Michael B Bober

The University of Edinburgh, Edinburgh, Scotland, United Kingdom

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Publications (50)301.89 Total impact


  • No preview · Article · Jan 2016 · American Journal of Medical Genetics Part A

  • No preview · Article · Jan 2016 · American Journal of Medical Genetics Part A
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    ABSTRACT: DNA lesions encountered by replicative polymerases threaten genome stability and cell cycle progression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism. We establish that TRAIP relocalizes to sites of DNA damage, where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to ultraviolet (UV) irradiation, as well as fork progression through UV-induced DNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes. Human genetics thus identifies TRAIP as a component of the DNA damage response to replication-blocking DNA lesions.
    Full-text · Article · Nov 2015 · Nature Genetics
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    ABSTRACT: Introduction: Following a Phase III, randomized, double-blind, placebo (PBO)-controlled, multinational study in subjects with mucopolysaccharidosis IVA (MPS IVA), enzyme replacement therapy (ERT) of elosulfase alfa has been approved in several countries. The study was designed to evaluate safety and efficacy of elosulfase alfa in patients with MPS IVA aged 5 years and older.Areas covered: Outcomes of clinical trials for MPS IVA have been described. Subjects received either 2.0 mg/kg/week, 2.0 mg/kg/every other week, or PBO, for 24 weeks. The primary endpoint was the change from baseline 6-min walk test (6MWT) distance compared to PBO. The 6MWT results improved in patients receiving 2 mg/kg weekly compared to PBO. The every other week regimen resulted in walk distances comparable to PBO. There was no change from baseline in the 3 Min Stair Climb Test in both treatment groups. Following completion of the initial study, patients, who continued to receive elosulfase alfa 2 mg/kg weekly (QW) for another 48
    No preview · Article · Oct 2015 · Expert Opinion on Orphan Drugs
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    ABSTRACT: Patients with severe tracheal obstruction in Morquio A syndrome are at risk of dying of sleep apnea and related complications. Tracheal obstruction also leads to life-threatening complications during anesthesia as a result of the difficulty in managing the upper airway due to factors inherent to the Morquio A syndrome, compounded by the difficulty in intubating the trachea. A detailed description of the obstructive pathology of the trachea is not available in the literature probably due to lack of a homogenous group of Morquio A patients to study at any one particular center. We present a series of cases with significant tracheal obstruction who were unrecognized due to the difficulty in interpreting tracheal narrowing airway symptoms. Our goal is to provide the guidelines in the management of these patients that allow earlier recognition and intervention of tracheal obstruction.
    Full-text · Article · Oct 2015 · Molecular Genetics and Metabolism
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    ABSTRACT: Purpose: Osteogenesis imperfecta (OI) predisposes to recurrent fractures. Patients with the moderate to severe forms of OI present with antenatal fractures, and the mode of delivery that would be safest for the fetus is not known. Methods: We conducted systematic analyses of the largest cohort of individuals with OI (n = 540) enrolled to date in the OI Linked Clinical Research Centers. Self-reported at-birth fracture rates were compared among individuals with OI types I, III, and IV. Multivariate analyses utilizing backward-elimination logistic regression model building were performed to assess the effect of multiple covariates, including method of delivery, on fracture-related outcomes. Results: When accounting for other covariates, at-birth fracture rates did not differ based on whether delivery was by vaginal route or by cesarean delivery (CD). Increased birth weight conferred higher risk for fractures irrespective of the delivery method. In utero fracture, maternal history of OI, and breech presentation were strong predictors for choosing CD. Conclusion: Our study, the largest to analyze the effect of various factors on at-birth fracture rates in OI, shows that CD is not associated with decreased fracture rate. With the limitation that the fracture data were self-reported in this cohort, these results suggest that CD should be performed only for other maternal or fetal indications, not for the sole purpose of fracture prevention in OI.Genet Med advance online publication 01 October 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.131.
    No preview · Article · Oct 2015 · Genetics in medicine: official journal of the American College of Medical Genetics

  • No preview · Article · Sep 2015 · American Journal of Medical Genetics Part A
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    ABSTRACT: Achondroplasia is the most common inherited disorder of bone growth (skeletal dysplasia). Despite this fact, consistent and evidence-based management approaches to recognized, life-threatening complications, such as foramen magnum stenosis, are lacking. This study aims to outline best practice, based on evidence and expert consensus, regarding the diagnosis, assessment, and management of foramen magnum stenosis in achondroplasia during infancy. A panel of 11 multidisciplinary international experts on skeletal dysplasia was invited to participate in a Delphi process. They were: 1) presented with a list of 26 indications and a thorough literature review, 2) given the opportunity to anonymously rate the indications and discuss in face to face discussion; 3) edit the list and rate it in a second round. Those indications with more than 80% agreement were considered as consensual. After two rounds of rating and a face-to-face meeting, consensus was reached to support 22 recommendations for the evaluation and treatment of foramen magnum stenosis in infants with achondroplasia. These recommendations include indications for surgical decompression, ventriculomegaly, and hydrocephalus, sleep-disordered breathing, physical exams and the use of polysomnography and imaging in this condition. We present a consensus-based best practice guidelines consisting of 22 recommendations. It is hoped that these guidelines will lead to more uniform and structured evaluation, standardizing care pathways, and improving mortality and morbidity outcomes for this cohort. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Sep 2015 · American Journal of Medical Genetics Part A
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    ABSTRACT: Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) is a polymodal modulated non-selective cation channel required for normal development and maintenance of bone and cartilage. Heterozygous mutations of this channel cause a variety of channelopathies, including metatropic dysplasia (MD). We analyzed the effect of a novel TRPV4 mutation c.2398G>A, p.Gly800Asp on intracellular calcium ([Ca(2+) ]i ) regulation in chondrocytes and compared this response to chondrocytes with a frequently observed mutation, c.2396C>T, p.Pro799Leu. We observed temperature-dependent [Ca(2+) ]i oscillations in both intact and MD chondrocytes however, MD mutations exhibited increased peak magnitudes of [Ca(2+) ]i during oscillations. We also found increased baseline [Ca(2+) ]i in MD primary cells, as well as increased [Ca(2+) ]i response to either hypotonic swelling or the TRVP4-specific agonist, GSK1016790A. Oscillations and stimulation responses were blocked with the TRPV4-specific antagonist, GSK205. Analysis of [Ca(2+) ]i response kinetics showed that MD chondrocytes had increased frequency of temperature-sensitive oscillations, and the magnitude and duration of [Ca(2+) ]i responses to given stimuli. Duration of the response of the p.Gly800Asp mutation to stimulation was greater than for the p.Pro799Leu mutation. These experiments show that this region of the channel is essential for proper [Ca(2+) ]i regulation. These studies of primary cells from patients show how both mutant and WT TRPV4 channels regulate cartilage and bone development. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Aug 2015 · American Journal of Medical Genetics Part A
  • Alfred Atanda · Maegen Wallace · Michael B. Bober · William Mackenzie
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    ABSTRACT: Background: Achondroplasia is the most common form of skeletal dysplasia that presents to the pediatric orthopaedist. More than half of achondroplasia patients are affected with knee pain. It is thought that the majority of this pain may be due to spinal stenosis, hip pathology, or knee malalignment. Discoid menisci can be a source of lateral knee joint pain in skeletally immature patients in general. We present the first case series of patients with achondroplasia who had symptomatic discoid lateral menisci treated with arthroscopic knee surgery. Methods: The charts of 6 patients (8 knees) with achondroplasia who underwent arthroscopic knee surgery for symptomatic discoid lateral menisci were collected. History and physical examination data, magnetic resonance imaging findings, and operative reports were reviewed. Meniscal tear configuration and treatment type (meniscectomy vs. repair) were noted. Results: Each patient was found to have a tear of the discoid meniscus. All menisci were treated with saucerization. In addition, meniscal repair was performed in 2 cases, partial meniscectomy in 3 cases, and subtotal meniscectomy in 3 cases. Two patients had bilateral discoid meniscal tears which were treated. Average follow-up was 2.4 years (range, 1 to 4.5 y) and the average pediatric International Knee Documentation Committee (pedi-IKDC) score was 85.3% (range, 75% to 95.4%). At final follow-up, all patients were pain free and able to return to full activities. Conclusions: Discoid meniscus tears may be a source of lateral joint line pain in patients with achondroplasia. These injuries can be successfully treated with arthroscopic surgery in this patient population. Future studies need to be done to determine the exact incidence of discoid menisci in achondroplasia patients and also to determine whether there is a genetic relationship between the 2 conditions. Level of Evidence: Level IV-case series. Copyright
    No preview · Article · Aug 2015 · Journal of Pediatric Orthopaedics
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    ABSTRACT: In clinical practice, respiratory function tests are difficult to perform in Morquio syndrome patients due to their characteristic skeletal dysplasia, small body size and lack of cooperation of young patients, where in some cases, conventional spirometry for pulmonary function is too challenging. To establish feasible clinical pulmonary endpoints and determine whether age impacts lung function in Morquio patients non-invasive pulmonary tests and conventional spirometry were evaluated. The non-invasive pulmonary tests: impulse oscillometry system, pneumotachography, and respiratory inductance plethysmography in conjunction with conventional spirometry were evaluated in twenty-two Morquio patients (18 Morquio A and 4 Morquio B) (7 males), ranging from 3 to 40years of age. Twenty-two patients were compliant with non-invasive tests (100%) with the exception of IOS (81.8%-18 patients). Seventeen patients (77.3%) were compliant with spirometry testing. All subjects had normal vital signs at rest including >95% oxygen saturation, end tidal CO2 (38-44mmHg), and age-appropriate heart rate (mean=98.3, standard deviation=19) (two patients were deviated). All patients preserved normal values in the impulse oscillometry system, pneumotachography, and respiratory inductance plethysmography, although predicted forced expiratory total (72.8±6.9 SE%) decreased with age and was below normal; phase angle (35.5±16.5°), %rib cage (41.6±12.7%), resonant frequency, and forced expiratory volume in 1s/forced expiratory volume total (110.0±3.2 SE%) were normal and not significantly impacted by age. The proposed non-invasive pulmonary function tests are able to cover a greater number of patients (young patients and/or wheel-chair bound), thus providing a new diagnostic approach for the assessment of lung function in Morquio syndrome which in many cases may be difficult to evaluate. Morquio patients studied herein demonstrated no clinical or functional signs of restrictive and/or obstructive lung disease. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jun 2015 · Molecular Genetics and Metabolism

  • No preview · Article · Jun 2015
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    ABSTRACT: Patients with mucopolysaccharidosis IVA (MPS IVA) can present with systemic skeletal dysplasia, leading to a need for multiple orthopedic surgical procedures, and often become wheelchair bound in their teenage years. Studies on patients with MPS IVA treated by enzyme replacement therapy (ERT) showed a sharp reduction on urinary keratan sulfate, but only modest improvement based on a 6-minute walk test and no significant improvement on a 3-minute climb-up test and lung function test compared with the placebo group, at least in the short-term. Surgical remnants from ERT-treated patients did not show reduction of storage materials in chondrocytes. The impact of ERT on bone lesions in patients with MPS IVA remains limited. ERT seems to be enhanced in a mouse model of MPS IVA by a novel form of the enzyme tagged with a bone-targeting moiety. The tagged enzyme remained in the circulation much longer than untagged native enzyme and was delivered to and retained in bone. Three-month-old MPS IVA mice treated wi
    Full-text · Article · Apr 2015 · Drug Design, Development and Therapy
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    ABSTRACT: Cartilage hair hypoplasia (CHH) is a rare metaphyseal chondrodysplasia characterized by short stature and short limbs, found primarily in Amish and Finnish populations. Cartilage hair hypoplasia is caused by mutations in the RMRP gene located on chromosome 9p13.3. The disorder has several characteristic orthopaedic manifestations, including joint laxity, limited elbow extension, ankle varus, and genu varum. Immunodeficiency is of concern in most cases. Although patients exhibit orthopaedic problems, the orthopaedic literature on CHH patients is scant at best. The objective of this study was to characterize the orthopaedic manifestations of CHH based on the authors' unique access to the largest collection of CHH patients ever reported. The authors examined charts and/or radiographs in 135 cases of CHH. We analyzed the orthopaedic manifestations to better characterize and further understand the orthopaedic surgeon's role in this disorder. In addition to describing the clinical characteristics, we report on our surgical experience in caring for CHH patients. Genu varum, with or without knee pain, is the most common reason a patient with CHH will seek orthopaedic consultation. Of the cases reviewed, 32 patients had undergone surgery, most commonly to correct genu varum. This paper characterizes the orthopaedic manifestations of CHH. Characterizing this condition in the orthopaedic literature will likely assist orthopaedic surgeons in establishing a correct diagnosis and appreciating the orthopaedic manifestations. It is important that the accompanying medical conditions are appreciated and evaluated.
    Preview · Article · Mar 2015 · Journal of Children s Orthopaedics

  • No preview · Article · Feb 2015 · Molecular Genetics and Metabolism
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    ABSTRACT: Achondroplasia is the most common form of skeletal dysplasia. Although the radiographic features are well described, MRI features of the knee in achondroplasia have not been reported. To describe common MRI characteristics of the knee joint in symptomatic children and adolescents with achondroplasia. We retrospectively evaluated 10 knee MRI examinations in 8 children and young adults (age range 11-20 years, mean 16.3 years) with achondroplasia. We measured modified Insall-Salvati index, knee flexion angle, anterior cruciate ligament (ACL)-Blumensaat line angle, ACL-tibial angle, posterior cruciate ligament (PCL) angle, intercondylar notch width index, and intercondylar notch depth index. We compared our findings with an age- and gender-matched control group of 20 children (age range 15-18 years; mean 16 years) with normal knee MRIs. All 10 knees in the achondroplasia group had discoid lateral meniscus; 8 meniscal tears were identified. Patella baja was present in half of the study cases. Greater knee flexion and increased ACL-Blumensaat line and PCL angles were seen in all achondroplasia knees. ACL-tibial angle was similar in the study and in the control group. Children with achondroplasia had deeper A-shape femoral notches that extended more anteriorly than those seen in the control group. MRI findings were confirmed in all seven knees with arthroscopic correlation. Discoid lateral meniscus, often with tear, is a consistent feature in knee MRIs of symptomatic children and adolescents with achondroplasia. Other findings include patella baja, knee flexion, deep A-shape intercondylar notch, increased ACL-Blumensaat line angle and taut PCL.
    No preview · Article · Nov 2014 · Pediatric Radiology
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    ABSTRACT: Context: C-type natriuretic peptide (CNP) is a crucial regulator of endochondral bone growth. In a previous report of a child with acromesomelic dysplasia, Maroteaux type (AMDM), due to loss-of-function of the CNP receptor (NPR-B), plasma levels of CNP were elevated. In vitro studies have shown that activation of the MEK/ERK MAP kinase pathway causes functional inhibition of NPR-B. Achondroplasia, hypochondroplasia, and thanatophoric dysplasia are syndromes of short-limbed dwarfism caused by activating mutations of fibroblast growth factor receptor-3, which result in over-activation of the MEK/ERK MAP kinase pathway. Objective: To determine if these syndromes exhibit evidence of CNP resistance as reflected by increases of plasma CNP and its amino terminal propeptide (NTproCNP). Design: This was a prospective, observational study. Subjects: Participants were 63 children and 20 adults with achondroplasia, 6 children with hypochondroplasia, 2 children with thanatophoric dysplasia, and 4 children and 1 adult with AMDM. Results: Plasma levels of CNP and NTproCNP were higher in children with achondroplasia with CNP SD scores (SDS) of 1.0 (0.3-1.4) [median (intraquartile range)] and NTproCNP SDS of 1.4 (0.4-1.8) (p<0.0005). NTproCNP levels correlated with height velocity. Levels were also elevated in adults with achondroplasia, CNP SDS 1.5 (0.7-2.1) and NTproCNP SDS 0.5 (0.1-1.0), p<0.005. In children with hypochondroplasia, CNP SDS were 1.3 (0.7-1.5)(p=0.08) and NTproCNP SDS were 1.9 (1.8-2.3)(p<0.05). In children with AMDM, CNP SDS were 1.6 (1.4-3.3) and NTproCNP SDS were 4.2 (2.7-6.2) (p<0.01). Conclusions: In these skeletal dysplasias, elevated plasma levels of proCNP products suggest the presence of tissue resistance to CNP.
    Full-text · Article · Nov 2014 · Journal of Clinical Endocrinology & Metabolism

  • No preview · Article · Oct 2014
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    ABSTRACT: Majewski osteodysplastic primordial dwarfism type II (MOPDII) is caused by mutations in the centrosome gene pericentrin (PCNT) that lead to severe pre- and postnatal growth retardation [1]. As in MOPDII patients, disruption of pericentrin (Pcnt) in mice caused a number of abnormalities including microcephaly, aberrant hemodynamics analyzed by in utero echocardiography, and cardiovascular anomalies; the latter being associated with mortality, as in the human condition [1]. To identify the mechanisms underlying these defects, we tested for changes in cell and molecular function. All Pcnt(-/-) mouse tissues and cells examined showed spindle misorientation. This mouse phenotype was associated with misdirected ventricular septal growth in the heart, decreased proliferative symmetric divisions in brain neural progenitors, and increased misoriented divisions in fibroblasts; the same phenotype was seen in fibroblasts from three MOPDII individuals. Misoriented spindles were associated with disrupted astral microtubules and near complete loss of a unique set of centrosome proteins from spindle poles (ninein, Cep215, centriolin). All these proteins appear to be crucial for microtubule anchoring and all interacted with Pcnt, suggesting that Pcnt serves as a molecular scaffold for this functionally linked set of spindle pole proteins. Importantly, Pcnt disruption had no detectable effect on localization of proteins involved in the cortical polarity pathway (NuMA, p150(glued), aPKC). Not only do these data reveal a spindle-pole-localized complex for spindle orientation, but they identify key spindle symmetry proteins involved in the pathogenesis of MOPDII.
    Full-text · Article · Sep 2014 · Current Biology
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    ABSTRACT: Study Design:A retrospective study.Objective:To report the early postoperative results of scoliosis surgery in osteogenesis imperfecta (OI) patients utilizing all pedicle screw constructs and present a novel cementing technique to increase pedicle screw purchase in the osteoporotic OI spine.Summary of Background Data:Scoliosis surgery utilizing hooks and wire systems have high complication rates in OI. Pedicle screw fixation systems have the biomechanical advantage of 3-column fixation, and cement augmentation of pedicle screws provides additional pull-out strength in the osteoporotic OI spine.Methods:The clinical and radiologic results of 10 consecutive OI patients treated with all pedicle screw instrumentation and fusion were retrospectively reviewed. The radiologic data included preoperative and postoperative major curve measurements: major curve Cobb angle, global coronal balance (GCB), apical vertebral translation (AVT), and the lowest instrumented vertebral (LIV) tilt. Operative findings included blood loss, surgery time, and additional procedures. All patients received intravenous pamidronate therapy preoperatively to increase bone mineral density.Results:Ten patients with OI were operated on between 2005 and 2009. Seven had cement-augmented pedicle screw insertion at the proximal and distal foundations. The mean hospital stay was 107.5 days (range, 4-27 d) and the average follow-up period was 25.7 +/- 13.1 months (range, 14-50 mo). Mean preoperative and postoperative major Cobb angles were 83.7 +/- 23.8 and 40.3 +/- 14.6 degrees, respectively (48% correction; P<0.05). Mean preoperative and postoperative GCB deviations were 26.7 +/- 18.6 and 14.1 +/- 13.3 mm, respectively (P=0.097). Mean preoperative and postoperative AVTs were 69.3 +/- 29.1 and 29 +/- 12.2 mm, respectively (P<0.05). Preoperative and postoperative LIV tilts were 18.5 +/- 8.9 and 5.2 +/- 3.9 degrees, respectively (P<0.05). At the latest follow-up, the mean major curve Cobb angle was 37.7 +/- 13.1 degrees, the GCB deviation was 13.8 +/- 5.1 mm, the AVT was 31.7 +/- 13.3 mm, and the LIV tilt was 11.3 +/- 8.8 degrees. There was no difference between the early postoperative and the latest follow-up major curve Cobb angle, GCB deviation, AVT, or LIV tilt, indicating maintenance of correction. The mean blood loss was 23,75 mL (range, 800-45,00 mL). The mean operative time was 375.4 minutes (range, 262-491 min). The mean postoperative Scoliosis Research Society-22 patient-based outcome scores were 4.6 +/- 0.7 (out of 5). There were no instrumentation failures or permanent neurological deficits in this series.Conclusions:Pedicle screw instrumentation in OI scoliosis is safe and effective. Cement augmentation in these patients may help to increase the pedicle pull-out strength and decrease the screw failure rates, especially at the proximal and the distal ends of instrumentation.
    No preview · Article · May 2014 · Journal of Spinal Disorders & Techniques

Publication Stats

555 Citations
301.89 Total Impact Points

Institutions

  • 2015
    • The University of Edinburgh
      Edinburgh, Scotland, United Kingdom
    • Akron Children's Hospital
      Akron, Ohio, United States
  • 2009
    • Thomas Jefferson University Hospitals
      Filadelfia, Pennsylvania, United States