Abstract
Phelan-McDermid syndrome (PMS) or 22q13.3 deletion syndrome is a rare neurodevelopmental disorder with at least 60 children and 35 adults diagnosed in the Netherlands. Clinical features are moderate to severe intellectual disability and behavioural problems in the autism spectrum. Other researchers had observed a beneficial effect of intranasal insulin on development and behaviour in a pilot study in six children with PMS. To validate this effect, we conducted a randomized, double-blind, placebo-controlled clinical trial using a stepped-wedge design. From March 2013 to June 2015, 25 children aged 1–16 years with a molecularly confirmed 22q13.3 deletion including the SHANK3 gene participated in the clinical trial for a period of 18 months. Starting 6 months before the trial, children were systematically assessed for cognitive, language and motor development and for adaptive, social and emotional behaviour every 6 months. The second, third and fourth assessments were followed by daily nose sprays containing either intranasal insulin or intranasal placebo for a 6-month period. A fifth assessment was done directly after the end of the trial. Intranasal insulin did not cause serious adverse events. It increased the level of developmental functioning by 0.4–1.4 months per 6-month period, but the effect was not statistically significant in this small group. We found a stronger effect of intranasal insulin, being significant for cognition and social skills, for children older than 3 years, who usually show a decrease of developmental growth. However, clinical trials in larger study populations are required to prove the therapeutic effect of intranasal insulin in PMS.
Highlights
Phelan-McDermid syndrome (PMS, OMIM 606232) is caused by a deletion on chromosome 22q13.3 that results in a neurodevelopmental disorder
The aim of this study was to evaluate whether the previously reported positive effect of intranasal insulin on development and behaviour in children with PMS could be confirmed in a randomized, double-blind and placebo-controlled clinical trial
Obtaining significant results from clinical trials in a small cohort of patients is a challenge, especially in a clinically variable disorder like PMS, and there are a number of factors that need to be considered that may have impacted the size of the signals we measured
Summary
Phelan-McDermid syndrome (PMS, OMIM 606232) is caused by a deletion on chromosome 22q13.3 that results in a neurodevelopmental disorder. The neurodevelopmental features in PMS are mainly caused by a deletion of the SHANK3 gene (OMIM 606230).[4] Mutations in this gene have been reported in humans with intellectual disability and with autism (reviewed by Leblond et al.),[5] and have been shown to cause deficits in social interaction and learning in animal models.[6,7] SHANK3 is a scaffold protein located at axon terminals and postsynaptic densities of neurons that has an important role in synaptic maturation and neuronal signalling.[8,9] Neurons derived from induced pluripotent stem cells of PMS patients showed reduced SHANK3 mRNA and protein expression, a decreased number of excitatory neurotransmitter-receptors and fewer excitatory synapses.[9] As the molecular mechanisms underlying the syndrome are uncovered, research is gradually focusing on developing therapeutic strategies at the biological level. Replication of these effects in a clinical trial with a larger number of participants is needed
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