The effect of intranasal insulin on development and behaviour of children with Phelan-McDermid syndrome.

In 2009, Schmidt et al. performed a pilot intervention study demonstrating that intranasal insulin may improve development and activity in children with Phelan-McDermid syndrome. This syndrome, characterised by severe developmental delay, generalised hypotonia, inability to reach various physical and mental milestones, severe speech delay and autistic behaviour, is due to a deletion of chromosome 22q13, including the SHANK3 gene. The severe developmental delay and behavioural problems are a social and emotional burden for the family, especially since common therapies for behavioural problems often have insufficient effect in these children. Therefore it is not surprising that already several parents have requested intranasal insulin therapy for their child. SHANK3 is involved in the development of dendritic spines and interacts with cerebral insulin receptors, which might explain the by Schmidt reported positive effect of intranasal insulin in children lacking one copy of the SHANK3 gene. Unfortunately, Schmidt's trial was not placebo-controlled and performed in only six children. Despite the positive results of this pilot study, no further studies are conducted by the initial researchers for financial reasons. Nonetheless, the first results justify a valid methodological study in a larger group to gain evidence for this promising therapy. We propose to conduct a double-blind, placebo-controlled study in 20 children with Phelan-McDermid syndrome using a matched-pairs design. Appropriate age-specific tests will be used to score the effect on development and behaviour. Two baseline tests (Bayley-III), obtained with a six-month interval in all patients, will be used to match at least 20 patients in pairs. Age, gender, developmental age and the six-month increase in development are all used together to match patients as good and close as possible. Both members of each pair enter the trial on the same day and will be treated for a period of 12 months. One member of the matched pair will receive the insulin treatment and the other member will receive the placebo, allocated in a double blind procedure. During treatment, re-assessment on the cognitive scale with Bayley-III is carried out at six months, at the end of the trial at 12 months, and 6 months after the end of the trial. The development of each patient after 6 months and 12 months of treatment will be used to investigate the mid-term and long-term improvement in developmental growth, specifically in cognitive, language and motor abilities, and improvement in behaviour. The test scores six months after the end of the trial are used to investigate a prolonged effect of the insulin treatment. ASQ- and CBCL/1.5-5- tests are performed by the parents at specific time-intervals, to obtain additional information on developmental and behavioural improvements. Additional results of this study will be increase in our knowledge of the developmental course and learning possibilities in children with Phelan-McDermid syndrome and insight in the practical problems that eventually may arise with intranasal administration of drugs in children with developmental delay. In addition, there is growing evidence that also haploinsufficiency of genes coding for proteins related to SHANK3 can result in developmental delay and autistic behaviour. So it is likely that in the future more chromosomal abnormalities are eligible for administration of intranasal insulin. However, the main goal of the present study is to confirm the improvement of psychomotor development, learning abilities and behaviour upon insulin therapy in Phelan-McDermid syndrome. Ultimately, we want to determine whether intranasal insulin should be recommended as standard therapy in these severely affected children.