Dataset Information

Two novel BMP-2 variants identified in patients with thoracic ossification of the ligamentum flavum.

ABSTRACT: Thoracic ossification of the ligamentum flavum (TOLF)is a common cause of thoracic spinal canal stenosis and has been reported almost exclusively in East Asian countries. In this study, we established a relationship between bone morphogenic protein 2 (BMP-2) and TOLF. We divided patients into two groups according to severity of ossification and identified susceptible loci through exome sequencing. We identified 39 novel likely pathogenic variants in 29 genes in the transforming growth factor-beta (TGF-?) superfamily or TGF-?/BMPs signaling pathway, including two missense variants in BMP-2 (NM_001200.3) exon region, c.460C>G:p.(R154G) and c.584G>T:p.(R195M). Further Sanger sequencing and genotyping suggested the variants were only found in patients with long regional OLF. Bioinformatic assays predicted the two BMP-2 variants to cause significant alterations to gene and protein expression. Functional assays showed upregulation of BMP-2 expression, increased osteogenic marker expression, and enhanced osteogenic differentiation. Collectively, these results suggest a genetic contribution to the pathogenesis of TOLF, particularly in patients with long segment disease, and that nucleotide substitutions associated with increased BMP-2 expression may be involved in TOLF pathogenesis.

SUBMITTER: Qu X

PROVIDER: S-EPMC5437907 | biostudies-other | 2017 May

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Two novel BMP-2 variants identified in patients with thoracic ossification of the ligamentum flavum.

Qu Xiaochen X Chen Zhongqiang Z Fan Dongwei D Xiang Shen S Sun Chuiguo C Zeng Yan Y Li Weishi W Guo Zhaoqing Z Qi Qiang Q Zhong Woquan W Jiang Yun Y

European journal of human genetics : EJHG 20170201 5

Thoracic ossification of the ligamentum flavum (TOLF)is a common cause of thoracic spinal canal stenosis and has been reported almost exclusively in East Asian countries. In this study, we established a relationship between bone morphogenic protein 2 (BMP-2) and TOLF. We divided patients into two groups according to severity of ossification and identified susceptible loci through exome sequencing. We identified 39 novel likely pathogenic variants in 29 genes in the transforming growth factor-bet ...[more]

PMID: 28145426

Similar Datasets

Project description:INTRODUCTION: Ossification of the ligamentum flavum (OLF) of the spine is associated with serious neurologic compromise, but the pathomechanism of this process remains unclear. The objective of this study was to investigate the pathomechanism of the ossification process, including the roles of various transcriptional factors in the ossification of human thoracic ligamentum flavum. METHODS: Sections of the thoracic ligamentum flavum were obtained from 31 patients with OLF who underwent posterior thoracic decompression, and from six control patients free of OLF. Cultured ligamentum flavum cells (n = 6, each) were examined with real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis for Sry-type high-mobility group box 9 (Sox9), runt-related transcription factor 2 (Runx2), muscle segment homeobox 2 (Msx2), Osterix, distal-less homeobox 5 (Dlx5), and AP-1. The harvested sections were examined with hematoxylin-eosin, the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method, and immunohistochemistry for the transcriptional factors. RESULTS: Compared with the control, the OLF showed disorganization of the elastic fiber bundles and abundant hypertrophic chondrocytes in the ossification front. TUNEL-positive chondrocytes were found near the ossified plaques. The mRNA expression levels of Sox9, Runx2, Msx2, and AP-1 in cultured cells from the ligamentum flavum of OLF patients were significantly different from those of the control. OLF samples were strongly immunoreactive to Sox9, Runx2, and Msx2 at proliferating chondrocytes in the fibrocartilage area. Hypertrophic chondrocytes were positive for Runx2, Osterix, Dlx5, and AP-1. CONCLUSIONS: The ossification process in OLF seems to involve chondrocyte differentiation under the unique expression of transcriptional factors. Accumulation of hypertrophic chondrocytes was evident around the calcified area at the ossification front, and we suggest that the differentiation of these cells seems to be concerned with the ossification process.

Project description:BackgroundDural ossification (DO) is the leading cause of surgery-related dural tear in patients with ossification of the ligamentum flavum (OLF). An accurate preoperative diagnosis of DO is conducive to the selection of appropriate surgical methods. Although several imaging signs, such as Banner cloud sign (BCs), tram-track sign (TTs), and comma sign (Cs) have been proposed for the preoperative diagnosis of DO, their diagnostic value has not been well studied. The aim of this study was to explore the diagnostic value of BCs, TTs, and Cs, and provide evidence-based data for their clinical application.MethodsThis is a blind, randomized diagnostic study using retrospectively collected data from 102 consecutive patients who were diagnosed with OLF and underwent decompression surgery between January 2018 and June 2019. A total of 8 surgeons with different qualifications were recruited to read these imaging signs to identify the presence of DO. Surgical records were used as the reference standard. Sensitivity, specificity, and the area under the receiver operating characteristic (ROC) curve (AUC) were used to evaluate the diagnostic accuracy of each imaging sign and their different combinations.ResultsOf the 102 patients, 21 were diagnosed with DO. BCs had a significantly higher diagnostic accuracy than TTs and Cs, with the AUC of 0.704, 0.607, and 0.593, respectively. The specificity of BCs, Cs, TTs, and their combination in diagnosing DO was 91.5%, 92.1%, 68.3%, and 62.2%, respectively. In the combined diagnostic test, the results showed that the combined diagnosis accuracy of BCs and Cs was the highest, and the AUC was 0.738. The combination of BCs, Cs, and TTs increased the sensitivity of diagnosing DO (77.5%), but did not improve the diagnostic accuracy, and the AUC was 0.699.ConclusionsBCs had higher diagnostic accuracy than TTs and Cs. BCs and Cs were highly specific for DO, whereas TTs could be confusing due to their non-specific presentations. The combination of BCs, TTs, and Cs improved the sensitivity of DO diagnosis, but not the specificity and accuracy.

Project description:Background and Objectives: Ossification of the ligamentum flavum (OLF) is a relatively common cause of thoracic myelopathy. Surgical treatment is recommended for patients with myelopathy. Generally, open posterior decompression, with or without fusion, is selected to treat OLF. We performed minimally invasive posterior decompression using a microendoscope and investigated the efficacy of this approach in treating limited type of thoracic OLF. Materials and Methods: Microendoscopic posterior decompression was performed for 19 patients (15 men and four women) with thoracic OLF with myelopathy aged between 35 to 81 years (mean age, 61.9 years). Neurological examination and preoperative magnetic resonance imaging (MRI) and computed tomography (CT) were used to identify the location and morphology of OLF. The surgery was performed using a midline approach or a unilateral paramedian approach depending on whether the surgeon used a combination of a tubular retractor and endoscope. The numerical rating scale (NRS) and modified Japanese Orthopedic Association (mJOA) scores were compared pre- and postoperatively. Perioperative complications and the presence of other spine surgeries before and after thoracic OLF surgery were also investigated. Results: Four midline and 15 unilateral paramedian approaches were performed. The average operative time per level was 99 min, with minor blood loss. Nine patients had a history of cervical or lumbar spine surgery before or after thoracic spine surgery. The mean pre- and postoperative NRS scores were 6.6 and 5.3, respectively. The mean recovery rate as per the mJOA score was 33.1% (mean follow-up period, 17.8 months), the recovery rates were significantly different between patients who underwent thoracic spine surgery alone (50.5%) and patients who underwent additional spine surgeries (13.7%). Regarding adverse events, one patient experienced dural tear, another experienced postoperative hematoma, and one other underwent reoperation for adjacent thoracic stenosis. Conclusion: Microendoscopic posterior decompression was applicable in limited type of thoracic OLF surgery including beak-shaped type and multi vertebral levels. However, whole spine evaluation is important to avoid missing other combined stenoses that may affect outcomes.

Project description:Background Unforeseen dural ossification (DO) increases the risk of complications in the surgical management of thoracic ossification of the ligamentum flavum (OLF). Several methods have been proposed to identify DO; however, these approaches either have low diagnostic accuracy or poor feasibility. Therefore, we aimed to determine the relationship between DO and the severity and range of thoracic OLF compression using a 3-dimensional (3D) imaging analysis and to evaluate its superiority in diagnosing DO over conventional measurement methods. Methods A total of 114 consecutive patients who underwent decompressive laminectomy for thoracic OLF in 4 institutions were retrospectively enrolled and divided into DO and non-DO groups. Univariate analysis was performed to determine the relationship between OLF compression and DO. We measured the 3D occupying ratio (OR; 3D OR = OLF volume/normal canal volume × 100%), calculated its cutoff values, and compared its diagnostic value in DO with that of conventional 1D and 2D radiological parameters in the whole thoracic spine. Results The 3D OR in the DO group (50.9%±7.9%) was significantly higher than that in the non-DO group (30.8%±7.5%; P<0.01). The overall reliability and reproducibility for measurements of the 3D OR (intra- and interobserver correlation coefficients 0.94 and 0.90, respectively) were excellent. Thus, the 3D OR could be used as an indicator to distinguish between DO and non-DO, with high diagnostic accuracy (91.2%). Moreover, a 3D OR of >43%, known as the “ossification zone”, was indicative of DO in OLF, whereas a value of <37% was considered the “safe zone”. Additionally, the 3D OR [area under the curve (AUC) =0.98, 95% confidence interval (CI): 0.93–0.99] showed a statistically higher diagnostic value for DO in the upper, middle, lower, and whole thoracic spine than did both 1D (AUC =0.81; 95% CI: 0.73–0.88) and 2D (AUC =0.87; 95% CI: 0.79–0.92) parameters (P<0.01). Conclusions DO was significantly associated with the severity and range of OLF compression. The 3D OR could be used as a critical diagnostic indicator for identifying DO in the whole thoracic spine, owing to its superiority over conventional radiological parameters. Classification of the 3D OR could maximize the clinical feasibility and thus help surgeons to decrease the incidence of DO-related surgical complications.

Project description:ObjectiveThere is a lack of studies on the quality of life (QoL) after posterior laminectomy in patients with thoracic ossification of the ligamentum flavum (TOLF), and risk factors associated with poor prognosis remain controversial. Therefore, the present study was conducted to illustrate the QoL for TOLF patients after surgery and determine its relationship with their demographic, surgery-related, clinical characteristics and imaging data.MethodsOne hundred and eighteen patients diagnosed with thoracic myelopathy because of TOLF were enrolled in this retrospective study. They all underwent posterior decompressive laminectomy from August 2010 to January 2022. The QoL was evaluated based on the EQ-5D-5L. Collecting gender, age, number of operations, compressed segments, Frankel grade, complications, body mass index (BMI), symptoms and duration, modified Japanese Orthopaedic Association (mJOA) score (preoperative), follow-up time and type of ossification, increased signal on Sagittal T2-weighted Images (ISST2I), occupancy rate and analyzing by Mann-Whitney U-test, Kruskal-Wallis test, the χ2 -test, and logistic regression tests.ResultsAverage follow-up 70.8 months (18-149), the mean age was 59.74 ± 9.81 years and the mean score for the QoL based on the EQ-5D-5 L and visual analogue scale (VAS) score were 0.71 ± 0.28 and 78.88 ± 10.21 at the final follow-up. Moderate and severe problems were found in the pain/discomfort in 22.0% of the patients. These mobility and usual activities numbers were slightly higher (24.6% and 30.4%, respectively). The mean scores for QoL and VAS were significantly higher in patients with mild and moderate neurological impairment, normal BMI, <60 years of age, no dural tears, symptom relief at hospital discharge, unilateral and bilateral ossification on axial CT scan, ≤ 50% spinal canal occupancy on CT and MRI, and none or fuzzy on ISST2I.ConclusionQoL after posterior laminectomy in TOLF patients is generally satisfactory compared to preoperative levels. Preoperative mJOA score, Age, comorbid diabetes, the major symptom is activity limitation, BMI, ISST2I, Intraoperative dural tears and spinal canal occupancy rate correlate significantly with the corresponding dimensions and are predictive. Age, spinal canal occupancy rate, ISST2I, preoperative mJOA score, BMI are significantly associated with and have predictive value for overall postoperative QoL.

Project description:BackgroundThe aim of the present study was to evaluate the curative effect and safety of thoracic full-endoscopic unilateral laminotomy with bilateral decompression (TE-ULBD) for treating ossification of the ligamentum flavum (OLF) with myelopathy.MethodsBetween January 2015 and December 2018, 23 consecutive patients with symptomatic thoracic OLF were treated with TE-ULBD. Of these, 21 (13 women and 8 men, aged 49-75 years) were included in the study and followed up for a minimum of 1 year. The mean blood loss was 15.48 mL (10-30 mL), operative duration was 78.86 min (55-115 min), and hospitalization was 5.05 days (3-15 days). The Japanese Orthopaedic Association (JOA) was used to evaluate spinal cord function, and the curative effect was defined by the JOA improvement rate. The area of OLF (AOLF), the maximum spinal cord compression (MSCC), and the area of spinal cord (ASC) were used to evaluate OLF clearance and spinal cord decompression status.ResultsAt the final follow up,the JOA score was 8.33 points (5-11 points), which was a significant improvement from the preoperative 5.33 points (3-9 points, P<0.01). The excellent and good rate was 76.19% (16/21). The average preoperative AOLF and AOLF ratio were 85.27±23.66 mm2 and 57.86%±11.86%, respectively, and the postoperative AOLF and AOLF ratio were 16.27±11.75 mm2 and 8.13%±5.38%, respectively. The MSCC increased from 27.99%±13.51% preoperatively to 48.02%±6.66% postoperatively. The ASC was 42.90±10.60 mm2 preoperatively and 64.54±21.36 mm2 postoperatively. There were statistically significant differences in all parameters preoperatively and postoperatively (P<0.01). One case had postoperative hematoma, and the symptoms gradually eased after 3 weeks of conservative treatment. There were no other complications. No recurrence of OLF was detected during the follow-up period.ConclusionsTE-ULBD is safe and effective for thoracic OLF with the advantages of reduced trauma and bleeding, and faster recovery.

Dataset Information

Two novel BMP-2 variants identified in patients with thoracic ossification of the ligamentum flavum.

Publications

Two novel BMP-2 variants identified in patients with thoracic ossification of the ligamentum flavum.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets