Progress in Rett Syndrome: from discovery to clinical trials

Abstract

SummaryFifty years ago, Andreas Rett described a disorder in 22 females featuring prominent regression of fine motor and communication skills, cognitive impairment, stereotypic movements, periodic breathing, and gait abnormalities. This disorder became known as Rett syndrome (RTT) following the report of Hagberg et al. in 1983. Although RTT was scarcely recognized at that time in the United States, here the efforts of Rett and Hagberg led to rapid progress in recognition and diagnosis, a clearer understanding of its clinical and pathological underpinnings, and, ultimately, identification of mutations in the methyl-CpG-binding protein 2 (MECP2) gene as the primary cause of this unique and challenging neurodevelopmental disorder. Thereafter, a natural history study and critical translational research in animal models paved the way for potential disease-modifying agents to be assessed in human clinical trials. To be successful, the energies of the international community at all levels, including researchers in clinical and basic science, funding agencies, pharmaceutical companies, patient advocates, and, above all, parents and their children are essential. Otherwise, hopes for effective treatment, if not, a cure, will remain unfulfilled.

Placebo‐controlled crossover assessment of mecasermin for the treatment of Rett syndrome

“…In-house Matlabbased software was used to calculate frontal power spectral density binned into bandwidths previously described. 25 Alpha asymmetry scores were calculated by subtracting the average natural log alpha power (6)(7)(8)(9)(10)(11)(12)(13) Hz) on the left side from the natural log alpha power on the right side, [26][27][28][29] with positive values corresponding to higher power in the right hemisphere but greater activation in the left hemisphere.…”

“…Other common features include growth retardation, seizures, breathing abnormalities, vasomotor disturbances, and abnormal behavior 1, 2, 3, 5, 6, 7, 8. The current standard of care is symptomatic management, with no available treatments aimed at ameliorating the cardinal symptoms of the disorder 9, 10, 11…”

“…[1][2][3][5][6][7][8] The current standard of care is symptomatic management, with no available treatments aimed at ameliorating the cardinal symptoms of the disorder. [9][10][11] Our initial understanding of the neurobiological bases of the disorder, primarily from tissue sample studies of children affected by RTT, served as the foundation for early drug trials. 9,12 More recently, work on the role of MECP2 in synaptic maturation and maintenance and assessment of interventions in MECP2-deficient mice has resulted in potential therapeutic strategies.…”

Breathing abnormalities in animal models of Rett syndrome a female neurogenetic disorder

“…The other is the transcriptional repression domain. In addition to transcriptional repression, the MeCP2 may regulate transcriptional activation and alternative splicing (Chahrour et al, 2008; Percy, 2016; Young et al, 2005). Although MeCP2 is expressed in almost all cell types, its mutations mainly affect neural development with mechanisms remaining to be fully understood (Dura et al, 2008).…”

“…Although there are reports of neuron loss in mouse models, neurodegeneration is not evident in human patients, which is supported by other studies in the mouse models. Thus, RTT is not considered as a neurodegenerative disease (Chahrour et al, 2008; Percy, 2016; Young et al, 2005). …”