Autism Spectrum Disorder: Neurodevelopmental Risk Factors, Biological Mechanism, and Precision Therapy

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 1819 - 1819

Published: Jan. 17, 2023

Autism spectrum disorder (ASD) is a heterogeneous, behaviorally defined neurodevelopmental disorder. Over the past two decades, prevalence of autism disorders has progressively increased, however, no clear diagnostic markers and specifically targeted medications for have emerged. As result, neurobehavioral abnormalities, neurobiological alterations in ASD, development novel ASD pharmacological therapy necessitate multidisciplinary collaboration. In this review, we discuss multiple animal models to contribute disease mechanisms as well new studies from disciplines assess behavioral pathology ASD. addition, summarize highlight mechanistic advances regarding gene transcription, RNA non-coding translation, abnormal synaptic signaling pathways, epigenetic post-translational modifications, brain-gut axis, immune inflammation neural loop abnormalities provide theoretical basis next step precision therapy. Furthermore, review existing tactics limits present challenges opportunities translating knowledge into clinical practice.

Language: Английский

---

SCN1A Mutation—Beyond Dravet Syndrome: A Systematic Review and Narrative Synthesis

Frontiers in Neurology, Journal Year: 2021, Volume and Issue: 12

Published: Dec. 24, 2021

Background:SCN1A is one of the most common epilepsy genes. About 80% SCN1A gene mutations cause Dravet syndrome (DS), which a severe and catastrophic epileptic encephalopathy. More than 1,800 have been identified in SCN1A. Although it known that main DS genetic with febrile seizures plus (GEFS+), there dearth information on other related diseases caused by Objective: The aim this study to systematically review literature associated non-DS-related disorders. Methods: We searched PubMed SCOPUS for all published cases until October 20, 2021. results reported each were summarized narratively. Results: search yielded 2,889 items. A total 453 studies between 2005 2020 met final inclusion criteria. Overall, 303 DS, 93 GEFS+, three Doose syndrome, nine infancy migrating focal (EIMFS), six West two Lennox-Gastaut (LGS), Rett seven nonsyndromic encephalopathy (NEE), 19 hemiplegia migraine, autism spectrum disorder (ASD), nonepileptic SCN1A-related sudden deaths, arthrogryposis multiplex congenital included. Conclusion: Aside from also causes encephalopathies, such as EIMFS, LGS, NEE. In addition epilepsy, hemiplegic ASD, death, can be

Language: Английский

---

Escitalopram Targets Oxidative Stress, Caspase-3, BDNF and MeCP2 in the Hippocampus and Frontal Cortex of a Rat Model of Depression Induced by Chronic Unpredictable Mild Stress

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(14), P. 7483 - 7483

Published: July 13, 2021

In recent years, escitalopram (ESC) has been suggested to have different mechanisms of action beyond its well known selective serotonin reuptake inhibition. The aim this study is investigate the effects on oxidative stress, apoptosis, brain-derived neurotrophic factor (BDNF), Methyl-CpG-binding protein 2 (MeCP2), and oligodendrocytes number in brain chronic unpredictable mild stress-induced depressed rats. animals were randomised four groups (8 each group): control, stress + ESC 5 5/10. was administered for 42 days a fixed dose (5 mg/kg b.w.) or an up-titration regimen (21 b.w. then 21 10 b.w.). Sucrose preference test (SPT) elevated plus maze (EPM) also performed. improved percentage sucrose preference, locomotion anxiety. ESC5/10 reduced damage hippocampus antioxidant defence frontal lobe. lowered caspase 3 activity hippocampus. Escitalopram had modulatory effect BDNF lobe MeCP2 expressions. results confirm multiple pathways implicated pathogenesis depression suggest that exerts antidepressant via intricate mechanisms.

Language: Английский

---

MeCP2 Is an Epigenetic Factor That Links DNA Methylation with Brain Metabolism

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(4), P. 4218 - 4218

Published: Feb. 20, 2023

DNA methylation, one of the most well-studied epigenetic modifications, is involved in a wide spectrum biological processes. Epigenetic mechanisms control cellular morphology and function. Such regulatory involve histone chromatin remodeling, non-coding RNA molecules, modifications. One modifications methylation that plays key roles development, health, disease. Our brain probably complex part our body, with high level methylation. A protein binds to different types methylated methyl-CpG binding 2 (MeCP2). MeCP2 acts dose-dependent manner its abnormally or low expression level, deregulation, and/or genetic mutations lead neurodevelopmental disorders aberrant Recently, some MeCP2-associated have emerged as neurometabolic disorders, suggesting role for metabolism. Of note, MECP2 loss-of-function mutation Rett Syndrome reported cause impairment glucose cholesterol metabolism human patients mouse models The purpose this review outline metabolic abnormalities currently no available cure. We aim provide an updated overview into defects associated MeCP2-mediated function consideration future therapeutic strategies.

Language: Английский

---

The Epigenetic Reader Methyl-CpG-Binding Protein 2 (MeCP2) Is an Emerging Oncogene in Cancer Biology

Cancers, Journal Year: 2023, Volume and Issue: 15(10), P. 2683 - 2683

Published: May 9, 2023

Epigenetic mechanisms are gene regulatory processes that control expression and cellular identity. factors include the "writers", "readers", "erasers" of epigenetic modifications such as DNA methylation. Accordingly, nuclear protein Methyl-CpG-Binding Protein 2 (MeCP2) is a reader methylation with key roles in identity function. Research studies have linked altered methylation, deregulation MeCP2 levels, or

Language: Английский

---

Umbelliprenin via increase in the MECP2 and attenuation of oxidative stress mitigates the autistic-like behaviors in mouse model of maternal separation stress

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 8, 2024

Introduction: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition. Maternal separation (MS) stress an early-life factor associated with behaviors resembling Autism. Both MECP2 and oxidative are implicated in the pathophysiology of Umbelliprenin (UMB) coumarin compound various pharmacological properties. Our study aimed to investigate potential effects UMB mitigating autistic-like mouse model subjected MS stress, focusing on probable alterations gene expression hippocampus. Methods: paradigm was performed, mice were treated saline or UMB. Behavioral tests consisting three-chamber test (evaluating social interaction), shuttle box (assessing passive avoidance memory), elevated plus-maze (measuring anxiety-like behaviors), marble-burying repetitive behaviors) conducted. Gene measurements total antioxidant capacity (TAC), nitrite level, malondialdehyde (MDA) level assessed Results: The findings demonstrated that MS-induced Autism, accompanied by decreased expression, nitrite, MDA levels, reduced TAC mitigated these induced attenuated adverse Conclusion: In conclusion, likely caused probably, through reduction increase expression.

Language: Английский

---

Sleep Disorders in Rett Syndrome and Rett-Related Disorders: A Narrative Review

Frontiers in Neurology, Journal Year: 2022, Volume and Issue: 13

Published: March 1, 2022

Rett Syndrome (RTT) is a rare and severe X-linked developmental brain disorder that occurs primarily in females, with ratio of 1:10.000. De novo mutations the Methyl-CpG Binding protein 2 (MECP2) gene on long arm X chromosome are responsible for more than 95% cases classical Rett. In remaining (atypical Rett), other genes involved such as cyclin-dependent kinase-like 5 (CDKL5) forkhead box G1 (FOXG1). Duplications MECP2 locus cause duplication syndrome (MDS) which concerns about 1% male patients intellectual disability. Sleep disorders common individuals disability, while prevalence children between 16 42%. Over 80% affected by RTT show sleep problems, higher first 7 years life some degree variability correlation to age genotype. Abnormalities circadian rhythm loss glutamate homeostasis play key role development these disorders. disorders, epilepsy, gastrointestinal problems characterize CDKL5 Deficiency Disorder (CDD). impairment an area overlap along regression others. dysfunction epilepsy deeply linked. deprivation could be aggravating factor anti-comitial therapy interfere structure. Epilepsy atypical clinical phenotype syndrome. However, present significant lifetime risk too. disturbances impact child's patients' families evidence its management still limited. The aim this review analyze pathophysiology, features, comorbidities Rett-related

Language: Английский

---

Trofinetide for Rett Syndrome: Highlights on the Development and Related Inventions of the First USFDA-Approved Treatment for Rare Pediatric Unmet Medical Need

Journal of Clinical Medicine, Journal Year: 2023, Volume and Issue: 12(15), P. 5114 - 5114

Published: Aug. 4, 2023

Rett syndrome (RTT) is a rare disability causing female-oriented pediatric neurodevelopmental unmet medical need. RTT was recognized in 1966. However, over the past 56 years, United States Food and Drug Administration (USFDA) has authorized no effective treatment for RTT. Recently, Trofinetide approved by USFDA on 10 March 2023 as first treatment. This article underlines pharmaceutical advancement, patent literature, prospects of Trofinetide. The data this study were gathered from PubMed database, authentic websites (Acadia Pharmaceuticals, Neuren USFDA), free databases. disclosed Pharmaceuticals 2000 methyl group containing analog naturally occurring neuroprotective tripeptide called glycine-proline-glutamate (GPE). joint efforts Acadia have developed mechanism action not yet well established. it supposed to improve neuronal morphology synaptic functioning. literature revealed handful inventions related Trofinetide, providing excellent unexplored broad research possibilities with development innovative Trofinetide-based molecules, combinations patient-compliant drug formulations, precise MECP2-mutation-related personalized medicines are foreseeable. clinical trials some disorders (NDDs), including treating Fragile X (FXS). It expected that may be FXS future. USFDA-approval one important milestones therapy beginning new era RTT, FXS, autism spectrum disorder (ASD), brain injury, stroke, other NDDs.

Language: Английский

---

Neurotrophins and Their Receptors: BDNF’s Role in GABAergic Neurodevelopment and Disease

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(15), P. 8312 - 8312

Published: July 30, 2024

Neurotrophins and their receptors are distinctly expressed during brain development play crucial roles in the formation, survival, function of neurons nervous system. Among these molecules, brain-derived neurotrophic factor (BDNF) has garnered significant attention due to its involvement regulating GABAergic system function. In this review, we summarize compare expression patterns neurotrophins both developing adult brains rodents, macaques, humans. Then, focus on implications BDNF from cortex striatum, as presence single nucleotide polymorphisms disruptions levels alter excitatory/inhibitory balance brain. This imbalance different pathogenesis neurodevelopmental diseases like autism spectrum disorder (ASD), Rett syndrome (RTT), schizophrenia (SCZ). Altogether, evidence shows that neurotrophins, especially BDNF, essential for development, maintenance, brain, or signaling common mechanisms pathophysiology diseases.

Language: Английский

---

Trofinetide receives FDA approval as first drug for Rett syndrome

Annals of Medicine and Surgery, Journal Year: 2024, Volume and Issue: 86(5), P. 2382 - 2385

Published: March 18, 2024

Introduction Rett syndrome (RTT) is a neurodevelopmental illness affecting around 1 in every 10,000 live births, almost exclusively females1. RTT's key traits are aberrant linguistic and psychomotor growth (it refers to abnormal or deviating patterns of development language skills motor coordination, this deviation may manifest as atypical abilities challenges developing skills), autistic behaviors, erratic breathing, uneven walking, hand wringing2. The early postnatal period saw regular neurological physical growth, which leads symptom emergence between 6 18 months age3. four phases the RTT progression (Table 1)3 Stage (early onset), 2 (regression), 3 (plateau), 4 (late deterioration). In children grow normally, albeit there be some developmental delay. 2, known regression, sees youngsters regress lose previously learned abilities, such deliberate gestures spoken speech. Children's cognitive stabilize at (plateau) when other medical issues start themselves like seizures. People with endure declining mobility degeneration), they exhibit parkinsonian symptoms4. Table - evolves via various phases3 Age Symptoms 1. Stagnation 6–18 Developmental delays (postural control, motor, language)Reduced eye contactHand-wringing occurMicrocephaly occur 2. Rapid regression 1–4 years Loss purposeful skillsStereotypical movements (wringing, washing, tapping)Loss languageWalking unsteadyBreathing irregularities occurAutistic-like featuresMicrocephaly progressionSeizures 3. Plateau/pseudo-stationary 2–potentially life Hand apraxia/dyspraxiaMotor coordination difficulties and/or loss skillsImprovement communication occurSeizures common 4. Late deterioration 10–life Severe disabilityMuscle weakness, rigidity, spasticityWheelchair dependency brain has diminished volume comparable that an ideal 1-year-old kid. associated reduction volume, particularly regions frontal temporal lobes. observed individuals often characterized by neurons decrease dendritic branching. Specific areas cerebral cortex, plays crucial role functions, reduced size altered structure. This abnormality contributes RTT. It stable for least 40 without exhibiting any signs neurodegeneration. Patients during pregnancy first year life, can result microcephaly. thought primary reasons imbalances arborization, synaptic density, neuronal soma size, increased cell density5. Several patients have impaired carbohydrate metabolism, dyslipidemia, raised plasma leptin adiponectin, mitochondrial structure, oxidative stress, lactate pyruvate levels, GI issues, QT intervals, bone mass, osteoporosis, gallbladder inflammation, scoliosis, urological dysfunction, sleep disruptions. fact several tissues systems involved emphasizes multi-systemic illness6. Pathogenesis An X chromosome-linked gene called Methyl-CpG-binding protein (MeCP2) produces MeCP2 protein, essential RTT7. highly produced nucleus differentiation, maturity, improvement neural circuits, maintenance synapses. Early embryonic process, it low. two isoforms, MeCP2-E1 MeCP2-E2, distinct amino (N)-terminal amino-acid residues8. conserved domains: transcriptional repression methyl-DNA binding7. Because its affinity methylated CpG sites linked silence, was recognized repressor9. However, binds 5-hydroxymethylcytosine, frequent alteration DNA concentrated active genes, also been proposed transcription activator10. RTT, C > T type nucleotide transition mutations found hotspots most likely represent variable site methylation male germline. Only female progeny affected mutations, develop spontaneously paternal germline cells11. More than 200 R106W, R133C, T158M, R168X, R255X, R270X, R294X, R306C prevalent point accounting nearly 60% instances4. Microarray research revealed WNT6 mRNA levels were 12-fold CA1 zone hippocampus MeCP2K412R sumo mutant mice (MeCP2 Lys-412 residue sumo-mutant animals)12. Wnt proteins Wnt/-catenin pathway proper development. emphasized hotspot autism signaling. Wnt6 signaling dysfunction downstream effectors etiology evidenced decreased SUMOylation animals7. Treatment Old treatments Due requires multifaceted strategy therapy management13. die heart failure, pulmonary infection, respiratory collapse6. majority treatment techniques aim stimulate expression control mechanisms. Actinomycin-D suppresses repression, Tamoxifen restores expression, IGF-1 tripeptide improves expectancy mice, Valproic acid HDAC blocker serves treat seizure disorder14. Ketamine administration bettered limb clasping, muscle breathlessness MeCP2-mutant mice. Desipramine, norepinephrine reuptake inhibitor, alleviated mice's ventilation abnormalities apneas. Sarizotan, serotonin 1a agonist Dopamine D2-like receptor agonist, lowered 15–30% but had no influence on function mice3. Fluoxetine buspirone positive effects cases. Levodopa benserazide alone refined traits, dendrite spine lifespan. Choline efficiency, grasping power, nerve behavioral impairments mouse models14. Vitamin E derivative Trolox alleviates cells hyperactivity while increasing remodeling hypoxia tolerance. N-acetylcysteine modulates stress intracellular glutathione MeCP2/y mice15. Fluvastatin Lovastatin restore cholesterol Phenytoin prevents arrhythmias, Zoledronic treats osteoporosis lowers incidence fractures, Folate Betaine recover morphology promoting binding proteins. Dextromethorphan NMDA entirely mental functioning convulsions, Topiramate TPM improved patients. Levetiracetam powerful anticonvulsant medication patients, whereas Naltrexone opiate used orally boosts breathing efficiency little impact anticipated handicap13,14. New Trofinetide Trofinetide, oral sold under brand name Daybue, just received FDA approval uncommon gene-related disorder impairs adults age older. Before 10 March 2023, FDA-endorsed available focus managing syndrome's symptoms impacts through multidisciplinary interprofessional approach. became inaugural FDA-approved 2023. (glycyl-L-2-methylprolyl-L-glutamic acid) brand-new synthetic analogue glycine-proline-glutamate (GPE). Vomiting diarrhea side twice-daily medication, according statement16. Diminution weight, Fever, anxiousness, satiety, exhaustion nasopharyngitis additional adverse effects. Trofinetide's mechanism action remains unclear. animal promote branching well plasticity signals17. phase placebo-controlled trial involving 82 aged 5–15 years, trofinetide, exhibited promising results. MeCP2-deficient GPE neurological, cardiovascular performance, rate, increases mass lengthens survival. Both prolonged half-life GPE, halted death infarct rat model hypoxic insult, showing dose-dependent volume18. highest trofinetide dose (200 mg/kg twice daily [BID]) showed significant (P ≤ 0.042) over placebo three measures: Behavior Questionnaire (RSBQ), Clinical Global Impression-Improvement (CGI-I), RTT-Clinician Domain Concerns-Visual Analog Scale (RTT-DSC-VAS). tolerated all doses tested (50, 100, BID). Encouraged these findings, now underway, employing disease-specific innovative scales further investigate efficacy safety RTT18. Variations bioavailability morning evening clinical implications. information guide more personalized plans, considering chronobiological factors tailoring align symptomatology patterns. Optimizing dosing schedules could potentially enhance ensuring patient adherence education importance consistent dosing. addition, monitoring potential adjustments dosage timing based individual responses necessary maintain therapeutic Overall, deeper understanding changes throughout day refine strategies achieve better outcomes RTT19. study, administered weight-based dosages (50 mg/kg, 100 mg/kg) weeks adolescents significantly measures determined care takers professionals20. Oral resulted linear kinetics pharmacokinetic studies (including population modeling healthy adult participants), time- parameters. did not induce inhibit metabolic processes range subject study (up mg/kg), systemic exposure dose-proportional throughout. Following numerous doses, buildup. change tests, caused dietary effect circadian oscillations metabolism absorption. two-compartment best represented parameters Trofinetide; nevertheless, noncompartmental analysis preferred characterizing pharmacokinetics single study. Concurrent food consumption alter profile delivered medications variety methods, postponing stomach emptying, altering gastrointestinal tract's pH, drug's luminal metabolism. main goal current investigation identify interactions after recommended (12 g). characteristics compared order diurnal fluctuation bioavailability. study's second exploratory describe urine. selection grounded determining optimal balance across diverse population. By different weight categories, researchers assess how variations body drug approach helps appropriate ranges investigation, aiming establish effective broad spectrum within target population21. Conclusion breakthrough families rare debilitating condition. For many cure options limited offers hope cognitive, behavioral, improved. While cure, represents major milestone undergone rigorous testing shown safe improving will formulations, offering flexibility choice their families. Looking ahead, hoped continue improve effectiveness developed address underlying causes now, step forward Ethical Ethics required editorial. Consent Informed consent Sources funding authors extramural Author contribution conceptualization done Z.U.N.M. B.S.R; literature drafting manuscript conducted Z.U.N.M., B.A., F.A., A.S., B.S.R., H.S.R., M.A., A.A.F.; editing supervision performed B.S.R. All read agreed final version manuscript. Conflicts interest disclosure declare conflicts concerning research, authorship, publication article. Research registration unique identifying number (UIN) Not applicable. Guarantor Data availability statement Provenance peer review

Language: Английский

---