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Biallelic pathogenic variants in CNTNAP2 , a gene encoding the contactin-associated protein-like 2, have been reported in patients with various clinical presentations including intellectual disability (ID), autistic spectrum disorders (ASD), psychiatric disorders, and focal epilepsy rarely associated to focal cortical dysplasia. We report four children carrying novel biallelic CNTNAP2 pathogenic variants. They present global developmental delay, psychiatric disorders, and focal epilepsy. All patients displayed brain MRI abnormalities consistent with focal temporal dysplasia. One patient had a temporal resection before the availability of genetic testing. Focal cortical dysplasia represents a frequent finding related to focal refractory epilepsy in CNTNAP2 affected patients, and surgery seems to be ineffective in this setting. The genetic testing could therefore be impactful on treatment choices in refractory focal epilepsies. [ABSTRACT FROM AUTHOR]

The molecular diagnosis of early-onset epileptic encephalopathy (EOEE), an expanding field in child neurology, is becoming increasingly possible thanks to the widespread availability of next-generation sequencing and whole-exome sequencing. In the past 15 years, mutations in STXBP1, KCNQ2, SCN2A, SCN8A and numerous other genes have been reported, giving a more accurate insight for these rare diseases. Among these genes, germline mutations in Phosphatidyl Inositol Glycan A (PIGA) gene were first reported in 2012. Located on Xp22.2, PIGA is involved in the synthesis of GPI (glycosylphosphatidylinositol) which acts as a membrane anchor for different proteins: enzymes, adhesion molecules, regulation of the complement way, and co-receptor in transduction signal. Children suffering from this condition exhibit developmental delay with early-onset epilepsy, severe dysmorphic signs, multi-visceral anomalies and early death in the most severe forms. Here, we report five cases of germline PIGA mutations, with two missense mutations that have not been reported to date. We provide a new insight into the electroclinical phenotype. At the onset, epileptic spasms and focal-onset seizures with upper limbs and ocular involvements were present. Epilepsy proved pharmacoresistant in 4 out of 5 cases. Interictal EEG may be normal at the onset of epilepsy, but abnormalities in electroencephalographic studies were eventually present in all cases. Different types of seizures may be present simultaneously, and epileptic phenotypes evolve with aging. • We provide a new insight on epilepsy onset and evolution in germline PIGA mutations. • Ocular jerks, epileptic spasms, and focal-onset seizures were mainly encountered. • Assessment of epilepsy can be difficult in the first stage of the condition. • Two patients harbored missense mutations that have not been reported to date. • Patients may exhibit subtle dysmorphic signs despite severe epilepsy. [ABSTRACT FROM AUTHOR]

Abstract Background and aims Phospholipase A2 associated neurodegeneration (PLAN) is a heterogeneous autosomal recessive disorder caused by mutations in the ubiquitously expressed PLA2G6 gene. It is responsible for delayed brain iron accumulation and induces progressive psychomotor regression. We report the concomitant clinical, radiological and neurophysiological findings in PLAN patients in an attempt to determine the contribution of each test to guide diagnosis. Methods Concomitant clinical, radiological, electroencephalographic (EEG) and electrodiagnostic testing (EDX) findings in a series of 8 consecutive genetically confirmed PLAN patients were collected. Results All patients presented marked motor axonal loss, with decreased or absent distal compound muscle action potentials, acute and chronic denervation at needle electromyography, in contrast with preservation of sensory conduction. EEG showed high-amplitude fast activity in all patients aged above 15 months. Two patients showing severe neonatal hypotonia displayed atypical hypsarhythmia and epileptic spasms. Iron deposition in globus pallidus was observed in only two patients aged above 6 years. Conclusions Peripheral involvement is an early feature in PLAN recognizable by EDX at an earlier stage than typical iron accumulation in the brain. Furthermore, the association of West syndrome and axonal motor neuropathy may represent positive clues in favor of PLAN. This results emphasize the interest of early and repeated EDX. Highlights • In PLAN, motor axonal neuropathy occurring before the iron accumulation on MRI. • Rare subtypes of PLAN consist in neonatal motor axonal neuropathy associated with West syndrome. [ABSTRACT FROM AUTHOR]

Freidreich ataxia (FRDA) is the most common hereditary ataxia, nearly 98% of patients harbouring homozygous GAA expansions in intron 1 of the FXN gene (NM_000144.4). The remaining patients are compound heterozygous for an expansion and a point mutation or an exonic deletion. Molecular screening for FXN expansion is therefore focused on (GAA)n expansion analysis, commonly performed by triplet repeat primed PCR (PT-PCR). We report on an initial pitfall in the molecular characterization of a 15 year-old girl with Freidreich ataxia (FRDA) who carried a rare deletion in intron 1 of the FXN gene. Due to this deletion TP-PCR failed to amplify the GAA expansion. This exceptional configuration induced misinterpretation of the molecular defect in this patient, who was first reported as having no FXN expansion. NGS analysis of a panel of 212 genes involved in nuclear mitochondrial disorders further revealed an intragenic deletion encompassing exons 4–5 of the FXN gene. Modified TP-PCR analysis confirmed the presence of a classical (GAA)n expansion located in trans . This case points out the possible pitfalls in molecular diagnosis of FRDA in affected patients and their relatives: detection of the FXN expansion may be impaired by several non-pathological or pathological variants around the FXN (GAA)n repeat. We propose a new molecular strategy to accurately detect expansion by TP-PCR in FRDA patients. [ABSTRACT FROM AUTHOR]

Summary Disease-causing mutations in ion channels generally alter intrinsic gating properties such as activation, inactivation, and voltage dependence. We examined nine different mutations of the KCNT1 (Slack) Na + -activated K + channel that give rise to three distinct forms of epilepsy. All produced many-fold increases in current amplitude compared to the wild-type channel. This could not be accounted for by increases in the intrinsic open probability of individual channels. Rather, greatly increased opening was a consequence of cooperative interactions between multiple channels in a patch. The degree of cooperative gating was much greater for all of the mutant channels than for the wild-type channel, and could explain increases in current even in a mutant with reduced unitary conductance. We also found that the same mutation gave rise to different forms of epilepsy in different individuals. Our findings indicate that a major consequence of these mutations is to alter channel-channel interactions. [ABSTRACT FROM AUTHOR]

Abstract: STXBP1 (MUNC18.1), encoding syntaxin binding protein 1, is a gene causing epileptic encephalopathy. Mutations in STXBP1 have first been reported in early onset epileptic encephalopathy with suppression-bursts, then in infantile spasms and, more recently, in patients with non syndromic mental retardation without epilepsy. We analyzed clinical evolution and brain magnetic resonance imaging in 7 patients (6 females, 1 male) with early onset epileptic encephalopathies associated with STXBP1 mutations. We documented a peculiar brain MRI aspect characterized by frontal hypoplasia and a thin and dysmorphic corpus callosum. The course of the epilepsy was relatively benign. These clinical and neuroradiological features could orient the clinician in selecting patients' candidate to genetic testing for STXBP1 gene. [Copyright &y& Elsevier]

Abstract: The occurrence of epilepsy in autism is variable; nevertheless, EEG paroxysmal abnormalities (PA) are frequently recorded in patients with autism, although the influence of epilepsy and/or EEG PA on the autistic regression has not been clarified yet. We examine a large sample of 345 inpatients with autism, divided into three groups: (1) patients without epilepsy and EEG PA; (2) patients with EEG PA but no seizures; (3) patients with epilepsy including febrile convulsions. The prevalence of epilepsy (24.9%) and EEG PA (45.5%) was higher than that reported in the general population. The significant differences among the three groups concerned autistic regression (comparison between groups 1 and 2, p <0.05; comparison between groups 1 and 3, p <0.01), cerebral lesions (comparison between groups 1 and 2, p <0.05; between groups 1 and 3, p <0.001), and symptomatic autism (comparison between groups 1 and 2 as much as comparison between groups 1 and 3, p <0.001), which were prevalent in groups 2 and 3; while severe/profound mental retardation was more frequent in group 3 compared to group 1 (p <0.01). Focal epilepsy (43.0%) and febrile convulsions (33.7%) were frequent in the third group with epilepsy. EEG PA were mainly localized in temporal and central areas (31.4%). Only 2.6% of patients had subcontinuous/continuous EEG PA during sleep. Seizures and EEG PA were not related to autistic regression. EEG PA occurred mainly in childhood, while epilepsy tended to occur (p <0.001) as age increased. The age at onset of seizures had two peaks: between 0 and 5 and between 10 and 15years with no difference between idiopathic and symptomatic cases. In 58.5% of subjects aged ⩾20years, epilepsy including febrile seizures occurred at some point of their lives, while cases with only EEG PA were less frequent (9.7%). The relationship among autism, EEG PA and epilepsy should be clarified and investigated. In autism, seizures and EEG PA could represent an epiphenomenon of a cerebral dysfunction independent of apparent lesions. [Copyright &y& Elsevier]

In the last few years, with the advent of next generation sequencing (NGS), our knowledge of genes associated with monogenic epilepsies has significantly improved. NGS is also a powerful diagnostic tool for patients with epilepsy, through gene panels, exomes and genomes. This has improved diagnostic yield, reducing the time between the first seizure and a definitive molecular diagnosis. However, these developments have also increased the complexity of data interpretation, due to the large number of variants identified in a given patient and due to the phenotypic variability associated with many of the epilepsy-related genes. In this paper, we present examples of variant classification in "real life" clinic situations. We emphasize the importance of accurate phenotyping of the epilepsies including recognising variable/milder phenotypes and expansion of previously described phenotypes. There are some important issues specific to rare epilepsies – mosaicism and reduced penetrance - which affect genetic counselling. These challenges may be overcome through multidisciplinary meetings including epileptologists, pediatric neurologists, and clinical and molecular geneticists, in which every specialist learns from the others in a process which leads to for rapid and accurate diagnosis. This is an important milestone to achieve as targeted therapiesbased on the functional effects of pathogenic variants become available. [ABSTRACT FROM AUTHOR]

The EPIGENE network was created in 2014 by four multidisciplinary teams composed of geneticists, pediatric neurologists and neurologists specialized in epileptology and neurophysiology. The ambition of the network was to harmonize and improve the diagnostic strategy of Mendelian epileptic disorders using next-generation sequencing, in France. Over the years, five additional centers have joined EPIGENE and the network has been working in close collaboration, since 2018, with the French reference center for rare epilepsies (CRéER). Since 2014, biannual meetings have led to the design of four successive versions of a monogenic epilepsy gene panel (PAGEM), increasing from 68 to 144 genes. A total of 4035 index cases with epileptic disorders have been analyzed with a diagnostic yield of 31% (n = 1265/4035). The top 10 genes, S CN1A, KCNQ2, STXBP1, SCN2A, SCN8A, PRRT2 , PCDH19, KCNT1, SYNGAP1 , and GRIN2A, account for one-sixth of patients and half of the diagnoses provided by the PAGEM. These results suggest that a gene-panel approach is an efficient first-tier test for the genetic diagnosis of Mendelian epileptic disorders. In a near future, French patients with "drug-resistant epilepsies with seizure-onset in the first two-years of life" can benefit from whole-genome sequencing (WGS), as a second line genetic screening with the implementation of the 2025 French Genomic Medicine Plan. The EPIGENE network has also promoted scientific collaborations on genetic epilepsies within CRéER. [ABSTRACT FROM AUTHOR]

Le phénotype érythrocytaire Emm- a été décrit en 1973 mais reste l'un des derniers groupes sanguins de base génétique inconnue (antigène de prévalence élevée de la série 901). Il avait été proposé qu'Emm serait porté par une protéine ancrée à la membrane du globule rouge (GR) par un glycosylphosphatidylinositol (GPI) car l'expression de cet antigène est fortement réduite dans les GRs de patients atteints d'hémoglobinurie paroxystique nocturne (HPN). Cette maladie est causée par des mutations somatiques du gène PIGA , impliqué dans la synthèse du GPI. En utilisant une approche génomique basée sur le séquençage d'exome chez 3 rarissimes individus Emm- (dont le cas index), nous avons identifié des mutations homozygotes sur un gène commun impliqué dans la synthèse du GPI, PIGG. En utilisant l'approche Crispr/Cas-9, nous avons développé des lignées cellulaires déficientes pour plusieurs gènes PIGs impliqués dans la synthèse et le trafic des protéines ancrées au GPI. L'analyse de ces cellules par cytométrie en flux et western blot en utilisant un anticorps anti-Emm a montré que Emm est porté par un GPI libre et que l'épitope est formé par le 2e et 3e éthanolamine du squelette du GPI. Nous avons montré que l'anticorps anti-Emm détecte parfaitement les défauts de synthèse du GPI, causés par des mutations germinales dans les gènes PIGs et responsables de pathologies neurologiques sévères. Il est à noter que le cas index était atteint d'un déficit intellectuel et que l'absence de PIGG semble donc être associée à des troubles du développement du système nerveux central. Ce travail a permis d'établir Emm comme un nouveau système de groupe sanguin chez l'Homme (n°42, ISBT 2020) (Fig. 1). [ABSTRACT FROM AUTHOR]