BACKGROUND More than 95% of individuals with RTT have mutations in methyl-CpG-binding protein 2 (MECP2), whose protein product modulates gene transcription. The disorder is caused by mutations in a single gene and the disease severity in affected individuals can be quite variable. Specific MECP2 mutations may lead phenotypic variability and different degrees of disease severity. It is known that low bone mass is a frequent and early complication of subjects with Rett syndrome. As a consequence of the low bone mass Rett girls are at an increased risk of fragility fractures. This study aimed to investigate if specific MECP2 mutations may affects the degree of involvement of the bone status in Rett subjects. METHODS In 232 women with Rett syndrome (mean age 13.8 ± 8.3 yrs) we measured bone mineral density at whole body and at femur (BMD-FN and BMD-TH) by using a DXA machine (Hologic QDR 4500). QUS parameters were assessed at phalanxes by Bone Profiler-IGEA (amplitude dependent speed of sound: AD-SoS and bone transmission time: BTT). Moreover, ambulation capacity (independent or assisted), fracture history and presence of scoliosis were assessed. We divided the subjects with the most common point mutations in two group based on genotype-phenotype severity; in particular, there has been consensus in recognising that the mutations R106T, R168X, R255X, R270X are considered more severe. RESULTS As aspect, BMD-WB, BMD-FN and BMD-TH were lower in subjects with Rett syndrome that present the most severe mutations with respect to subjects with Rett syndrome with less severe mutations, but the difference was statistically significant only for BMD-FN and BMD-TH (p < 0.05). Also both AD-SoS and BTT values were lower in subjects that present the most severe mutations with respect to less severe mutations but the difference was not statistically significant. Moreover, subjects with Rett syndrome with more severe mutations present a higher prevalence of scoliosis (p < 0.05) and of inability to walk (p < 0.05). CONCLUSION This study confirms that MECP2 mutation type is a strong predictor of disease severity in subjects with Rett syndrome. In particular, the subjects with more severe mutation present a greater deterioration of bone status, and a higher prevalence of scoliosis and inability to walk.

中文翻译：

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甲基CpG结合蛋白2（MECP2）突变类型与雷特综合征的骨病严重程度有关。

背景技术超过95％的具有RTT的个体的甲基CpG结合蛋白2（MECP2）突变，其蛋白产物调节基因转录。该疾病是由单个基因的突变引起的，受影响个体的疾病严重程度可能会很大。特定的MECP2突变可能导致表型变异和疾病严重程度不同。众所周知，低骨量是患有Rett综合征的受试者的一种常见的早期并发症。由于骨量少，瑞特女孩的脆弱性骨折风险增加。这项研究旨在调查特定的MECP2突变是否会影响Rett受试者的骨状态参与程度。方法在232名Rett综合征妇女中（平均年龄13.8±8）。3年），我们使用DXA机器（Hologic QDR 4500）测量了整个身体和股骨（BMD-FN和BMD-TH）的骨矿物质密度。QUS参数由骨轮廓仪-IGEA在方骨处评估（与振幅有关的声音速度：AD-SoS和骨骼传输时间：BTT）。此外，评估了步行能力（独立或辅助），骨折史和脊柱侧弯的存在。我们根据基因型-表型的严重程度将具有最常见点突变的受试者分为两组。特别是，在认识到认为突变R106T，R168X，R255X，R270X更为严重方面已达成共识。结果就这一方面而言，与具有较轻度突变的Rett综合征患者相比，具有最严重突变的Rett综合征患者的BMD-WB，BMD-FN和BMD-TH较低，但差异仅在BMD-FN和BMD-TH上具有统计学意义（p <0.05）。相对于较不严重的突变，呈现最严重突变的受试者的AD-SoS和BTT值均较低，但差异无统计学意义。此外，具有更严重突变的雷特综合征患者表现出较高的脊柱侧凸患病率（p <0.05）和无法行走（p <0.05）。结论本研究证实MECP2突变类型是Rett综合征患者疾病严重程度的强力预测指标。特别地，具有更严重突变的受试者表现出更大的骨骼状态恶化，并且脊柱侧弯的患病率更高并且不能行走。相对于较不严重的突变，呈现最严重突变的受试者的AD-SoS和BTT值均较低，但差异无统计学意义。此外，具有更严重突变的雷特综合征患者表现出较高的脊柱侧凸患病率（p <0.05）和无法行走（p <0.05）。结论本研究证实MECP2突变类型是Rett综合征患者疾病严重程度的强力预测指标。特别地，具有更严重突变的受试者表现出更大的骨骼状态恶化，并且脊柱侧弯的患病率更高并且不能行走。相对于较不严重的突变，呈现最严重突变的受试者的AD-SoS和BTT值均较低，但差异无统计学意义。此外，具有更严重突变的雷特综合征患者表现出较高的脊柱侧凸患病率（p <0.05）和无法行走（p <0.05）。结论本研究证实MECP2突变类型是Rett综合征患者疾病严重程度的强力预测指标。特别地，具有更严重突变的受试者表现出更大的骨骼状态恶化，并且脊柱侧弯的患病率更高并且不能行走。具有更严重突变的Rett综合征患者表现出较高的脊柱侧弯患病率（p <0.05）和无法行走（p <0.05）。结论本研究证实MECP2突变类型是Rett综合征患者疾病严重程度的强力预测指标。特别地，具有更严重突变的受试者表现出更大的骨骼状态恶化，并且脊柱侧弯的患病率更高并且不能行走。具有更严重突变的Rett综合征患者表现出较高的脊柱侧弯患病率（p <0.05）和无法行走（p <0.05）。结论本研究证实MECP2突变类型是Rett综合征患者疾病严重程度的强力预测指标。特别地，具有更严重突变的受试者表现出更大的骨骼状态恶化，并且脊柱侧弯的患病率更高并且不能行走。