# Electrophysiological Markers for Interventions in Phelan-McDermid Syndrome and Idiopathic Autism

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $678,016

## Abstract

PROJECT SUMMARY
Recent work suggests that up to 2% of individuals with autism spectrum disorder (ASD) and
intellectual disability (ID) have deletions or point mutations in the SHANK3 gene, resulting in
Phelan-McDermid syndrome (PMS), and approximately 85% of people with PMS meet criteria
for ASD. SHANK3 codes for a master scaffolding protein that forms a key framework in the
postsynaptic density of glutamatergic (excitatory) synapses and plays a critical role in synaptic
function. SHANK3 and glutamate pathways are implicated in multiple forms of ASD and this
convergence implies shared biochemical pathways with potentially overlapping therapeutic
targets. Thus, targeting SHANK3 deficiency in PMS as a specific genetic cause of ASD allows
us to inform treatment in broader idiopathic ASD (iASD). Our ongoing studies provide in-depth
phenotyping of PMS, pointing toward a specific clinical and electrophysiological (EEG) profile.
However, the efficacy of potential EEG biomarkers as a measure of treatment response remains
to be determined.
 Preliminary data using visual evoked potentials (VEPs) to examine cortical excitatory
postsynaptic potentials demonstrate promising links to disease mechanisms in PMS and iASD.
Biomarkers and novel clinical measures for evaluating response to intervention have also been
piloted successfully at our site in cohorts of patients with PMS and iASD. We have identified a
unique VEP profile of excitatory deficits in PMS (markedly reduced P60-N75 amplitude) that is
also present in a subset of children with iASD. Here, we propose to extend this work to a larger
sample in PMS and to parallel excitatory processes in the auditory domain, in order to stratify
individuals with iASD and select those we predict will show response to IGF-1.
 We will enroll 150 children (60 PMS; 90 iASD; age 5-12 years), specifically recruiting
intellectually disabled and minimally verbal children given the prominence of this profile in PMS
and the critical need to address this group in broader ASD research. Our short-term goal is to
show that select electrophysiological markers in PMS are relevant to iASD and predictive of
treatment response. Our long-term goal is to optimize treatment selection in iASD by
establishing biological signature(s) derived from PMS that are: a) useful for predicting treatment
responders, and b) responsive to intervention. The expected outcome of this study is to
establish the feasibility of electrophysiological biomarkers for use in clinical trials in PMS and
iASD and to define a biological profile that will mark a subset of patients with iASD likely to show
neural and clinical response to IGF-1.

## Key facts

- **NIH application ID:** 10383750
- **Project number:** 5R01NS105845-05
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** ALEXANDER KOLEVZON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $678,016
- **Award type:** 5
- **Project period:** 2018-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10383750

## Citation

> US National Institutes of Health, RePORTER application 10383750, Electrophysiological Markers for Interventions in Phelan-McDermid Syndrome and Idiopathic Autism (5R01NS105845-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10383750. Licensed CC0.

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