"Progressive myoclonic ataxia and developmental/epileptic encephalopathy associated with a novel homozygous mutation in TCN2 gene".

BACKGROUND: Transcobalamin II (TCN2) defect is a rare metabolic disorder associated with a range of neurological manifestations, including mild developmental delay, severe intellectual disability, ataxia, and, in some cases, seizures. Cobalamin, an essential nutrient, plays a crucial role in central nervous system myelination. CLINICAL PRESENTATION: We present a family with an index patient who exhibited progressive neurodevelopmental regression starting at 9 months of age, accompanied by myoclonic seizures, ataxia, and tremor. No significant hematological abnormalities were observed. Exome sequencing analysis identified a novel homozygous mutation, c.3G>A - P(Met1I), affecting the acceptor site of intron 4 of the TCN2 gene (chromosome 22: 31003321, NM_000355.4), leading to likely pathogenic variant potentially affecting translation. Following treatment with hydroxocobalamin, the patient demonstrated partial clinical improvement. He has a sibling with overt hematological abnormalities and subtle neurological abnormalities who is homozygous to the same mutation. Both parents are heterozygous for the same mutation. CONCLUSIONS: In infants presenting with unexplained non-specific neurological symptoms, irrespective of classical signs of vitamin B12 deficiency, evaluation for TCN2 defect should be considered. Early diagnosis and appropriate management can lead to favorable outcomes.

Epilepsias generalizadas idiopáticas / Idiopathic generalized epilepsies

Resumen Las epilepsias generalizadas idiopáticas (EGI) son un grupo de epilepsias generalizadas edad de pendientes, subgrupo de las Epilepsias genéticas generalizadas(EGG), con hallazgos electro-clínicos característicos y herencia poligénica. Las EGI inclu yen las cuatro epilepsias generalizadas clásicas más comunes de las EGG: la epilepsia de ausencias de la infancia (EAI), epilepsia de ausencias juveniles (EAJ), epilepsia mioclónica juvenil (EMJ) y la epilepsia con crisis tónico clónicas generalizadas. Clínicamente caracterizadas por la presencia de una o una com binación de crisis de ausencias, mioclonías, tónica-clónicas omioclónica-tónica-clónicas con patrón elec troencefalográfico de punta onda lenta de 2.5 a 6cps y activación con la hiperventilación y fotoestimula ción, Sobresalen de las EGG por compartir atributos particulares como el buen pronóstico con control frecuente de las crisis, la no evolución a encefalopa tías epilépticas, frecuente superposición clínica entre las tres primeras, pudiendo evolucionar entre ellas; la probabilidad y edad de remisión varía en cada una.Más del 80% se controlan adecuadamente con medicamentos anticrisis de amplio espectro como el ácido valproico y pueden empeorar con bloqueadores de sodio o gabaérgicos. Si bien los pacientes son previamente sanos con neurodesarrollo normal, frecuentemente se asocian con trastornos del ánimo, déficit de atención e hiperactividad (TDAH) y problemas del aprendizaje pero no presentan déficit cognitivo. El reconocimiento de este grupo de EGI es importan te para el uso adecuado del recurso, evitando estudios innecesarios, adecuada orientación del pronóstico y un tratamiento óptimo.

Abstract Idiopathic generalized epilepsies (IGE) is a group of epilepsies age-dependent, a subgroup of EGG genetic generalized epilepsies, with electro-clinical features and polygenic inheritance. Four syndromes comprising the IGEs: childhood absence epilepsy (CAD), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and generalized tonic-clonic seizures epilepsy. Clinically characterized by the presence of one or a combination of absence seizures, myoclonus, tonic-clonic, or myoclonic-tonic-clonic with common electroencephalographic pat terns of 2.5-5.5 Hz generalized spike-wave and activated by hyperventilation or photic stimulation. They generally have a good prognosis for seizure control, not evolve to an epileptic encephalopathy. Frequent clinical overlap between the first three, being able to evolve between them; the probability and age of remission varies in each one. About 80% responding to broad-spectrum anti-seizure drugs such as valproic acid, may worsen with sodium or GABAergic blockers. Development is typically normal; however, they are frequently associated with mood disorders, attention-deficit/hyperactivity disorder (ADHD), and learning dis abilities, but do not have cognitive deficits. The recognition of this group of EGI is important for the adequate use of the resources, avoiding unnecessary studies, adequate orientation of the prognosis and an optimal treatment.

[Idiopathic generalized epilepsies]. / Epilepsias generalizadas idiopáticas.

Idiopathic generalized epilepsies (IGE) is a group of epilepsies age-dependent, a subgroup of EGG genetic generalized epilepsies, with electro-clinical features and polygenic inheritance. Four syndromes comprising the IGEs: childhood absence epilepsy (CAD), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and generalized tonic-clonic seizures epilepsy. Clinically characterized by the presence of one or a combination of absence seizures, myoclonus, tonic-clonic, or myoclonictonic- clonic with common electroencephalographic patterns of 2.5-5.5 Hz generalized spike-wave and activated by hyperventilation or photic stimulation. They generally have a good prognosis for seizure control, not evolve to an epileptic encephalopathy. Frequent clinical overlap between the first three, being able to evolve between them; the probability and age of remission varies in each one. About 80% responding to broad-spectrum anti-seizure drugs such as valproic acid, may worsen with sodium or GABAergic blockers. Development is typically normal; however, they are frequently associated with mood disorders, attentiondeficit/ hyperactivity disorder (ADHD), and learning disabilities, but do not have cognitive deficits. The recognition of this group of EGI is important for the adequate use of the resources, avoiding unnecessary studies, adequate orientation of the prognosis and an optimal treatment.

Las epilepsias generalizadas idiopáticas (EGI) son un grupo de epilepsias generalizadas edad dependientes, subgrupo de las Epilepsias genéticas generalizadas(EGG), con hallazgos electro-clínicos característicos y herencia poligénica. Las EGI incluyen las cuatro epilepsias generalizadas clásicas más comunes de las EGG: la epilepsia de ausencias de la infancia (EAI), epilepsia de ausencias juveniles (EAJ), epilepsia mioclónica juvenil (EMJ) y la epilepsia con crisis tónico clónicas generalizadas. Clínicamente caracterizadas por la presencia de una o una combinación de crisis de ausencias, mioclonías, tónicaclónicas omioclónica-tónica-clónicas con patrón electroencefalográfico de punta onda lenta de 2.5 a 6cps y activación con la hiperventilación y fotoestimulación, Sobresalen de las EGG por compartir atributos particulares como el buen pronóstico con control frecuente de las crisis, la no evolución a encefalopatías epilépticas, frecuente superposición clínica entre las tres primeras, pudiendo evolucionar entre ellas; la probabilidad y edad de remisión varía en cada una. Más del 80% se controlan adecuadamente con medicamentos anticrisis de amplio espectro como el ácido valproico y pueden empeorar con bloqueadores de sodio o gabaérgicos. Si bien los pacientes son previamente sanos con neurodesarrollo normal, frecuentemente se asocian con trastornos del ánimo, déficit de atención e hiperactividad (TDAH) y problemas del aprendizaje pero no presentan déficit cognitivo. El reconocimiento de este grupo de EGI es importante para el uso adecuado del recurso, evitando estudios innecesarios, adecuada orientación del pronóstico y un tratamiento óptimo.

Perampanel for the treatment of people with idiopathic generalized epilepsy in clinical practice.

OBJECTIVE: This study was undertaken to evaluate perampanel (PER) when used under real-world conditions to treat people with idiopathic generalized epilepsy (IGE) included in the PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) study. METHODS: The multinational, retrospective, pooled analysis PERMIT explored the use of PER in people with focal and generalized epilepsy treated in clinical practice across 17 countries. This subgroup analysis included PERMIT participants with IGE. Time points for retention and effectiveness measurements were 3, 6, and 12 months (last observation carried forward, defined as "last visit," was also applied to effectiveness). Effectiveness was evaluated by seizure type (total seizures, generalized tonic-clonic seizures [GTCS], myoclonic seizures, absence seizures) and included ≥50% responder rate and seizure freedom rate (defined as no seizures since at least the previous visit). Safety/tolerability was monitored throughout PER treatment and evaluated by documenting the incidence of adverse events (AEs), including psychiatric AEs and those leading to treatment discontinuation. RESULTS: The Full Analysis Set included 544 people with IGE (51.9% women, mean age = 33.3 years, mean epilepsy duration = 18.1 years). At 3, 6, and 12 months, 92.4%, 85.5%, and 77.3% of participants were retained on PER treatment, respectively (Retention Population, n = 497). At the last visit, responder and seizure freedom rates were, respectively, 74.2% and 54.6% (total seizures), 81.2% and 61.5% (GTCS), 85.7% and 66.0% (myoclonic seizures), and 90.5% and 81.0% (absence seizures) (Effectiveness Population, n = 467). AEs occurred in 42.9% of patients and included irritability (9.6%), dizziness/vertigo (9.2%), and somnolence (6.3%) (Tolerability Population, n = 520). Treatment discontinuation due to AEs was 12.4% over 12 months. SIGNIFICANCE: This subgroup analysis of the PERMIT study demonstrated the effectiveness and good tolerability of PER in people with IGE when administered under everyday clinical practice conditions. These findings are in line with clinical trial evidence, supporting PER's use as broad-spectrum antiseizure medication for the treatment of IGE.

A novel INPP4A mutation with pontocerebellar hypoplasia, myoclonic epilepsy, microcephaly, and severe developmental delay.

BACKGROUND: The inositol polyphosphate 4-phosphatase intracellular signaling pathway is susceptible to genetic or epigenetic alterations that may result in major neurological illnesses with clinically significant pons and cerebellum involvement. CASE REPORTS: A seven-year-old girl with pontocerebellar hypoplasia, resistant myoclonic epilepsy with axial hypotonia, microcephaly, atypical facial appearance, nystagmus, ophthalmoplegia, hyperactive tendon reflexes, spasticity, clonus, extensor plantar response, contractures in wrists and ankles and growth retardation, whole-exome sequencing was performed and a homozygous "NM_001134225.2:c.646C > T, p.(Arg216Ter)" variant was found in the INPP4A gene. CONCLUSION: INPP4A mutations should be kept in mind in cases with severely delayed psychomotor development, progressive microcephaly, resistant myoclonic epilepsy, isolated cerebellum, and pons involvement.

TRIT1 defect leads to a recognizable phenotype of myoclonic epilepsy, speech delay, strabismus, progressive spasticity, and normal lactate levels.

TRIT1 defect is a rare, autosomal-recessive disorder of transcription, initially described as a condition with developmental delay, myoclonic seizures, and abnormal mitochondrial function. Currently, only 13 patients have been reported. We reviewed the genetic, clinical, and metabolic aspects of the disease in all known patients, including two novel, unrelated TRIT1 cases with abnormalities in oxidative phosphorylation complexes I and IV in fibroblasts. Taken together the features of all 15 patients, TRIT1 defect could be identified as a potentially recognizable syndrome including myoclonic epilepsy, speech delay, strabismus, progressive spasticity, and variable microcephaly, with normal lactate levels. Half of the patients had oxidative phosphorylation complex measurements and had multiple complex abnormalities.

Perampanel for the treatment of patients with myoclonic seizures in clinical practice: Evidence from the PERMIT study.

PURPOSE: To investigate the effectiveness, safety and tolerability of perampanel (PER) in treating myoclonic seizures in clinical practice, using data from the PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) study. METHODS: PERMIT was a pooled analysis of 44 real-world studies from 17 countries, in which patients with focal and generalised epilepsy were treated with PER. This post-hoc analysis included patients with myoclonic seizures at baseline. Retention and effectiveness were assessed after 3, 6, and 12 months; effectiveness was additionally assessed at the last visit (last observation carried forward). Effectiveness assessments included responder rate (≥50% seizure frequency reduction from baseline) and seizure freedom rate (no seizures since at least the prior visit). Safety and tolerability were assessed by evaluating adverse events (AEs) and discontinuation due to AEs. RESULTS: 156 patients had myoclonic seizures (59.0% female; mean age, 32.1 years; idiopathic generalised epilepsy, 89.1%; Juvenile Myoclonic Epilepsy, 63.1%; monthly median myoclonic seizure frequency [interquartile range], 1.7 [1.0-10.0]; mean [standard deviation] prior antiseizure medications, 2.9 [2.6]). Retention was assessed for 133 patients (mean time, 12.1 months), effectiveness for 142, and safety/tolerability for 156. Responder and seizure freedom rates were, respectively, 89.5% and 68.8% at 12 months, and 85.9% and 63.4% at the last visit. Incidence of AEs was 46.8%, the most frequent being dizziness/vertigo (19.2%), irritability (18.6%) and somnolence (9.6%). AEs led to discontinuation of 14.0% of patients over 12 months. CONCLUSION: PER was associated with reduction in myoclonic seizure frequency in patients with myoclonic seizures treated in everyday clinical practice.

A systematic review of the efficacy of perampanel as treatment for myoclonic seizures and symptomatic myoclonus

Epileptic myoclonus or myoclonic seizures can occur in idiopathic generalized epilepsy (IGE) and progressive myoclonus epilepsy (PME). However, symptomatic myoclonus which is stimulus-sensitive and provoked by movement is typically seen in PME and Lance-Adams syndrome. Symptomatic myoclonus is not always associated with epileptiform discharges on the electroencephalogram. Therapeutic interventions such as anti-seizure medications (ASMs), the ketogenic diet and vagus nerve stimulation are not always effective. There is emerging evidence that perampanel (PER), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, may be effective for the treatment of myoclonic seizures and symptomatic myoclonus. We performed a systematic review of the literature to assess the efficacy of PER as treatment for myoclonic seizures and symptomatic myoclonus. Twenty-seven studies with a total sample size of 260 patients were included. The efficacy of PER was analysed separately for myoclonic seizures and symptomatic myoclonus. In the group with myoclonic seizures, 50% responder, 75% responder and seizure freedom rates were reported as 74.3% (101/ 136), 60.3% (82/136) and 57.4% (78/136), respectively, with a follow-up duration of 6-12 months. However, in one post-hoc analysis of data from patients with IGE, the efficacy of PER as treatment for myoclonic seizures during the double-blind phase showed no significant difference compared to placebo. The efficacy of PER for symptomatic myoclonus was reported in a total of 119 patients. Four studies (n=88 patients) reported the efficacy of PER as a decrease in myoclonus score/scale. In the remaining 31 patients, symptomatic myoclonus resolved in three patients, decreased in 21 patients and seven patients showed no improvement. We also analysed the number of patients who were already on levetiracetam (LEV) or valproic acid (VPA) at the time of PER initiation; these data were available for 153 patients. Of these, 56.8% were on LEV and 75.1% were on VPA when PER was initiated. This systematic review suggests that PER maybe effective as treatment for drug-resistant myoclonic seizures and symptomatic myoclonus. It may also be effective in patients who have already failed to respond to LEV and VPA. These findings are preliminary yet encouraging. This study has several limitations, particularly given the scarcity of high-quality randomized controlled trials and marked heterogeneity regarding the type and results of the studies. Hence, the findings of this review should be viewed with considerable reservation.

Successful use of perampanel in GABRA1-related myoclonic epilepsy with photosensitivity.

Pathogenic variants in gamma-aminobutyric acid type A receptor subunit alpha1 (GABRA1) is a protein coding gene that has been associated with a broad phenotypic spectrum of epilepsies. These have ranged from mild generalized forms to early-onset severe epileptic encephalopathies. Both in mild and in severe forms, tonic-clonic and myoclonic seizures with generalized spike and wave discharges and photoparoxysmal responses are common clinical manifestations. We present the case of a 14-year-old girl referred to our clinic with uncontrolled epilepsy. She was found to carry a heterozygous variant (c.335G > A) in GABRA1, already described in the literature and classified as "pathogenic" according to ACMG guidelines. The patient showed severe drug resistance with seizures often triggered by photic stimulation. The introduction of perampanel therapy led to overall reduction of the focal and generalized myoclonic seizures and complete clinical control of the light-triggered seizures. To our knowledge this is the first report of perampanel efficacy in photosensitive epilepsy, and in particular in the presence of a GABRA1 variant. New evidence is needed to confirm our findings in this case.

De novo truncating NOVA2 variants affect alternative splicing and lead to heterogeneous neurodevelopmental phenotypes.

Alternative splicing (AS) is crucial for cell-type-specific gene transcription and plays a critical role in neuronal differentiation and synaptic plasticity. De novo frameshift variants in NOVA2, encoding a neuron-specific key splicing factor, have been recently associated with a new neurodevelopmental disorder (NDD) with hypotonia, neurological features, and brain abnormalities. We investigated eight unrelated individuals by exome sequencing (ES) and identified seven novel pathogenic NOVA2 variants, including two with a novel localization at the KH1 and KH3 domains. In addition to a severe NDD phenotype, novel clinical features included psychomotor regression, attention deficit-hyperactivity disorder (ADHD), dyspraxia, and urogenital and endocrinological manifestations. To test the effect of the variants on splicing regulation, we transfected HeLa cells with wildtype and mutant NOVA2 complementary DNA (cDNA). The novel variants NM_002516.4:c.754_756delCTGinsTT p.(Leu252Phefs*144) and c.1329dup p.(Lys444Glnfs*82) all negatively affected AS events. The distal p.(Lys444Glnfs*82) variant, causing a partial removal of the KH3 domain, had a milder functional effect leading to an intermediate phenotype. Our findings expand the molecular and phenotypic spectrum of NOVA2-related NDD, supporting the pathogenic role of AS disruption by truncating variants and suggesting that this is a heterogeneous condition with variable clinical course.

ILAE definition of the Idiopathic Generalized Epilepsy Syndromes: Position statement by the ILAE Task Force on Nosology and Definitions.

In 2017, the International League Against Epilepsy (ILAE) Classification of Epilepsies described the "genetic generalized epilepsies" (GGEs), which contained the "idiopathic generalized epilepsies" (IGEs). The goal of this paper is to delineate the four syndromes comprising the IGEs, namely childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone. We provide updated diagnostic criteria for these IGE syndromes determined by the expert consensus opinion of the ILAE's Task Force on Nosology and Definitions (2017-2021) and international external experts outside our Task Force. We incorporate current knowledge from recent advances in genetic, imaging, and electroencephalographic studies, together with current terminology and classification of seizures and epilepsies. Patients that do not fulfill criteria for one of these syndromes, but that have one, or a combination, of the following generalized seizure types: absence, myoclonic, tonic-clonic and myoclonic-tonic-clonic seizures, with 2.5-5.5 Hz generalized spike-wave should be classified as having GGE. Recognizing these four IGE syndromes as a special grouping among the GGEs is helpful, as they carry prognostic and therapeutic implications.

Headache in idiopathic/genetic epilepsy: Cluster analysis in a large cohort.

OBJECTIVE: The link between headache and epilepsy is more prominent in patients with idiopathic/genetic epilepsy (I/GE). We aimed to investigate the prevalence of headache and to cluster patients with regard to their headache and epilepsy features. METHODS: Patients aged 6-40 years, with a definite diagnosis of I/GE, were consecutively enrolled. The patients were interviewed using standardized epilepsy and headache questionnaires, and their headache characteristics were investigated by experts in headache. Demographic and clinical variables were analyzed, and patients were clustered according to their epilepsy and headache characteristics using an unsupervised K-means algorithm. RESULTS: Among 809 patients, 508 (62.8%) reported having any type of headache; 87.4% had interictal headache, and 41.2% had migraine. Cluster analysis revealed two distinct groups for both adults and children/adolescents. In adults, subjects having a family history of headache, ≥5 headache attacks, duration of headache ≥ 24 months, headaches lasting ≥1 h, and visual analog scale scores > 5 were grouped in one cluster, and subjects with juvenile myoclonic epilepsy (JME), myoclonic seizures, and generalized tonic-clonic seizures (GTCS) were clustered in this group (Cluster 1). Self-limited epilepsy with centrotemporal spikes and epilepsy with GTCS alone were clustered in Cluster 2 with the opposite characteristics. For children/adolescents, the same features as in adult Cluster 1 were clustered in a separate group, except for the presence of JME syndrome and GTCS alone as a seizure type. Focal seizures were clustered in another group with the opposite characteristics. In the entire group, the model revealed an additional cluster, including patients with the syndrome of GTCS alone (50.51%), with ≥5 attacks, headache lasting >4 h, and throbbing headache; 65.66% of patients had a family history of headache in this third cluster (n = 99). SIGNIFICANCE: Patients with I/GE can be clustered into distinct groups according to headache features along with seizures. Our findings may help in management and planning for future studies.

Children With Trisomy 21 and Lennox-Gastaut Syndrome With Predominant Myoclonic Seizures.

INTRODUCTION: Lennox-Gastaut syndrome is a severe form of pediatric epilepsy that is classically defined by a triad of drug-resistant seizures, including atonic, tonic, and atypical absence seizures; slow spike-and-wave discharges and paroxysmal fast activity on electroencephalography (EEG); and cognitive and behavioral dysfunction. In the vast majority, Lennox-Gastaut syndrome develops in patients with an identified etiology, including genetic or structural brain abnormalities. Long-term prognosis is generally poor with progressive intellectual deterioration and persistent seizures. At present, there are few reported cases of Lennox-Gastaut syndrome and trisomy 21 in the literature. To further delineate the spectrum of epilepsy in trisomy 21, we reviewed children with trisomy 21 and Lennox-Gastaut syndrome at one center over 28 years. METHODS: This is a retrospective case series. At our institution, all EEG results are entered into a database, which was queried for patients with trisomy 21 from 1992 to 2019. Pertinent electroclinical data was obtained from medical records. RESULTS: Of 63 patients with trisomy 21 and epilepsy, 6 (10%) had Lennox-Gastaut syndrome and were included in the study. Four of the 6 patients were male and 5 of 6 had neuroimaging, which was normal. Follow-up ranged from 3 to 20 years. Notably, 5 of 6 had predominant myoclonic seizures throughout the course of their epilepsy, associated with generalized spike-wave discharges, <100 milliseconds. CONCLUSION: We observed myoclonic seizures to be a predominant seizure type in patients with trisomy 21, suggestive that trisomy 21 patients may have a unique pattern of Lennox-Gastaut syndrome.

CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity.

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.

Morphometric analysis of spike-wave complexes (SWCs) causing myoclonic seizures in children with idiopathic myoclonic epilepsies - A positive SWC component correlates with myoclonic intensity.

AIM: To elucidate the morphological characteristics of spike-wave complexes (SWCs) causing myoclonic seizures (MS) in childhood-onset idiopathic myoclonic epilepsies. SUBJECTS AND METHODS: The subjects were 8 patients, including 4 with epilepsy with myoclonic-atonic seizures (EMAS), 3 with myoclonic epilepsy in infancy (MEI) and 1 with idiopathic unclassifiable myoclonic epilepsy. Morphometric parameters of the SWCs were compared between those with MS [SWC-MS (+)] and those without MS [SWC-MS (-)], and a correlation coefficient analysis was performed between the SWC parameters and the duration of myoclonic electromyogram (EMG) potentials. RESULTS: A total of 155 SWC-MS (+) (range: 7 ∼ 34) and 80 SWC-MS (-) (10 each as a control) were analyzed. Comparison of the parameters of the SWCs between SWC-MS (+) and SWC-MS (-) demonstrated that the depth and the width of the positive-sharp-components (PSC) in the SWC-MS (+) were significantly deeper in amplitude and longer in duration than those in the SWC-MS (-), respectively, in all 8 patients (P < 0.05), whereas the number of the polyphasic-multiple-spike-components (PMSC) and the height of negative-spike-components (NSC) were not significantly different in most of the patients, respectively. The depth and the width of PSC were also significantly correlated with the duration of myoclonic EMG potentials in all patients except one [depth of PSC (n = 7): r = 0.623 ∼ 0.888; width of PSC (n = 8): r = 0.676 ∼ 0.948, P < 0.05]. CONCLUSIONS: This study revealed that the depth and width of PSC of the SWC are positively correlated with the MS intensity in childhood-onset idiopathic myoclonic epilepsies and are an important neurophysiological marker to generate MS.

SYNGAP1-DEE: A visual sensitive epilepsy.

OBJECTIVE: To further delineate the electroclinical features of individuals with SYNGAP1 pathogenic variants. METHODS: Participants 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. RESULTS: We 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. CONCLUSIONS: Fixation-off and eye closure were the main triggers for seizures in this SYNGAP1 cohort. SIGNIFICANCE: Combining these clinical and electroencephalographic features could help guide genetic diagnosis.

Epilepsy and electroencephalogram evolution in YWHAG gene mutation: A new phenotype and review of the literature.

A male patient with a de novo mutation in the YWHAG gene and mild phenotype is presented. He had normal delivery and normal development, with normal speech and social milestones. At the age of 9 months, myoclonic seizures started, with generalized epileptiform discharges. The child responded well to levetiracetam monotherapy with complete seizure resolution. Levetiracetam was stopped and he remained seizure-free for 10 months. His development was appropriate for age according to psychological evaluation and he attended a regular kindergarten. At the age of approximately 4 years, the seizures reappeared with different semiology of staring with eye blinking. Electroencephalogram (EEG) showed multifocal spikes. Brain magnetic resonance imaging did not reveal any structural abnormality. Genetic analysis revealed a de novo likely pathogenic missense variant in the YWHAG gene (c.619G>A p.Glu207Lys). We compared our case to the other cases published in the literature. Our case is unique in its seizure semiology and evolution of EEG. Moreover, in contrast to our case, the majority of cases described in the literature have dysmorphism and intellectual disability or autistic spectrum disorder. This report emphasizes the phenotypic heterogeneity of YWHAG mutation as is the case in other developmental encephalopathies.

The phenotype caused by recessive variations in SLC25A22: Report of a new case and literature review.

We describe the clinical, electroencephalography (EEG), and developmental features of a patient with developmental and epileptic encephalopathy due to a homozygous pathogenic variation of mitochondrial glutamate/H+ symporter SLC25A22. Epilepsy began during the first week of life with focal onset seizures. Interictal EEG revealed a suppression-burst pattern with extensive periods of non-activity. The prospective follow-up confirmed developmental encephalopathy as well as ongoing active epilepsy and almost no sign of development at 8 years of age. We confirm in the following paper that SLC25A22 recessive variations may cause a severe developmental and epileptic encephalopathy characterized by a suppression-burst pattern. On the basis of an in-depth literature review, we also provide an overview of this rare genetic cause of neonatal onset epilepsy.

Add-on cannabidiol significantly decreases seizures in 3 patients with SYNGAP1 developmental and epileptic encephalopathy.

Mutations in SYNGAP1 are associated with developmental delay, epilepsy, and autism spectrum disorder (ASD). Epilepsy is often drug-resistant in this syndrome with frequent drop attacks. In a prospective study of add-on cannabidiol (CBD), we identified three patients with SYNGAP1 mutations: two boys and one girl. Seizure onset was at 3.5, 8, and 18 months (M), respectively, with numerous atypical absences per day associated with eyelid myoclonia (2/3 patients), upper limb myoclonic jerks (2/3 patients), and drop attacks (all patients). Seizures were resistant to at least 5 antiepileptic drugs (AEDs). After CBD introduction, two patients were responders since M2 and achieve a seizure reduction of 90% and 80%, respectively, at M9 with disappearance of drop attacks. EEGs showed an improvement regarding background activity and interictal anomalies. The last patient showed a late response at M7 of treatment with an 80% decrease in seizure frequency. Caregiver in all three evaluated as much improved the status of their children. Treatment was well-tolerated in all, and no major adverse events (AEs) were reported. CBD showed efficacy in patients with drug-resistant epilepsy due to SYNGAP1 mutations. Other patients with rare genetic developmental and epileptic encephalopathies with drug-resistant epilepsies might benefit from CBD.