Stratification of a Phelan-McDermid Syndrome Population Based on Their Response to Human Growth Hormone and...

Area of Science:

• Genetics and Metabolism
• Neurodevelopmental Disorders

Background:

• Phelan-McDermid syndrome (PMS) is a genetic disorder linked to SHANK3 gene variants or 22q13 deletions, causing intellectual disability, autism, and developmental delays.
• Human growth hormone (hGH) and insulin-like growth factor 1 (IGF-1) have shown promise in reversing neurobehavioral deficits in PMS patients.

Purpose of the Study:

• To investigate the metabolic profiles of individuals with PMS and their response to hGH and IGF-1.
• To identify distinct metabolic subpopulations within the PMS cohort based on treatment response.
• To explore shared and distinct metabolic pathways targeted by hGH and IGF-1 in PMS.

Main Methods:

• Metabolic profiling was performed on 48 individuals with PMS and 50 controls.
• Subpopulations were defined as the top and bottom 25% of responders to hGH and IGF-1.
• Correlation analysis was used to compare metabolic responses, particularly for glucose metabolism, between subgroups.

Main Results:

• Individuals with PMS exhibited a unique metabolic profile with reduced major energy source metabolism and increased alternative energy source metabolism.
• A significant overlap in metabolic response was observed between high and low responders to hGH and IGF-1, suggesting shared target pathways.
• Glucose metabolism correlations differed between high-responder subgroups but remained similar in low-responders.

Conclusions:

• Metabolic profiling can differentiate PMS patients and reveal altered energy metabolism.
• hGH and IGF-1 share common therapeutic pathways in PMS, with distinct effects on glucose metabolism subgroups.
• Subgroup classification based on treatment response may facilitate biomarker discovery and personalized therapeutic development for PMS.