Multikingdom and functional gut microbiota markers for autism spectrum disorder

Nature Microbiology, Journal Year: 2024, Volume and Issue: 9(9), P. 2344 - 2355

Published: July 8, 2024

Language: Английский

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Consensus guidelines for the diagnosis and management of succinic semialdehyde dehydrogenase deficiency

Molecular Genetics and Metabolism, Journal Year: 2024, Volume and Issue: 142(1), P. 108363 - 108363

Published: March 4, 2024

Language: Английский

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Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder

Journal of Neurodevelopmental Disorders, Journal Year: 2024, Volume and Issue: 16(1)

Published: April 24, 2024

Abstract Background Succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a model neurometabolic disease at the fulcrum of translational research within Boston Children’s Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC), including NIH-sponsored natural history study clinical, neurophysiological, neuroimaging, molecular markers, patient-derived induced pluripotent stem cells (iPSC) characterization, development murine for tightly regulated, cell-specific gene therapy. Methods SSADHD subjects underwent clinical evaluations, neuropsychological assessments, biochemical quantification γ-aminobutyrate (GABA) related metabolites, electroencephalography (standard high density), magnetoencephalography, transcranial magnetic stimulation, resonance imaging spectroscopy, genetic tests. This was parallel to laboratory investigations in vitro GABAergic neurons derived from human (hiPSCs) analyses performed on versatile that uses an inducible reversible rescue strategy allowing on-demand Results The 62 [53% females, median (IQR) age 9.6 (5.4–14.5) years] included had reported symptom onset ∼ 6 months were diagnosed 4 years. Language developmental delays more prominent than motor. Autism, epilepsy, movement disorders, sleep disturbances, various psychiatric behaviors constituted core disorder’s phenotype. Lower severity scores, indicating worst severity, coincided with older ( R = -0.302, p 0.03), as well age-adjusted lower values plasma 0.337, 0.02) γ-hydroxybutyrate (GHB) 0.360, 0.05). While epilepsy increase age, communication abilities motor function tend improve. iPSCs, which differentiated into neurons, represent first neuronal express marker microtubule-associated protein 2 (MAP2), GABA. GABA-metabolism could be reversed using CRISPR correction pathogenic variants or mRNA transfection iPSCs associated excessive glutamatergic activity synaptic excitation. Conclusions Findings Natural History Study converge iPSC animal work focused common disorder our IDDRC, deepening knowledge pathophysiology longitudinal course complex neurodevelopmental disorder. further enables identification biomarkers changes throughout will essential upcoming targeted trials enzyme replacement

Language: Английский

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The neuropsychological profile of SSADH deficiency, a neurotransmitter disorder of GABA metabolism

Molecular Genetics and Metabolism, Journal Year: 2025, Volume and Issue: 144(3), P. 109051 - 109051

Published: Feb. 5, 2025

Language: Английский

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The mechanisms of perineuronal net abnormalities in contributing aging and neurological diseases

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 92, P. 102092 - 102092

Published: Oct. 13, 2023

Language: Английский

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The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency

Journal of Inherited Metabolic Disease, Journal Year: 2024, Volume and Issue: 47(3), P. 447 - 462

Published: March 18, 2024

Abstract The objective of the study is to evaluate evolving phenotype and genetic spectrum patients with succinic semialdehyde dehydrogenase deficiency (SSADHD) in long‐term follow‐up. Longitudinal clinical biochemical data 22 pediatric 9 adult individuals SSADHD from patient registry International Working Group on Neurotransmitter related Disorders (iNTD) were studied silico analyses, pathogenicity scores molecular modeling ALDH5A1 variants. Leading initial symptoms, onset infancy, developmental delay hypotonia. Year birth specific symptoms influenced diagnostic delay. Clinical 26 (median 12 years, range 1.8–33.4 years) showed a diversifying course follow‐up: 77% behavioral problems, 76% coordination 73% speech disorders, 58% epileptic seizures 40% movement disorders. After ataxia, dystonia (19%), chorea (11%) hypokinesia (15%) most frequent Involvement dentate nucleus brain imaging was observed together disorders or problems. Short attention span (78.6%) distractibility (71.4%) frequently behavior traits mentioned by parents while impulsiveness, problems communicating wishes needs compulsive addressed as strongly interfering family life. Treatment mainly aimed control psychiatric symptoms. Four new pathogenic variants identified. In scoring system, protein activity score revealed high correlation. A genotype/phenotype correlation not observed, even siblings. This presents characteristics disease during course, highlighting widens knowledge genotypic emphasizes reliable application approaches.

Language: Английский

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Phenotypic correlates of structural and functional protein impairments resultant from ALDH5A1 variants

Human Genetics, Journal Year: 2023, Volume and Issue: 142(12), P. 1755 - 1776

Published: Nov. 14, 2023

Language: Английский

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Astragaloside IV ameliorates autism-like behaviors in BTBR mice by modulating Camk2n2-dependent OXPHOS and neurotransmission in the mPFC

Journal of Advanced Research, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Autism spectrum disorder (ASD) represents a multifaceted set of neurodevelopmental conditions marked by social deficits and repetitive behaviors. Astragaloside IV (ASIV), natural compound derived from the traditional Chinese herb Astragali Radix, exhibits robust neuroprotective effects. However, whether ASIV can ameliorate behavioral in ASD remains unknown. This work aimed to determine efficacy molecular mechanisms ASD. The autistic BTBR T + tf/J (BTBR) mice were used this study. Behavioral tests performed assess ASD-like phenotypes. neurotransmitter levels synaptic transmission evaluated high-performance liquid chromatography whole-cell patch clamp recordings, respectively. Molecular biological techniques, immunostaining, RNA-sequencing (RNA-seq) combined uncover underlying mechanisms. Our study showed that both impairment behaviors significantly improved after treatment dose-dependent manner mice. normalized (GABA glutamate) their corresponding vesicular transporters (vGAT, vGLUT1) medial prefrontal cortex (mPFC). Furthermore, excitation-inhibition imbalance layer V mPFC was reversed administration. Mechanistically, bulk RNA-seq PPI network analysis identified Camk2n2 as crucial bridging gene regulating oxidative phosphorylation neurotransmission. overexpression abolished beneficial effects on symptoms via Camk2/CREB pathway. evidence demonstrates may become promising option for implies targeting Camk2n2/Camk2/CREB axis is warranted investigate these individuals further.

Language: Английский

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Update on Inherited Disorders of GABA Metabolism

European Journal of Paediatric Neurology, Journal Year: 2025, Volume and Issue: 56, P. 10 - 16

Published: April 13, 2025

Language: Английский

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The neurology of creativity: 2023 Hower lecture

Annals of the Child Neurology Society, Journal Year: 2024, Volume and Issue: 2(1), P. 6 - 14

Published: March 1, 2024

Abstract The neurology of creativity implies network activity; no singular cerebral area is invoked. A clinician‐scientist can develop a creative research project from single patient, combined with critical scientific alliances, careful observations, and correlations. developing nervous system poses additional complexity, as changes are expected over time in physiologic circumstances, to which must be added compensatory responses underlying pathology. arts represent an especially productive study the creativity, functional imaging, tractography, intracranial electrophysiology. Music activates widespread bilateral areas, including temporal, orbitofrontal, insular, fusiform, cerebellar cortex. There different neuronal clusters for levels sound volume, duration, timbre, pitch. Heschl's gyrus arcuate fasciculus correlate orbitofrontal cortex involved expectancy generation appears active music then deactivates music, if has editing function. This default mode being key during improvisation, whereas central executive invoked effortful, repetitive playing. Furthermore, plasticity associated pathologic development musicogenic seizures, protection musician's dystonia pianists who begin lessons before age 9 years, benefits increased temporal older adults taking piano after six months. Creativity, reducing negativity bias, juggling life s priorities countering burnout building resilience.

Language: Английский

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