Myoclonic Absences Research Articles

Epilepsy with Myoclonic Absence: Proximal Myoclonus in Absence Seizures Is the Clue

Epilepsy with Myoclonic Absence: Proximal Myoclonus in Absence Seizures Is the Clue

Molecular and Phenotypic Characterization of the RORB-Related Disorder.

Heterozygous variants in RAR-related orphan receptor B (RORB) have recently been associated with susceptibility to idiopathic generalized epilepsy. However, few reports have been published so far describing pathogenic variants of this gene in patients with epilepsy and intellectual disability (ID). In this study, we aimed to delineate the epilepsy phenotype associated with RORB pathogenic variants and to provide arguments in favor of the pathogenicity of variants. Through an international collaboration, we analyzed seizure characteristics, EEG data, and genotypes of a cohort of patients with heterozygous variants in RORB. To gain insight into disease mechanisms, we performed ex vivo cortical electroporation in mouse embryos of 5 selected variants, 2 truncating and 3 missense, and evaluated on expression and quantified changes in axonal morphology. We identified 35 patients (17 male, median age 10 years, range 2.5-23 years) carrying 32 different heterozygous variants in RORB, including 28 single-nucleotide variants or small insertions/deletions (12 missense, 12 frameshift or nonsense, 2 splice-site variants, and 2 in-frame deletions), and 4 microdeletions; de novo in 18 patients and inherited in 10. Seizures were reported in 31/35 (89%) patients, with a median age at onset of 3 years (range 4 months-12 years). Absence seizures occurred in 25 patients with epilepsy (81%). Nineteen patients experienced a single seizure type: absences, myoclonic absences, or absences with eyelid myoclonia and focal seizures. Nine patients had absence seizures combined with other generalized seizure types. One patient had presented with absences associated with photosensitive occipital seizures. Three other patients had generalized tonic-clonic seizures without absences. ID of variable degree was observed in 85% of the patients. Expression studies in cultured neurons showed shorter axons for the 5 tested variants, both truncating and missense variants, supporting an impaired protein function. In most patients, the phenotype of the RORB-related disorder associates absence seizures with mild-to-moderate ID. In silico and in vitro evaluation of the variants in our cohort, including axonal morphogenetic experiments in cultured neurons, supports their pathogenicity, showing a hypomorphic effect.

Phenotypic Spectrum of SETD1B-Related Disorder: Myoclonic Absence Seizures and Concurrent Intellectual Disability - Insights from Two Cases

Phenotypic Spectrum of SETD1B-Related Disorder: Myoclonic Absence Seizures and Concurrent Intellectual Disability - Insights from Two Cases

Status epilepticus in patients with genetic generalized epilepsy: a case series study

BackgroundGenetic generalized epilepsy (GGE) accounts for nearly one-third of all epilepsies. The feature of status epilepticus (SE) in patients with GGE has been rarely studied. We aimed to determine the electroclinical characteristics of SE in patients with GGE.MethodsIn this retrospective study, nine patients with GGE were enrolled at Xijing Hospital, Xi’an, China from May 2014 to May 2020. SE was confirmed by 24-h video-EEG recording. The demography, clinical manifestation, brain MRI and SE pattern were analyzed.ResultsOf the nine patients in the study, seven were female. The mean age of the patients at the time of inclusion was 16.8 years (range 7–31 years), and the mean age at the onset of epilepsy was 10.9 years (range 6–17 years). The follow-up time ranged from 3 months to 6 years. Myoclonic absence status was identified in four patients showing eyelid myoclonia with absence and one patient showing perioral myoclonia with absences. Myoclonic SE was identified in three patients showing juvenile myoclonic epilepsy. Autonomic SE was found in one patient with eyelid myoclonia with absence. SE was terminated by oral midazolam in four patients. In the other five patients, SE terminated spontaneously.ConclusionsThe seizure type of SE in patients with GGE is often consistent with their major symptoms. Oral midazolam may be an option to terminate SE in patients with GGE.

Efficacy of cannabidiol in convulsive and nonconvulsive seizure types associated with treatment-resistant epilepsies in the Expanded Access Program.

The cannabidiol (CBD) Expanded Access Program (EAP), initiated in 2014, provided CBD (Epidiolex) to patients with treatment-resistant epilepsy (TRE). In the final pooled analysis of 892 patients treated through January 2019 (median exposure = 694 days), CBD treatment was associated with a 46%-66% reduction in median monthly total (convulsive plus nonconvulsive) seizure frequency. CBD was well tolerated, and adverse events were consistent with previous findings. We used pooled EAP data to investigate the effectiveness of add-on CBD therapy for individual convulsive seizure types (clonic, tonic, tonic-clonic, atonic, focal to bilateral tonic-clonic), nonconvulsive seizure types (focal with and without impaired consciousness, absence [typical and atypical], myoclonic, myoclonic absence), and epileptic spasms. CBD treatment was associated with a reduction in the frequency of convulsive seizure types (median percentage reduction = 47%-100%), and nonconvulsive seizure types and epileptic spasms (median percentage reduction = 50%-100%) across visit intervals through 144 weeks of treatment. Approximately 50% of patients had ≥50% reduction in convulsive and nonconvulsive seizure types and epileptic spasms at nearly all intervals. These results show a favorable effect of long-term CBD use in patients with TRE, who may experience various convulsive and nonconvulsive seizure types. Future controlled trials are needed to confirm these findings.

Precision medicine: Vinpocetine as a potential treatment for GABRG2-related epilepsy.

Pathogenic variants of the GABRG2 gene, encoding a GABAA receptor subunit, have been associated with various epileptic syndromes and drug-resistant epilepsy. Vinpocetine has been previously reported efficacious in a patient harboring a GABRB3 pathogenic variant, encoding another GABAA receptor subunit. We describe a patient with GABRG2-related drug-resistant epilepsy who improved after vinpocetine treatment. An 8-year-old boy with a family history of epilepsy was diagnosed with early onset absence epilepsy at 6 months of age and was treated unsuccessfully with sodium valproate and ethosuximide. At 6 years of age, he developed generalized tonic-clonic seizures and increasing absences despite lamotrigine add-on as well as learning difficulties. Brain MRI was normal and video-EEG telemetry showed multiple myoclonic absences. An epilepsy gene panel analysis showed a GABRG2 pathogenic variant, c.254 T > A p.(Ile85Lys) (NM_198903.2), inherited from the proband's father. Seizures were resistant to several medications. After treatment with vinpocetine add-on, the patient showed a dramatic initial response, further reduction of seizures, and improvement of his cognitive functions. This case illustrates that vinpocetine could be considered in drug-resistant epilepsies related to GABRG2 in accordance with the principles of precision medicine.

Epilepsy with myoclonic absences: A case series

Epilepsy with myoclonic absences (EMA) is a very rare childhood generalized epilepsy syndrome (<1% of all generalized epilepsies) associated with frequent myoclonic absence seizures that was described in 1969 by Tassinari et al. [ [1] Tassinari C.A. Lyagoubi S. Santos V. et al. Study on spike and wave discharges in man. II. Clinical and electroencephalographic aspects of myoclonic absences. Rev Neurol. 1969; 121: 379-383 PubMed Google Scholar ]. Seizures are characterized by bilateral rhythmic jerks of the upper limbs, superimposed on tonic abduction of the arms [ [2] Bureau M. Tassinari C.A. Epilepsy with myoclonic absences. Brain Dev. 2005; 27: 178-184 Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar ]. Ictal EEG consists of 3-Hz generalized spike-and-wave complexes that are time-locked with the upper limb myoclonus, while the EMG generally shows myoclonic jerks followed by tonic contraction of both deltoids. These seizures differ from typical absences of childhood absence epilepsy, since myoclonic jerks are generally not seen in typical absences and, if present, are subtle and spare the arms. The lack of an atonic component also distinguishes these seizures from myoclonic-atonic seizures [ [3] Specchio N. Wirrell E.C. Scheffer I.E. et al. International league against epilepsy classification and definition of epilepsy syndromes with onset in childhood: position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022; 63: 1398-1442 Crossref PubMed Scopus (46) Google Scholar ]. A recent position paper by the International League Against Epilepsy for the classification of epilepsy syndromes with onset in childhood retained EMA as an independent epilepsy syndrome and defined its diagnostic criteria [ [3] Specchio N. Wirrell E.C. Scheffer I.E. et al. International league against epilepsy classification and definition of epilepsy syndromes with onset in childhood: position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022; 63: 1398-1442 Crossref PubMed Scopus (46) Google Scholar ]. The mandatory requirements are myoclonic absences as the predominant type of seizures, and regular 3 Hz generalized spike-and-wave complexes synchronous with myoclonus.

Epilepsy with myoclonic absence presenting with unilateral jerks: A case of 2q13 microdeletion syndrome

Epilepsy with myoclonic absence (EMA), which was originally depicted by Tassinari in 1969 and 1971, is now classified by the International League Against Epilepsy (ILAE) as a genetic generalised epilepsy syndrome of childhood. EMA is characterised by rhythmic jerks and tonic contractions with impaired consciousness accompanied by synchronous and symmetric 3 Hz spike-and-wave discharges. It is generally bilateral, but it must be differentiated from focal impaired awareness motor seizures when it is unilateral [1].

Electro-clinical features and management of the late stage of Lafora disease.

PurposeThe aim of this study was to elucidate the electro-clinical features and management of the late stage of Lafora disease (LD).MethodsWe investigated the electro-clinical data and medical complications of three LD patients with mutations in EPM2A and two in NHLRC1 genes during the LD late stage.ResultsThe late stage emerged after a mean period of 7 ± 1.41 years from the onset of the disease. All patients developed gait ataxia becoming bedbound with severe dementia. Pluri-monthly and drug-resistant myoclonic seizures, and myoclonic absence and tonic–clonic seizures were associated with daily/pluri-daily myoclonus, while the EEG/polygraphic findings showed diffusely slow activity with epileptiform abnormalities, often correlated with myoclonic jerks. Seizure emergencies with motor cluster/status epilepticus and medical complications dominated the clinical picture. In particular, video-EEG/polygraphic recordings disclosed status epilepticus with prominent motor symptoms of different subtypes refractory to IV new anti-seizure medications and responsive in 75% of cases to IV phenytoin. The main complications were dysphagia, aspiration pneumonia, acute respiratory failure, sepsis, immobility, and spasticity with bedsores. A coordinated and multidisciplinary management of the three patients with EPM2A mutations has demonstrated a reduction in seizure emergencies, medical complications and days of hospitalization, and a prolongation of the years of disease compared to the two patients with NHLRC1 mutations.ConclusionStatus epilepticus with prominent motor symptoms of different subtypes, often responsive to IV phenytoin, and multiple medical complications characterize the LD late stage. An effective management requires a multidisciplinary medical and nursing team, coordinated by an epileptologist with the aim of reducing seizure emergencies and medical complications.

Difficult to treat absence seizures in children: A single-center retrospective study.

ObjectivesThe aim of this study was to analyse the characteristics of typical absence seizures (AS), myoclonic AS and AS with eyelid myoclonia in children and to find associations between these characteristics and difficult to treat absence seizures (DTAS).MethodsThis was a single-center retrospective study. Electronic health records of pediatric patients with a clinical diagnosis of AS treated at a single tertiary epilepsy center between January 2013 and June 2020 were reviewed. Clinical characteristics, seizure information, ASM, and therapeutic response of patients were recorded. All patients were followed up for at least 1 year. DTAS were defined as failure to achieve remission after treatment with at least 2 anti-seizure medications (ASM), regardless of whether remission was achieved eventually in the study period.ResultsData from 131 patients were available for analysis. Remission was achieved after the first ASM treatment in 81 (61.8%) patients, and eventually in 120 (91.6%) during the study period. Epilepsy was classified as DTAS in 18 (13.7%) patients. AS were more often difficult to treat in patients with myoclonic AS and AS with eyelid myoclonia (40.0%), compared with patients with typical AS (11.4%; p = 0.012, 95% CI 1.480–25.732). A positive family history of epilepsy (p = 0.046; 95% CI 1.021–8.572), a higher seizure frequency (p = 0.023, 95% CI 1.009–1.126) prior to ASM treatment, and longer time between seizure onset and treatment onset (p = 0.026; 95% CI 1.006–1.099) were also associated with DTAS.SignificanceOur study suggests that several clinical characteristics of AS are associated with DTAS. One of these was the time between onset of AS and initiation of ASM treatment, which can be shortened with better care, suggesting that early diagnosis and treatment may improve prognosis in pediatric patients with AS. These findings remain to be confirmed in larger prospective studies.

Hyperperfusion in the cerebellum lobule VIIb in patients with epileptic seizures

BackgroundThe cerebellum plays an important role in motor control, however, its involvement in epilepsy has not been fully understood. Arterial spin labelling perfusion magnetic resonance image (ASL) is a noninvasive method to evaluate cerebral and cerebellar blood flow. We investigated cerebellar perfusion in patients with epileptic seizures using ASL.MethodsAdult patients with epileptic seizures who underwent ASL in three post labeling delay (PLD) conditions (1525, 1800, and 2500 msec) and conventional electroencephalography (EEG) on the same day were investigated. Clinical and EEG characteristics of them were retrospectively analyzed.ResultsSix patients (6 women, age; 36.2 ± 17.9 years (mean ± SD)) showed hyperperfusion in selective areas in the cerebellar paravermis of lobule VIIb. One patient with generalized epilepsy (tentative diagnosis of juvenile myoclonic epilepsy or epilepsy with myoclonic absences) showed unilateral hypoperfusion in PLD 1525 msec and hyperperfusion in PLD 1800 and 2500 msec at the area while EEG showed generalized spike-wave complexes. After successful treatment, these perfusion abnormalities disappeared. In two patients with focal epilepsy manifesting with asymmetrical motor symptoms, cerebellar hyperperfusion was found on the opposite side to the seizure focus estimated by seizure semiology. Besides hyperperfusion of the VIIb lobule, hypoperfusion at the same area was detected in shorter PLD condition in four patients and in longer PLD condition in one patient.ConclusionThe cerebellar paravermis of lobule VIIb can be a component of motor circuit and participate in epileptic network in humans. Cerebellar perfusion abnormalities can be associated with neurovascular coupling via capillary bed.

Epilepsy with myoclonic absences: a case series highlighting clinical heterogeneity and surgical management

AbstractObjective. Epilepsy with myoclonic absences is a rare epilepsy syndrome with distinct features and high rates of drug resistance. Identifying this syndrome may help guide treatment decisions. We highlight clinical heterogeneity in this case series and two cases in which corpus callosotomy was performed.Methods. Medical records were reviewed between 2017 and 2021 to identify demographics, comorbidities, age at onset, EEG findings, diagnostic evaluations, seizure semiologies, seizure frequency, anti‐seizure medications, diet therapy and surgical treatments in patients with myoclonic absences.Results. Ten patients were identified including twins with myoclonic absence status epilepticus. Forty percent had an atonic component, 20% presented with myoclonic absence status epilepticus and 60% had incomplete control of seizures at last follow‐up visit. Two patients with epilepsy with myoclonic absences with atonia underwent corpus callosotomy; one patient was seizurefree eight months after surgery and the other had greater than 50% seizure reduction over a five‐month period.Significance. Phenotypic heterogeneity was evident based on seizure semiologies, comorbidities, seizure frequency and response to anti‐seizure medications and non‐medication treatments. Of patients with an atonic component, 75% did not achieve seizure freedom with medication alone. Corpus callosotomy was performed in two of these patients with encouraging seizure response thus far, however, the efficacy of this treatment should be further evaluated in a larger study.

C.3 Childhood Absence Epilepsy: Prevalence of neuropsychiatric comorbidities and predictors of treatment resistance

Background: Seizures in childhood absence epilepsy (CAE) are typically easily controlled with anti-seizure medications (ASMs). Factors predictive of treatment resistance remain unclear. Our objectives were to assess prevalence of neuropsychiatric problems and factors influencing treatment resistance in a cohort of CAE at a single centre. Methods: We retrospectively reviewed patients with CAE diagnosed between January 1999 and December 2016 with at least 1-year follow-up. Treatment resistance was defined as failure to respond to two appropriate ASMs. Exclusion criteria included eyelid myoclonia with absence, myoclonic absence, and generalized tonic-clonic (GTC) seizures prior to absence seizures. Results: The study population comprised 164 patients (65 males) with mean age at seizures onset of 6.1years. 21% had treatment-resistant seizures. The first ASM was Ethosuximide (63.4%), Valproic acid (23.2%), and Lamotrigine (6.7%). 32.9% of children had learning disabilities, 28.7% ADHD, and 12.8 % anxiety.A stepwise binary logistic regression analysis identified GTC seizures, learning disability (LD) and ongoing general spike and wave on EEG as predictors of treatment resistance. At last follow-up (average of 5.4 years), 43.3% of children were seizure-free off ASMs. Conclusions: 21% of children with CAE had treatment-resistant seizures. LD, GTC and failure of normalization of the EEG were associated with treatment resistance.

International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: Position paper by the ILAE Task Force on Nosology and Definitions

The 2017 International League Against Epilepsy classification has defined a three-tier system with epilepsy syndrome identification at the third level. Although a syndrome cannot be determined in all children with epilepsy, identification of a specific syndrome provides guidance on management and prognosis. In this paper, we describe the childhood onset epilepsy syndromes, most of which have both mandatory seizure type(s) and interictal electroencephalographic (EEG) features. Based on the 2017 Classification of Seizures and Epilepsies, some syndrome names have been updated using terms directly describing the seizure semiology. Epilepsy syndromes beginning in childhood have been divided into three categories: (1) self-limited focal epilepsies, comprising four syndromes: self-limited epilepsy with centrotemporal spikes, self-limited epilepsy with autonomic seizures, childhood occipital visual epilepsy, and photosensitive occipital lobe epilepsy; (2) generalized epilepsies, comprising three syndromes: childhood absence epilepsy, epilepsy with myoclonic absence, and epilepsy with eyelid myoclonia; and (3) developmental and/or epileptic encephalopathies, comprising five syndromes: epilepsy with myoclonic-atonic seizures, Lennox-Gastaut syndrome, developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep, hemiconvulsion-hemiplegia-epilepsy syndrome, and febrile infection-related epilepsy syndrome. We define each, highlighting the mandatory seizure(s), EEG features, phenotypic variations, and findings from key investigations.

Generalized Fast Discharges Along the Genetic Generalized Epilepsy Spectrum: Clinical and Prognostic Significance.

ObjectiveTo investigate the electroclinical characteristics and the prognostic impact of generalized fast discharges in a large cohort of genetic generalized epilepsy (GGE) patients studied with 24-h prolonged ambulatory electroencephalography (paEEG).MethodsThis retrospective multicenter cohort study included 202 GGE patients. The occurrence of generalized paroxysmal fast activity (GPFA) and generalized polyspike train (GPT) was reviewed. GGE patients were classified as having idiopathic generalized epilepsy (IGE) or another GGE syndrome (namely perioral myoclonia with absences, eyelid myoclonia with absences, epilepsy with myoclonic absences, generalized epilepsy with febrile seizures plus, or GGE without a specific epilepsy syndrome) according to recent classification proposals.ResultsGPFA/GPT was found in overall 25 (12.4%) patients, though it was significantly less frequent in IGE compared with other GGE syndromes (9.3 vs. 25%, p = 0.007). GPFA/GPT was found independently of seizure type experienced during history, the presence of mild intellectual disability/borderline intellectual functioning, or EEG features. At multivariable analysis, GPFA/GPT was significantly associated with drug resistance (p = 0.04) and with a higher number of antiseizure medications (ASMs) at the time of paEEG (p < 0.001) and at the last medical observation (p < 0.001). Similarly, GPFA/GPT, frequent/abundant generalized spike-wave discharges during sleep, and a higher number of seizure types during history were the only factors independently associated with a lower chance of achieving 2-year seizure remission at the last medical observation. Additionally, a greater number of GPFA/GPT discharges significantly discriminated between patients who achieved 2-year seizure remission at the last medical observation and those who did not (area under the curve = 0.77, 95% confidence interval 0.57–0.97, p = 0.02)ConclusionWe found that generalized fast discharges were more common than expected in GGE patients when considering the entire GGE spectrum. In addition, our study highlighted that GPFA/GPT could be found along the entire GGE continuum, though their occurrence was more common in less benign GGE syndromes. Finally, we confirmed that GPFA/GPT was associated with difficult-to-treat GGE, as evidenced by the multivariable analysis and the higher ASM load during history.

Phenotypes in Children With SYNGAP1 Encephalopathy in China.

Objective: We aimed to explore the associated clinical phenotype and the natural history of patients with SYNGAP1 gene variations during early childhood and to identify their genotype–phenotype correlations.Methods: This study used a cohort of 13 patients with epilepsy and developmental disorder due to SYNGAP1 mutations, namely, 7 patients from Shenzhen Children’s Hospital between September 2014 and January 2020 and 6 patients from previously published studies. Their clinical data were studied.Results: A total of 13 children with SYNGAP1 gene variants (eight boys and five girls) were identified. The age of disease onset was in infancy. Mutations were located between exons 8 and 15; most were frameshift or truncated mutations. Four mutation sites (c.924G > A, c.1532-2_1532del, c.1747_1755dup, and c.1735_1738del) had not been reported before. All patients had global developmental delay within the first year of life, and intellectual impairment became gradually apparent. Some of them developed behavioral problems. The developmental delay occurred before the onset of seizures. All seven patients in our cohort presented with epilepsy; myoclonic seizures, absence seizures, and epileptic spasms were the most common seizure types. Abnormal electroencephalograms were identified from five patients before the onset of their seizures. All patients suffered from drug-resistance seizures. However, comorbidities such as behavioral problems were less frequently observed.Conclusion: The most common age of disease onset in SYNGAP1 gene mutations is in infancy, while neurodevelopmental delay and epilepsy are the major phenotypes. They have a higher percentage of drug-resistant epilepsy and epileptic spasms than those in previous reports. We should give attention to the patients with abnormal EEGs without seizures and think about the suitable time of the anti-seizure medications for them. We have not found the genotype–phenotype correlation.Trial registration: Chinese Clinical Trial Registry, Registration number: ChiCTR2100049289 (https://www.chictr.org.cn/listbycreater.aspx).

P.102 Childhood Absence Epilepsy: Prevalence of treatment resistance and neuropsychiatric comorbidity.

Background: Seizures in childhood absence epilepsy (CAE) are usually easily controlled with anti-seizure medications (ASMs). Factors predictive of treatment resistance remain unclear. Our objectives were to assess prevalence of neuropsychiatric problems and factors influencing refractoriness in a cohort of CAE at a single centre. Methods: We retrospectively reviewed patients with CAE (ILAE 2017 classification) diagnosed between January 1999 and December 2016 with at least 1-year follow-up. Treatment resistance was defined as failure to respond to two or more appropriate ASMs. Exclusion criteria included eyelid myoclonia with absence, myoclonic absence, and generalized tonic-clonic (GTC) seizure before developing absences. Results: The study population comprised 164 patients (65 males) 6.25-year-old on average at absence onset. 22% had treatment-resistant seizures. The first ASM was Ethosuximide in 63.4%, Valproic acid in 23.2%, and Lamotrigine in 6.7%. Statistical differences between response groups included developing a second seizure type specifically GTC, the second and third ASM, and absence of EEG normalization. At last follow-up, 43.3% of children were seizure-free off ASMs. 32.9% of children had learning disabilities, 28% ADHD, and 12.8 % anxiety. Conclusions: 22% of children with CAE had treatment-resistant seizures. Photoparoxysmal response was not predictive of treatment resistance. Neuropsychiatric problems were common with learning disabilities increased with refractory absences.

In vitro identification of CACN1h 9 axonal SNP in epileptic patients

Childhood absence epilepsy (CAE) is an autosomal dominant disorder and a heterogeneous familial condition in which family members express absence seizures initially and then show multiple phenotypes of myoclonic epilepsy, including partial or absence seizures and generalized tonic conic seizures. Multiple types of genetic mutations are involved in epilespy. This study was aimed at investigating the coding regions of CACNA1H gene for analyzing the mutations involved in epilepsy. Blood samples of mutually unrelated true representatives of CAE were collected from the psychiatry department of various hospitals in Lahore. DNA was extracted using the standard protocol and the amplification of the CACNA1H region was achieved with specially designed primers. Later on, the analysis of the results was carried out via the sequencing of target fragments. Sequences were analyzed using the BioEdit software and then aligned with the help of the ClustalW2 software. A series of 12 unrelated patients with CAE were screened for mutations in the CACNA1H gene. No mutation was found in exon 9a. As already reported, mutations in the exonic sequence of CACNA1H gene were found in 5 out of 14 CAE patients. These changes were observed in a PCR fragment amplified by primer 2 in the region of the 9th exon. Subsequent analysis of these fragments identified transition mutations (2025G&gt;A) in exon 9. To conclude, there is a need to explore the site of the gene along with other gene mutations causing epilepsy in the local population of Punjab, Pakistan. It will help to develop genetic counseling strategies, gene therapies, and prenatal diagnostic procedures for the said population.

Association Analysis of Candidate Variants in Admixed Brazilian Patients With Genetic Generalized Epilepsies.

Genetic generalized epilepsies (GGEs) include well-established epilepsy syndromes with generalized onset seizures: childhood absence epilepsy, juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), myoclonic absence epilepsy, epilepsy with eyelid myoclonia (Jeavons syndrome), generalized tonic–clonic seizures, and generalized tonic–clonic seizures alone. Genome-wide association studies (GWASs) and exome sequencing have identified 48 single-nucleotide polymorphisms (SNPs) associated with GGE. However, these studies were mainly based on non-admixed, European, and Asian populations. Thus, it remains unclear whether these results apply to patients of other origins. This study aims to evaluate whether these previous results could be replicated in a cohort of admixed Brazilian patients with GGE. We obtained SNP-array data from 87 patients with GGE, compared with 340 controls from the BIPMed public dataset. We could directly access genotypes of 17 candidate SNPs, available in the SNP array, and the remaining 31 SNPs were imputed using the BEAGLE v5.1 software. We performed an association test by logistic regression analysis, including the first five principal components as covariates. Furthermore, to expand the analysis of the candidate regions, we also interrogated 14,047 SNPs that flank the candidate SNPs (1 Mb). The statistical power was evaluated in terms of odds ratio and minor allele frequency (MAF) by the genpwr package. Differences in SNP frequencies between Brazilian and Europeans, sub-Saharan African, and Native Americans were evaluated by a two-proportion Z-test. We identified nine flanking SNPs, located on eight candidate regions, which presented association signals that passed the Bonferroni correction (rs12726617; rs9428842; rs1915992; rs1464634; rs6459526; rs2510087; rs9551042; rs9888879; and rs8133217; p-values <3.55e–06). In addition, the two-proportion Z-test indicates that the lack of association of the remaining candidate SNPs could be due to different genomic backgrounds observed in admixed Brazilians. This is the first time that candidate SNPs for GGE are analyzed in an admixed Brazilian population, and we could successfully replicate the association signals in eight candidate regions. In addition, our results provide new insights on how we can account for population structure to improve risk stratification estimation in admixed individuals.

SYNGAP1-DEE: A visual sensitive epilepsy

ObjectiveTo further delineate the electroclinical features of individuals with SYNGAP1 pathogenic variants. MethodsParticipants with pathogenic SYNGAP1 variants and available video-electroencephalogram (EEG) recordings were recruited within five European epilepsy reference centers. We obtained molecular and clinical data, analyzed EEG recordings and archived video-EEGs of seizures and detailed characteristics of interictal and ictal EEG patterns for every patient. ResultsWe recruited 15 previously unreported patients and analyzed 72 EEGs. Two distinct EEG patterns emerged, both triggered by eye closure. Pattern 1 (14/15 individuals) consisted of rhythmic posterior/diffuse delta waves appearing with eye-closure and persisting until eye opening (strongly suggestive of fixation-off sensitivity). Pattern 2 (9/15 individuals) consisted of diffuse polyspike-and-wave discharges triggered by eye closure (eye-closure sensitivity). Both patterns presented in 8/15. Including archived video-EEG clips of seizures from 9/15 patients, we analyzed 254 seizures. Of 224 seizures experienced while awake, 161 (72%) occurred at or following eye closure. In 119/161, pattern 1 preceded an atypical absence, myoclonic seizure or myoclonic absence; in 42/161, pattern 2 was associated with eyelid myoclonia, absences and myoclonic or atonic seizures. ConclusionsFixation-off and eye closure were the main triggers for seizures in this SYNGAP1 cohort. SignificanceCombining these clinical and electroencephalographic features could help guide genetic diagnosis.