Mapping the Phenotype of Phelan McDermid Syndrome

Background: Phelan McDermid Syndrome (PMS), also called 22q13 Deletion Syndrome, is caused by deletion or mutation of the SHANK3 gene located at the terminal end of chromosome 22 (Durand et al., 2007). The SHANK3 gene codes for a master scaffolding protein which forms a key framework in the postsynaptic density of glutamatergic synapses and plays a critical role in synaptic function (Boeckers et al., 2006).  PMS is characterized by global developmental delays, severely delayed or absent speech, motor skill deficits, and autism spectrum disorder (ASD) (Soorya et al., 2013). The clinical presentation has been described in several case report series and some prospective analyses yet no study has comprehensively described the neurobehavioral phenotype.

Objectives: The aim of this study was to refine the ASD phenotype within PMS and preliminary results presented herein focus on the restricted and repetitive behavior domain.  

Methods: Subjects were recruited as part of ongoing studies in PMS at the Seaver Autism Center at Mount Sinai.  The following questionnaires were administered to caregivers of affected children in person, via telephone or mail: Aberrant Behavior Checklist (ABC; Aman et al., 1985); Repetitive Behavior Scale-Revised (RBS; Bodfish et al. 2000); Nisonger Child Behavior Rating Form (NCBRF; Aman et al., 1996); Sensory Profile (Dunn, 1999).

Results: Of 30 recruited subjects, 86.7% completed all parent questionnaires (56.7% male; mean age=10.8 years; SD=8.06). Results were compared to published samples in ASD or intellectual disability (ID). One-way analysis of variance (ANOVA) was performed for each domain on each assessment to determine whether there were significant differences between groups.

Results suggest that differences exist between children with PMS and those with ASD and/or ID with regard to restricted and repetitive behaviors. Specifically, children with PMS show: (a) less irritability, evidenced by lower mean levels of Irritability on the ABC (p<0.003); (b) fewer repetitive behaviors in all but one domain (Self-Injurious) on the RBS [Stereotypic and Ritualistic (p<0.003), Sameness (p<0.03), Compulsive and Restricted (p<0.05)]; (c) less anxiety according to the NCBRF Anxiety domain (p<0.003). No differences were observed in the following domains: (a) stereotypies on the ABC or NCBRF; (b) ritualistic behavior on the NCBRF; (c) self-injurious behavior on the RBS; (d) sensory reactivity or sensory seeking on the Sensory Profile.

Results for stereotypic and ritualistic behavior conflicted across instruments. The RBS suggested lower levels of stereotypic and ritualistic behavior in PMS compared to ASD while the NCBRF showed no difference compared to ID.  This discrepancy may be due to the types of items included in the assessment of these domains across instruments and/or differences in comparison samples.  

Conclusions: These results suggest that the ASD phenotype within PMS may be distinguished from idiopathic ASD and/or ID. Future studies will focus on refining the understanding of the social, cognitive, and language domains in PMS, and will explore whether a correlation exists between genotype and phenotypic severity. Characterizing the neurobehavioral phenotype in PMS is critical for developing appropriate assessment tools and outcome measures for use in treatment studies.