# A novel approach to metabolic profiling in case models of MECP2-related disorders

## TL;DR

This study explores metabolic profiles in MECP2-related disorders using a functional approach, revealing shared and contrasting metabolic trends that could inform future treatments.

## Contribution

The study introduces a novel functional metabolic profiling approach for MECP2-related disorders using PM-M technology.

## Key findings

- Shared metabolic trends included increased energy production with pectin, adenosine, and pyruvic acid.
- Opposing trends were observed for IL-1 beta, with decreased energy in RTT and increased in MRXSL.
- Metabolic profiling shows potential for identifying biomarkers and therapeutic targets in MECP2-related disorders.

## Abstract

Genetic abnormalities of the MECP2 gene cause several conditions grouped under the umbrella term of MECP2-related disorders and characterized by a variety of phenotypes. We applied a functional approach to identify metabolic profiles in two patients with Rett syndrome (RTT) and one patient with MECP2 duplication syndrome (MRXSL). Such an approach is based on the Phenotype Mammalian Microarray (PM-M) technology, which is designed to assess the cellular production of energy in the presence of different compounds generating distinct metabolic environments. The findings in the three case models were compared versus 50 controls. Although the small number of samples prevented most results from reaching significant p-values when adjusted with the Benjamini-Hochberg correction, some interesting trends emerged. Some compounds indicated metabolic trends shared by the two conditions, like increased energy production in the presence of energy sources such as pectin, adenosine, and pyruvic acid, or decreased metabolic response to certain hormones. Other compounds showed opposite trends for the two disorders, like interleukin-1 beta (IL-1 beta), which caused decreased energy production in the RTT group but increased energy production in the patient with MRXSL. The response to IL-1 beta also offers valuable insights into the pathogenic mechanism and potential therapeutic approaches. The metabolic profiling of MECP2-related disorders bears a remarkable translational potential since it may be helpful to investigate the molecular abnormalities underlying the phenotypical variety in this spectrum of conditions, develop biomarkers for the identification of ideal candidates for treatments like the recently approved trofenatide, and identify potential targets for the development of novel therapeutic approaches.

The online version contains supplementary material available at 10.1007/s11011-025-01546-5.