2026-01-15 | Functional skills in MECP2 duplication syndrome: developmental dynamics and regression.
MECP2 duplication syndrome (MDS) is an ultrarare, X-linked neurodevelopmental disorder that is poorly understood in terms of its natural history and phenotypic variability. There is limited information on how individuals with MDS acquire, retain or lose fundamental functional skills (gross motor, purposeful hand function and communication) - that of which this study aimed to better characterise in the largest case series to date.For 160 individuals with MDS (median age 9.06 y, range: 0.57-51.63 y; 84% male), we report that phenotypic penetrance in females can, in some, result in a similar functional skill deficits to males. However, a higher proportion of females acquired gross motor and fine motor skills compared to males. Use of words was the most common parent-reported skill regression (34/90 [38%]) followed by fine motor/hand function (26/90 [29%]), independent walking (25/90 [28%]) and feeding (25/90 [28%]). Additionally, lower proportions of functional ability were present in those with seizures compared to those without. A general trend was also observed for decreasing functional skills with increasing age. Additionally, those with a larger duplication length (1 + Mb) were less likely to be able to acquire independent walking compared with those with less than a 1 + Mb duplication (p < 0.001).This is the first study to comprehensively map the developmental trajectory of functional skills in MDS and provides a seminal baseline for better characterising the natural history of this disorder. Further investigations are required to understand the importance of interventional therapy on the retainment of functional skills.
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2026-01-07 | MECP2 Duplication Uncouples Mitochondrial and Purine Metabolism During neuronal maturation.
Mitochondria and nucleotide metabolism are critical for cellular and developmental homeostasis, yet their potential interdependence and role in neurodevelopmental disease remain unclear. In MECP2 Duplication Syndrome (MDS), we identify a conserved correlation between mitochondrial function and purine metabolism that is disrupted across human, organoid, and mouse models. Multiomics integration reveals Complex III as the focal point of mitochondrial collapse, leading to redox stress, DNA damage, and hyperactivation of the de novo purine biosynthesis via purinosome assembly. The breakdown of mitochondria-purinosome coupling compromises genome stability, impairs radial glia proliferation, and delays neuronal maturation. By linking a defined genetic dosage imbalance to metabolic network failure, our study positions the mitochondria-purinosome coordination as a fundamental control axis for neurodevelopment and a therapeutic entry point across metabolic and neurodevelopmental disorders.
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2025-12-18 | Mesodermal-specific MECP2 expression in Drosophila induces visceral and skeletal muscle defects rescued by butyrate supplementation
Abstract Background Patients affected by Rett syndrome (RTT) and MECP2 duplication syndrome (MDS) experience disabling muscle weakness and gastrointestinal dysmotility of unclear origin. Whether these defects arise cell-autonomously, rather than secondarily to neural dysfunction, and which developmental windows are most vulnerable to MeCP2 disfunction remains unresolved. MeCP2 is a dosage-sensitive transcriptional regulator, whose functions are tightly linked to chromatin states. Because short-chain fatty acids (SCFAs) are known to inhibit histone deacetylases (HDACs), a tractable in vivo model is needed to test the effect of HDAC modulation on muscle defects. Methods We misexpressed human MECP2 in the Drosophila melanogaster mesoderm that gives rise to skeletal and visceral muscles. We analyzed quantitatively their morphology and function. To assess the effects of SCFA supplementation, we also supplemented diets with sodium butyrate (NaB), Lalbaay®, a NaB-containing supplement, acetate (AcOH), and valproate (VPA). Findings MECP2 misexpression caused pre-eclosion lethality, thinning of larval skeletal fibers with nuclear mispositioning and altered mitochondria. Functionally, it reduced locomotion, decreased food transit and gut peristalsis. Phenotypes were strongest when expression began during development. NaB and VPA supplementation rescue most of these phenotypes, consistent with their histone-deacetylase (HDAC) activity. Defects were not observed upon comparable misexpression of an RTT-associated MeCP2 loss-of-function variant, indicating that they might be relevant to pathogenesis of MECP2-related disorders. Interpretation Our genetic in vivo analysis models peripheral effects of MeCP2 dysregulation and their amelioration, supporting the possibility of HDAC-targeted strategies for MECP2-related muscle and gastrointestinal dysfunction.
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