Metabolic changes in mTOR pathway-associated cortical malformation

Area of Science:

• Neuroscience
• Developmental Biology
• Metabolic Disorders

Background:

• Malformations of cortical development (MCD) are a leading cause of epilepsy, autism spectrum disorder (ASD), and intellectual disability (ID).
• The heterogeneity of MCD subtypes has hindered the identification of unifying mechanistic etiologies.
• Dysfunctional brain metabolism is increasingly recognized as a potential convergent mechanism across various neurodevelopmental disorders.

Purpose of the Study:

• To comprehensively review metabolic alterations in MCD associated with mTOR pathway gene mutations (mTORopathies), the most common cause of MCD.
• To identify key cellular and molecular metabolic pathways involved in MCD pathogenesis during prenatal development.
• To explore how these metabolic dysfunctions may contribute to common mTORopathy phenotypes and persistent abnormal brain activity.

Main Methods:

• Literature review focusing on studies investigating brain metabolism in mTORopathies.
• Analysis of findings related to macromolecule processing and mitochondrial metabolism in MCD.
• Discussion of cellular and molecular metabolic pathways implicated in mTORopathies.

Main Results:

• mTORopathies are characterized by dysfunctional brain metabolism, including aberrant macromolecule processing.
• Mitochondrial metabolism is significantly altered in MCD associated with mTOR pathway gene mutations.
• Specific metabolic pathways are identified as crucial for in utero MCD development and sustained abnormal brain activity.

Conclusions:

• Disrupted brain metabolism, particularly involving macromolecule and mitochondrial processes, is a key feature of mTORopathies.
• Understanding these metabolic pathways offers potential therapeutic avenues for conditions like epilepsy, ASD, and ID.
• Targeting metabolic dysfunctions may provide a unifying therapeutic strategy for diverse mTORopathy phenotypes.