scholarly journals Modulating effects of FGF12 variants on NaV1.2 and NaV1.6 associated with Developmental and Epileptic Encephalopathy and Autism Spectrum Disorder

2021 ◽  
Author(s):  
Simone Seiffert ◽  
Manuela Pendziwiat ◽  
Tatjana Bierhals ◽  
Himanshu Goel ◽  
Niklas Schwarz ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Sodium Channel ◽  
Neuronal Network ◽  
Case Reports ◽  
Autism Spectrum ◽  
Epileptic Encephalopathy ◽  
Spectrum Disorder ◽  
Network Activity ◽  
Channel Blockers ◽  
Neuronal Network Activity

AbstractObjectiveFibroblast growth factor 12 (FGF12) may represent an important modulator of neuronal network activity and has been associated with developmental and epileptic encephalopathy (DEE). We sought to identify the underlying pathomechanism of FGF12-related disorders.MethodsPatients with pathogenic variants in FGF12 were identified through published case reports, GeneMatcher and whole exome sequencing of own case collections. The functional consequences of two missense variants and two copy number variants (CNVs) were studied by co-expression of wild-type and mutant FGF12 in neuronal-like cells (ND7/23) with the sodium channels NaV1.2 or NaV1.6, including their functional active beta-1 and beta-2 sodium channel subunits (SCN1B and SCN2B).ResultsFour variants in FGF12 were identified for functional analysis: one novel FGF12 variant in a patient with autism spectrum disorder and three variants from previously published patients affected by developmental and epileptic encephalopathy (DEE). We demonstrate the differential regulating effects of wildtype and mutant FGF12 on NaV1.2 and NaV1.6 channels. Here, FGF12 variants lead to a complex kinetic influence on Nav1.2 and Nav 1.6, including loss- as well as gain-of function changes in fast inactivation as well as loss-of function changes in slow inactivation.InterpretationFor the first time, we could demonstrate the detailed regulating effect of FGF12 on NaV1.2 and NaV1.6 and confirmed the complex effect of FGF12 on neuronal network activity. Our findings expand the phenotypic spectrum related to FGF12 variants and elucidate the underlying pathomechanism. Specific variants in FGF12-associated disorders may be amenable to precision treatment with sodium channel blockers.

scholarly journals The Pentapeptide QYNAD Does Not Inhibit Neuronal Network Activity

2005 ◽  
Vol 32 (3) ◽  
pp. 344-348 ◽  
Author(s):  
F. Otto ◽  
B.C. Kieseier ◽  
P. Görtz ◽  
H.-P. Hartung ◽  
M. Siebler
Keyword(s):  
Sodium Channel ◽  
Neuronal Network ◽  
Single Cells ◽  
Network Activity ◽  
Channel Blockers ◽  
Sodium Currents ◽  
Electrode Arrays ◽  
Sodium Channel Blockers ◽  
Neuronal Network Activity ◽  
The Impact

ABSTRACT:Background:Controversial data was published about the sodium channel-blocking effect of the endogenous pentapeptide QYNAD, which is elevated in patients with multiple sclerosis and Guillain-Barré-syndrome. In some experiments with single cells and nerve preparations QYNAD inhibited sodium currents to the same extent as the known sodium channel blocker lidocaine whereas in other laboratory testing QYNAD failed to show any effect at all.Methods:Micro-electrode arrays with cultured neuronal networks are highly suitable to determine neuroactive activity of applied substances. The impact on electrophysiological parameter changes was compared between QYNAD and the established sodium channel blockers lidocaine and tetrodotoxin (TTX).Results:QYNAD did not alter network activity whereas the sodium channel blockers lidocaine (IC50 14.9 µM) and tetrodotoxin (IC50 1.1 nM) reversibly decreased network activity in similar concentrations as in patch-clamp experiments. This decrease of spontaneous electrophysiological activity was achieved by prolonging the interburst-interval.Conclusion:Although QYNAD might have mild effects on single-cell sodium currents, there is no significant effect on neuronal network function. These results raise concerns about QYNAD exhibiting a relevant impact on functional disability of the central nervous system in patients.

scholarly journals Pharmacological intervention to restore connectivity deficits of neuronal networks derived from ASD patient iPSC with a TSC2 mutation

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Mouhamed Alsaqati ◽  
Vivi M. Heine ◽  
Adrian J. Harwood
Keyword(s):  
Neuronal Network ◽  
Electrode Array ◽  
Network Connectivity ◽  
Autism Spectrum ◽  
Network Activity ◽  
Inhibitory Synapses ◽  
Pharmacological Intervention ◽  
Spatial Connectivity ◽  
Neuronal Network Activity

Abstract Background Tuberous sclerosis complex (TSC) is a rare genetic multisystemic disorder resulting from autosomal dominant mutations in the TSC1 or TSC2 genes. It is characterised by hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway and has severe neurodevelopmental and neurological components including autism, intellectual disability and epilepsy. In human and rodent models, loss of the TSC proteins causes neuronal hyperexcitability and synaptic dysfunction, although the consequences of these changes for the developing central nervous system are currently unclear. Methods Here we apply multi-electrode array-based assays to study the effects of TSC2 loss on neuronal network activity using autism spectrum disorder (ASD) patient-derived iPSCs. We examine both temporal synchronisation of neuronal bursting and spatial connectivity between electrodes across the network. Results We find that ASD patient-derived neurons with a functional loss of TSC2, in addition to possessing neuronal hyperactivity, develop a dysfunctional neuronal network with reduced synchronisation of neuronal bursting and lower spatial connectivity. These deficits of network function are associated with elevated expression of genes for inhibitory GABA signalling and glutamate signalling, indicating a potential abnormality of synaptic inhibitory–excitatory signalling. mTORC1 activity functions within a homeostatic triad of protein kinases, mTOR, AMP-dependent protein Kinase 1 (AMPK) and Unc-51 like Autophagy Activating Kinase 1 (ULK1) that orchestrate the interplay of anabolic cell growth and catabolic autophagy while balancing energy and nutrient homeostasis. The mTOR inhibitor rapamycin suppresses neuronal hyperactivity, but does not increase synchronised network activity, whereas activation of AMPK restores some aspects of network activity. In contrast, the ULK1 activator, LYN-1604, increases the network behaviour, shortens the network burst lengths and reduces the number of uncorrelated spikes. Limitations Although a robust and consistent phenotype is observed across multiple independent iPSC cultures, the results are based on one patient. There may be more subtle differences between patients with different TSC2 mutations or differences of polygenic background within their genomes. This may affect the severity of the network deficit or the pharmacological response between TSC2 patients. Conclusions Our observations suggest that there is a reduction in the network connectivity of the in vitro neuronal network associated with ASD patients with TSC2 mutation, which may arise via an excitatory/inhibitory imbalance due to increased GABA-signalling at inhibitory synapses. This abnormality can be effectively suppressed via activation of ULK1.

scholarly journals Pharmacological intervention to restore connectivity deficits of neuronal networks derived from ASD patient iPSCs with a TSC2 mutation

2020 ◽  
Author(s):  
Mouhamed Alsaqati ◽  
Vivi M Heine ◽  
Adrian J. Harwood
Keyword(s):  
Neuronal Network ◽  
Electrode Array ◽  
Network Connectivity ◽  
Autism Spectrum ◽  
Network Activity ◽  
Inhibitory Synapses ◽  
Pharmacological Intervention ◽  
Spatial Connectivity ◽  
Neuronal Network Activity

Abstract Background Tuberous sclerosis complex (TSC) is a rare genetic multisystemic disorder resulting from autosomal dominant mutations in the TSC1 or TSC2 genes. It is characterised by hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway and has severe neurodevelopmental and neurological components including autism, intellectual disability and epilepsy. In human and rodent models, loss of the TSC proteins causes neuronal hyperexcitability and synaptic dysfunction, although the consequences of these changes for the developing central nervous system is currently unclear.MethodsHere we apply Multi-electrode array (MEA)-based assays to study the effects of TSC2 loss on neuronal network activity using Autism Spectrum Disorder (ASD) patient-derived iPSCs. We examine both temporal synchronisation of neuronal bursting, and spatial connectivity between electrodes across the network. Results We find that ASD patient-derived neurons with a functional loss of TSC2, in addition to possessing neuronal hyperactivity, develop a dysfunctional neuronal network with reduced synchronisation of neuronal bursting and lower spatial connectivity. These deficits of network function are associated with elevated expression of genes for inhibitory GABA signalling and glutamate signalling, indicating a potential abnormality of synaptic inhibitory-excitatory signalling. mTORC1 activity functions within a homeostatic triad of protein kinases, mTOR, AMP-dependent protein Kinase 1 (AMPK), and Unc-51 like Autophagy Activating Kinase 1 (ULK1) that orchestrate the interplay of anabolic cell growth and catabolic autophagy while balancing energy and nutrient homeostasis. The mTOR inhibitor rapamycin suppresses neuronal hyperactivity, but does not increase synchronised network activity, whereas activation of AMPK restores some aspects of network activity. In contrast, the ULK1 activator, LYN-1604 increases the network behaviour, shortens the network burst lengths, and reduces the number of uncorrelated spikes.LimitationsAlthough a robust and consistent phenotype is observed across multiple independent iPSC cultures, the results are based on one patient. There may be more subtle differences between patients with different TSC2 mutations or differences of polygenic background within their genomes. This may affect the severity of the network deficit or the pharmacological response between TSC2 patients.ConclusionsOur observations suggest that there is a reduction in the network connectivity of the in vitro neuronal network associated with ASD patients with TSC2 mutation, which may arise via an excitatory/inhibitory imbalance due to increased GABA-signalling at inhibitory synapses. This abnormality can be effectively suppressed via activation of ULK1.

scholarly journals Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2aK1422E mice

2021 ◽  
Author(s):  
Dennis M Echevarria-Cooper ◽  
Nicole A Hawkins ◽  
Sunita N Misra ◽  
Alexandra Huffman ◽  
Tyler Thaxton ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Action Potential ◽  
Sodium Channel ◽  
Developmental Delay ◽  
Neuronal Excitability ◽  
Autism Spectrum ◽  
Mixed Effects ◽  
Spectrum Disorder ◽  
Channel Function ◽  
Eeg Abnormalities

Genetic variants in SCN2A, encoding the NaV1.2 voltage-gated sodium channel, are associated with a range of neurodevelopmental disorders with overlapping phenotypes. Some variants fit into a framework wherein gain-of-function missense variants that increase neuronal excitability lead to infantile epileptic encephalopathy, while loss-of-function variants that reduce neuronal excitability lead to developmental delay and/or autism spectrum disorder with or without co-morbid seizures. One unique case less easily classified using this binary paradigm is the de novo missense variant SCN2A-p.K1422E, associated with infant-onset developmental delay, infantile spasms, and features of autism spectrum disorder. Prior structure-function studies demonstrated that K1422E substitution alters ion selectivity of NaV1.2, conferring Ca2+ permeability, lowering overall conductance, and conferring resistance to tetrodotoxin (TTX). Based on heterologous expression of K1422E, we developed a compartmental neuron model that predicted mixed effects on channel function and neuronal activity. We also generated Scn2aK1422E mice and characterized effects on neurons and neurological/neurobehavioral phenotypes. Dissociated neurons from heterozygous Scn2aK1422E/+ mice exhibited a novel TTX-resistant current with a reversal potential consistent with mixed ion permeation. Cortical slice recordings from Scn2aK1422E/+ tissue demonstrated impaired action potential initiation and larger Ca2+ transients at the axon initial segment during the rising phase of the action potential, suggesting mixed effects on channel function. Scn2aK1422E/+ mice exhibited rare spontaneous seizures, interictal EEG abnormalities, altered response to induced seizures, reduced anxiety-like behavior and alterations in olfactory-guided social behavior. Overall, Scn2aK1422E/+ mice present with phenotypes similar yet distinct from Scn2a knockout models, consistent with mixed effects of K1422E on NaV1.2 channel function.

Music Therapy for People with Autism Spectrum Disorder

2015 ◽  
Author(s):  
Thomas Bergmann
Keyword(s):  
Autism Spectrum Disorder ◽  
Music Therapy ◽  
Interpersonal Relationships ◽  
Case Reports ◽  
Empirical Studies ◽  
Autism Spectrum ◽  
Emotional Dysregulation ◽  
Spectrum Disorder ◽  
Verbal Form ◽  
Diagnostic Approaches

Music as a non-verbal form of communication and play addresses the core features of autism, such as social impairments, limited speech, stereotyped behaviors, sensory-perceptual impairments, and emotional dysregulation; thus music-based interventions are well established in therapy and education. Music therapy approaches are underpinned by behavioral, creative, sensory-perceptional, developmental, and educational theory and research. The effectiveness of music therapy in the treatment of children with autism spectrum disorder (ASD) is reflected by a huge number of studies and case reports; current empirical studies aim to support evidence-based practice. A treatment guide for improvisational music therapy provides unique interventions to foster social skills, emotionality, and flexibility; in developmental approaches, the formation of interpersonal relationships is key. Since ASD is a lifelong neurodevelopmental condition, music therapy is also appropriate in the treatment of adults with intellectual disability. Diagnostic approaches using musical-interactional settings to assess ASD symptomatology are promising, especially in non-speakers.

scholarly journals Interventions for paediatric surgery patients with comorbid autism spectrum disorder: a systematic literature review

2016 ◽  
Vol 101 (12) ◽  
pp. 1090-1094 ◽  
Author(s):  
Scott Koski ◽  
Robin L Gabriels ◽  
Carol Beresford
Keyword(s):  
Autism Spectrum Disorder ◽  
Management Practices ◽  
Perioperative Management ◽  
Case Reports ◽  
Empirical Studies ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Paediatric Surgery ◽  
Paediatric Patients ◽  
Final Sample

AimsTo survey perioperative management practices for paediatric patients diagnosed with autism spectrum disorder (ASD).MethodsA systematic review was carried out of empirical studies and case reports published in peer-reviewed journals of current best practices and behavioural interventions for paediatric patients with ASD who had undergone surgery.ResultsThe final sample included 11 articles published between 1997 and 2016 that met broad inclusion criteria of surveying perioperative interventions for the ASD population. There is broad endorsement across the scant publications on this topic of the following practices: increased attention to individual patient needs, rehearsal and other desensitisation efforts, departure from a sole focus on sedation or restraint of the combative or uncooperative patient and engaging caregivers in tuning perioperative management to individual needs.ConclusionsThis review supports the need for an individualised structure and approach to the perioperative care of these unique patients.

scholarly journals Lehetséges összefüggés egy autizmusspektrum-zavarban érintett gyermek metilfenidát-kezelése és az azt követően kialakult gynaecomastia között

2021 ◽  
Vol 162 (42) ◽  
pp. 1703-1708
Author(s):  
Nóra Kollárovics ◽  
Péter Nagy ◽  
Judit Balázs
Keyword(s):  
Autism Spectrum Disorder ◽  
Attention Deficit Hyperactivity Disorder ◽  
Attention Deficit ◽  
Case Reports ◽  
Autism Spectrum ◽  
Point Of View ◽  
Spectrum Disorder ◽  
Child Psychiatrist ◽  
Hyperactivity Disorder ◽  
The Relationship

Összefoglaló. Bár a figyelemhiányos hiperaktivitási zavar kezelése során alkalmazott metilfenidát-monoterápiával összefüggésben jelentkező gynaecomastiáról bizonyos nemkívánatos hatások adatbázisai beszámolnak, a szakirodalom áttekintése alapján ez idáig mindössze 5 esettanulmányt publikáltak a témában. Tanulmányunkban egy autizmusspektrum-zavarral és figyelemhiányos hiperaktivitási zavarral egyaránt diagnosztizált gyermek esetét mutatjuk be, akinél 6 hónapon át tartó, folyamatos metilfenidát-monoterápiájával összefüggésben kétoldali gynaecomastia kialakulását tapasztaltuk. A kezelés azonnali leállítása mellett 10 napos klomifénkezelés történt. A metilfenidát-terápia azonnali leállítását követően 14 nappal a gynaecomastia mindkét oldalon visszahúzódott. 3 hónapos, gyermekpszichiátriai szempontból gyógyszermentes időszakot követően a metilfenidát-terápia újraindítása történt, de 1 hónap elteltével a nem kívánt mellékhatás ismét jelentkezett. A metilfenidát-terápia és a gynaecomastia kialakulása közötti kapcsolat számos mechanizmussal kapcsolatban kérdéseket vet fel. Gyermekpszichiátriai szempontból érdekes kérdés, hogy releváns lehet-e a gyógyszeres terápia következményeként kialakuló nemkívánatos mellékhatás megjelenésében az autizmusspektrum-zavar és a figyelemhiányos hiperaktivitási zavar komorbid fennállása. A jelenség hátterében felmerül továbbá a neuroendokrin-immunológiai rendszer szabályozásának esetleges megváltozása. Esettanulmányunk felhívja a gyakorló orvoskollégák figyelmét a metilfenidát-terápia alkalmazása mellett potenciálisan kialakuló gynaecomastia monitorozására. Orv Hetil. 2021; 162(42): 1703–1708. Summary. Although gynecomastia associated with methylphenidate monotherapy in the treatment of attention deficit hyperactivity disorder has already been reported in some adverse event databases, based on a review of the literature it appears that only five case reports have been published. In our study, we present the case of a child diagnosed with both autism spectrum disorder and attention deficit/hyperactivity disorder, who developed bilateral gynecomastia in association with continuous methylphenidate monotherapy for 6 months. With immediate cessation of methylphenidate therapy, clomiphene treatment was given for 10 days. A total of 14 days after cessation of methylphenidate treatment gynecomastia receded on both sides. After a methylphenidate drug-free period of 3 months, methylphenidate therapy was restarted, but 1 month later the side effect reappeared. The relationship between methylphenidate and the development of gynecomastia raises questions about a number of mechanisms. From a child psychiatrist point of view, it is an interesting question whether the presence of comorbid autism spectrum disorder and attention deficit/hyperactivity disorder may be relevant in the onset of adverse events by medication. The phenomenon may also be caused by altered regulation of the neuroendocrine-immune system. Our case report draws the attention of practicing physicians to monitoring of potential gynecomastia during methylphenidate therapy. Orv Hetil. 2021; 162(42): 1703–1708.

scholarly journals Antipsychotic Medication and Risk of Incident Seizure in People with Autism Spectrum Disorder: Analyses with Cohort and Within Individual Study Designs

2021 ◽  
Author(s):  
Basmah H. Alfageh ◽  
Frank M. C. Besag ◽  
Le Gao ◽  
Tian-Tian Ma ◽  
Kenneth K. C. Man ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Chart Review ◽  
Case Reports ◽  
Case Series ◽  
Antipsychotic Agents ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Increased Risk ◽  
Study Designs ◽  
Time Invariant

AbstractThere are many case reports of seizures apparently associated with the prescription of antipsychotics. This study aimed to examine whether there is an association between the prescription of antipsychotics and incident seizures in individuals with autism spectrum disorder using retrospective data based on patients’ chart review. A cohort study was conducted to compare the rate of incident seizure between 3923 users of antipsychotics with 10,086 users of other psychotropics. This was followed by a self-controlled case series (SCCS) analysis of 149 patients to eliminate the effect of time-invariant confounders. The results showed no evidence of increased risk of seizure after exposure to antipsychotic agents (Hazard Ratio 1.28, 95% CI 0.74–2.19) compared to other psychotropics.

Treating Stuttering in Children With Autism Spectrum Disorder

2021 ◽  
pp. 208-222
Author(s):  
Shoko Miyamoto ◽  
Masayoshi Tsuge
Keyword(s):  
Autism Spectrum Disorder ◽  
Attention Deficit Hyperactivity Disorder ◽  
Case Reports ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Language Ability ◽  
Spectrum Disorder ◽  
Hyperactivity Disorder ◽  
Children With Asd ◽  
Factors Influencing

The number of case reports of children with autism spectrum disorder (ASD) who stutter is increasing. The duration of intervention for stuttering in children with attention-deficit hyperactivity disorder (ADHD) is often greater than for children who only stutter. Whether there is a similar pattern in children with ASD who stutter should also be examined. In this study, the factors influencing the prognoses of two children with stuttering and ASD were investigated. One child's stuttering had improved and had almost been eliminated, and the other's stuttering continued. The results of the investigation showed that a significant increase in language ability and the absence of physiological problems assisted in eliminating stuttering. The child who continued to stutter originally showed a higher than average language level and high anxiety. Preventing and eliminating anxiety that accompanies ASD, in addition to intervention for stuttering, may be indispensable to reduce stuttering and improve fluency.

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