How rare and common risk variation jointly affect liability for autism spectrum disorder / L. KLEI in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 66 p. Titre : How rare and common risk variation jointly affect liability for autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : L. KLEI, Auteur ; L. L. MCCLAIN, Auteur ; B. MAHJANI, Auteur ; K. PANAYIDOU, Auteur ; S. DE RUBEIS, Auteur ; A. S. GRAHNAT, Auteur ; G. KARLSSON, Auteur ; Y. LU, Auteur ; N. MELHEM, Auteur ; X. XU, Auteur ; A. REICHENBERG, Auteur ; S. SANDIN, Auteur ; C. M. HULTMAN, Auteur ; Joseph D. BUXBAUM, Auteur ; K. ROEDER, Auteur ; B. DEVLIN, Auteur Article en page(s) : 66 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  De novo mutation  Genomic-Best Linear Unbiased Prediction (G-BLUP)  Liability  Polygenic risk score Index. décimale : PER Périodiques Résumé : BACKGROUND: Genetic studies have implicated rare and common variations in liability for autism spectrum disorder (ASD). Of the discovered risk variants, those rare in the population invariably have large impact on liability, while common variants have small effects. Yet, collectively, common risk variants account for the majority of population-level variability. How these rare and common risk variants jointly affect liability for individuals requires further study. METHODS: To explore how common and rare variants jointly affect liability, we assessed two cohorts of ASD families characterized for rare and common genetic variations (Simons Simplex Collection and Population-Based Autism Genetics and Environment Study). We analyzed data from 3011 affected subjects, as well as two cohorts of unaffected individuals characterized for common genetic variation: 3011 subjects matched for ancestry to ASD subjects and 11,950 subjects for estimating allele frequencies. We used genetic scores, which assessed the relative burden of common genetic variation affecting risk of ASD (henceforth "burden"), and determined how this burden was distributed among three subpopulations: ASD subjects who carry a potentially damaging variant implicated in risk of ASD ("PDV carriers"); ASD subjects who do not ("non-carriers"); and unaffected subjects who are assumed to be non-carriers. RESULTS: Burden harbored by ASD subjects is stochastically greater than that harbored by control subjects. For PDV carriers, their average burden is intermediate between non-carrier ASD and control subjects. Both carrier and non-carrier ASD subjects have greater burden, on average, than control subjects. The effects of common and rare variants likely combine additively to determine individual-level liability. LIMITATIONS: Only 305 ASD subjects were known PDV carriers. This relatively small subpopulation limits this study to characterizing general patterns of burden, as opposed to effects of specific PDVs or genes. Also, a small fraction of subjects that are categorized as non-carriers could be PDV carriers. CONCLUSIONS: Liability arising from common and rare risk variations likely combines additively to determine risk of any individual diagnosed with ASD. On average, ASD subjects carry a substantial burden of common risk variation, even if they also carry a rare PDV affecting risk. En ligne : http://dx.doi.org/10.1186/s13229-021-00466-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] How rare and common risk variation jointly affect liability for autism spectrum disorder [Texte imprimé et/ou numérique] / L. KLEI, Auteur ; L. L. MCCLAIN, Auteur ; B. MAHJANI, Auteur ; K. PANAYIDOU, Auteur ; S. DE RUBEIS, Auteur ; A. S. GRAHNAT, Auteur ; G. KARLSSON, Auteur ; Y. LU, Auteur ; N. MELHEM, Auteur ; X. XU, Auteur ; A. REICHENBERG, Auteur ; S. SANDIN, Auteur ; C. M. HULTMAN, Auteur ; Joseph D. BUXBAUM, Auteur ; K. ROEDER, Auteur ; B. DEVLIN, Auteur . - 66 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 66 p. Mots-clés : Autism spectrum disorder  De novo mutation  Genomic-Best Linear Unbiased Prediction (G-BLUP)  Liability  Polygenic risk score Index. décimale : PER Périodiques Résumé : BACKGROUND: Genetic studies have implicated rare and common variations in liability for autism spectrum disorder (ASD). Of the discovered risk variants, those rare in the population invariably have large impact on liability, while common variants have small effects. Yet, collectively, common risk variants account for the majority of population-level variability. How these rare and common risk variants jointly affect liability for individuals requires further study. METHODS: To explore how common and rare variants jointly affect liability, we assessed two cohorts of ASD families characterized for rare and common genetic variations (Simons Simplex Collection and Population-Based Autism Genetics and Environment Study). We analyzed data from 3011 affected subjects, as well as two cohorts of unaffected individuals characterized for common genetic variation: 3011 subjects matched for ancestry to ASD subjects and 11,950 subjects for estimating allele frequencies. We used genetic scores, which assessed the relative burden of common genetic variation affecting risk of ASD (henceforth "burden"), and determined how this burden was distributed among three subpopulations: ASD subjects who carry a potentially damaging variant implicated in risk of ASD ("PDV carriers"); ASD subjects who do not ("non-carriers"); and unaffected subjects who are assumed to be non-carriers. RESULTS: Burden harbored by ASD subjects is stochastically greater than that harbored by control subjects. For PDV carriers, their average burden is intermediate between non-carrier ASD and control subjects. Both carrier and non-carrier ASD subjects have greater burden, on average, than control subjects. The effects of common and rare variants likely combine additively to determine individual-level liability. LIMITATIONS: Only 305 ASD subjects were known PDV carriers. This relatively small subpopulation limits this study to characterizing general patterns of burden, as opposed to effects of specific PDVs or genes. Also, a small fraction of subjects that are categorized as non-carriers could be PDV carriers. CONCLUSIONS: Liability arising from common and rare risk variations likely combines additively to determine risk of any individual diagnosed with ASD. On average, ASD subjects carry a substantial burden of common risk variation, even if they also carry a rare PDV affecting risk. En ligne : http://dx.doi.org/10.1186/s13229-021-00466-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

Optimal interpregnancy interval in autism spectrum disorder: A multi-national study of a modifiable risk factor / G. PEREIRA in Autism Research, 14-11 (November 2021)  

Public ISBD [article]  inAutism Research > 14-11 (November 2021) . - p.2432-2443 Titre : Optimal interpregnancy interval in autism spectrum disorder: A multi-national study of a modifiable risk factor Type de document : Texte imprimé et/ou numérique Auteurs : G. PEREIRA, Auteur ; R. W. FRANCIS, Auteur ; M. GISSLER, Auteur ; S. N. HANSEN, Auteur ; A. KODESH, Auteur ; H. LEONARD, Auteur ; S. Z. LEVINE, Auteur ; V. R. MITTER, Auteur ; Erik T. PARNER, Auteur ; A. K. REGAN, Auteur ; A. REICHENBERG, Auteur ; S. SANDIN, Auteur ; A. SUOMINEN, Auteur ; Diana SCHENDEL, Auteur Article en page(s) : p.2432-2443 Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/epidemiology  Birth Intervals  Female  Finland/epidemiology  Humans  Pregnancy  Retrospective Studies  Risk Factors  autism spectrum disorder  family planning services  longitudinal studies Index. décimale : PER Périodiques Résumé : It is biologically plausible that risk of autism spectrum disorder (ASD) is elevated by both short and long interpregnancy intervals (IPI). We conducted a retrospective cohort study of singleton, non-nulliparous live births, 1998-2007 in Denmark, Finland, and Sweden (N = 925,523 births). Optimal IPI was defined as the IPI at which minimum risk was observed. Generalized additive models were used to estimate relative risks (RR) of ASD and 95% Confidence Intervals (CI). Population impact fractions (PIF) for ASD were estimated under scenarios for shifts in the IPI distribution. We observed that the association between ASD (N = 9302) and IPI was U-shaped for all countries. ASD risk was lowest (optimal IPI) at 35?months for all countries combined, and at 30, 33, and 39?months in Denmark, Finland, and Sweden, respectively. Fully adjusted RRs at IPIs of 6, 12, and 60?months were 1.41 (95% CI: 1.08, 1.85), 1.26 (95% CI: 1.02, 1.56), and 1.24 (95% CI: 0.98, 1.58) compared to an IPI of 35?months. Under the most conservative scenario PIFs ranged from 5% (95% CI: 1%-8%) in Denmark to 9% (95% CI: 6%-12%) in Sweden. The minimum ASD risk followed IPIs of 30-39?months across three countries. These results reflect both direct IPI effects and other, closely related social and biological pathways. If our results reflect biologically causal effects, increasing optimal IPIs and reducing their indications, such as unintended pregnancy and delayed age at first pregnancy has the potential to prevent a salient proportion of ASD cases. LAY SUMMARY: Waiting 35?months to conceive again after giving birth resulted in the least risk of autism. Shorter and longer intervals resulted in risks that were up to 50% and 85% higher, respectively. About 5% to 9% of autism cases might be avoided by optimizing birth spacing. En ligne : http://dx.doi.org/10.1002/aur.2599 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=450 [article] Optimal interpregnancy interval in autism spectrum disorder: A multi-national study of a modifiable risk factor [Texte imprimé et/ou numérique] / G. PEREIRA, Auteur ; R. W. FRANCIS, Auteur ; M. GISSLER, Auteur ; S. N. HANSEN, Auteur ; A. KODESH, Auteur ; H. LEONARD, Auteur ; S. Z. LEVINE, Auteur ; V. R. MITTER, Auteur ; Erik T. PARNER, Auteur ; A. K. REGAN, Auteur ; A. REICHENBERG, Auteur ; S. SANDIN, Auteur ; A. SUOMINEN, Auteur ; Diana SCHENDEL, Auteur . - p.2432-2443. Langues : Anglais (eng) in Autism Research > 14-11 (November 2021) . - p.2432-2443 Mots-clés : Autism Spectrum Disorder/epidemiology  Birth Intervals  Female  Finland/epidemiology  Humans  Pregnancy  Retrospective Studies  Risk Factors  autism spectrum disorder  family planning services  longitudinal studies Index. décimale : PER Périodiques Résumé : It is biologically plausible that risk of autism spectrum disorder (ASD) is elevated by both short and long interpregnancy intervals (IPI). We conducted a retrospective cohort study of singleton, non-nulliparous live births, 1998-2007 in Denmark, Finland, and Sweden (N = 925,523 births). Optimal IPI was defined as the IPI at which minimum risk was observed. Generalized additive models were used to estimate relative risks (RR) of ASD and 95% Confidence Intervals (CI). Population impact fractions (PIF) for ASD were estimated under scenarios for shifts in the IPI distribution. We observed that the association between ASD (N = 9302) and IPI was U-shaped for all countries. ASD risk was lowest (optimal IPI) at 35?months for all countries combined, and at 30, 33, and 39?months in Denmark, Finland, and Sweden, respectively. Fully adjusted RRs at IPIs of 6, 12, and 60?months were 1.41 (95% CI: 1.08, 1.85), 1.26 (95% CI: 1.02, 1.56), and 1.24 (95% CI: 0.98, 1.58) compared to an IPI of 35?months. Under the most conservative scenario PIFs ranged from 5% (95% CI: 1%-8%) in Denmark to 9% (95% CI: 6%-12%) in Sweden. The minimum ASD risk followed IPIs of 30-39?months across three countries. These results reflect both direct IPI effects and other, closely related social and biological pathways. If our results reflect biologically causal effects, increasing optimal IPIs and reducing their indications, such as unintended pregnancy and delayed age at first pregnancy has the potential to prevent a salient proportion of ASD cases. LAY SUMMARY: Waiting 35?months to conceive again after giving birth resulted in the least risk of autism. Shorter and longer intervals resulted in risks that were up to 50% and 85% higher, respectively. About 5% to 9% of autism cases might be avoided by optimizing birth spacing. En ligne : http://dx.doi.org/10.1002/aur.2599 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=450

Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder / B. MAHJANI in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 65 p. Titre : Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : B. MAHJANI, Auteur ; S. DE RUBEIS, Auteur ; C. GUSTAVSSON MAHJANI, Auteur ; M. MULHERN, Auteur ; X. XU, Auteur ; L. KLEI, Auteur ; F. K. SATTERSTROM, Auteur ; J. FU, Auteur ; Michael E. TALKOWSKI, Auteur ; A. REICHENBERG, Auteur ; S. SANDIN, Auteur ; C. M. HULTMAN, Auteur ; D. E. GRICE, Auteur ; K. ROEDER, Auteur ; B. DEVLIN, Auteur ; Joseph D. BUXBAUM, Auteur Article en page(s) : 65 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Copy number variant  Intellectual disability  Pages  Single nucleotide variant  Whole exome sequencing  that they have no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: The Autism Sequencing Consortium identified 102 high-confidence autism spectrum disorder (ASD) genes, showing that individuals with ASD and with potentially damaging single nucleotide variation (pdSNV) in these genes had lower cognitive levels and delayed age at walking, when compared to ASD participants without pdSNV. Here, we made use of a Swedish sample of individuals with ASD (called PAGES, for Population-Based Autism Genetics & Environment Study) to evaluate the frequency of pdSNV and their impact on medical and psychiatric phenotypes, using an epidemiological frame and universal health reporting. We then combine findings with those for potentially damaging copy number variation (pdCNV). METHODS: SNV and CNV calls were generated from whole-exome sequencing and chromosome microarray data, respectively. Birth and medical register data were used to collect phenotypes. RESULTS: Of 808 individuals assessed by sequencing, 69 (9%) had pdSNV in the 102 ASC genes, and 144 (18%) had pdSNV in the 102 ASC genes or in a larger set of curated neurodevelopmental genes (from the Deciphering Developmental Disorders study, the gene2phenotype database, and the Radboud University gene lists). Three or more individuals had pdSNV in GRIN2B, POGZ, SATB1, DYNC1H1, SCN8A, or CREBBP. In comparison, out of the 996 individuals from whom CNV were called, 105 (11%) carried one or more pdCNV, including four or more individuals with CNV in the recurrent 15q11q13, 22q11.2, and 16p11.2 loci. Carriers of pdSNV were more likely to have intellectual disability (ID) and epilepsy, while carriers of pdCNV showed increased rates of congenital anomalies and scholastic skill disorders. Carriers of either pdSNV or pdCNV were more likely to have ID, scholastic skill disorders, and epilepsy. LIMITATIONS: The cohort only included individuals with autistic disorder, the more severe form of ASD, and phenotypes are defined from medical registers. Not all genes studied are definitively ASD genes, and we did not have de novo information to aid in classification. CONCLUSIONS: In this epidemiological sample, rare pdSNV were more common than pdCNV and the combined yield of potentially damaging variation was substantial at 27%. The results provide compelling rationale for the use of high-throughout sequencing as part of routine clinical workup for ASD and support the development of precision medicine in ASD. En ligne : http://dx.doi.org/10.1186/s13229-021-00465-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder [Texte imprimé et/ou numérique] / B. MAHJANI, Auteur ; S. DE RUBEIS, Auteur ; C. GUSTAVSSON MAHJANI, Auteur ; M. MULHERN, Auteur ; X. XU, Auteur ; L. KLEI, Auteur ; F. K. SATTERSTROM, Auteur ; J. FU, Auteur ; Michael E. TALKOWSKI, Auteur ; A. REICHENBERG, Auteur ; S. SANDIN, Auteur ; C. M. HULTMAN, Auteur ; D. E. GRICE, Auteur ; K. ROEDER, Auteur ; B. DEVLIN, Auteur ; Joseph D. BUXBAUM, Auteur . - 65 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 65 p. Mots-clés : Autism spectrum disorder  Copy number variant  Intellectual disability  Pages  Single nucleotide variant  Whole exome sequencing  that they have no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: The Autism Sequencing Consortium identified 102 high-confidence autism spectrum disorder (ASD) genes, showing that individuals with ASD and with potentially damaging single nucleotide variation (pdSNV) in these genes had lower cognitive levels and delayed age at walking, when compared to ASD participants without pdSNV. Here, we made use of a Swedish sample of individuals with ASD (called PAGES, for Population-Based Autism Genetics & Environment Study) to evaluate the frequency of pdSNV and their impact on medical and psychiatric phenotypes, using an epidemiological frame and universal health reporting. We then combine findings with those for potentially damaging copy number variation (pdCNV). METHODS: SNV and CNV calls were generated from whole-exome sequencing and chromosome microarray data, respectively. Birth and medical register data were used to collect phenotypes. RESULTS: Of 808 individuals assessed by sequencing, 69 (9%) had pdSNV in the 102 ASC genes, and 144 (18%) had pdSNV in the 102 ASC genes or in a larger set of curated neurodevelopmental genes (from the Deciphering Developmental Disorders study, the gene2phenotype database, and the Radboud University gene lists). Three or more individuals had pdSNV in GRIN2B, POGZ, SATB1, DYNC1H1, SCN8A, or CREBBP. In comparison, out of the 996 individuals from whom CNV were called, 105 (11%) carried one or more pdCNV, including four or more individuals with CNV in the recurrent 15q11q13, 22q11.2, and 16p11.2 loci. Carriers of pdSNV were more likely to have intellectual disability (ID) and epilepsy, while carriers of pdCNV showed increased rates of congenital anomalies and scholastic skill disorders. Carriers of either pdSNV or pdCNV were more likely to have ID, scholastic skill disorders, and epilepsy. LIMITATIONS: The cohort only included individuals with autistic disorder, the more severe form of ASD, and phenotypes are defined from medical registers. Not all genes studied are definitively ASD genes, and we did not have de novo information to aid in classification. CONCLUSIONS: In this epidemiological sample, rare pdSNV were more common than pdCNV and the combined yield of potentially damaging variation was substantial at 27%. The results provide compelling rationale for the use of high-throughout sequencing as part of routine clinical workup for ASD and support the development of precision medicine in ASD. En ligne : http://dx.doi.org/10.1186/s13229-021-00465-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

A proof-of-concept study of growth hormone in children with Phelan-McDermid syndrome / S. SETHURAM in Molecular Autism, 13 (2022)  

Public ISBD [article]  inMolecular Autism > 13 (2022) . - 6p. Titre : A proof-of-concept study of growth hormone in children with Phelan-McDermid syndrome Type de document : Texte imprimé et/ou numérique Auteurs : S. SETHURAM, Auteur ; T. LEVY, Auteur ; J. FOSS-FEIG, Auteur ; Danielle B. HALPERN, Auteur ; S. SANDIN, Auteur ; P. M. SIPER, Auteur ; H. WALKER, Auteur ; Joseph D. BUXBAUM, Auteur ; R. RAPAPORT, Auteur ; A. KOLEVZON, Auteur Article en page(s) : 6p. Langues : Anglais (eng) Mots-clés : Asd  Autism spectrum disorder  Growth hormone  Igf-1  Insulin-like growth factor-1  Pms  Phelan–McDermid syndrome  Shank3  Jaguar, Neuren, GW Pharma, and Ovid Therapeutics. JDB has a shared patent with Mount  Sinai for IGF-1 in Phelan–McDermid syndrome. No other authors have competing  interests to disclose. Index. décimale : PER Périodiques Résumé : 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 . En ligne : http://dx.doi.org/10.1186/s13229-022-00485-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] A proof-of-concept study of growth hormone in children with Phelan-McDermid syndrome [Texte imprimé et/ou numérique] / S. SETHURAM, Auteur ; T. LEVY, Auteur ; J. FOSS-FEIG, Auteur ; Danielle B. HALPERN, Auteur ; S. SANDIN, Auteur ; P. M. SIPER, Auteur ; H. WALKER, Auteur ; Joseph D. BUXBAUM, Auteur ; R. RAPAPORT, Auteur ; A. KOLEVZON, Auteur . - 6p. Langues : Anglais (eng) in Molecular Autism > 13 (2022) . - 6p. Mots-clés : Asd  Autism spectrum disorder  Growth hormone  Igf-1  Insulin-like growth factor-1  Pms  Phelan–McDermid syndrome  Shank3  Jaguar, Neuren, GW Pharma, and Ovid Therapeutics. JDB has a shared patent with Mount  Sinai for IGF-1 in Phelan–McDermid syndrome. No other authors have competing  interests to disclose. Index. décimale : PER Périodiques Résumé : 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 . En ligne : http://dx.doi.org/10.1186/s13229-022-00485-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

A randomized controlled trial of intranasal oxytocin in Phelan-McDermid syndrome / J. FASTMAN in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 62 p. Titre : A randomized controlled trial of intranasal oxytocin in Phelan-McDermid syndrome Type de document : Texte imprimé et/ou numérique Auteurs : J. FASTMAN, Auteur ; J. FOSS-FEIG, Auteur ; Y. FRANK, Auteur ; Danielle B. HALPERN, Auteur ; Hala HARONY-NICOLAS, Auteur ; C. LAYTON, Auteur ; S. SANDIN, Auteur ; P. SIPER, Auteur ; L. TANG, Auteur ; P. TRELLES, Auteur ; J. ZWEIFACH, Auteur ; Joseph D. BUXBAUM, Auteur ; A. KOLEVZON, Auteur Article en page(s) : 62 p. Langues : Anglais (eng) Mots-clés : Asd  Autism spectrum disorder  Oxytocin  Pms  Phelan-McDermid syndrome  Shank3  Ovid Therapeutics. JDB has a shared patent with Mount Sinai for IGF-1 in  Phelan-McDermid syndrome. No other authors have competing interests to disclose. Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene and characterized by global developmental delays, deficits in speech and motor function, and autism spectrum disorder (ASD). Monogenic causes of ASD such as PMS are well suited to investigations with novel therapeutics, as interventions can be targeted based on established genetic etiology. While preclinical studies have demonstrated that the neuropeptide oxytocin can reverse electrophysiological, attentional, and social recognition memory deficits in Shank3-deficient rats, there have been no trials in individuals with PMS. The purpose of this study is to assess the efficacy and safety of intranasal oxytocin as a treatment for the core symptoms of ASD in a cohort of children with PMS. METHODS: Eighteen children aged 5-17 with PMS were enrolled. Participants were randomized to receive intranasal oxytocin or placebo (intranasal saline) and underwent treatment during a 12-week double-blind, parallel group phase, followed by a 12-week open-label extension phase during which all participants received oxytocin. Efficacy was assessed using the primary outcome of the Aberrant Behavior Checklist-Social Withdrawal (ABC-SW) subscale as well as a number of secondary outcome measures related to the core symptoms of ASD. Safety was monitored throughout the study period. RESULTS: There was no statistically significant improvement with oxytocin as compared to placebo on the ABC-SW (Mann-Whitney U?=?50, p?=?0.055), or on any secondary outcome measures, during either the double-blind or open-label phases. Oxytocin was generally well tolerated, and there were no serious adverse events. LIMITATIONS: The small sample size, potential challenges with drug administration, and expectancy bias due to relying on parent reported outcome measures may all contribute to limitations in interpreting results. CONCLUSION: Our results suggest that intranasal oxytocin is not efficacious in improving the core symptoms of ASD in children with PMS. Trial registration NCT02710084. En ligne : http://dx.doi.org/10.1186/s13229-021-00459-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] A randomized controlled trial of intranasal oxytocin in Phelan-McDermid syndrome [Texte imprimé et/ou numérique] / J. FASTMAN, Auteur ; J. FOSS-FEIG, Auteur ; Y. FRANK, Auteur ; Danielle B. HALPERN, Auteur ; Hala HARONY-NICOLAS, Auteur ; C. LAYTON, Auteur ; S. SANDIN, Auteur ; P. SIPER, Auteur ; L. TANG, Auteur ; P. TRELLES, Auteur ; J. ZWEIFACH, Auteur ; Joseph D. BUXBAUM, Auteur ; A. KOLEVZON, Auteur . - 62 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 62 p. Mots-clés : Asd  Autism spectrum disorder  Oxytocin  Pms  Phelan-McDermid syndrome  Shank3  Ovid Therapeutics. JDB has a shared patent with Mount Sinai for IGF-1 in  Phelan-McDermid syndrome. No other authors have competing interests to disclose. Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene and characterized by global developmental delays, deficits in speech and motor function, and autism spectrum disorder (ASD). Monogenic causes of ASD such as PMS are well suited to investigations with novel therapeutics, as interventions can be targeted based on established genetic etiology. While preclinical studies have demonstrated that the neuropeptide oxytocin can reverse electrophysiological, attentional, and social recognition memory deficits in Shank3-deficient rats, there have been no trials in individuals with PMS. The purpose of this study is to assess the efficacy and safety of intranasal oxytocin as a treatment for the core symptoms of ASD in a cohort of children with PMS. METHODS: Eighteen children aged 5-17 with PMS were enrolled. Participants were randomized to receive intranasal oxytocin or placebo (intranasal saline) and underwent treatment during a 12-week double-blind, parallel group phase, followed by a 12-week open-label extension phase during which all participants received oxytocin. Efficacy was assessed using the primary outcome of the Aberrant Behavior Checklist-Social Withdrawal (ABC-SW) subscale as well as a number of secondary outcome measures related to the core symptoms of ASD. Safety was monitored throughout the study period. RESULTS: There was no statistically significant improvement with oxytocin as compared to placebo on the ABC-SW (Mann-Whitney U?=?50, p?=?0.055), or on any secondary outcome measures, during either the double-blind or open-label phases. Oxytocin was generally well tolerated, and there were no serious adverse events. LIMITATIONS: The small sample size, potential challenges with drug administration, and expectancy bias due to relying on parent reported outcome measures may all contribute to limitations in interpreting results. CONCLUSION: Our results suggest that intranasal oxytocin is not efficacious in improving the core symptoms of ASD in children with PMS. Trial registration NCT02710084. En ligne : http://dx.doi.org/10.1186/s13229-021-00459-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

Reproductive stoppage in autism spectrum disorder in a population of 2.5 million individuals / R. KUJA-HALKOLA in Molecular Autism, 10 (2019)  

Permalink

---

1 (1 - 6 / 6)