Department of Medicine, Surgery and Neuroscience, University of Siena, Policlinico Le Scotte, Viale Bracci 2, 53100, Siena, Italy.
Paediatrics Neuropsychiatry Unit, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
BMC Med Genet. 2020 Jan 31;21(1):21. doi: 10.1186/s12881-020-0960-2.
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.
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.
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).
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.
超过 95%的 RTT 患者存在甲基-CpG 结合蛋白 2（MECP2）突变，其蛋白产物可调节基因转录。这种疾病是由单个基因突变引起的，受影响个体的疾病严重程度可能差异很大。特定的 MECP2 突变可能导致表型的可变性和不同程度的疾病严重程度。已知低骨量是 Rett 综合征患者的常见且早期并发症。由于低骨量，Rett 女孩更容易发生脆性骨折。本研究旨在探讨特定的 MECP2 突变是否会影响 Rett 患者的骨骼状况受累程度。
在 232 名 Rett 综合征女性（平均年龄 13.8±8.3 岁）中，我们使用 DXA 仪（Hologic QDR 4500）测量全身和股骨的骨矿物质密度（BMD-FN 和 BMD-TH）。通过 Bone Profiler-IGEA（声速依赖性振幅：AD-SoS 和骨传输时间：BTT）评估指骨的 QUS 参数。此外，评估了步行能力（独立或辅助）、骨折史和脊柱侧凸的存在。我们根据基因型-表型严重程度将最常见的点突变患者分为两组；特别是，人们一致认为 R106T、R168X、R255X、R270X 突变被认为更严重。
在 Rett 综合征患者中，与 MECP2 突变程度较轻的患者相比，具有最严重突变的患者的 BMD-WB、BMD-FN 和 BMD-TH 均较低，但仅 BMD-FN 和 BMD-TH 的差异具有统计学意义（p<0.05）。此外，与 MECP2 突变程度较轻的患者相比，具有最严重突变的患者的 AD-SoS 和 BTT 值也较低，但差异无统计学意义。此外，具有更严重突变的 Rett 综合征患者脊柱侧凸的患病率较高（p<0.05），无法行走的比例较高（p<0.05）。
本研究证实，MECP2 突变类型是 Rett 综合征患者疾病严重程度的重要预测因素。特别是，具有更严重突变的患者骨骼状况恶化更严重，脊柱侧凸和无法行走的患病率更高。
