585 GGE patients, recruited by the Epilepsy Phenome-Genome Project (EPGP), and performed functional analysis using two-electrode voltage clamp recordings from Xenopus oocytes. The p.S632W variant was identified in a patient with idiopathic photosensitive occipital epilepsy and segregated in the family. This variant was also independently identified in an unrelated patient with childhood absence seizures from a European cohort of 238 familial GGE cases. The p.V246M variant was identified in a patient with photo-sensitive GGE and his father diagnosed with juvenile myoclonic epilepsy. Functional studies revealed that both p.S632W and p.V246M had an identical functional impact including a depolarizing shift in the voltage dependence of activation that is consistent with a gain-of-function. In contrast, no biophysical changes resulted from the introduction of common population variants, p.E280K and p.A705T, and the p.R756C variant from EPGP that did not segregate with disease. Our data suggest that HCN2 variants can confer susceptibility to GGE via a gain-of-function mechanism.
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ItemILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology(WILEY, 2017-04)The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for diagnosis of patients, but it is also critical for epilepsy research, development of antiepileptic therapies, and communication around the world. The new classification originates from a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It presents three levels, starting with seizure type, where it assumes that the patient is having epileptic seizures as defined by the new 2017 ILAE Seizure Classification. After diagnosis of the seizure type, the next step is diagnosis of epilepsy type, including focal epilepsy, generalized epilepsy, combined generalized, and focal epilepsy, and also an unknown epilepsy group. The third level is that of epilepsy syndrome, where a specific syndromic diagnosis can be made. The new classification incorporates etiology along each stage, emphasizing the need to consider etiology at each step of diagnosis, as it often carries significant treatment implications. Etiology is broken into six subgroups, selected because of their potential therapeutic consequences. New terminology is introduced such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self-limited and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the 21st century.
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ItemFrequency of CNKSR2 mutation in the X-linked epilepsy-aphasia spectrum(WILEY, 2017-03)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.
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ItemDe novo SCN1A pathogenic variants in the GEFS plus spectrum: Not always a familial syndrome(WILEY, 2017-02)Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome characterized by heterogeneous phenotypes ranging from mild disorders such as febrile seizures to epileptic encephalopathies (EEs) such as Dravet syndrome (DS). Although DS often occurs with de novo SCN1A pathogenic variants, milder GEFS+ spectrum phenotypes are associated with inherited pathogenic variants. We identified seven cases with non-EE GEFS+ phenotypes and de novo SCN1A pathogenic variants, including a monozygotic twin pair. Febrile seizures plus (FS+) occurred in six patients, five of whom had additional seizure types. The remaining case had childhood-onset temporal lobe epilepsy without known febrile seizures. Although early development was normal in all individuals, three later had learning difficulties, and the twin girls had language impairment and working memory deficits. All cases had SCN1A missense pathogenic variants that were not found in either parent. One pathogenic variant had been reported previously in a case of DS, and the remainder were novel. Our finding of de novo pathogenic variants in mild phenotypes within the GEFS+ spectrum shows that mild GEFS+ is not always inherited. SCN1A screening should be considered in patients with GEFS+ phenotypes because identification of pathogenic variants will influence antiepileptic therapy, and prognostic and genetic counseling.
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ItemHippocampal malrotation is an anatomic variant and has no clinical significance in MRI-negative temporal lobe epilepsy(WILEY-BLACKWELL, 2016-10)OBJECTIVE: There is considerable difficulty in diagnosing hippocampal malrotation (HIMAL), with different criteria of variable reliability. Here we assess qualitative and quantitative criteria in HIMAL diagnosis and explore the role of HIMAL in magnetic resonance imaging (MRI)-negative temporal lobe epilepsy (TLE). METHODS: We studied the MRI of 155 adult patients with MRI-negative TLE and 103 healthy volunteers, and we asked (1) what are the qualitative and quantitative features that allow a reliable diagnosis of HIMAL, (2) how common is HIMAL in a normal control population, and (3) is HIMAL congruent with the epileptogenic side in MRI-negative TLE. RESULTS: We found that the features that are most correlated with the expert diagnosis of HIMAL are hippocampal shape change with hippocampal diameter ratio > 0.8, lack of normal lateral convex margin, and a deep dominant inferior temporal sulcus (DITS) with DITS height ratio > 0.6. In a blinded analysis, a consensus diagnosis of unilateral or bilateral HIMAL was made in 25 of 103 controls (24.3% of people, 14.6% of hippocampi-14 left, six right, 10 bilateral) that did not differ from 155 lesion-negative TLE patients where 25 had HIMAL (16.1% of patients, 11.6% of hippocampi-12 left, two right, 11 bilateral). Of the 12 with left HIMAL only, 9 had seizures arising from the left temporal lobe, whereas 3 had right-sided seizures. Of the two with right HIMAL only, both had seizures arising from the left temporal lobe. SIGNIFICANCE: HIMAL is an anatomic variant commonly found in controls. HIMAL is also an incidental nonpathologic finding in adult MRI-negative TLE and should not influence surgical decision making.
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ItemExome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy(WILEY, 2016-04)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.
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ItemThe Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures(WILEY, 2019-12)OBJECTIVE: Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe developmental and epileptic encephalopathies. We delineate the genetic causes and genotype-phenotype correlations of a large EIMFS cohort. METHODS: Phenotypic and molecular data were analyzed on patients recruited through an international collaborative study. RESULTS: We ascertained 135 patients from 128 unrelated families. Ninety-three of 135 (69%) had causative variants (42/55 previously reported) across 23 genes, including 9 novel EIMFS genes: de novo dominant GABRA1, GABRB1, ATP1A3; X-linked CDKL5, PIGA; and recessive ITPA, AIMP1, KARS, WWOX. The most frequently implicated genes were KCNT1 (36/135, 27%) and SCN2A (10/135, 7%). Mosaicism occurred in 2 probands (SCN2A, GABRB3) and 3 unaffected mothers (KCNT1). Median age at seizure onset was 4 weeks, with earlier onset in the SCN2A, KCNQ2, and BRAT1 groups. Epileptic spasms occurred in 22% patients. A total of 127 patients had severe to profound developmental impairment. All but 7 patients had ongoing seizures. Additional features included microcephaly, movement disorders, spasticity, and scoliosis. Mortality occurred in 33% at median age 2 years 7 months. INTERPRETATION: We identified a genetic cause in 69% of patients with EIMFS. We highlight the genetic heterogeneity of EIMFS with 9 newly implicated genes, bringing the total number to 33. Mosaicism was observed in probands and parents, carrying critical implications for recurrence risk. EIMFS pathophysiology involves diverse molecular processes from gene and protein regulation to ion channel function and solute trafficking. ANN NEUROL 2019;86:821-831.
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ItemQuantitative analysis of phenotypic elements augments traditional electroclinical classification of common familial epilepsies(WILEY, 2019-11)OBJECTIVE: Classification of epilepsy into types and subtypes is important for both clinical care and research into underlying disease mechanisms. A quantitative, data-driven approach may augment traditional electroclinical classification and shed new light on existing classification frameworks. METHODS: We used latent class analysis, a statistical method that assigns subjects into groups called latent classes based on phenotypic elements, to classify individuals with common familial epilepsies from the Epi4K Multiplex Families study. Phenotypic elements included seizure types, seizure symptoms, and other elements of the medical history. We compared class assignments to traditional electroclinical classifications and assessed familial aggregation of latent classes. RESULTS: A total of 1120 subjects with epilepsy were assigned to five latent classes. Classes 1 and 2 contained subjects with generalized epilepsy, largely reflecting the distinction between absence epilepsies and younger onset (class 1) versus myoclonic epilepsies and older onset (class 2). Classes 3 and 4 contained subjects with focal epilepsies, and in contrast to classes 1 and 2, these did not adhere as closely to clinically defined focal epilepsy subtypes. Class 5 contained nearly all subjects with febrile seizures plus or unknown epilepsy type, as well as a few subjects with generalized epilepsy and a few with focal epilepsy. Family concordance of latent classes was similar to or greater than concordance of clinically defined epilepsy types. SIGNIFICANCE: Quantitative classification of epilepsy has the potential to augment traditional electroclinical classification by (1) combining some syndromes into a single class, (2) splitting some syndromes into different classes, (3) helping to classify subjects who could not be classified clinically, and (4) defining the boundaries of clinically defined classifications. This approach can guide future research, including molecular genetic studies, by identifying homogeneous sets of individuals that may share underlying disease mechanisms.
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ItemSplice variant in ARX leading to loss of C-terminal region in a boy with intellectual disability and infantile onset developmental and epileptic encephalopathy(WILEY, 2019-08)Pathogenic variants in the X-chromosome Aristaless-related homeobox (ARX) gene contribute to intellectual disability, epilepsy, and associated comorbidities in affected males. Here, we report a novel splice variant in ARX in a family with three affected individuals. The proband had early onset developmental and epileptic encephalopathy, his brother and mother had severe and mild intellectual disability, respectively. Massively parallel sequencing identified a novel c.1449-1G>C in intron 4 of the ARX gene, predicted to abolish the splice acceptor site, retaining intron 4 and leading to a premature termination codon immediately after exon 4. As exon 5 is the last exon of the ARX gene, the premature termination codon at position p.L484* would be predicted to escape nonsense-mediated mRNA decay, potentially producing at least some C-terminally truncated protein. Analysis of cDNA from patient lymphoblastoid cells confirmed retention of intron 4 and loss of detectable expression of ARX mRNA across exon 4 to exon 5. We review published cases of variants that lead to altered or early termination of the ARX protein, but not complete loss of function, and are associated with phenotypes of intellectual disability and infantile onset developmental and epileptic encephalopathies, including Ohtahara and West syndromes. Taken together, this novel splice variant retaining intron 4 is likely to be the cause of the early onset developmental and epileptic encephalopathy in the proband.
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ItemEpilepsy in families: Age at onset is a familial trait, independent of syndrome(WILEY, 2019-07)OBJECTIVE: We tested 2 hypotheses regarding age at onset within familial epilepsies: (1) family members with epilepsy tend to have similar ages at onset, independent of epilepsy syndrome; and (2) age at onset is younger in successive generations after controlling for sampling bias. METHODS: We analyzed clinical data collected by the Epi4K Consortium (303 multiplex families, 1,120 individuals). To test hypothesis 1, we used both linear mixed models commonly used for heritability analysis and Cox regression models with frailty terms to assess clustering of onset within families after controlling for other predictors. To test hypothesis 2, we used mixed effects models, pairwise analyses, and survival analysis to address sampling-related bias that may mimic anticipation. RESULTS: Regarding hypothesis 1, age at seizure onset was significantly heritable (intraclass correlation coefficient = 0.17, p < 0.001) after adjusting for epilepsy type, sex, site, history of febrile seizure, and age at last observation. This finding remained significant after adjusting for epilepsy syndromes, and was robust across statistical methods in all families and in generalized families. Regarding hypothesis 2, the mean age at onset decreased in successive generations (p < 0.001). After adjusting for age at last observation, this effect was not significant in mixed effects models (p = 0.14), but remained significant in pairwise (p = 0.0003) and survival analyses (p = 0.02). INTERPRETATION: Age at seizure onset is an independent familial trait, and may have genetic determinants distinct from the determinants of particular epilepsy syndromes. Younger onsets in successive generations can be explained in part by sampling bias, but the presence of genetic anticipation cannot be excluded. ANN NEUROL 2019.