Abstract
Rett syndrome (RTT) is a monogenic neurodevelopmental disorder primarily caused by mutations in X-linked MECP2 gene, encoding for methyl-CpG binding protein 2 (MeCP2), a multifaceted modulator of gene expression and chromatin organization. Based on the type of mutation, RTT patients exhibit a broad spectrum of clinical phenotypes with various degrees of severity. In addition, as a complex multisystem disease, RTT shows several clinical manifestations ranging from neurological to non-neurological symptoms. The most common non-neurological comorbidities include, among others, orthopedic complications, mainly scoliosis but also early osteopenia/osteoporosis and a high frequency of fractures. A characteristic low bone mineral density dependent on a slow rate of bone formation due to dysfunctional osteoblast activity rather than an increase in bone resorption is at the root of these complications. Evidence from human and animal studies supports the idea that MECP2 mutation could be associated with altered epigenetic regulation of bone-related factors and signaling pathways, including SFRP4/WNT/β-catenin axis and RANKL/RANK/OPG system. More research is needed to better understand the role of MeCP2 in bone homeostasis. Indeed, uncovering the molecular mechanisms underlying RTT bone problems could reveal new potential pharmacological targets for the treatment of these complications that adversely affect the quality of life of RTT patients for whom the only therapeutic approaches currently available include bisphosphonates, dietary supplements, and physical activity.
Highlights
Rett SyndromeRett syndrome (RTT; OMIM ID 312750) is a devastating neurodevelopmental disorder, which mainly affects female subjects with a prevalence rate of approximately 1:10,000 live births [1,2,3,4,5]
The X-chromosome inactivation, a known mechanism of gene dosage compensation, leads cells and tissues of RTT patients to show a mosaic pattern for MECP2; the ratio between the wildtype and mutated versions of methyl-CpG binding protein 2 (MeCP2) protein can in part be responsible for the severity of the disorder phenotype [24,25,26,27]
RTT is a monogenic disorder with a complex multisystem phenotype predominantly characterized by neurological deficits, which are associated with a broad spectrum of other peripheral anomalies
Summary
Rett syndrome (RTT; OMIM ID 312750) is a devastating neurodevelopmental disorder, which mainly affects female subjects with a prevalence rate of approximately 1:10,000 live births [1,2,3,4,5]. The X-chromosome inactivation, a known mechanism of gene dosage compensation, leads cells and tissues of RTT patients to show a mosaic pattern for MECP2; the ratio between the wildtype and mutated versions of MeCP2 protein can in part be responsible for the severity of the disorder phenotype [24,25,26,27]. RTT is considered a monogenic neurologic disorder, it presents a highly complex nature, which reflects the wide range of both cellular/systemic alterations and co-morbidities, indicating the importance of MeCP2 expression even outside the central nervous system. RTT is considered a multisystem pathology, and common co-morbidities include periodic breathing disorder, various sleep disturbances, abnormal pubertal development, electrocardiograms with prolonged cardiac QT interval, numerous gastrointestinal disorders, osteopenia, and scoliosis [28,29,30,31,32,33]. Several efforts are oriented towards the study of bone mass, bone health, and fracture occurrence in RTT [34,35,36], the molecular mechanisms underlying the altered bone status in RTT patients are not well clarified yet
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