Profiling Scoliosis in Rett Syndrome

Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Pediatric Research (Impact Factor: 2.31). 04/2010; 67(4):435-9. DOI: 10.1203/PDR.0b013e3181d0187f
Source: PubMed


To understand scoliosis, related comorbidities, and phenotype-genotype correlations in individuals with Rett syndrome (RTT), the Rare Disease Clinical Research Network database for RTT was probed. Clinical evaluations included a detailed history and physical examination, comprehensive anthropometric measurements, and two quantitative measures of clinical status, Clinical Severity Scale (CSS) and motor-behavioral analysis (MBA). All data were exported to the Data Technology Coordinating Center (DTCC) at the University of South Florida. Scoliosis assessment was based on direct examination and curvature measurements by radiography (Cobb angle). Statistical analyses included univariate and multiple logistic regression models, adjusting for age at enrollment or mutation type. Scoliosis data were available from 554 classic RTT participants, mean age = 10 y (0-57 y). Scoliosis was noted in 292 (53%); mean age = 15 y with scoliosis and 6 y without. Using multiple regression analysis, MBA severity score, later acquisition, loss or absent walking, and constipation were associated with scoliosis. Two common methyl-CpG-binding protein 2 (MECP2) mutations, R294X and R306C, had reduced risk for scoliosis. These findings corroborated previous reports on scoliosis and extended understanding of comorbidities, clinical severity, and relative risk reduction for specific mutations. Clinical trial design should account for scoliosis and related factors judiciously.

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Available from: Jeffrey L Neul
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    • "However, it is also expressed throughout the body [7] [8] [9] and in addition to the neurological phenotypes , a number of overt peripheral phenotypes are also common in RTT. For instance, spinal deformity (principally scoliosis and excessive kyphosis) is a very common feature, with ~50–90% of patients developing severe scoliosis [10] [11] [12], many of whom require corrective surgery. Other prominent skeletal anomalies include early osteoporosis, osteopenia, bone fractures and hip deformities [13] [14] [15] [16] [17]. "
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    ABSTRACT: 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 Mecp2(stop/y) male mice in which Mecp2 is silenced in all cells and female Mecp2(stop/+) mice in which Mecp2 is silenced in similar to 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. (C) 2014 The Authors. Published by Elsevier Inc.
    Full-text · Article · Oct 2014 · Bone
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    • "Additional movement abnormalities include tremor, myoclonus, chorea, facial grimacing and severe teeth grinding. Most individuals with RTT have scoliosis, and some require surgical intervention (Percy et al., 2010). Nutrition and gastrointestinal function are also major clinical issues in RTT, and there is marked growth failure in most affected individuals (Tarquinio et al., 2012). "
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    ABSTRACT: In September of 2011, the National Institute of Neurological Disorders and Stroke (NINDS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the International Rett Syndrome Foundation (IRSF) and the Rett Syndrome Research Trust (RSRT) convened a workshop involving a broad cross-section of basic scientists, clinicians and representatives from the National Institutes of Health (NIH), the US Food and Drug Administration (FDA), the pharmaceutical industry and private foundations to assess the state of the art in animal studies of Rett syndrome (RTT). The aim of the workshop was to identify crucial knowledge gaps and to suggest scientific priorities and best practices for the use of animal models in preclinical evaluation of potential new RTT therapeutics. This review summarizes outcomes from the workshop and extensive follow-up discussions among participants, and includes: (1) a comprehensive summary of the physiological and behavioral phenotypes of RTT mouse models to date, and areas in which further phenotypic analyses are required to enhance the utility of these models for translational studies; (2) discussion of the impact of genetic differences among mouse models, and methodological differences among laboratories, on the expression and analysis, respectively, of phenotypic traits; and (3) definitions of the standards that the community of RTT researchers can implement for rigorous preclinical study design and transparent reporting to ensure that decisions to initiate costly clinical trials are grounded in reliable preclinical data.
    Full-text · Article · Nov 2012 · Disease Models and Mechanisms
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    • "It also increases when regression occurs before 6 months, when there has been no prior experience of walking, or when regression of gait has begun before musculoskeletal maturation.20 These findings, according to Ager and Alan, are due to mutations of R294X and R306C in the MECP2 gene in chromosome Xq28, which are related to mild developmental problems and to a decreased risk of scoliosis development.21,22 In this study, about 60% of patients had scoliosis, and it was more frequent in the high function than in the low function group as in other studies. "
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    ABSTRACT: To identify the clinical characteristics and investigate function related aspects of Korean children with Rett syndrome. A total of 26 patients diagnosed as Rett syndrome were clinically observed until the age of five or over. We surveyed past history, developmental history, and presence of typical clinical features of Rett syndrome. Furthermore, we investigated differences in clinical characteristics according to functional status and changes in clinical features related to growth. There were no problems related to gestational, perinatal or neonatal history. Only 12 patients had an ultimate head circumference of less than 3 percentile. Developmental regression was definite in all patients. At final assessment, only 14 patients were able to walk. Twenty patients had an epileptic history requiring medication. Sixteen patients with scoliosis showed progression during serial follow-up. The percentage of patients who were able to walk before 16 months was higher in the high function group than the low function group. The age of regression was 5.4 and 4.0 years in the high and low function group respectively, but the difference was not statistically significant. Scoliosis was more severe and seizure onset age was younger in the low function group. We investigated 26 clinical characteristics in Korean children with Rett syndrome. Their clinical features change according to age, and we believe such knowledge could be utilized in rehabilitation to minimize their disabilities.
    Full-text · Article · Jun 2012 · Annals of Rehabilitation Medicine
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