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INTERNEURONOPATHIES AND THEIR ROLE IN EARLY LIFE EPILEPSIES AND NEURODEVELOPMENTAL DISORDERS.

ABSTRACT: GABAergic interneurons control the neural circuitry and network activity in the brain. The advances in genetics have identified genes that control the development, maturation and integration of GABAergic interneurons and implicated them in the pathogenesis of epileptic encephalopathies or neurodevelopmental disorders. For example, mutations of the Aristaless-Related homeobox X-linked gene (ARX) may result in defective GABAergic interneuronal migration in infants with epileptic encephalopathies like West syndrome (WS), Ohtahara syndrome or X-linked lissencephaly with abnormal genitalia (XLAG). The concept of "interneuronopathy", i.e. impaired development, migration or function of interneurons, has emerged as a possible etiopathogenic mechanism for epileptic encephalopathies. Treatments that enhance GABA levels, may help seizure control but do not necessarily show disease modifying effect. On the other hand, interneuronopathies can be seen in other conditions in which epilepsy may not be the primary manifestation, such as autism. In this review, we plan to outline briefly the current state of knowledge on the origin, development, and migration and integration of GABAergic interneurons, present neurodevelopmental conditions, with or without epilepsy, that have been associated with interneuronopathies and discuss the evidence linking certain types of interneuronal dysfunction with epilepsy and/or cognitive or behavioral deficits.

SUBMITTER: Katsarou AM

PROVIDER: S-EPMC5650248 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceEarly-life epilepsies are often a consequence of numerous neurodevelopmental disorders, most of which are proving to have genetic origins. The role of genetic testing in the initial evaluation of these epilepsies is not established.ObjectiveTo provide a contemporary account of the patterns of use and diagnostic yield of genetic testing for early-life epilepsies.Design, setting, and participantsIn this prospective cohort, children with newly diagnosed epilepsy with an onset at less than 3 years of age were recruited from March 1, 2012, to April 30, 2015, from 17 US pediatric hospitals and followed up for 1 year. Of 795 families approached, 775 agreed to participate. Clinical diagnosis of the etiology of epilepsy were characterized based on information available before genetic testing was performed. Added contributions of cytogenetic and gene sequencing investigations were determined.ExposuresGenetic diagnostic testing.Main outcomes and measuresLaboratory-confirmed pathogenic variant.ResultsOf the 775 patients in the study (367 girls and 408 boys; median age of onset, 7.5 months [interquartile range, 4.2-16.5 months]), 95 (12.3%) had acquired brain injuries. Of the remaining 680 patients, 327 (48.1%) underwent various forms of genetic testing, which identified pathogenic variants in 132 of 327 children (40.4%; 95% CI, 37%-44%): 26 of 59 (44.1%) with karyotyping, 32 of 188 (17.0%) with microarrays, 31 of 114 (27.2%) with epilepsy panels, 11 of 33 (33.3%) with whole exomes, 4 of 20 (20.0%) with mitochondrial panels, and 28 of 94 (29.8%) with other tests. Forty-four variants were identified before initial epilepsy presentation. Apart from dysmorphic syndromes, pathogenic yields were highest for children with tuberous sclerosis complex (9 of 11 [81.8%]), metabolic diseases (11 of 14 [78.6%]), and brain malformations (20 of 61 [32.8%]). A total of 180 of 446 children (40.4%), whose etiology would have remained unknown without genetic testing, underwent some testing. Pathogenic variants were identified in 48 of 180 children (26.7%; 95% CI, 18%-34%). Diagnostic yields were greater than 15% regardless of delay, spasms, and young age. Yields were greater for epilepsy panels (28 of 96 [29.2%]; P < .001) and whole exomes (5 of 18 [27.8%]; P = .02) than for chromosomal microarray (8 of 101 [7.9%]).Conclusions and relevanceGenetic investigations, particularly broad sequencing methods, have high diagnostic yields in newly diagnosed early-life epilepsies regardless of key clinical features. Thorough genetic investigation emphasizing sequencing tests should be incorporated into the initial evaluation of newly presenting early-life epilepsies and not just reserved for those with severe presentations and poor outcomes.

Project description:BackgroundNeurodevelopmental disorders (NDDs), including intellectual disability, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD), are pervasive, lifelong disorders for which pharmacological interventions are not readily available. Substantial increases in the prevalence of NDDs over a relatively short period may not be attributed solely to genetic factors and/or improved diagnostic criteria. There is now a consensus that multiple genetic loci combined with environmental risk factors during critical periods of neurodevelopment influence NDD susceptibility and symptom severity. Organophosphorus (OP) pesticides have been identified as potential environmental risk factors. Epidemiological studies suggest that children exposed prenatally to the OP pesticide chlorpyrifos (CPF) have significant mental and motor delays and strong positive associations for the development of a clinical diagnosis of intellectual delay or disability, ADHD, or ASD.MethodsWe tested the hypothesis that developmental CPF exposure impairs behavior relevant to NDD phenotypes (i.e., deficits in social communication and repetitive, restricted behavior). Male and female rat pups were exposed to CPF at 0.1, 0.3, or 1.0 mg/kg (s.c.) from postnatal days 1-4.ResultsThese CPF doses did not significantly inhibit acetylcholinesterase activity in the blood or brain but significantly impaired pup ultrasonic vocalizations (USV) in both sexes. Social communication in juveniles via positive affiliative 50-kHz USV playback was absent in females exposed to CPF at 0.3 mg/kg and 1.0 mg/kg. In contrast, this CPF exposure paradigm had no significant effect on gross locomotor abilities or contextual and cued fear memory. Ex vivo magnetic resonance imaging largely found no differences between the CPF-exposed rats and the corresponding vehicle controls using strict false discovery correction; however, there were interesting trends in females in the 0.3 mg/kg dose group.ConclusionsThis work generated and characterized a rat model of developmental CPF exposure that exhibits adverse behavioral phenotypes resulting from perinatal exposures at levels that did not significantly inhibit acetylcholinesterase activity in the brain or blood. These data suggest that current regulations regarding safe levels of CPF need to be reconsidered.

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INTERNEURONOPATHIES AND THEIR ROLE IN EARLY LIFE EPILEPSIES AND NEURODEVELOPMENTAL DISORDERS.

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