Phelan-McDermid Syndrome and SHANK3: Implications for Treatment

Neurotherapeutics. 2015 Jul;12(3):620-30. doi: 10.1007/s13311-015-0352-z.


Phelan-McDermid syndrome (PMS), also called 22q13.3 deletion syndrome, is a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, severe speech delays, poor motor tone and function, and autism spectrum disorder (ASD). Although the overall prevalence of PMS is unknown, there have been at least 1200 cases reported worldwide, according to the Phelan-McDermid Syndrome Foundation. PMS is now considered to be a relatively common cause of ASD and intellectual disability, accounting for between 0.5% and 2.0% of cases. The cause of PMS has been isolated to loss of function of one copy of SHANK3, which codes for a master scaffolding protein found in the postsynaptic density of excitatory synapses. Reduced expression of SH3 and multiple ankyrin repeat domains 3 (SHANK3) leads to reduced numbers of dendrites, and impaired synaptic transmission and plasticity. Recent mouse and human neuronal models of PMS have led to important opportunities to develop novel therapeutics, and at least 2 clinical trials are underway, one in the USA, and one in the Netherlands. The SHANK3 pathway may also be relevant to other forms of ASD, and many of the single-gene causes of ASD identified to date appear to converge on several common molecular pathways that underlie synaptic neurotransmission. As a result, treatments developed for PMS may also affect other forms of ASD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Autism Spectrum Disorder / genetics*
  • Autism Spectrum Disorder / therapy*
  • Brain / metabolism
  • Chromosome Deletion
  • Chromosome Disorders / complications
  • Chromosome Disorders / diagnosis
  • Chromosome Disorders / genetics*
  • Chromosome Disorders / therapy*
  • Chromosomes, Human, Pair 22 / genetics
  • Humans
  • Mice
  • Nerve Tissue Proteins / genetics*
  • Neurons / metabolism
  • Synaptic Transmission / genetics


  • Nerve Tissue Proteins
  • SHANK3 protein, human

Supplementary concepts

  • Telomeric 22q13 Monosomy Syndrome