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Pathogenesis of lumbar spine disease in mucopolysaccharidosis VII.

ABSTRACT: Mucopolysaccharidosis type VII (MPS VII) is characterized by deficient ?-glucuronidase (GUSB) activity, which leads to accumulation of chondroitin, heparan and dermatan sulfate glycosaminoglycans (GAGs), and multisystemic disease. MPS VII patients can develop kypho-scoliotic deformity and spinal cord compression due to disease of intervertebral disks, vertebral bodies, and associated tissues. We have previously demonstrated in MPS VII dogs that intervertebral disks degenerate, vertebral bodies have irregular surfaces, and vertebral body epiphyses have reduced calcification, but the pathophysiological mechanisms underlying these changes are unclear. We hypothesized that some of these manifestations could be due to upregulation of destructive proteases, possibly via the binding of GAGs to Toll-like receptor 4 (TLR4), as has been proposed for other tissues in MPS models. In this study, the annulus fibrosus of the intervertebral disk of 6-month-old MPS VII dogs had cathepsin B and K activities that were 117- and 2-fold normal, respectively, which were associated with elevations in mRNA levels for these cathepsins as well as TLR4. The epiphyses of MPS VII dogs had a marked elevation in mRNA for the cartilage-associated gene collagen II, consistent with a developmental delay in the conversion of the cartilage to bone in this region. The spine obtained at autopsy from a young man with MPS VII exhibited similar increased cartilage in the vertebral bodies adjacent to the end plates, disorganization of the intervertebral disks, and irregular vertebral end plate morphology. These data suggest that the pathogenesis of destructive changes in the spine in MPS VII may involve upregulation of cathepsins. Inhibition of destructive proteases, such as cathepsins, might reduce spine disease in patients with MPS VII or related disorders.

SUBMITTER: Smith LJ

PROVIDER: S-EPMC3428127 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Pathogenesis of lumbar spine disease in mucopolysaccharidosis VII.

Smith Lachlan J LJ Baldo Guilherme G Wu Susan S Liu Yuli Y Whyte Michael P MP Giugliani Roberto R Elliott Dawn M DM Haskins Mark E ME Ponder Katherine P KP

Molecular genetics and metabolism 20120330 1-2

Mucopolysaccharidosis type VII (MPS VII) is characterized by deficient β-glucuronidase (GUSB) activity, which leads to accumulation of chondroitin, heparan and dermatan sulfate glycosaminoglycans (GAGs), and multisystemic disease. MPS VII patients can develop kypho-scoliotic deformity and spinal cord compression due to disease of intervertebral disks, vertebral bodies, and associated tissues. We have previously demonstrated in MPS VII dogs that intervertebral disks degenerate, vertebral bodies h ...[more]

PMID: 22513347

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Project description:Mucopolysaccharidosis (MPS) VII is a lysosomal storage disorder characterized by deficient activity of β-glucuronidase, leading to progressive accumulation of incompletely degraded heparan, dermatan and chondroitin sulfate glycosaminoglycans (GAGs). Patients with MPS VII exhibit progressive skeletal deformity including kyphoscoliosis and joint dysplasia, which decrease quality of life and increase mortality. Previously, using the naturally-occurring canine model, we demonstrated that one of the earliest skeletal abnormalities to manifest in MPS VII is failed initiation of secondary ossification in vertebrae and long bones at the requisite postnatal developmental stage. The objective of this study was to obtain global insights into the molecular mechanisms underlying this failed initiation of secondary ossification using whole transcriptome sequencing (RNA-Seq). Epiphyseal tissue was isolated from the vertebrae of control and MPS VII affected dogs at 9 and 14 days-of-age (n=5 for each group). Differences in global gene expression across this developmental window for both cohorts were established using RNA-Seq. A targeted analysis focused on signaling pathways important in the regulation of endochondral ossification, and a subset of gene expression changes were validated using qPCR. Principal Component Analysis revealed clustering of samples from each group, indicating clear effects of both age and disease state. At 9 days-of-age, 1375 genes were significantly differentially expression between MPS VII and control, and by 14 days-of-age, this increased to 4719 genes. Osteoactivin (GPNMB) was the top upregulated gene in MPS VII at both ages. Targeted analysis revealed temporal changes in gene expression from 9 to 14 days-of-age in control samples consistent with chondrocyte maturation, cartilage resorption, and osteogenesis. In MPS VII samples, however, elements of key osteogenic pathways such as Wnt/β-catenin and BMP signaling were dysregulated. In conclusion, this study represents the first step towards identifying druggable therapeutic targets and putative biomarkers for bone disease in MPS VII patients during postnatal growth.

Project description:BackgroundMucopolysaccharidosis VII (MPS VII) is an ultra-rare disease characterised by the deficiency of β-glucuronidase (GUS). Patients' phenotypes vary from severe forms with hydrops fetalis, skeletal dysplasia and mental retardation to milder forms with fewer manifestations and mild skeletal abnormalities. Accurate assessments on the frequency and clinical characteristics of the disease have been scarce. The aim of this study was to collect such data.MethodsWe have conducted a survey of physicians to document the medical history of patients with MPS VII. The survey included anonymous information on patient demographics, family history, mode of diagnosis, age of onset, signs and symptoms, severity, management, clinical features and natural progression of the disease.ResultsWe collected information on 56 patients from 11 countries. Patients with MPS VII were classified based on their phenotype into three different groups: (1) neonatal non-immune hydrops fetalis (NIHF) (n=10), (2) Infantile or adolescent form with history of hydrops fetalis (n=13) and (3) Infantile or adolescent form without known hydrops fetalis (n=33). Thirteen patients with MPS VII who had the infantile form with history of hydrops fetalis and survived childhood, had a wide range of clinical manifestations from mild to severe. Five patients underwent bone marrow transplantation and one patient underwent enzyme replacement therapy with recombinant human GUS.ConclusionsMPS VII is a pan-ethnic inherited lysosomal storage disease with considerable phenotypical heterogeneity. Most patients have short stature, skeletal dysplasia, hepatosplenomegaly, hernias, cardiac involvement, pulmonary insufficiency and cognitive impairment. In these respects it resembles MPS I and MPS II. In MPS VII, however, one unique and distinguishing clinical feature is the unexpectedly high proportion of patients (41%) that had a history of NIHF. Presence of NIHF does not, by itself, predict the eventual severity of the clinical course, if the patient survives infancy.

Project description:BackgroundAdjacent segment disease (ASDz) is a potential complication following lumbar spinal fusion. A common nomenclature based on etiology and ASDz type does not exist and is needed to assist with clinical prognostication, decision making, and management.Questions/purposesThe objective of this study was to develop an etiology-based classification system for ASDz following lumbar fusion.MethodsWe conducted a retrospective chart review of 65 consecutive patients who had undergone both a lumbar fusion performed by a single surgeon and a subsequent procedure for ASDz. We established an etiology-based classification system for lumbar ASDz with the following six categories: "degenerative" (degenerative disc disease or spondylosis), "neurologic" (disc herniation, stenosis), "instability" (spondylolisthesis, rotatory subluxation), "deformity" (scoliosis, kyphosis), "complex" (fracture, infection), or "combined." Based on this scheme, we determined the rate of ASDz in each etiologic category.ResultsOf the 65 patients, 27 (41.5%) underwent surgery for neurogenic claudication or radiculopathy for adjacent-level stenosis or disc herniation and were classified as "neurologic." Ten patients (15.4%) had progressive degenerative disc pathology at the adjacent level and were classified as "degenerative." Ten patients (15.4%) had spondylolisthesis or instability and were classified as "instability," and three patients (4.6%) required revision surgery for adjacent-level kyphosis or scoliosis and were classified as "deformity." Fifteen patients (23.1%) had multiple diagnoses that included a combination of categories and were classified as "combined."ConclusionThis is the first study to propose an etiology-based classification scheme of ASDz following lumbar spine fusion. This simple classification system may allow for the grouping and standardization of patients with similar pathologies and thus for more specific pre-operative diagnoses, personalized treatments, and improved outcome analyses.

Dataset Information

Pathogenesis of lumbar spine disease in mucopolysaccharidosis VII.

Publications

Pathogenesis of lumbar spine disease in mucopolysaccharidosis VII.

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