Rett Syndrome
A rare neurodevelopmental disorder (approximately 1 in 10,000-15,000 female births) caused by MECP2 gene mutations, leading to regression of acquired skills, stereotypical hand movements, and severe impairment. Trofinetide became the first approved treatment in 2023, modulating neuroinflammation and synaptic function.
Technical Context
MECP2 (methyl-CpG binding protein 2) function: binds methylated CpG dinucleotides in DNA → recruits co-repressor complexes → regulates gene expression in neurons. MECP2 loss → widespread transcriptional dysregulation affecting: BDNF expression (reduced), glutamate signalling (altered excitatory/inhibitory balance), synaptic maturation (impaired), and microglial function (inflammatory phenotype). Clinical stages: Stage I (6-18 months — developmental stagnation), Stage II (1-4 years — rapid regression, loss of hand skills and speech, onset of stereotypies), Stage III (preschool-adult — pseudo-stationary, some improvement in social interaction, seizures), Stage IV (late motor deterioration — reduced mobility, scoliosis). Trofinetide (Daybue): synthetic GPE tripeptide (Gly-Pro-Glu, N-terminal tripeptide of IGF-1), 2× daily oral solution. LAVENDER Phase III trial: significant improvement in RTTCGS (Rett Syndrome Clinician Global Impression Scale) and CSBS-DP-IT (Communication and Symbolic Behavior Scales). FDA approval March 2023 — the first drug specifically approved for Rett syndrome. Mechanism: proposed modulation of neuroinflammation, glutamate-mediated excitotoxicity, and synaptic function.