A study of incidence, causative factors, symptoms, and prognosis in epilepsy with onset in the first two years of life

Background: The motivation to start this thesis work came from the meetings with infants just having presented with epileptic seizures and from speaking to their parents. I found two issues to be particularly urgent. The first was to give the parents, and myself, an overall map of the situation. A map that had to address questions like: What are the implications of the seizures in this specific infant? What should be done next? What are the alternative future scenarios and their respective probabilities? When the population-based studies in this thesis started, the knowledge-base to answer such questions was poor, studies were few and the numbers of infants studied were small. The second issue concerned the cause of disease in the individual child. For decades the cause of epilepsy has been revealed in only a minority of cases. Especially in severe disease, like drug-resistant epilepsy, not knowing the cause places a heavy psychological burden on the family. In addition, treatment will be symptomatic, not directed at the (unknown) disease mechanisms and often ineffective. Methods: Two circumstances offered the opportunity to deal with these issues. The Stockholm Incidence Registry of Epilepsy (SIRE) registered all new cases of epilepsy in the Northern Stockholm region from September 2001 and onwards. All children with epilepsy in this area are managed at the Karolinska University Hospital. This provides a population-based perspective, which is the best way to study a disease and all aspects of it including etiology, clinical characteristics, and outcome. The other favorable condition was the development of genetic diagnostics, in particular massively parallel DNA sequencing, where Science for Life Laboratory was very early to establish whole exome and whole genome sequencing for both research and clinical healthcare purposes, in a close collaboration between the Clinical Genomic facility and the Karolinska University Laboratory. Results: The population-based studies of this thesis include 116 children with onset of epilepsy during the first 2 years of life. A majority of the cases could be assigned to an epilepsy syndrome and have the etiology revealed. Massively parallel sequencing contributed substantially to reveal genetic etiologies. About half of the children were diagnosed with intellectual disability and half of the cases were in seizure remission for 2 years or longer at age 7 years. Type of etiology is the main predictor of outcome. Two new disease genes, closely related and both with a central role in neuronal inhibition-excitation, were uncovered and described as part of the thesis. Significance: Together with a few other recent population-based studies, this thesis contributes to a firm knowledge-base when managing infants with epilepsy and counselling their parents. The important role of massively parallel DNA sequencing in revealing monogenic etiologies in early onset epilepsy has been clearly shown. In addition to enabling genetic counselling and prenatal diagnostics, the inclusion of genetic diagnostics in the work-up of children with epilepsy, will henceforth further the development of more effective and even curative precision medicine treatments of epilepsy

Case report: Fatal outcome of pyridoxine-dependent epilepsy presenting as respiratory distress followed by a circulatory collapse

Pyridoxine-dependent epilepsy is a rare autosomal recessive disease usually associated with neonatal seizures that do not respond to common antiseizure medications but are controlled by pyridoxine administration. Because the symptoms can mimic common neonatal disorders, the diagnosis can be initially missed or delayed. We report a fatal case of a boy who was initially diagnosed with respiratory distress, birth asphyxia, and persistent pulmonary hypertension and whose condition rapidly deteriorated during the first day of life

Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome

Mutations in PNPO are a known cause of neonatal onset seizures that are resistant to pyridoxine but responsive to pyridoxal phosphate (PLP). Mills etal. show that PNPO mutations can also cause neonatal onset seizures that respond to pyridoxine but worsen with PLP, as well as PLP-responsive infantile spasm

Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease

International audienceWe investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi–Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64–25.71) compared with controls (median: 0.93, IQR: 0.57–1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context

Fronto-parietal connection asymmetry regulates working memory distractibility

Recent functional magnetic resonance imaging studies demonstrate that increased taskrelated neural activity in parietal and frontal cortex during development and training is positively correlated with improved visuospatial working memory (vsWM) performance. Yet, the analysis of the corresponding underlying functional reorganization of the frontoparietal network has received little attention. Here, we perform an integrative experimental 567 568 Edin et al. and computational analysis to determine the effective balance between the superior frontal sulcus (SFS) and intraparietal sulcus (IPS) and their putative role(s) in protecting against distracters. To this end, we performed electroencephalographic (EEG) recordings during a vsWM task. We utilized a biophysically based computational cortical network model to analyze the effects of different neural changes in the underlying cortical networks on the directed transfer function (DTF) and spiking activity. Combining a DTF analysis of our EEG data with the DTF analysis of the computational model, a directed strong SFS → IPS network was revealed. Such a configuration offers protection against distracters, whereas the opposite is true for strong IPS → SFS connections. Our results therefore suggest that the previously demonstrated improvement of vsWM performance during development could be due to a shift in the control of the effective balance between the SFS-IPS networks

Unraveling GRIA1 neurodevelopmental disorders: Lessons learned from the p.(Ala636Thr) variant

Ionotropic glutamate receptors (iGluRs), specifically α-amino-3-hydroxy-5-methyl-4-isoxazole propi-onic acid receptors (AMPARs), play a crucial role in orchestrating excitatory neurotransmission in the brain. AMPARs are intricate assemblies of subunits encoded by four paralogous genes: GRIA1-4. Functional studies have established that rare GRIA variants can alter AMPAR currents leading to a loss- or gain-of-function. Patients affected by rare heterozygous GRIA variants tend to have family specific variants and only few recurrent variants have been reported. We deep-phenotyped a cohort comprising eight unrelated children and adults, harboring a recurrent and well-established disease-causing GRIA1 variant (NM_001114183.1: c.1906G>A, p.(Ala636Thr)). Recurrent symptoms in-cluded motor and/or language delay, mild-severe intellectual disability, behavioral and psychiatric comorbidities, hypotonia and epilepsy. We also report challenges in social skills, autonomy, living and work situation, and occupational levels. Furthermore, we compared their clinical manifestations in relation to those documented in patients presenting with rare heterozygous variants at analogous positions within paralogous genes. This study provides unprecedented details on the neurodevelop-mental outcomes, cognitive abilities, seizure profiles, and behavioral abnormalities associated with p.(Ala636Thr) refining and broadening the clinical phenotype

SLC25A22 is a novel gene for migrating partial seizures in infancy

ObjectiveTo identify a genetic cause for migrating partial seizures in infancy (MPSI).MethodsWe characterized a consanguineous pedigree with MPSI and obtained DNA from affected and unaffected family members. We analyzed single nucleotide polymorphism 500K data to identify regions with evidence of linkage. We performed whole exome sequencing and analyzed homozygous variants in regions of linkage to identify a candidate gene and performed functional studies of the candidate gene SLC25A22.ResultsIn a consanguineous pedigree with 2 individuals with MPSI, we identified 2 regions of linkage, chromosome 4p16.1-p16.3 and chromosome 11p15.4-pter. Using whole exome sequencing, we identified 8 novel homozygous variants in genes in these regions. Only 1 variant, SLC25A22 c.G328C, results in a change of a highly conserved amino acid (p.G110R) and was not present in control samples. SLC25A22 encodes a glutamate transporter with strong expression in the developing brain. We show that the specific G110R mutation, located in a transmembrane domain of the protein, disrupts mitochondrial glutamate transport.InterpretationWe have shown that MPSI can be inherited and have identified a novel homozygous mutation in SLC25A22 in the affected individuals. Our data strongly suggest that SLC25A22 is responsible for MPSI, a severe condition with few known etiologies. We have demonstrated that a combination of linkage analysis and whole exome sequencing can be used for disease gene discovery. Finally, as SLC25A22 had been implicated in the distinct syndrome of neonatal epilepsy with suppression bursts on electroencephalogram, we have expanded the phenotypic spectrum associated with SLC25A22