Lithium as a possible therapeutic strategy for Cornelia de Lange syndrome

Area of Science:

• Developmental Biology
• Neuroscience
• Genetics

Background:

• Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder causing widespread developmental issues, including neurodevelopmental delay.
• CdLS is linked to the dysregulation of crucial developmental pathways, notably the canonical WNT pathway.
• Brain structural abnormalities, particularly in hindbrain structures, are associated with behavioral disturbances in CdLS patients.

Purpose of the Study:

• To investigate the relationship between MRI anomalies, clinical manifestations, and brain structure in CdLS.
• To explore the therapeutic potential of activating the WNT pathway using lithium chloride in CdLS models.

Main Methods:

• Evaluation of MRI scans, behavioral, and neurological data in CdLS patients.
• Utilizing a Drosophila melanogaster CdLS model to assess mushroom body morphology.
• Employing mouse neural stem cells and patient-derived lymphoblastoid cell lines to study cellular proliferation and differentiation.
• Administering lithium chloride to activate the WNT pathway in experimental models.

Main Results:

• A significant association was found between behavioral disturbances and structural abnormalities in hindbrain-derived brain structures in CdLS patients.
• Lithium chloride treatment rescued mushroom body morphology in a Drosophila CdLS model.
• In mouse neural stem cells, lithium restored normal proliferation and neuronal differentiation.
• Lithium treatment normalized proliferation rates and increased CyclinD1 expression in CdLS lymphoblastoid cell lines.

Conclusions:

• The WNT pathway plays a critical role in the brain and behavioral abnormalities observed in CdLS.
• Chemical activation of the WNT pathway with lithium chloride demonstrates a consistent phenotype rescue across multiple experimental models.
• These findings suggest WNT pathway modulation as a potential therapeutic strategy for CdLS.