Pubmed du 31/01/22
1. Abuaish S, Al-Otaibi NM, Aabed K, Abujamel TS, Alzahrani SA, Alotaibi SM, Bhat RS, Arzoo S, Algahtani N, Moubayed NM, El-Ansary A. The Efficacy of Fecal Transplantation and Bifidobacterium Supplementation in Ameliorating Propionic Acid-Induced Behavioral and Biochemical Autistic Features in Juvenile Male Rats. Journal of molecular neuroscience : MN. 2022; 72(2): 372-81.
Gut microbiota plays a major role in neurological disorders, including autism. Modulation of the gut microbiota through fecal microbiota transplantation (FMT) or probiotic administration, such as Bifidobacteria, is suggested to alleviate autistic symptoms; however, their effects on the brain are not fully examined. We tested both approaches in a propionic acid (PPA) rodent model of autism as treatment strategies. Autism was induced in Sprague-Dawley rats by administering PPA orally (250 mg/kg) for 3 days. Animals were later treated with either saline, FMT, or Bifidobacteria for 22 days. Control animals were treated with saline throughout the study. Social behavior and selected brain biochemical markers related to stress hormones, inflammation, and oxidative stress were assessed. PPA treatment induced social impairments, which was rescued by the treatments. In the brain, Bifidobacteria treatment increased oxytocin relative to control and PPA groups. Moreover, Bifidobacteria treatment rescued the PPA-induced increase in IFN-γ levels. Both treatments increased GST levels, which was diminished by the PPA treatment. These findings indicate the potential of gut microbiota-targeted therapeutics in ameliorating behavioral deficit and underlying neural biochemistry.
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2. Gofin Y, Wang T, Gillentine MA, Scott TM, Berry AM, Azamian MS, Genetti C, Agrawal PB, Picker J, Wojcik MH, Delgado MR, Lynch SA, Scherer SW, Howe JL, Bacino CA, DiTroia S, VanNoy GE, O’Donnell-Luria A, Lalani SR, Graf WD, Rosenfeld JA, Eichler EE, Earl RK, Scott DA. Delineation of a novel neurodevelopmental syndrome associated with PAX5 haploinsufficiency. Human mutation. 2022; 43(4): 461-70.
PAX5 is a transcription factor associated with abnormal posterior midbrain and cerebellum development in mice. PAX5 is highly loss-of-function intolerant and missense constrained, and has been identified as a candidate gene for autism spectrum disorder (ASD). We describe 16 individuals from 12 families who carry deletions involving PAX5 and surrounding genes, de novo frameshift variants that are likely to trigger nonsense-mediated mRNA decay, a rare stop-gain variant, or missense variants that affect conserved amino acid residues. Four of these individuals were published previously but without detailed clinical descriptions. All these individuals have been diagnosed with one or more neurodevelopmental phenotypes including delayed developmental milestones (DD), intellectual disability (ID), and/or ASD. Seizures were documented in four individuals. No recurrent patterns of brain magnetic resonance imaging (MRI) findings, structural birth defects, or dysmorphic features were observed. Our findings suggest that PAX5 haploinsufficiency causes a neurodevelopmental disorder whose cardinal features include DD, variable ID, and/or ASD.
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3. Scahill L, Shillingsburg MA, Ousley O, Pileggi ML, Kilbourne RL, Buckley D, Gillespie SE, McCracken C. A Randomized Trial of Direct Instruction Language for Learning in Children With Autism Spectrum Disorder. Journal of the American Academy of Child and Adolescent Psychiatry. 2022.
OBJECTIVE: To compare Direct Instruction Language for Learning (DI) plus treatment as usual (TAU) with TAU alone in children with autism spectrum disorder and moderate language delay. METHOD: In this study, 83 children (age range, 4 years to 7 years 11 months) were randomly assigned to DI+TAU (n = 42) or TAU (n = 41) for 6 months. Trained therapists delivered DI in twice-weekly, 90-minute sessions for 24 weeks. The primary outcome was the standard score on the age-appropriate version of the Clinical Evaluation of Language Fundamentals (CELF). The key secondary measure was the proportion of children rated by a clinician blinded to treatment as « much improved » or « very much improved » on the Clinical Global Impressions-Improvement (CGI-I) scale. RESULTS: Attrition was 12%. At end point, DI+TAU participants showed a 4.8-point (8.1%) increase on CELF vs 2.3 points (4.1%) in TAU participants (difference = 2.55, p = .14, effect size = 0.25), rendering this a negative trial on the prespecified primary outcome. In post hoc analysis that adjusted for IQ, mean difference was 3.5 (p = .04, effect size = 0.33). On CGI-I, 54.8% (23/42) of DI+TAU participants were rated much improved or very much improved compared with 21.9% (9/41) of TAU participants (χ(2) = 9.4, p = .002). On the clinically meaningful threshold of >5 points on CELF, 55.5% of DI+TAU participants achieved this benchmark vs 29.3% of TAU participants (χ(2) = 3.6, p = .06). Complete CELF data were available for 72 participants. In the combined sample, baseline CELF scores ≤50 were associated with no improvement. CONCLUSION: On CELF, DI+TAU did not meet the prespecified difference from TAU. When adjusted for IQ, DI+TAU was superior to TAU on CELF at end point. DI+TAU was superior to TAU on CGI-I. CLINICAL TRIAL REGISTRATION INFORMATION: Direct Instruction Language for Learning in Autism Spectrum Disorder; https://clinicaltrials.gov/; NCT02483910.
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4. Sethuram S, Levy T, Foss-Feig J, Halpern D, Sandin S, Siper PM, Walker H, Buxbaum JD, Rapaport R, Kolevzon A. A proof-of-concept study of growth hormone in children with Phelan-McDermid syndrome. Molecular autism. 2022; 13(1): 6.
BACKGROUND: Phelan-McDermid syndrome (PMS) is caused by 22q13 deletions including SHANK3 or pathogenic sequence variants in SHANK3 and is among the more common rare genetic findings in autism spectrum disorder (ASD). SHANK3 is critical for synaptic function, and preclinical and clinical studies suggest that insulin-like growth factor-1 (IGF-1) can reverse a range of deficits in PMS. IGF-1 release is stimulated by growth hormone secretion from the anterior pituitary gland, and this study sought to assess the feasibility of increasing IGF-1 levels through recombinant human growth hormone (rhGH) treatment, in addition to establishing safety and exploring efficacy of rhGH in children with PMS. METHODS: rhGH was administered once daily for 12 weeks to six children with PMS using an open-label design. IGF-1 levels, safety, and efficacy assessments were measured every 4 weeks throughout the study. RESULTS: rhGH administration increased levels of IGF-1 by at least 2 standard deviations and was well tolerated without serious adverse events. rhGH treatment was also associated with clinical improvement in social withdrawal, hyperactivity, and sensory symptoms. LIMITATIONS: Results should be interpreted with caution given the small sample size and lack of a placebo control. CONCLUSIONS: Overall, findings are promising and indicate the need for larger studies with rhGH in PMS. Trial registration NCT04003207. Registered July 1, 2019, https://clinicaltrials.gov/ct2/show/NCT04003207 .
