Abstract
BackgroundPhelan-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.MethodsEighteen 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.ResultsThere 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.LimitationsThe 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.ConclusionOur results suggest that intranasal oxytocin is not efficacious in improving the core symptoms of ASD in children with PMS.Trial registration NCT02710084.
Highlights
Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by haploinsuffi‐ ciency of the SHANK3 gene and characterized by global developmental delays, deficits in speech and motor function, and autism spectrum disorder (ASD)
Our results suggest that intranasal oxytocin is not efficacious in improving the core symptoms of ASD in children with PMS
Seventeen of 18 participants met criteria for ASD based on clinical consensus using the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) [56], the Autism Diagnostic Interview-Revised (ADI-R) [55], and the Diagnostic Manual for Mental Disorders, Fifth Edition (DSM-5; [4])
Summary
Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by haploinsuffi‐ ciency of the SHANK3 gene and characterized by global developmental delays, deficits in speech and motor function, and autism spectrum disorder (ASD). ASD is understood to have multiple distinct genetic risk loci, and one Fastman et al Molecular Autism (2021) 12:62 example is SHANK3, where haploinsufficiency through deletion or sequence variants causes Phelan-McDermid syndrome (PMS), which is characterized by global developmental delay, motor skills deficits, delayed or absent speech, and ASD [71]. Studies in Shank3-deficient rats have demonstrated that oxytocin reverses synaptic plasticity deficits in the hippocampus and the medial prefrontal cortex, in addition to reversing behavioral deficits in long-term social recognition memory and attention [45]. Oxytocin has recently been shown to stimulate neurite outgrowth and increase gene expression of Shank protein in human neuroblastoma cells [84] and to reverse neurite abnormalities in Shank3-deficient mice [65]
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