Advances in Research on Rett Syndrome

A study conducted by the Paediatric Neurometabolic Disorders: Neural Communication Mechanisms and Personalised Therapies Group at IRSJD · SJD Barcelona Children’s Hospital confirms mitochondrial dysfunction in two distinct models of Rett syndrome, highlighting the significance of distinguishing between brain regions and stages of the disease. The findings of this study open up new avenues for treatment development.

Rett syndrome is a neurodevelopmental disorder that predominantly affects girls and is typically attributed to mutations in MECP2, a transcription-regulating gene located on the X chromosome. Currently, there is no effective treatment for this condition. The condition is characterized by a decline in neuronal development subsequent to normal postnatal growth, resulting in the loss of acquired abilities such as speech or deliberate use of hands. Disruptions in neurotransmission and brain development are regarded as the fundamental cause of its pathophysiology. However, recent discoveries have identified impairments in mitochondrial homeostasis, thereby offering a novel therapeutic avenue.

In this research, researchers examined mitochondrial function in two Rett syndrome models, namely primary fibroblasts from patients and the brains of female mice deficient in MeCP2. The study of mouse brains revealed distinct patterns in mitochondrial dysfunction in three brain regions (cortex, hippocampus, and cerebellum) and two developmental stages (3 months for pre-symptomatic mice and 7 months for post-symptomatic mice).

"During the analysis of patient fibroblasts, we observed alterations in mitochondrial shape and function. We further examined the structure of the mitochondrial network and found that in Rett syndrome, it appeared less interconnected with shorter branches". Dr. Alfonso de Oyarzábal, study coordinator and researcher in the Paediatric Neurometabolic Disorders: Neural Communication Mechanisms and Personalised Therapies, emphasized this. "We also observed that the bioenergetics function of fibroblasts revealed a decrease in mitochondrial ATP production correlated with oxidative stress."

Bioenergetic alterations were also observed in Rett syndrome model mice, with a notable impact on the cerebellum, even in stages where the initial symptoms had not yet surfaced.


After characterizing mitochondrial dysfunction in both pathology models, the research team investigated the potential modulating effect of the PPARγ agonist leriglitazone, developed by Minoryx.

The recovery of bioenergetics alterations in fibroblasts from patients was partially exhibited after the treatment. Rett’s mice that were administered leriglitazone from weaning also demonstrated a significant improvement in bioenergetics function, particularly in the cerebellum. An anti-inflammatory effect was observed in the cerebral cortex. Finally, an improvement in the phenotype of treated mice was noted compared to untreated Rett mice. The mice that underwent treatment displayed enhancements in various parameters, including but not limited to their overall condition and exploratory activity.

In two different Rett syndrome models, the study confirms mitochondrial dysfunction, emphasizing the importance of distinguishing between brain areas and disease stages. The treatment of this condition, as well as other mitochondrial disorders, may involve modulating mitochondrial function through the administration of leriglitazone. This research provides the essential preclinical evidence to initiate a clinical trial in patients with Rett syndrome, which is scheduled to commence in the upcoming months. Dr. Alfonso de Oyarzábal has been emphasized.

In addition to the Institut de Recerca Sant Joan de Déu · SJD Barcelona Children's Hospital group, part of CIBER, researchers from the University of Barcelona and CIBER at the Autonomous University of Madrid also collaborated. The study is co-financed by the State Research Agency and patient associations Mi Princesa Rett and Rettando al Síndrome de Rett.

Reference paper

Musokhranova U, Grau C, Vergara C, Rodríguez-Pascau L, Xiol C, Castells AA, Alcántara S, Rodríguez-Pombo P, Pizcueta P, Martinell M, García-Cazorla A, Oyarzábal A. Mitochondrial modulation with leriglitazone as a potential treatment for Rett syndrome. J Transl Med. 2023 Oct 26;21(1):756. doi: 10.1186/s12967-023-04622-5. PMID: 37884937; PMCID: PMC10601217.

"This research provides the essential preclinical evidence to initiate a clinical trial in patients with Rett syndrome, which is scheduled to commence in the upcoming months"