KCNQ2 R144 variants cause neurodevelopmental disability with language impairment and autistic features without neonatal seizures through a gain-of-function mechanism

Prior studies have revealed remarkable phenotypic heterogeneity in KCNQ2-related disorders, correlated with effects on biophysical features of heterologously expressed channels. Here, we assessed phenotypes and functional properties associated with KCNQ2 missense variants R144W, R144Q, and R144G. We also explored in vitro blockade of channels carrying R144Q mutant subunits by amitriptyline

<i>GRIN2A</i>-related disorders:genotype and functional consequence predict phenotype

Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals. The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. We found that pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+LBD) and null variants led to less severe developmental phenotypes, which we confirmed in a discovery (P = 10-6) as well as validation cohort (P = 0.0003). Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+LBD exclusively caused NMDAR loss-of-function. With respect to null variants, we show that Grin2a+/- cortical rat neurons also had reduced NMDAR function and there was no evidence of previously postulated compensatory overexpression of GluN2B. We demonstrate that null variants and misATD+LBD of GRIN2A do not only share the same clinical spectrum (i.e. milder phenotypes), but also result in similar electrophysiological consequences (loss-of-function) opposing those of misTMD+Linker (severe phenotypes; predominantly gain-of-function). This new pathomechanistic model may ultimately help in predicting phenotype severity as well as eligibility for potential precision medicine approaches in GRIN2A-related disorders

Devenir après trois ans d'évolution de nourrissons hospitalisés pour un premier épisode convulsif sans étiologie identifiée survenant entre l'âge de 3 mois et 2 ans

LYON1-BU Santé (693882101) / SudocSudocFranceF

Etiologies des spasmes infantiles (panorama actuel et discussion de la démarche diagnostique)

LYON1-BU Santé (693882101) / SudocSudocFranceF

Early-onset epileptic encephalopathy with migrating focal seizures associated with a FARS2 homozygous nonsense variant

International audienceEpilepsy of infancy with migrating focal seizures (EIMFS) is now a well-recognized early-onset syndrome included in the ILAE classification of the epilepsies. KCNT1 gain-of-function variants are identified in about half of patients. In the remaining cases, the underlying genetic component is far more heterogeneous with sporadic mutations occasionally reported in SCN1A, SCN2A, SLC12A5, TBC1D24, PLCB1, SLC25A22, and KCNQ2. Here, we report, for the first time, a homozygous deleterious variant in the FARS2 gene, identified using a 115-gene panel for monogenic epilepsies, in a patient with EIMFS. This boy was the second child born to healthy consanguineous parents. The first seizures occurred at six weeks of age. The patient rapidly developed severe epilepsy with focal discharges on EEG, migrating from one brain region to another, highly suggestive of EIMFS. At five months of age, he had daily multifocal clonic seizures and erratic myoclonic fits, which were not consistently related to spikes or spike-and-wave discharges. Neurological status was severely abnormal from onset and the patient died at 10 months of age from respiratory distress. Using the gene panel, a homozygous missense variant of FARS2 was identified, at Chr6 (GRCh37):g.5404829C>T, c.667C>T (NM₀01318872.1), inherited from both parents, leading to an arginine-to-cysteine substitution, p.(Arg223Cys). FARS2 is a member of the mitochondrial aminoacyl tRNA transferase (ARS) enzymes. ARS variants are increasingly recognized causes of early-onset epileptic and neurodevelopmental encephalopathies, however, the associated epileptic phenotype is not completely described. This case shows that FARS2-related seizures can mimic EIMFS in the early stage of the disease. Furthermore, in the setting of migrating focal seizures of infancy, FARS2 should be considered as a further candidate gene, and increased lactate level and occurrence of refractory myoclonic seizures are possible key features to suspect FARS deficiency

Exceptional verbal intelligence after hemispherotomy in a child with Rasmussen encephalitis

International audienceWe report a longitudinal case study of a left-handed girl who underwent left hemispherotomy at 7 years for Rasmussen encephalitis (RE). Presurgical evaluation showed mild hemiparesis, no visual defect, and light neuropsychological impairment with short-term memory weakness. Language fMRI showed a right hemispheric dominance. Postoperatively, the patient exhibited right hemiplegia and hemianopsia but preserved intellectual capacities. She became seizure-free, and antiepileptic medication was discontinued. Long-term follow-up showed very high verbal intelligence at 11 years of age (VCI of 155) and improvement in working memory as well as language and reading abilities. Furthermore, a significant visuoverbal discrepancy became increasingly pronounced. Thus, early surgical treatment of epilepsy avoided the global cognitive deterioration usually associated with RE. Finally, such a high level of verbal functioning combined with low spatial reasoning with a single hemisphere provides additional information on the neurocognitive profile of children with RE after hemispherotomy

A New Observation of an Atypical and Severe Variant of the Guillain-Barre Syndrome in a Child

Guillain-Barré syndrome is a rare acute polyradiculoneuropathy. Several variants and unusual presentations have been described, particularly in pediatrics. In most cases, making an early diagnosis is challenging due to the treatments that consist in the rapid administration of intravenous immunoglobulin or plasma exchange. The authors present the case of a 7-year-old boy with an atypical and severe axonal Guillain-Barré syndrome, associated with Mycoplasma pneumonia . When he was admitted, febrile respiratory failure was the main focus, and then he presented signs of acute polyneuropathy with cranial nerve palsy and brief hyperreflexia. Mechanical ventilation was required for 48 days as well as 2 cycles of intravenous immunoglobulin. The authors describe all the medical challenges that the authors encountered. This case highlights the fact that respiratory distress can be the main clinical symptom in children. This delays the establishment of a correct diagnosis, even more so when neurological manifestations are abundant and unusual

Prenatal diagnosis of 'isolated' Dandy-Walker malformation: imaging findings and prenatal counselling.

International audienceOBJECTIVE: The purpose of this article is to improve prenatal imaging diagnosis and counselling for cases of 'isolated' Dandy-Walker malformation (DWM) in the light of recent literature, which has demonstrated a potential good clinical and intellectual outcome of fetuses presenting with DWM characterised by partial vermian agenesis (identification of two fissures and three lobes) and absence of associated anatomical anomalies. METHODS: This is a retrospective observational study of six consecutive prenatal cystic posterior fossa malformations, diagnosed as DWM, encountered in a national reference centre for posterior fossa malformations over a 2-year period. RESULTS: In all cases, DWM was diagnosed as isolated (without any associated central nervous system or extra-central nervous system malformations and normal standard karyotype). Despite good-quality imaging, including fetal magnetic resonance imaging (MRI), prenatal analysis of the vermis was impossible because of limited identification of fissuration and lobulation. In three cases, a cytogenetic anomaly was found, including 6p subtelomeric deletion (n = 2) and partial 4 qter deletion associated with partial 7p trisomy (n = 1). One fetus with 6p deletion was terminated. In four of the five postnatal cases, MRI confirmed the diagnosis of DWM but provided only limited information for vermian analysis. In one case, postnatal MRI showed a large Blake's pouch cyst with rotated but complete vermis associated with a marked mass effect on the distal part of the tentorium. Of the four babies born with postnatal diagnosis of DWM, all required ventriculoperitoneal shunting because of early postnatal hydrocephalus. CONCLUSION: When fetal MRI is necessary to exclude additional cerebral lesions in the diagnosis of DWM, we highlight the inaccuracy of magnetic resonance for anatomical analysis of the vermis. We also emphasise the potential high incidence of subtelomeric anomalies in isolated DWM, especially 6p deletion. In the postnatal period, paediatricians should look for postnatal hydrocephalus even if the ventricular size is normal or slightly dilated on prenatal imaging

Ring 14 chromosome presenting as early-onset isolated partial epilepsy.

International audienceWe report four infants (two males, two females) with ring 14 chromosome presenting with early-onset partial epilepsy. The first seizure occurred between 3 and 6 months (3, 3, 4, and 6mo respectively). In all four cases, diagnosis was based on early focal seizures, rather than on psychomotor retardation or morphological features, which were not prominent at seizure onset. Moreover, despite the young age of the patients and the high frequency of seizures, neither epileptic spasms nor progression to 'epileptic encephalopathy', such as hypsarrhythmia, were observed. Epilepsy remained partial in these patients. At the most recent follow-up, all four children had slight or mild psychomotor delay, and two of them had moderate non-specific dysmorphic traits. Data from the literature about epilepsy in ring 14 chromosome syndrome were also reviewed. Ring 14 chromosome syndrome may be revealed by isolated, early-onset focal epilepsy suggestive of focal lesions with only mild mental retardation and morphological features at the time of diagnosis. The characteristics of these observations differ from classic ring 14 syndrome, and may enlarge this clinical spectrum. Many unanswered questions remain concerning phenotype-genotype correlation and identification of the potential genes and molecular mechanisms responsible for epilepsy in patients with ring 14 syndrome

Homozygous TBC1D24 mutation in two siblings with familial infantile myoclonic epilepsy (FIME) and moderate intellectual disability

International audienceMutations in the TBC1D24 gene were first reported in an Italian family with a unique epileptic phenotype consisting of drug-responsive, early-onset idiopathic myoclonic seizures. Patients presented with isolated bilateral or focal myoclonia, which could evolve to long-lasting attacks without loss of consciousness, with a peculiar reflex component, and were associated with generalized tonic—clonic seizures. This entity was named ''familial infantile myoclonic epilepsy'' (FIME). More recently, TBC1D24 mutations have been shown to cause a variable range of disorders, including epilepsy of various seizure types and severity, non-syndromic deafness, and DOORS syndrome. We report on the electro-clinical features of two brothers, born to first-cousin parents, affected with infantile-onset myoclonic epilepsy. The peculiar epileptic presentation prompted us to perform direct sequencing of the TBC1D24 gene. The patients had very early onset of focal myoclonic fits with variable topography, lasting a few minutes to several hours, without loss of consciousness, which frequently evolved to generalized myoclonus or myoclonic status. Reflex myoclonia were noticed in one patient. Neurological outcome was marked by moderate intellectual disability. Despite the high frequency of seizures, repeated EEG recordings showed normal background rhythm and rare interictal spikes and waves. We found a homozygous missense mutation , c.457G>A/p.Glu153Lys, in the two affected brothers. This observation combined with recent data from the literature, suggest that mutations in TBCD24 cause a pathological continuum, with FIME at the ''benign'' end and severe drug-refractory epileptic encephalopathy on the severe end. Early-onset myoclonic epilepsy with focal and generalized myoclonic seizures is a common characteristic of this continuum