In idiopathic scoliosis distances of spinal cord to thoracic pedicle are within 2 mm in a large region of the thoracic apex.

Despite a 15% misplacement rate of screws in idiopathic scoliosis surgery, little is known about the relationship between pedicles and nerve structures in the entire thoracic curve. This study aimed to explore the spinal cord's proximity to the pedicle wall at each thoracic vertebra in the entire thoracic curve, while considering different anatomical changes. Spinal cord to medial pedicle distances were measured on magnetic resonance imaging in 73 patients who underwent posterior spinal fusion with pedicle screw instrumentation. Associations with different variables were examined. A total of 51 patients (69.9%) showed a distance within 2 mm at the apex vertebra on the concave side, more than 50% had a distance within 2 mm in the next thoracic vertebra level above and below, and more than 25% two levels above and below. Weak correlations were found between proximity of the spinal cord at the apex vertebra and vertebra's level and Cobb angle on the concave side (r = - 0.310, P = 0.008, r = 0.380, P = 0.001, respectively). These results emphasize the importance of thorough assessment when placing thoracic pedicle screws in idiopathic scoliosis patients. Further research is warranted to develop surgical strategies aimed at preventing potentially neurological complications resulting from screw misplacement.

Rare variant association analyses reveal the significant contribution of carbohydrate metabolic disturbance in severe adolescent idiopathic scoliosis.

BACKGROUND: Adolescent idiopathic scoliosis (AIS), the predominant genetic-influenced scoliosis, results in spinal deformities without vertebral malformations. However, the molecular aetiology of AIS remains unclear. METHODS: Using genome/exome sequencing, we studied 368 patients with severe AIS (Cobb angle >40°) and 3794 controls from a Han Chinese cohort. We performed gene-based and pathway-based weighted rare variant association tests to assess the mutational burden of genes and established biological pathways. Differential expression analysis of muscle tissues from 14 patients with AIS and 15 controls was served for validation. RESULTS: SLC16A8, a lactate transporter linked to retinal glucose metabolism, was identified as a novel severe AIS-associated gene (p=3.08E-06, false discovery rate=0.009). Most AIS cases with deleterious SLC16A8 variants demonstrated early onset high myopia preceding scoliosis. Pathway-based burden test also revealed a significant enrichment in multiple carbohydrate metabolism pathways, especially galactose metabolism. Patients with deleterious variants in these genes demonstrated a significantly larger spinal curve. Genes related to catabolic processes and nutrient response showed divergent expression between AIS cases and controls, reinforcing our genomic findings. CONCLUSION: This study uncovers the pivotal role of genetic variants in carbohydrate metabolism in the development of AIS, unveiling new insights into its aetiology and potential treatment.

Identification of Epigenetic Biomarkers of Adolescent Idiopathic Scoliosis Progression: A Workflow to Assess Local Gene Expression.

Adolescent idiopathic scoliosis (AIS) is a three-dimensional structural deformity of the spine that affects 2-3% of adolescents under the age of 16. AIS etiopathogenesis is not completely understood; however, the disease phenotype is correlated to multiple genetic loci and results from genetic-environmental interactions. One of the primary, still unresolved issues is the implementation of reliable diagnostic and prognostic markers. For clinical management improvement, predictors of curve progression are particularly needed. Recently, an epigenetic contribution to AIS development and progression was proposed; nevertheless, validation of data obtained in peripheral tissues and identification of the specific mechanisms and genes under epigenetic control remain limited. In this study, we propose a methodological approach for the identification of epigenetic markers of AIS progression through an original workflow based on the preliminary characterization of local expression of candidate genes in tissues directly involved in the pathology. The feasibility of the proposed methodological protocol has been originally tested here in terms of identification of the putative epigenetic markers of AIS progression, collection of the different tissues, retrieval of an appropriate amount and quality of RNA and DNA, and identification of suitable reference genes.

Histology and chronological magnetic resonance images of congenital spinal deformity: An experimental study in mice model.

BACKGROUND: The natural history of the congenital spinal deformity and its clinical magnitude vary widely in human species. However, we previously reported that the spinal deformities of congenital scoliosis mice did not progress throughout our observational period according to soft X-ray and MRI data. In this study, congenital vertebral and intervertebral malformations in mice were assessed via magnetic resonance (MR) and histological images. METHODS: Congenital spinal anomalies were chronologically assessed via soft X-ray and 7 T MR imaging. MR images were compared to the histological images to validate the findings around the malformations. RESULTS: Soft X-ray images showed the gross alignment of the spine and the contour of the malformed vertebrae, with the growth plate and cortical bone visible as higher density lines, but could not be used to distinguish the existence of intervertebral structures. In contrast, MR images could be used to distinguish each structure, including the cortical bone, growth plate, cartilaginous end plate, and nucleus pulposus, by combining the signal changes on T1-weighted imaging (T1WI) and T2-weighted imaging (T2WI). The intervertebral structure adjacent to the malformed vertebrae also exhibited various abnormalities, such as growth plate and cartilaginous end plate irregularities, nucleus pulposus defects, and bone marrow formation. In the chronological observation, the thickness and shape of the malformed structures on T1WI did not change. CONCLUSIONS: Spinal malformations in mice were chronologically observed via 7 T MRI and histology. MR images could be used to distinguish the histological structures of normal and malformed mouse spines. Malformed vertebrae were accompanied by adjacent intervertebral structures that corresponded to the fully segmented structures observed in human congenital scoliosis, but the intervertebral conditions varied. This study suggested the importance of MRI and histological examinations of human congenital scoliosis patients with patterns other than nonsegmenting patterns, which may be used to predict the prognosis of patients with spinal deformities associated with malformed vertebrae.

Three-dimensional vertebral shape changes confirm growth modulation after anterior vertebral body tethering for idiopathic scoliosis.

PURPOSE: To evaluate three-dimensional (3D) vertebra and disk shape changes over 2 years following anterior vertebral body tether (AVBT) placement in patients with idiopathic scoliosis (IS). METHODS: Patients with right thoracic IS treated with AVBT were retrospectively evaluated. 3D reconstructions were created from biplanar radiographs. Vertebral body and disk height (anterior, posterior, left and right) and shape (wedging angle) were recorded over the three apical segments in the local vertebral reference planes. Changes in height and wedging were measured through 2 years postoperatively. Change in patient height was correlated with changes in the spine dimensions. RESULTS: Forty-nine patients (Risser 0-3, Sanders 2-4) were included. The mean age was 12.2 ± 1.4 years (range 8-14). The mean coronal curve was 51 ± 10° preoperatively, 31 ± 9° at first postoperative time point and 27 ± 11° at 2-year follow-up (p < 0.001). The mean patient height increased 8 cm by 2 years (p < 0.001). The left side of the spine (vertebra + disc) grew in height by 2.2 mm/level versus 0.7 mm/level on the right side (p < 0.001). This differential growth was composed of 0.5 mm/vertebral level and 1.0 mm/disk level. Evaluation of the change in disk heights showed significantly decreased height anteriorly (- 0.4 mm), posteriorly (- 0.3 mm) and on the right (- 0.5 mm) from FE to 2 years. Coronal wedging reduced 2.3°/level with 1.1°/vertebral level change and 1.2°/disk level. There was no differential growth in the sagittal plane (anterior/posterior height). Patient height change moderately correlated with 3D measures of vertebra + disk shape changes. CONCLUSIONS: Three-dimensional analysis confirms AVBT in skeletally immature patients results in asymmetric growth of the apical spine segments. The left (untethered) side length increased more than 3 × than the right (tethered) side length with differential effects observed within the vertebral bodies and disks, each correlating with overall patient height change.

The widths of the medial and lateral pedicle walls in adolescent idiopathic scoliosis with major thoracic curves.

BACKGROUND CONTEXT: The widths of medial and lateral pedicle walls in the normal spine of middle-aged and elderly adults have been investigated and these studies found that the medial pedicle wall was thicker than the lateral pedicle wall. However, none had evaluated the widths of medial and lateral pedicle walls on adolescent or young adult scoliotic spines. PURPOSE: This study aims to identify the distribution and variation of medial and lateral pedicle wall widths throughout the different vertebral levels of the scoliotic spine and its differences according to age, gender, body mass index (BMI), maturity, curve types and curve severity in adolescent idiopathic scoliotic (AIS) patients with major thoracic curves. STUDY DESIGN: Retrospective study. PATIENT SAMPLE: A total of 6,230 pedicles (right: 3,064, left: 3,166) from 191 patients were included in this study, with 264 (right: 183, left: 81) fully corticalized pedicles excluded from analysis. OUTCOME MEASURES: Demographic data were age, gender, height, weight, BMI, Risser grade, Lenke curve types and Cobb angles. The main outcome measures were medial and lateral pedicle wall widths. Associations between pedicle wall widths and demographic data were calculated. METHODS: This was a subanalytical retrospective study done on the same patient population as the previously published study on pedicle grading. The data was obtained from the main computed tomography (CT) scan pedicle study dataset. Medial and lateral pedicle wall widths were measured in the axial slices of CT scans from T1 to L5 vertebrae. RESULTS: A total of 6,230 pedicles (right: 3,064, left: 3,166) from 191 patients were included in this study with 264 (right: 183, left: 81) fully corticalized pedicles excluded from analysis. Right-sided medial pedicle wall widths were narrower from T4-T10 (0.75±0.23 mm) compared to T1-T3 (0.89±0.28 mm) and T11-L5 (0.92±0.30 mm). Left-sided medial pedicle wall widths were narrower from T4 to T7 (0.76±0.24 mm) compared to T1-T3 (0.88±0.26 mm) and T8-L5 (0.90±0.27 mm). Medial cortical wall widths were significantly thicker compared to lateral cortical wall widths for all vertebras from T1 to L5 (right medial 0.85±0.28 mm vs lateral 0.64±0.26 mm (p<.001), left medial 0.86±0.26 mm vs lateral 0.64±0.26 mm (p<.001)). The left medial pedicle wall widths were marginally significantly (p<.001) thicker than the right side (right medial 0.85±0.28 mm vs left 0.86±0.26 mm). The main notable significant differences were located at the periapical region of the thoracic curve between T7 to T10 with the left concave medial pedicle width being thicker than the right convex medial pedicle width. The thinnest medial pedicle walls were located at right concave T7 (0.73±0.24 mm) and T8 (0.73±0.23 mm). We generally found no significant associations between the medial and lateral pedicle wall widths with age, gender, BMI, Risser grade, Cobb angle and curve types. CONCLUSIONS: Knowledge on the widths of medial and lateral pedicle walls, their distribution and differences in a scoliotic spine is important for pedicle screw fixation, especially during pedicle probing to find the pedicle channel. The medial pedicle wall widths were significantly thicker than the lateral pedicle wall widths in AIS patients with major thoracic curves. The right concave periapical region had the thinnest medial pedicle walls.

Adolescent idiopathic scoliosis: is there a relationship between Risser staging and the proximal humerus ossification system?

PURPOSE: To evaluate whether there is a mismatch between Risser staging and the proximal humerus ossification system (PHOS); and to analyze the correlation in the skeletal maturity stages between the two humeral epiphyses. METHODS: Data from patients aged 10 to 18 years with adolescent idiopathic scoliosis (AIS) seen between 2018 to 2021 were analyzed. In an anteroposterior (AP) spine radiograph the ossification process was evaluated using the Risser classification method and bilateral PHOS (if both humeral epiphyses were visualized). A mismatch between methods was defined as a Risser 0-1 (relatively skeletally immature) with a PHOS 4-5 (skeletally mature), or a Risser 2-5 (relatively skeletally mature) with a PHOS 1-3 (skeletally immature). The McNemar test was used to calculate the significance of the mismatch. RESULTS: A mismatch between Risser and PHOS stages was observed in 28.5% of 105 patients, which was statistically significant (p < 0.001). Of the 49 patients with a Risser 0-1, 55.1% (n = 27) had a PHOS 4-5. None of the patients with a Risser 2-5 had a PHOS 1-3. In the 47 patients in whom both humeri were visualized, the absolute correlation between the left and right PHOS values was 95.7%. CONCLUSION: Of AIS patients who are relatively skeletally immature according to Risser staging, more than half may be skeletally mature when measured with PHOS. In patients with a Risser 0-1, it is recommended to measure skeletal maturity in an AP spine radiograph using the PHOS method, which may more accurately guide treatment decision-making, without the need to visualize both humeral epiphyses in this radiographic projection. LEVEL OF EVIDENCE: IV.

Scoliosis and kyphosis in blue-spotted and marbled flathead fish associated with a Myxobolus acanthogobii-like parasite.

Spinal deformities in finfish have the potential to impact aquaculture industries and wild populations by increasing morbidity, mortality, and reducing growth rates. Myxobolus acanthogobii has been implicated in causing scoliosis and lordosis in various aquatic species in Japan. We investigated 4 cases of spinal deformity in 2 flathead (Platycephalus) species that were submitted to the Elizabeth Macarthur Agricultural Institute (EMAI) in New South Wales (NSW), Australia, between 2015 and 2021. Flathead are commercially significant species that are popular among Australian consumers, and are also sought-after species targeted by recreational fishers. Gross deformities are concerning to the community and may impact the quality and quantity of specimens available for consumption. Three blue-spotted flathead (P. caeruleopunctatus) and one marbled flathead (P. marmoratus) were submitted, all with marked scoliosis and kyphosis; 1-2-mm cysts were present on the dorsum of the brain, most often over the optic lobe or cerebellum. Cytology and differential interference microscopy of cyst material revealed numerous oval spores, x̄ 14 ± SD 0.75 µm × x̄ 11.5 ± SD 0.70 µm, with 2 pyriform polar capsules, the morphology of which is consistent with a Myxobolus sp. PCR assay and 18S rDNA sequencing of the cyst material identified a Myxobolus sp. with 96% identity to M. acanthogobii. The identification of this Myxobolus sp. confirms the presence of parasites with the potential to cause spinal deformity in significant aquatic species in NSW waterways.

The Whole-Exome Sequencing of a Cohort of 19 Families with Adolescent Idiopathic Scoliosis (AIS): Candidate Pathways.

A significant genetic involvement has been known for decades to exist in adolescent idiopathic scoliosis (AIS), a spine deformity affecting 1-3% of the world population. However, though biomechanical and endocrinological theories have emerged, no clear pathophysiological explanation has been found. Data from the whole-exome sequencing performed on 113 individuals in 19 multi-generational families with AIS have been filtered and analyzed via interaction pathways and functional category analysis (Varaft, Bingo and Panther). The subsequent list of 2566 variants has been compared to the variants already described in the literature, with an 18% match rate. The familial analysis in two families reveals mutations in the BICD2 gene, supporting the involvement of the muscular system in AIS etiology. The cellular component analysis revealed significant enrichment in myosin-related and neuronal activity-related categories. All together, these results reinforce the suspected role of the neuronal and muscular systems, highlighting the calmodulin pathway and suggesting a role of DNA-binding activities in AIS physiopathology.

BMP6 participates in the pathogenesis of adolescent idiopathic scoliosis by regulating osteopenia.

Adolescent idiopathic scoliosis (AIS) is a complex disease characterized by three-dimensional structural deformities of the spine. Its pathogenesis is associated with osteopenia. Bone-marrow-derived mesenchymal stem cells (BMSCs) play an important role in bone metabolism. We detected 1919 differentially expressed mRNAs and 744 differentially expressed lncRNAs in BMSCs from seven patients with AIS and five patients without AIS via high-throughput sequencing. Multiple analyses identified bone morphogenetic protein-6 (BMP6) as a hub gene that regulates the abnormal osteogenic differentiation of BMSCs in AIS. BMP6 expression was found to be decreased in AIS and its knockdown in human BMSCs significantly altered the degree of osteogenic differentiation. Additionally, CAP1-217 has been shown to be a potential upstream regulatory molecule of BMP6. We showed that CAP1-217 knockdown downregulated the expression of BMP6 and the osteogenic differentiation of BMSCs. Simultaneously, knockout of BMP6 in zebrafish embryos significantly increased the deformity rate. The findings of this study suggest that BMP6 is a key gene that regulates the abnormal osteogenic differentiation of BMSCs in AIS via the CAP1-217/BMP6/RUNX2 axis.

Adolescent idiopathic scoliosis is associated with muscle area asymmetries in the lumbar spine.

PURPOSE: While the etiopathogenesis of adolescent idiopathic scoliosis (AIS) remains unclear, it is assumed that muscular asymmetries contribute to curve progression. As previous studies have found asymmetries of the thoracic paraspinal muscles in AIS patients, our study's aim was to analyze differences in the erector spinae, multifidus, quadratus lumborum, and psoas muscles of the lumbar spine depending on the curve's radiographic characteristics. METHODS: We retrospectively included all patients who received posterior reposition spondylodesis for AIS treatment at our institution. Patients were classified according to the Lenke classification. Muscle cross-sectional areas were obtained from magnetic resonance imaging of the lumbar spine. Data were analyzed with the Wilcoxon rank sum test, the Kruskal-Wallis test with post hoc testing, or the Spearman's correlation coefficient. RESULTS: Seventy-four (14 males and 60 females) AIS patients with a median age of 16 (IQR ± 4) years and a mean Cobb angle of 56.0° (± 18.0°) were included. In curve types Lenke 1 and 2 (n = 45), the erector spinae (p < 0.001) and multifidus (p < 0.001) muscles had a significantly larger cross-sectional area on the convex side, whereas the quadratus lumborum (p = 0.034) and psoas (p < 0.001) muscles each had a significantly larger cross-sectional area on the lumbar contralateral side. CONCLUSION: Our results show an asymmetry of the lumbar spine's muscles which depends on both the convexity and the extent of the scoliotic curve. While our results cannot prove whether these differences are the deformity's cause or effect, they may contribute to a better understanding of AIS pathogenesis and may allow for more specific preoperative physiotherapy.

Quantifying Typical Progression of Adolescent Idiopathic Scoliosis: Longitudinal Three-Dimensional MRI Measures of Disk and Vertebral Deformities.

STUDY DESIGN: A prospective cohort study. OBJECTIVE: Detail typical three-dimensional segmental deformities and their rates of change that occur within developing adolescent idiopathic scoliosis (AIS) spines over multiple timepoints. SUMMARY OF BACKGROUND DATA: AIS is a potentially progressive deforming condition that occurs in three dimensions of the scoliotic spine during periods of growth. However, there remains a gap for multiple timepoint segmental deformity analysis in AIS cohorts during development. MATERIALS AND METHODS: Thirty-six female patients with Lenke 1 AIS curves underwent two to six sequential magnetic resonance images. Scans were reformatted to produce images in orthogonal dimensions. Wedging angles and rotatory values were measured for segmental elements within the major curve. Two-tailed, paired t tests compared morphologic differences between sequential scans. Rates of change were calculated for variables given the actual time between successive scans. Pearson correlation coefficients were determined for multidimensional deformity measurements. RESULTS: Vertebral bodies were typically coronally convexly wedged, locally lordotic, convexly axially rotated, and demonstrated evidence of local mechanical torsion. Between the first and final scans, apical measures of coronal wedging and axial rotation were all greater in both vertebral and intervertebral disk morphology than nonapical regions (all reaching differences where P <0.05). No measures of sagittal deformity demonstrated a statistically significant change between scans. Cross-planar correlations were predominantly apparent between coronal and axial planes, with sagittal plane parameters rarely correlating across dimensions. Rates of segmental deformity changes between earlier scans were characterized by coronal plane convex wedging and convexly directed axial rotation. The major locally lordotic deformity changes that did occur in the sagittal plane were static between scans. CONCLUSIONS: This novel investigation documented a three-dimensional characterization of segmental elements of the growing AIS spine and reported these changes across multiple timepoints. Segmental elements are typically deformed from initial presentation, and subsequent changes occur in separate orthogonal planes at unique times.

Reduced volume and altered composition of paraspinal muscles in Marfan syndrome: A retrospective cohort study.

Retrospective cohort study. Spinal deformities in patients with Marfan syndrome (MFS) are distinct from those in patients with idiopathic scoliosis (IS). It is more prone to progression and more likely to present with sagittal malalignment than IS. However, the etiology of this characteristic spinal deformity in MFS remains unclear. This study aimed to determine the spinal musculature characteristics in patients with MFS on the hypothesis that the paraspinal muscles of patients with MFS would be qualitatively or quantitatively different from those of patients with IS. Seventeen consecutive patients with MFS aged 25 years or younger undergoing surgery for scoliosis in our hospital were compared with age- and sex-matched patients with IS undergoing surgery for scoliosis. The body size-adjusted relative cross-sectional area (rCSA), fatty infiltration ratio (FI%), and relative functional cross-sectional area (rFCSA) of the psoas muscles (PM) and paravertebral muscles (PVM) at L3/4 and L4/5 were measured using preoperative T2-weighted magnetic resonance imaging. Functional CSA was defined as total CSA minus the fatty infiltration area of each muscle and rFCSA was calculated as the body size-adjusted functional CSA. The rCSA of the PM at L3/4 and L4/5 was significantly smaller in the MFS group than in the IS group (L3/4, P = .021; L4/5, P = .002). The FI% of the PM at L4/5 was significantly higher in the MFS group (P = .044). Consequently, the rFCSA of the PM at L3/4 and L4/5 and the rFCSA of the PVM at L3/4 in the MFS group were significantly smaller than those in the IS group (PM at L3/4, P = .021; PM at L4/5, P = .001; PVM at L3/4, P = .025). Compared with patients with IS, patients with MFS exhibited significantly decreased body-size-adjusted CSA of the PM and reduced body-size-adjusted functional CSA of the PVM and PM. These findings may partially explain the characteristics of distinctive spinal deformities in patients with MFS.

Characteristics of paraspinal muscle degeneration in patients with adult degenerative scoliosis.

INTRODUCTION: Adult degenerative scoliosis (ADS) is a 3D deformity that greatly affects the quality of life of patients and is closely related to the quality of paraspinal muscles (PSMs), but the specific degenerative characteristics have not been described. METHODS: This study included ADS patients who were first diagnosed in our hospital from 2018 to 2022. Muscle volume (MV) and fat infiltration (FI) of PSM were measured by 3D reconstruction, and spinal parameters were assessed by X-ray. The values of convex side (CV) and concave side (CC) were compared. RESULTS: Fifty patients were enrolled with a mean age of 64.1 ± 5.8 years old. There were significant differences in MV, FI, and Cobb angle between male and female groups. The MV of MF and PS on the CC was significantly larger than that on the CV. In the apex and the segments above the apex, the FI of the MF on the CC is greater than the CV, and in the CV of the segment below the apex, the FI of the MF is greater than the CC. Besides, there was a significant positive correlation between the FI and Cobb angle in the MF of the CC-CV. CONCLUSION: There were significant differences in the MV and FI of PSM on both sides of the spine in ADS patients. It was determined that the PSM of ADS showed different degrees of degeneration in different levels of the lumbar spine and were positively correlated with Cobb angle.

Quantifying Muscle Size Asymmetry in Adolescent Idiopathic Scoliosis Using Three-dimensional Magnetic Resonance Imaging.

STUDY DESIGN: This is a case-control study of prospectively collected data. OBJECTIVE: To quantify paraspinal muscle size asymmetry in adolescent idiopathic scoliosis (AIS) and determine if this asymmetry is (i) greater than observed in adolescent controls with symmetrical spines; and (ii) positively associated with skeletal maturity using Risser grade, scoliosis severity using the Cobb angle, and chronological age in years. SUMMARY OF BACKGROUND DATA: AIS is a three-dimensional deformity of the spine which occurs in 2.5% to 3.7% of the Australian population. There is some evidence of asymmetry in paraspinal muscle activation and morphology in AIS. Asymmetric paraspinal muscle forces may facilitate asymmetric vertebral growth during adolescence. METHODS: An asymmetry index [Ln(concave/convex volume)] of deep and superficial paraspinal muscle volumes, at the level of the major curve apex (Thoracic 8-9 th vertebral level) and lower-end vertebrae ( LEV , Thoracic 10-12 th vertebral level), was determined from three-dimensional Magnetic Resonance Imaging of 25 adolescents with AIS (all right thoracic curves), and 22 healthy controls (convex=left); all female, 10 to 16 years. RESULTS: Asymmetry index of deep paraspinal muscle volumes was greater in AIS (0.16±0.20) than healthy spine controls (-0.06±0.13) at the level of the apex ( P <0.01, linear mixed-effects analysis) but not LEV ( P >0.05). Asymmetry index was positively correlated with Risser grade ( r =0.50, P <0.05) and scoliosis Cobb angle ( r =0.45, P <0.05), but not age ( r =0.34, P >0.05). There was no difference in the asymmetry index of superficial paraspinal muscle volumes between AIS and controls ( P >0.05). CONCLUSIONS: The asymmetry of deep apical paraspinal muscle volume in AIS at the scoliosis apex is greater than that observed at equivalent vertebral levels in controls and may play a role in the pathogenesis of AIS.

Early onset horizontal gaze palsy and progressive scoliosis due to a noncanonical splicing-site variant and a missense variant in the ROBO3 gene.

BACKGROUND: Homozygous or compound heterozygous ROBO3 gene mutations cause horizontal gaze palsy with progressive scoliosis (HGPPS). This is an autosomal recessive disorder that is characterized by congenital absence or severe restriction of horizontal gaze and progressive scoliosis. To date, almost 100 patients with HGPPS have been reported and 55 ROBO3 mutations have been identified. METHODS: We described an HGPPS patient and performed whole-exome sequencing (WES) to identify the causative gene. RESULTS: We identified a missense variant and a splice-site variant in the ROBO3 gene in the proband. Sanger sequencing of cDNA revealed the presence of an aberrant transcript with retention of 700 bp from intron 17, which was caused by a variation in the noncanonical splicing site. We identified five additional ROBO3 variants, which were likely pathogenic, and estimated the overall allele frequency in the southern Chinese population to be 9.44 × 10-4 , by a review of our in-house database. CONCLUSION: This study has broadened the mutation spectrum of the ROBO3 gene and has expanded our knowledge of variants in noncanonical splicing sites. The results could help to provide more accurate genetic counseling to affected families and prospective couples. We suggest that the ROBO3 gene should be included in the local screening strategy.

Bioinformatics analysis of paravertebral muscles atrophy in adult degenerative scoliosis.

Paravertebral muscles (PVM) act as one of the major dynamic factors to maintain human upright activities and play a remarkable role in maintaining the balance of the trunk. Adult degenerative scoliosis (ADS) has become one of the important causes of disability in the elderly population owing to the changes in spinal biomechanics, atrophy and degeneration of PVM, and imbalance of the spine. Previously, many studies focused on the physical evaluation of PVM degeneration. However, the molecular biological changes are still not completely known. In this study, we established a rat model of scoliosis and performed the proteomic analysis of the PVM of ADS. The results showed that the degree of atrophy, muscle fat deposition, and fibrosis of the PVM of rats positively correlated with the angle of scoliosis. The proteomic results showed that 177 differentially expressed proteins were present in the ADS group, which included 105 upregulated proteins and 72 downregulated proteins compared with the PVM in individuals without spinal deformities. Through the construction of a protein-protein interaction network, 18 core differentially expressed proteins were obtained, which included fibrinogen beta chain, apolipoprotein E, fibrinogen gamma chain, thrombospondin-1, integrin alpha-6, fibronectin-1, platelet factor 4, coagulation factor XIII A chain, ras-related protein Rap-1b, platelet endothelial cell adhesion molecule 1, complement C1q subcomponent subunit A, cathepsin G, myeloperoxidase, von Willebrand factor, integrin beta-1, integrin alpha-1, leukocyte surface antigen CD47, and complement C1q subcomponent subunit B. Further analysis of the Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) and immunofluorescence showed that the neutrophil extracellular traps (NETs) formation signaling pathway plays a major role in the pathogenesis of PVM degeneration in ADS. The results of the present study preliminarily laid the molecular biological foundation of PVM atrophy in ADS, which will provide a new therapeutic target for alleviating PVM atrophy and decreasing the occurrence of scoliosis.

Ependymal polarity defects coupled with disorganized ciliary beating drive abnormal cerebrospinal fluid flow and spine curvature in zebrafish.

Idiopathic scoliosis (IS) is the most common spinal deformity diagnosed in childhood or early adolescence, while the underlying pathogenesis of this serious condition remains largely unknown. Here, we report zebrafish ccdc57 mutants exhibiting scoliosis during late development, similar to that observed in human adolescent idiopathic scoliosis (AIS). Zebrafish ccdc57 mutants developed hydrocephalus due to cerebrospinal fluid (CSF) flow defects caused by uncoordinated cilia beating in ependymal cells. Mechanistically, Ccdc57 localizes to ciliary basal bodies and controls the planar polarity of ependymal cells through regulating the organization of microtubule networks and proper positioning of basal bodies. Interestingly, ependymal cell polarity defects were first observed in ccdc57 mutants at approximately 17 days postfertilization, the same time when scoliosis became apparent and prior to multiciliated ependymal cell maturation. We further showed that mutant spinal cord exhibited altered expression pattern of the Urotensin neuropeptides, in consistent with the curvature of the spine. Strikingly, human IS patients also displayed abnormal Urotensin signaling in paraspinal muscles. Altogether, our data suggest that ependymal polarity defects are one of the earliest sign of scoliosis in zebrafish and disclose the essential and conserved roles of Urotensin signaling during scoliosis progression.

Effects of spinal deformities on lung development in children: a review.

Scoliosis before the age of 5 years is referred to as early-onset scoliosis (EOS). While causes may vary, EOS can potentially affect respiratory function and lung development as children grow. Moreover, scoliosis can lead to thoracic insufficiency syndrome when aggravated or left untreated. Therefore, spinal thoracic deformities often require intervention in early childhood, and solving these problems requires new methods that include the means for both deformity correction and growth maintenance. Therapeutic strategies for preserving the growing spine and thorax include growth rods, vertically expandable titanium artificial ribs, MAGEC rods, braces and casts. The goals of any growth-promoting surgical strategy are to alter the natural history of cardiorespiratory development, limit the progression of underlying spondylarthrosis deformities and minimize negative changes in spondylothorax biomechanics due to the instrumental action of the implant. This review further elucidates EOS in terms of its aetiology, pathogenesis, pathology and treatment.