Low bone turnover phenotype in Rett syndrome: results of biochemical bone marker analysis

Roende, Gitte; Petersen, Janne; Ravn, Kirstine; Fuglsang, Kathrine; Andersen, H.; Nielsen, Jan Kresten; Brøndum‐Nielsen, Karen; Jensen, Jens–Erik Beck

doi:10.1038/pr.2013.252

Cited by 10 publications

(9 citation statements)

References 39 publications

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“…As collagen is the most abundant gene product and structural determinant in bone, we conducted an initial analysis of collagen content and distribution using sirius red staining. The decreased levels of intense sirius red stain observed in the MeCP2-deficient mice is consistent with reduced collagen [56] and the patches of reduced staining resemble those features characteristic of early osteoporosis [17] . Indeed, the osteopathic features of RTT (minimal bone deformity, low energy bone fractures, and tendency towards spinal curvature) are similar to those reported in collagen type 1 genetic disorder (osteogenesis imperfecta; brittle bone disease) [62] pointing towards the possible importance of collagen defects in RTT.…”

Section: Discussionsupporting

confidence: 65%

“…The results of our current study show that MeCP2-deficiency in mice results in altered material, structural and functional properties of bone tissues. There is a growing awareness of skeletal anomalies (low energy fractures, scoliosis, kyphosis) in Rett patients [8,10,11,13–15,18–21,40–56] and the aim of the current project was to assess further the nature and tractability of bone phenotypes. Our morphometric analysis showed a reduction in long bone weight and, in the case of the tibia, a reduction in length in Mecp2 stop/y mice.…”

Section: Discussionmentioning

confidence: 99%

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Biomechanical properties of bone in a mouse model of Rett syndrome

Kamal

Russell

Payne

et al. 2015

Bone

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Rett syndrome (RTT) is an X-linked genetic disorder and a major cause of intellectual disability in girls. Mutations in the methyl-CpG binding protein 2 (MECP2) gene are the primary cause of the disorder. Despite the dominant neurological phenotypes, MECP2 is expressed ubiquitously throughout the body and a number of peripheral phenotypes such as scoliosis, reduced bone mineral density and skeletal fractures are also common and important clinical features of the disorder. In order to explore whether MeCP2 protein deficiency results in altered structural and functional properties of bone and to test the potential reversibility of any defects, we have conducted a series of histological, imaging and biomechanical tests of bone in a functional knockout mouse model of RTT. Both hemizygous Mecp2stop/y male mice in which Mecp2 is silenced in all cells and female Mecp2stop/+ mice in which Mecp2 is silenced in ~ 50% of cells as a consequence of random X-chromosome inactivation, revealed significant reductions in cortical bone stiffness, microhardness and tensile modulus. Microstructural analysis also revealed alterations in both cortical and cancellous femoral bone between wild-type and MeCP2-deficient mice. Furthermore, unsilencing of Mecp2 in adult mice cre-mediated stop cassette deletion resulted in a restoration of biomechanical properties (stiffness, microhardness) towards wild-type levels. These results show that MeCP2-deficiency results in overt, but potentially reversible, alterations in the biomechanical integrity of bone and highlights the importance of targeting skeletal phenotypes in considering the development of pharmacological and gene-based therapies.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Biomechanical properties of bone in a mouse model of Rett syndrome

Kamal

Russell

Payne

et al. 2015

Bone

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“…In the previous studies, the average age was 20 years or younger, whereas the participants of this study were 23 years old or older. It is known that bone metabolism is more active in younger population [19,26]. In addition, measurements of u-NTX obtained the day after moderate exercise was reported to be no different from measurements obtained before exercise [28].…”

Section: Discussionmentioning

confidence: 96%

Stress Fracture Influences Bone Resorption marker (u-NTX) in Female Long Distance Runners

et al. 2017

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In this study, we aim to clarify the influence based on bone resorption markers at onset of stress fracture. Also, we will clarify the state of the bone resorption markers of female long distance runners who have a history of stress fracture and also ones who routinely practices running long distances. Participants comprised 19 female long distance athletes. The survey period was 2011–2014, and we measured u-NTX as a bone resorption marker at least twice a year, taking the mean±SD of the periodic measured values without stress fracture as the mean value. Measurements were collected sample when stress fractures developed. 132 u-NTX measurements were taken from 19 participants. As a result, the average was 41.03±12.31 nmolBCE/mmolCRE (Q1: 33.15, Q2: 40.55, Q3: 47.95). In six of the 19 participants, u-NTX could be measured following a stress fracture. The mean value of u-NTX for those participants was 40.16±9.10 nmolBCE/mmolCRE, increasing to 64.08±16.07 nmolBCE/mmol CRE with the stress fracture (p<0.01). The findings showed that, in adult female long distance runners, u-NTX values when there was no stress fracture were within the standard value for mean premenopausal women, but increased when the athletes suffered from a stress fracture.

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“…178 A recent Danish study concluded that the comparatively reduced levels of biochemical bone markers in RTT signified a a low bone turnover state. 182 Nonrepresentative and small sample sizes, often without longitudinal collection, lack of childhood population bone parameter norms and accommodation for decreased stature and different analytical methods all make cross-study comparison difficult. Yet understanding the role of bone health in RTT and the role of MeCP2 in bone development is crucial especially since MeCP2-deficiency has now been shown to alter the biomechanical integrity of bone in a mouse model.…”

Section: Bone Healthmentioning

confidence: 99%

Clinical and biological progress over 50 years in Rett syndrome

2016

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It is fifty years since Andreas Rett first described Rett syndrome, a disorder now known to be caused by a mutation in the MECP2 gene. A compelling blend of astute clinical observations, clinical and laboratory research has already built our understanding of Rett syndrome and its biological underpinnings. We document the contributions of the early pioneers and describe the evolution of knowledge in terms of diagnostic criteria, clinical variation and the interplay with other Rett-related disorders. We provide a synthesis of what is known about the neurobiology of MeCP2, the lessons from both cell and animal models and how they may inform future clinical trials. With a focus on the core criteria, we examine the relationships that have been demonstrated between genotype and clinical severity. We review what is known about the many comorbidities that occur in this disorder and how genotype may also modify their presentation. We acknowledge the important drivers that are accelerating this research program including the roles of research infrastructure, international collaboration and advocacy groups. Finally, we conclude by highlighting the major milestones since 1966 and what they mean for the day-to-day lives of those with Rett syndrome and their families. Key pointsThere has been an explosion of knowledge about Rett syndrome in relation to its genetic basis, clinical characteristics and their relationships during the fifty years since the disorder was first described by Andreas Rett.Whilst initially the diagnosis of Rett syndrome was based only on clinical criteria, identifying its genetic cause has had a major positive impact on how clinicians diagnose the disorder but also provides new challenges as we enter the era of next generation sequencing.

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Low bone turnover phenotype in Rett syndrome: results of biochemical bone marker analysis

Cited by 10 publications

References 39 publications

Biomechanical properties of bone in a mouse model of Rett syndrome

Biomechanical properties of bone in a mouse model of Rett syndrome

Stress Fracture Influences Bone Resorption marker (u-NTX) in Female Long Distance Runners

Clinical and biological progress over 50 years in Rett syndrome

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