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In SCN2A-related disorders, there is an urgent demand to establish efficient methods for determining the gain- (GoF) or loss-of-function (LoF) character of variants, to identify suitable candidates for precision therapies. Here we classify clinical phenotypes of 179 individuals with 38 recurrent SCN2A variants as early-infantile or later-onset epilepsy, or intellectual disability/autism spectrum disorder (ID/ASD) and assess the functional impact of 13 variants using dynamic action potential clamp (DAPC) and voltage clamp. Results show that 36/38 variants are associated with only one phenotypic group (30 early-infantile, 5 later-onset, 1 ID/ASD). Unexpectedly, we revealed major differences in outcome severity between individuals with the same variant for 40% of early-infantile variants studied. DAPC was superior to voltage clamp in predicting the impact of mutations on neuronal excitability and confirmed GoF produces early-infantile phenotypes and LoF later-onset phenotypes. For one early-infantile variant, the co-expression of the alpha(1) and beta(2) subunits of the Na(v)1.2 channel was needed to unveil functional impact, confirming the prediction of 3D molecular modeling. Neither DAPC nor voltage clamp reliably predicted phenotypic severity of early-infantile variants. Genotype, phenotypic group and DAPC are accurate predictors of the biophysical impact of SCN2A variants, but other approaches are needed to predict severity.A comprehensive biophysical analysis of disease-associated mutations in the voltage-gated sodium channel gene, SCN2A, suggests that dynamic action potential clamp may be a better predictor than voltage clamp of how these mutations alter neuronal excitability, though other approaches are needed to predict severity.

Background: Self-limited (familial) infantile epilepsy (S(F)IE), formerly known as benign (familial) infantile convulsions (13(F)1C), is an infantile cluster epilepsy with in rule a complete recovery. This form of epilepsy is most often caused by variations in the PRRT2 gene (OMIM #605751). Aim: To describe the clinical and genetic spectrum of sudden onset clusters of focal seizures in infancy. Methods: We retrospectively reviewed all individuals, who presented with unprovoked infantile seizures and selected all infants who had unprovoked clustered focal seizures between 1 and 20 months of age. We described the clinical and genetic spectrum of this cohort. Results: The data of 23 patients from 21 families were collected. All had an initial diagnosis of S(F)IE which was adjusted in 5 individuals. In 12 individuals a pathogenic variation in PRRT2 gene or complete deletion was identified. Pathogenic variants in PCDHI9 and KCNQ2 were found in respectively 3 and 1 individuals. One individual had a non-pathogenic variant in ATP1A3 and in 6 others no variants were identified. The mean cluster duration was 2.9 days (range 1-13) (see Table 1). Twelve infants had only one cluster. All patients had focal motor or non-motor seizures, in 12 (52%) followed by bilateral (tonic) clonic seizures. Positive family history was present in 74% of individuals. In 11/12 (92%) tested families, >= 1 family member carried the pathogenic PRRT2 variant. Age of seizure onset (ASO) averaged 6.2 months (range 2-20 months). Age of latest seizure averaged 16 months (range 2-92). In several interictal EEG (electroencephalogram) recordings multifocal spikes or spike-wave abnormalities were detected. Ictal EEG recordings detected primary focal abnormalities. Conclusion: We described 23 individuals with unprovoked cluster(s) of focal seizures at infancy. It appears to be a heterogeneous group. Half of them had a pathogenic variation in PRRT2 gene. Most had only one cluster of seizures. When clusters reoccur frequently, when seizures are more therapy-resistant and when seizures persist beyond the age of 2 years, another diagnosis or causative gene is likely. (C) 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Seizures are a reflection of acute brain injury in the neonatal period, and status epilepticus reflects a state of high seizure burden. Neonatal status epilepticus has been reported in 8 to 43% of newborns with seizures. There is no separate definition for neonatal status epilepticus, and it has been commonly defined as a continuous seizure lasting at least 30 minutes and/or a series of seizures whose total duration exceeds 50% of a given epoch. The causes of status epilepticus in the neonatal period mirror the causes of neonatal seizures. It is symptomatic, usually associated with hypoxic–ischemic encephalopathy, inherited metabolic disorders, infections, and cerebral hemorrhage. Management guidelines are not separately outlined for neonatal status epilepticus and are commonly derived from the recommendations for neonatal and infantile seizures. The presence of neonatal status epilepticus significantly increases the odds for development of cerebral palsy, global developmental delay, and epilepsy later in life. Further research is needed into the role of current antiepileptic drugs in causing neuronal injury and use of neuroprotective agents during neonatal status epilepticus.

Febrile seizures (FS) are nosological entities that affect 2–5% of children aged 6 months to 5 years. In most cases, these seizures are isolated or sporadic; they are defined as simple febrile seizures. However, a febrile seizure that lasts more than 15 min, which has focal signs, or that recurs within 24 h is defined as “complex” febrile seizure. Prolonged febrile seizure (PFS) is therefore a particular type of complex febrile seizure. In case the duration exceeds 30 min, the more appropriate definition is febrile status epilepticus (FSE).

Hereditary hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal recessive disease caused by mutations in the transient receptor potential melastatin 6 (TRPM6) gene. Affected individuals present in early infancy with seizures caused by the severe hypocalcemia and hypomagnesemia. By presenting this case report, we also aimed to highlight the need for molecular genetic analysis in inbred or familial cases with hypomagnesemia. A Turkish inbred girl, now aged six years, had presented to another hospital at age two months with seizures diagnosed to be due to hypomagnesemia. She was on magnesium replacement therapy when she was admitted to our clinic with complaints of chronic diarrhea at age 3.6 years. During her follow-up in our clinic, she showed an age-appropriate physical and neurological development. In molecular genetic analysis, a novel homozygous frame-shift mutation (c.3447delT>p.F1149fs) was identified in the TRPM6 gene. This mutation leads to a truncation of the TRPM6 protein, thereby complete loss of function. We present the clinical follow-up findings of a pediatric HSH case due to a novel mutation in the TRPM6 gene and highlight the need for molecular genetic analysis in inbred or familial cases with hypomagnesemia.

Advances in gene discovery for neurodevelopmental disorders have identified SCN2A dysfunction as a leading cause of infantile seizures, autism spectrum disorder, and intellectual disability. SCN2A encodes the neuronal sodium channel NaV1.2. Functional assays demonstrate strong correlation between genotype and phenotype. This insight can help guide therapeutic decisions and raises the possibility that ligands that selectively enhance or diminish channel function may improve symptoms. The well-defined function of sodium channels makes SCN2A an important test case for investigating the neurobiology of neurodevelopmental disorders more generally. Here, we discuss the progress made, through the concerted efforts of a diverse group of academic and industry scientists as well as policy advocates, in understanding and treating SCN2A-related disorders.

Background Benign infantile seizures are a common form of idiopathic seizures in infants, but infrequently reported. Case characteristics Four cases identified over a 9-month period. Observation All had a cluster of focal seizures, normal development and no abnormality on hematological and biochemical work-up. Outcome No recurrence of seizures over a follow-up of 5 to 9 months. Message Identification of this syndrome has important therapeutic and prognostic implications.

Background Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals.Methods Through a search of available case studies and communication with collaborators, we identified families that included at least one individual with at least three of the five main features of the DOORS syndrome: deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. Participants were recruited from 26 centres in 17 countries. Families described in this study were enrolled between Dec 1, 2010, and March 1, 2013. Collaborating physicians enrolling participants obtained clinical information and DNA samples from the affected child and both parents if possible. We did whole-exome sequencing in affected individuals as they were enrolled, until we identified a candidate gene, and Sanger sequencing to confirm mutations. We did expression studies in human fibroblasts from one individual by real-time PCR and western blot analysis, and in mouse tissues by immunohistochemistry and real-time PCR.Findings 26 families were included in the study. We did whole-exome sequencing in the first 17 enrolled families; we screened for TBC1D24 by Sanger sequencing in subsequent families. We identified TBC1D24 mutations in 11 individuals from nine families (by exome sequencing in seven families, and Sanger sequencing in two families). 18 families had individuals with all five main features of DOORS syndrome, and TBC1D24 mutations were identified in half of these families. The seizure types in individuals with TBC1D24 mutations induded generalised tonic-donic, complex partial, focal clonic, and infantile spasms. Of the 18 individuals with DOORS syndrome from 17 families without TBC1D24 mutations, eight did not have seizures and three did not have deafness. In expression studies, some mutations abrogated TBC1D24 mRNA stability. We also detected Tbc1d24 expression in mouse phalangeal chondrocytes and calvaria, which suggests a role of TBC1D24 in skeletogenesis.Interpretation Our findings suggest that mutations in TBC1D24 seem to be an important cause of DOORS syndrome and can cause diverse phenotypes. Thus, individuals with DOORS syndrome without deafness and seizures but with the other features should still be screened for TBC1D24 mutations. More information is needed to understand the cellular roles of TBC1D24 and identify the genes responsible for DOORS phenotypes in individuals who do not have a mutation in TBC1D24.

Seizures in the infant (1 month–1 year) are a common presentation to the paediatrician and paediatric neurologists. Seizure semiology includes several seizure types. The phenotypes of the seizures are important to recognize to guide investigations and management. The multiple electro-clinical syndromes with many different causes make this a challenging group to investigate and manage. The epileptic encephalopathies are the group with refractory epilepsy with particularly poor prognosis. In contrast to this, are the benign infantile seizures with relatively good prognosis. Magnetic resonance imaging and the availability of detailed genetic investigations, has shed light on these complex group of epilepsies. The therapeutic options include anti-epileptic drugs and ketogenic diet. Surgical treatment is reserved for the few children where focus of the seizure is proved by detailed investigations. This review article focuses on the various infantile epilepsy syndromes, underlying aetiology, an approach to clinical diagnoses, investigations and management, useful for a paediatrician and paediatric neurologists.

Provoked seizures are a common pediatric problem and can be caused by multiple etiologies. However, there have been few reports of benign infantile seizures associated with gastrointestinal tract abnormality. We report on a 3-month-old male infant who presented with multiple afebrile seizures, EEG abnormalities and a midgut malrotation. Surgical treatment of the malrotation resulted in seizure resolution and EEG normalization. This case emphasizes that patients presenting with multiple seizures and symptoms of gastroenteritis should be evaluated for abnormalities of the gastrointestinal tract.

Familial progressive hyper- and hypopigmentation (FPHH) is characterized by diffuse hyperpigmentation with variable intensity. Cafe'-au-lait macules and larger hypopigmented ash-leaf macules are also present. Herein, we reported a variant case of FPHH. The patient was a two-year-old Chinese girl showing diffuse hyper- and hypopigmented lesions, longitudinal melanonychia in both thumbs, and infantile seizures, without any lentigines.

We report two patients, the first one had benign infantile seizures (BIS) associated with gastroenteritis (BISG), followed by BIS without gastroenteritis, in the second patient BIS was followed by BISG related to anti-rotavirus vaccine. After 12 and 6 months of follow-up, both patients had normal psychomotor development. BISG may be a situation-related seizure, a coincidental entity associated with BIS. However the case evolutions suggested that both BIS and BISG are related syndromes.

Seizure semiology in infants defies the typical characteristics and classification schemata that have been developed for older children and adults. A clear classification system is a necessary first step to facilitate proper diagnosis, choice of treatment, and determination of prognosis. This is an especially challenging task with seizures in infants. A semiologic system based upon simple descriptive terms has been proposed, which the neurologist and pediatrician will recognize as closer to clinical experience.

Mutations in SCN2A cause epilepsy syndromes of variable severity including neonatal-infantile seizures. In one case, we previously described additional childhood-onset episodic ataxia. Here, we corroborate and detail the latter phenotype in three further cases. We describe the clinical characteristics, identify the causative SCN2A mutations and determine their functional consequences using whole-cell patch-clamping in mammalian cells. In total, four probands presented with neonatal-onset seizures remitting after five to 13 months. In early childhood, they started to experience repeated episodes of ataxia, accompanied in part by headache or back pain lasting minutes to several hours. In two of the new cases, we detected the novel mutation p.Arg1882Gly. While this mutation occurred de novo in both patients, one of them carries an additional known variant on the same SCN2A allele, inherited from the unaffected father (p.Gly1522Ala). Whereas p.Arg1882Gly alone shifted the activation curve by -4 mV, the combination of both variants did not affect activation, but caused a depolarizing shift of voltage-dependent inactivation, and a significant increase in Na+ current density and protein production. p.Gly1522Ala alone did not change channel gating. The third new proband carries the same de novo SCN2A gain-of-function mutation as our first published case (p.Ala263Val). Our findings broaden the clinical spectrum observed with SCN2A gain-of-function mutations, showing that fairly different biophysical mechanisms can cause a convergent clinical phenotype of neonatal seizures and later onset episodic ataxia.

Purpose To describe the electro-clinical expression of seizures in infants (1–24 months). Methods We reviewed the video and EEG files of all infantile seizures recorded at Children's Memorial Hospital, Chicago, IL, from 2000 to 2005. Electrographic and clinical features were entered into separate databases. The electrographic component of the database analyzed the predominant location and pattern at onset, the evolution, the termination and the duration of each seizure. The clinical data sheet included 25 items. Each seizure was assigned to a specific category according to its most prominent clinical feature, according to the opinion of both observers. Results Thirteen seizure types were identified. In a significant number of cases, the EEG correlate could not be predicted on the basis of clinical observations only. Generalized seizures were observed, on average, at a later age than focal seizures. Excluding spasms, the mean duration of seizures was short (36 s). Conclusions The results of this study are useful in describing the clinical and electrographic repertoire of infantile seizures. The findings show that video-EEG recordings in infants with frequent, recurrent seizures are useful by fully allowing complete recognition of subtle events, and in fully categorizing the true nature of the ictus. Video-EEG findings and accurate seizure classification may add fundamental information with regards to epilepsy syndrome diagnosis and specific treatment options, including surgery.

The 6th annual meeting of the Infantile Seizure Society (ISS) was held at the Lecture Hall, Tokyo Women’s Medical University in Tokyo, Japan, on March 15 and 16, 2003.The meeting was devoted in its entirety to the International Symposium on Chromosomal Aberrations and Epileptic Syndromes with dual purposes; to approach the delineation of clinico-electrical characteristics of epileptic seizures in association with any particular chromosomal aberration, and to review the current knowledge on the molecular genetic analysis of chromosomal aberrations with frequently associated epileptic seizures. Eleven lectures by invitation and 22 free papers were presented at the meeting. There were about 130 participants including 10 from Europe and North America, and 5 from Asian and Oceanian countries. The next ISS meeting will be held in Tokyo, on April 16 and 17, 2004, with the main theme of “Neuronal Migration Disorders and Childhood Epilepsies–Clinical Manifestations, Pathomechanisms and Epileptogenesis”. Further information is available at the website: http://www.field.gr.jp/ISS

We recently reported mutations in the sodium channel gene SCN2A in two families with benign familial neonatal-infantile seizures (BFNISs). Here, we aimed to refine the molecular-clinical correlation of SCN2A mutations in early childhood epilepsies. SCN2A was analyzed in 2 families with probable BFNIS, 9 with possible BFNIS, 10 with benign familial infantile seizures, and in 93 additional families with various early childhood epilepsies. Mutations effecting changes in conserved amino acids were found in two of two probable BFNIS families, in four of nine possible BFNIS families, and in none of the others. Our eight families had six different SCN2A mutations; one mutation (R1319Q) occurred in three families. BFNIS is an autosomal dominant disorder presenting between day 2 and 7 months (mean, 11.2 +/- 9.2 weeks) with afebrile secondarily generalized partial seizures; neonatal seizures were not seen in all families. The frequency of seizures varied; some individuals had only a few attacks without treatment and others had clusters of many per day. Febrile seizures were rare. All cases remitted by 12 months. Ictal recordings in four subjects showed onset in the posterior quadrants. SCN2A mutations appear specific for BFNIS; the disorder can now be strongly suspected clinically and the families can be given an excellent prognosis.

Purpose We investigated whether benign infantile seizures can be diagnosed in the acute phase. Methods We retrospectively analyzed the medical records of 44 patients initially diagnosed with acute phase benign infantile seizures. All patients were followed for more than 12 months, and we reviewed patients' psychomotor development and presence or absence of seizure recurrence at the last visit. Patients were divided into the following three groups according to the final diagnosis: benign infantile seizures, benign infantile seizures associated with mild gastroenteritis, and non-benign infantile seizures. We defined benign infantile seizures associated with mild gastroenteritis and benign infantile seizures as those associated with normal psychomotor development and no seizure recurrence 3 months after onset of the first seizure, whereas non-benign infantile seizures were associated with delayed psychomotor development and/or seizure recurrence after 3 months of onset of the first seizure. We analyzed the clinical features in the acute phase and compared them between the groups. Results The median age of seizure onset was 7.6 months. A final diagnosis of benign infantile seizures associated with mild gastroenteritis was made in three patients. In the remaining 41 patients, the final diagnosis was benign infantile seizures in 30 (73.2%) and non-benign infantile seizures in 11 (26.8%). In the non-benign infantile seizure group, intellectual disability was diagnosed in eight patients and seizure recurrence in six. There were no significant differences in clinical features between the groups in the acute phase, such as seizure type or seizure duration. Conclusion About 30% of patients initially diagnosed as having benign infantile seizures did not experience a benign clinical course. Our findings suggest that clinical features in the acute phase are not helpful for predicting benign outcomes in benign infantile seizures and that only long-term follow-up can discriminate benign infantile seizures from non-benign infantile seizures.

A benign prognosis has been claimed in benign familial infantile seizures (BFIS). However, few studies have assessed the long-term evolution of these patients. The objective of this study is to describe atypical courses and presentations in BFIS families with mutations in PRRT2 gene. We studied clinically affected individuals from five BFIS Spanish families. We found mutations in PRRT2 in all 5 families. A non-BFIS phenotype or an atypical BFIS course was found in 9/25 (36%) patients harbouring a PRRT2 mutation. Atypical features included neonatal onset, mild hemiparesis, learning difficulties or mental retardation, and recurrent seizures during adulthood. We also report a novel PRRT2 mutation (c.121_122delGT). In BFIS families an atypical phenotype was present in a high percentage of the patients. These findings expand the clinical spectrum of PRRT2 mutations including non-benign epileptic phenotypes.

BACKGROUND: \ud \ud Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals.\ud \ud METHODS: \ud \ud Through a search of available case studies and communication with collaborators, we identified families that included at least one individual with at least three of the five main features of the DOORS syndrome: deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. Participants were recruited from 26 centres in 17 countries. Families described in this study were enrolled between Dec 1, 2010, and March 1, 2013. Collaborating physicians enrolling participants obtained clinical information and DNA samples from the affected child and both parents if possible. We did whole-exome sequencing in affected individuals as they were enrolled, until we identified a candidate gene, and Sanger sequencing to confirm mutations. We did expression studies in human fibroblasts from one individual by real-time PCR and western blot analysis, and in mouse tissues by immunohistochemistry and real-time PCR.\ud \ud FINDINGS: \ud \ud 26 families were included in the study. We did exome sequencing in the first 17 enrolled families; we screened for TBC1D24 by Sanger sequencing in subsequent families. We identified TBC1D24 mutations in 11 individuals from nine families (by exome sequencing in seven families, and Sanger sequencing in two families). 18 families had individuals with all five main features of DOORS syndrome, and TBC1D24 mutations were identified in half of these families. The seizure types in individuals with TBC1D24 mutations included generalised tonic-clonic, complex partial, focal clonic, and infantile spasms. Of the 18 individuals with DOORS syndrome from 17 families without TBC1D24 mutations, eight did not have seizures and three did not have deafness. In expression studies, some mutations abrogated TBC1D24 mRNA stability. We also detected Tbc1d24 expression in mouse phalangeal chondrocytes and calvaria, which suggests a role of TBC1D24 in skeletogenesis.\ud \ud INTERPRETATION: \ud \ud Our findings suggest that mutations in TBC1D24 seem to be an important cause of DOORS syndrome and can cause diverse phenotypes. Thus, individuals with DOORS syndrome without deafness and seizures but with the other features should still be screened for TBC1D24 mutations. More information is needed to understand the cellular roles of TBC1D24 and identify the genes responsible for DOORS phenotypes in individuals who do not have a mutation in TBC1D24.\ud \ud FUNDING: \ud \ud US National Institutes of Health, the CIHR (Canada), the NIHR (UK), the Wellcome Trust, the Henry Smith Charity, and Action Medical Research.

The nosology of early infantile seizures and epilepsy syndromes is controversial. There are two age-related early infantile epileptic encephalopathy syndromes that are characterized by early onset of spasms, a burst-suppression EEG pattern, poor response to treatment, and poor prognosis. This paper examines the early myoclonic epilepsies.

The authors present Japanese siblings of a 6-year-old girl and a 4-year-old boy, who concurrently experienced convulsions with mild gastroenteritis. These siblings, their father and paternal grandfather had afebrile seizures that intermittently occurred without symptoms of gastroenteritis and terminated within a few days at their infancy. An underlying genetic factor might not only cause benign familial infantile seizures but it might also confer the susceptibility to the convulsions with mild gastroenteritis in these siblings.