2026-08-11 | Characteristics of adult individuals with Rett syndrome treated or untreated with trofinetide in the United States.

Rett syndrome (RTT) is a rare, progressive MECP2-related neurodevelopmental disorder with substantial lifelong morbidity that persists into adulthood. Although survival has improved, adults often experience evolving multisystem complications and fragmented transition care. Trofinetide (TROF) is approved for ages ≥2 years old, yet data on adults with RTT in the real-world setting remains limited; this study evaluated demographics and characteristics of adults >20 years of age who are treated vs. untreated with TROF. A retrospective analysis of individuals with RTT diagnosis (ICD-10-CM: F84.2) from a linked medical claims and specialty pharmacy database from 01/01/2021 to 09/30/2024 was conducted. RTT individuals were categorized into two groups based on treatment status: treated group (index date: 1st TROF prescription (RX) 04/01/2023 to 03/31/2024) and untreated group (index date: assigned date using a risk set sampling method). Individuals who were ≤20 years of age at index date or had diagnosis for brain trauma or cerebrovascular disease prior to RTT diagnosis were excluded. RTT individuals were required to have continuous enrollment for ≥6 months pre-index and post-index. Demographics and clinical characteristics were assessed during pre-index among the treated and untreated groups. Continuous variables were summarized as means and SD; categorical variables as counts and percentages. There were 1,820 adult RTT individuals (>20 year old) eligible for the analysis: treated group (n = 290 [15.9%]) and untreated group (n = 1,530 [84.1%]). Mean age (SD) at index date was 30.9 (9.9) years (treated group) vs. 33.5 (10.0) years (untreated); and 5.5% vs. 6.7% were males in the treated vs. untreated groups, respectively. Treated group had higher rates of differential diagnoses, but similar rates of baseline comorbidities among both. Treated group also had higher rates of RTT related clinical features vs. untreated group. In this real-world analysis, only 16% of eligible adult RTT individuals were initiated on TROF, while 84% remain untreated. There is a high unmet need for adult individuals with RTT to initiate treatment with TROF. Treated group had higher rates of RTT related clinical features and differential diagnoses; however, the observation that TROF is being used in adults with greater to similar baseline complexity compared to untreated may provide reassurance for prescribers to consider TROF in adults who were untreated.

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2026-08-10 | Translational reading frame predicts the pathogenicity of C-terminal frameshift deletions in MeCP2.

Mutations in the MECP2 gene cause the severe neurological disorder Rett syndrome. A cluster of frameshift-causing C-terminal deletions (CTDs) removes ~100 amino acids and accounts for approximately 10% of RTT-causing mutations. Their pathogenicity is unexpected because this C-terminal domain is dispensable in mice. Analysis of pathogenic and benign human MECP2 variants reveals that some individuals with apparently typical CTDs do not develop Rett syndrome, confirming that C-terminal truncations are not intrinsically pathogenic. Using human sequence data and mouse models we show that pathogenicity results from a marked reduction in MeCP2 levels and depends on the presence of a proline proline stop motif (-PPX) generated by a shift to the +2 reading frame. CTDs that shift to the +1 frame avoid this motif and are benign. Replacing the stop codon of the PPX motif with tryptophan restores MeCP2 expression and rescues RTT-like phenotypes in a CTD mouse model. An adenine base editor efficiently introduces this substitution in cultured cells. These findings define a reliable prognostic distinction between benign and pathogenic CTDs and establish a potential editing strategy for correcting disease-causing CTD mutations.

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2026-07-31 | Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome

Abstract Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder caused by loss-of-function mutations in the MECP2 gene and characterized by profound impairments in neuronal maturation and synaptic connectivity. Increasing evidence indicates that astrocyte dysfunction contributes to RTT pathogenesis through non-cell-autonomous mechanisms, although the molecular pathways underlying defective astrocyte-neuron communication are only partially understood. Astrocytes are the primary source of cholesterol in the brain and support neuronal maturation and synaptic function by supplying cholesterol through ApoE-containing lipoproteins. Although alterations in brain cholesterol metabolism have been reported in RTT, the underlying cellular mechanisms and their functional consequences remain poorly investigated. Here, we studied cholesterol homeostasis in Mecp2 knock-out (KO) astrocytes and its impact on neuron-astrocyte communication. Mecp2 KO astrocytes exhibited reduced nuclear localization of the transcriptional regulator Srebp2, together with the downregulation of genes involved in cholesterol biosynthesis and transport. These molecular alterations were associated with intracellular cholesterol and desmosterol accumulation, reduced Abca1 expression and defective ApoE lipidation, despite preserved ApoE expression and cholesterol secretion. Importantly, similar alterations were detected in acutely isolated astrocytes and in the cerebral cortex of Mecp2 deficient mice, demonstrating that impaired cholesterol homeostasis extends beyond in vitro models. Functionally, cholesterol supplementation of astrocyte-conditioned medium rescued the synaptic defects induced in wild-type neurons by Mecp2 KO astrocytes. Moreover, cholesterol treatment restored pre- and post-synaptic density, as well as axon initial segment length in Mecp2 heterozygous (HET) neurons. Together, these findings identify defective astrocyte-to- neuron cholesterol trafficking as a key mechanism contributing to neuronal dysfunction in RTT and suggest that strategies aimed at restoring cholesterol functional availability might represent a promising therapeutic avenue for RTT.

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2026-07-30 | Mapping Trofinetide Polypharmacology in Rett Syndrome: A Multi-Stage Computational Analysis.

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by mutations in the MECP2 gene. Although trofinetide is the first FDA-approved drug for RTT, its pharmacological mechanism remains unclear. We present a structure-based in silico workflow that integrates target prediction, molecular docking, and 100 ns molecular dynamics (MD) simulations to prioritize potential RTT-relevant targets. Candidate receptors were ranked using a comparative pleiotropic score (PS), as well as an interaction similarity index (SSI) relative to endogenous substrates and reference modulators. Five targets emerged as high-priority candidates (GAT1, GABAA, CHRM1, AMPA, and GSK3β) and were further examined using MD. The simulations supported several binding hypotheses: (i) stable occupation of the orthosteric site in GAT1 and CHRM1, with persistent contacts with ligand-recognition-associated residues (Tyr60 in GAT1 and Asp105 in CHRM1); (ii) sustained binding within the catalytic cleft of GSK3β with recurrent interactions near key catalytic elements (including Lys85); and (iii) dynamic, surface-associated binding modes in GABAA and AMPA, with peripheral residues. In different targets, the proline fragment frequently contributes to hydrophobic anchoring. Taken together, these results provide testable structural hypotheses for the multi-target interaction of trofinetide in RTT and a computational framework to guide experimental validation and next-generation multi-target design.

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2026-07-24 | How I treat Rett syndrome: impact of trofinetide on symptoms and comorbidities of the disease

Rett syndrome (RTT) is a rare neurodevelopmental disorder primarily associated with mutations in the MECP2 gene that lead to developmental regression and difficulties with language, motor skills, and hand use. Additionally, patients with RTT suffer from seizures, scoliosis, issues with sleep, and behavioral and gastrointestinal issues. Trofinetide is approved for the treatment of RTT in patients aged ≥2 years in the US and Canada. Before this approval, core symptoms of RTT lacked pharmacological intervention, and other symptoms and comorbidities were managed individually causing significant polypharmacy. Additionally, some of these symptoms that lack treatment options rank among the most important symptoms to address according to caregivers of patients with RTT. Here, I present the current pharmacological and nonpharmacological approach I use to manage the symptoms and most prevalent comorbidities of RTT in my practice, highlighting areas where trofinetide is positively impactful and overlaying corresponding caregiver ranking of importance. Future research is needed to determine the effect of trofinetide and concomitant medications on the improvement of RTT symptoms.

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