Michael B Bober

The University of Edinburgh, Edinburgh, Scotland, United Kingdom

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Publications (30)236.63 Total impact

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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.
    Pediatric Radiology 11/2014; · 1.57 Impact Factor
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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.
    The Journal of clinical endocrinology and metabolism. 11/2014;
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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.
    Current Biology 09/2014; · 9.49 Impact Factor
  • Journal of Spinal Disorders & Techniques 05/2014; 27(3):174-180. · 1.77 Impact Factor
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    ABSTRACT: Majewski osteodysplastic primordial dwarfism type II (MOPDII) is characterized by severe prenatal and postnatal growth failure with microcephaly, characteristic skeletal dysplasia, an increased risk for cerebrovascular disease, and insulin resistance. MOPDII is caused by mutations in the pericentrin (PCNT) gene and is inherited in an autosomal-recessive manner. This study aimed to determine the incidence of hip pathology in patients with molecularly confirmed MOPDII and to describe the functional outcomes of surgical treatment. Thirty-three enrolled patients had a clinical diagnosis of MOPDII. Biallelic PCNT mutations or absent pericentrin protein was confirmed in 25 of these patients. Twelve patients (7 female) had appropriate clinical and radiographic records at this institution and were included in this study. The data collected included age at presentation, age at surgery, sex, body weight and height, weight-bearing status at diagnosis, and the clinical examination. Four patients (31%) had coxa vara: 3 unilateral and 1 bilateral. Three unilateral patients had in situ pinning at a mean age 4 years. The patient with bilateral coxa vara had valgus osteotomy at the age of 5 years. Two children had bilateral hip dysplasia and subluxation with no surgery. One patient had bilateral developmental hip dislocations. The patient was treated by open reduction-spica cast and 2 years after surgery, coxa valga was noted. Another patient was diagnosed at an age of 12 years with bilateral avascular necrosis of the hips. Four patients did not have hip pathology. Hip pathology is common among children with MOPDII; coxa vara is the most frequent diagnosis. Routine clinical and radiographic hip evaluation is important. The capital femoral epiphysis appears to slip down along the shaft, giving the appearance of a proximal femoral epiphysiolysis. A hip diagnosed with slipped capital femoral epiphysis in early life may progress to severe coxa vara. Level IV.
    Journal of pediatric orthopedics 04/2014; · 1.23 Impact Factor
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    ABSTRACT: Ligase IV syndrome is a rare differential diagnosis for Nijmegen Breakage syndrome owing to a shared predisposition to lympho-reticular malignancies, significant microcephaly and radiation hypersensitivity. Only 16 cases with mutations in LIG4 have been described to date with phenotypes varying from malignancy in developmentally normal individuals, to severe combined immunodeficiency and early mortality. Here we report the identification of biallelic truncating LIG4 mutations in 11 patients with microcephalic primordial dwarfism presenting with restricted prenatal growth and extreme postnatal global growth failure (average OFC -10.1 s.d., height -5.1 s.d.). Subsequently most patients developed thrombocytopenia and leucopenia later in childhood and many were found to have previously unrecognised immunodeficiency following molecular diagnosis. None have yet developed malignancy, though all patients tested had cellular radiosensitivity. A genotype:phenotype correlation was also noted with position of truncating mutations corresponding to disease severity. This work extends the phenotypic spectrum associated with LIG4 mutations, establishing that extreme growth retardation with microcephaly is a common presentation of bilallelic truncating mutations. Such growth failure is therefore sufficient to consider a diagnosis of LIG4 deficiency and early recognition of such cases is important as bone marrow failure, immunodeficiency and sometimes malignancy are long term sequelae of this disorder. This article is protected by copyright. All rights reserved.
    Human Mutation 10/2013; · 5.21 Impact Factor
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    ABSTRACT: A retrospective study: case series report. To report cervicothoracic stenosis resulting in neurological deterioration, in 4 patients with Morquio type A syndrome. Craniovertebral junction anomalies and C1-C2 instability resulting in myelopathy have been well described in the literature on mucopolysaccharidosis IV (MPS-IV). Spinal involvement in MPS-IV patients, with neurological impairment, other than atlanto-axial instability and thoracolumbar kyphosis, has been scarcely mentioned in the literature. Retrospective clinical and radiologic review of the medical records and imaging studies of 4 individuals with Morquio A syndrome, who had undergone decompression and fusion of the cervicothoracic spine for myelopathy secondary to cervicothoracic stenosis between 1990 and 2009. Data regarding the presence of kyphosis at the cervicothoracic and upper thoracic spine, and neurological symptoms and signs were obtained. There were 3 girls and 1 boy with an average age of 5 years and 11 months at presentation with neurological symptoms. Half of the patients had previously undergone occipitocervical fusion for atlanto-axial instability, whereas the other half were noted to have spinal cord compression at both the upper cervical and cervicothoracic regions, and underwent decompression and fusion at both levels concomitantly. All patients showed postoperative neurological improvement. All patients presented with the classical Morquio syndrome vertebral morphology. Cervicothoracic kyphosis was found in all of our patients in a varying severity (10 to 35 degrees). Levels of stenosis were similar in 3 patients, C7-T2; and occurred at a lower spinal level, T1-T4, in the remaining patient. Posterior disk bulging and thecal sac indentation were found in all 4 patients. Neurological problems secondary to progressive kyphosis and stenosis at the cervicothoracic and upper thoracic spine are seen in children with Morquio syndrome. Early detection with a careful neurological assessment, whole spine MR imaging, and appropriate surgical treatment can prevent permanent neurological sequelae.
    Journal of pediatric orthopedics 10/2013; · 1.23 Impact Factor
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    ABSTRACT: Study Design. Retrospective case seriesObjective. To report the outcomes of distraction-based, growth-sparing spinal instrumentation (GSSI) in patients with skeletal dysplasia.Summary of Background Data. Skeletal dysplasia patients with spinal deformity often undergo early fusion, further compromising an already small chest. Non-fusion techniques may provide a safe alternative and allow for thoracic growth.Methods. Between 2004 and 2010, 12 children with a diagnosis of various types of skeletal dysplasia underwent GSSI for severe spinal deformities. The mean duration of treatment with growing rods was 57 months (42 to 84 months). Nine patients were treated with growing rods (8 dual, 1single), and 3 were treated with vertical expandable prosthetic titanium rib (VEPTR; Synthes, West Chester, PA) Preoperative, initial postoperative, and final follow-up anteroposterior and lateral spine radiographs were measured for magnitude of deformity, junctional kyphosis, and implant failure.Results. The major curve Cobb angle improved from a mean of 79° preoperatively to a mean of 41° at the last follow-up (52%). There was a decrease in mean thoracic kyphosis from 77° preoperatively to 64° at final follow-up and an increase in mean lumbar lordosis from 58° preoperatively to 63° at final follow-up. The mean space available for the lungs increased by 26 mm on the concave and 24 mm on the convex side. Six patients required revision surgery for proximal junctional kyphosis. There were four rod failures and six hook and eight screw dislodgements. One patient with VEPTR had failed rib fixation that required revision.Conclusion. GSSI in patients with skeletal dysplasia and severe spinal deformity has a high complication and revision rate and surgeons should closely monitor these patients. The complication rate is comparable with previous reports on patients with other diagnoses. However, deformities were well controlled, some trunk growth was achieved, and fusion surgery was delayed in all cases.
    Spine 08/2013; · 2.16 Impact Factor
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    ABSTRACT: Mucopolysaccharidosis IVA (MPS IVA) is caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), leading to systemic skeletal dysplasia because of excessive storage of keratan sulfate (KS) in chondrocytes. In an effort to determine a precise prognosis and personalized treatment, we aim to characterize clinical, biochemical, and molecular findings in MPS IVA patients, and to seek correlations between genotype, phenotype, and blood and urine KS levels. Mutation screening of GALNS gene was performed in 55 MPS IVA patients (severe: 36, attenuated: 13, undefined: 6) by genomic PCR followed by direct sequence analysis. Plasma and urine KS levels were measured by ELISA method. Genotype/phenotype/KS correlations were assessed when data were available. Fifty-three different mutations including 19 novel ones (41 missense, 2 nonsense, 4 small deletions, 1 insertion, and 5 splice-site) were identified in 55 patients and accounted for 93.6% of the analyzed mutant alleles. Thirty-nine mutations were associated with a severe phenotype and ten mutations with an attenuated one. Blood and urine KS concentrations in MPS IVA patients were age-dependent and markedly higher than those in age-matched normal controls. Plasma and urine KS levels in MPS IVA patients with the severe phenotype were higher than in those with an attenuated form. This study provides evidence for extensive allelic heterogeneity of MPS IVA. Accumulation of mutations as well as clinical descriptions and KS levels allows us to predict clinical severity more precisely and should be used for evaluation of responses to potential treatment options.
    Molecular Genetics and Metabolism 06/2013; · 2.83 Impact Factor
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    ABSTRACT: : Skeletal dysplasias may be associated with cervical spinal instability or stenosis. Cervical spine flexion-extension plain radiographs in children with skeletal dysplasia are difficult to interpret. The purpose of this study was to review the indications, efficacy, and safety of performing flexion-extension magnetic resonance imaging (MRI) under sedation/anesthesia in these children. : Retrospective, Institutional Review Board-approved review of 31 children with skeletal dysplasia who underwent 38 cervical spine flexion-extension MRI studies under sedation/anesthesia. Indications included abnormal neurological examination, suspected instability, stenosis, or inconclusive findings on flexion-extension radiographs. Studies were performed by the radiology technologist as directed by the radiologist with an anesthesiologist present. MRI was evaluated for odontoid hypoplasia, os odontoideum, cerebrospinal fluid effacement, cord compression, spinal cord changes, cervical canal narrowing in the neutral, flexion, and extension positions. Neurological examinations were recorded before and after MRI to assess safety. : The average age at MRI was 3 years, 2 months. In 6 patients whose plain radiographs showed C1-C2 or subaxial instability, flexion-extension MRI showed no cord compression. Nine patients with inconclusive plain radiographs had abnormal MRI findings. An os odontoideum not seen on plain radiographs was diagnosed in 3 patients on flexion-extension MRI. On the basis of the MRI findings, 14 patients underwent surgery, 9/14 had increased cord compression in flexion or extension compared with neutral, and observation was continued in 17 others. Patients who underwent surgery had significant cord compression on MRI. There were no significant changes in the neurological examinations after MRI. : Cervical spine flexion-extension MRI under sedation/anesthesia in children with skeletal dysplasia is safe under adequate supervision and is necessary to guide accurate medical and surgical decision making. Flexion-extension MRI is useful for identifying dynamic changes in canal diameter resulting in cord compression not seen on plain radiographs, and it is also useful for identifying patients with suspected plain film instability who may not have stenosis or cord compression on MRI. : Level IV-retrospective case series.
    Journal of pediatric orthopedics 01/2013; 33(1):91-8. · 1.23 Impact Factor
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    ABSTRACT: Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recently, mutations in the ORC1, ORC4, ORC6, CDT1, and CDC6 genes, encoding components of the pre-replication complex, have been identified. This complex is essential for DNA replication and therefore mutations are expected to impair cell proliferation and consequently could globally reduce growth. However, detailed growth characteristics of MGS patients have not been reported, and so this is addressed here through study of 45 MGS patients, the largest cohort worldwide. Here, we report that growth velocity (length) is impaired in MGS during pregnancy and first year of life, but, thereafter, height increases in paralleled normal reference centiles, resulting in a mean adult height of -4.5 standard deviations (SD). Height is dependent on ethnic background and underlying molecular cause, with ORC1 and ORC4 mutations causing more severe short stature and microcephaly. Growth hormone therapy (n = 9) was generally ineffective, though in two patients with significantly reduced IGF1 levels, growth was substantially improved by GH treatment, with 2SD and 3.8 SD improvement in height. Growth parameters for monitoring growth in future MGS patients are provided and as well we highlight that growth is disproportionately affected in certain structures, with growth related minor genital abnormalities (42%) and mammary hypoplasia (100%) frequently present, in addition to established effects on ears and patellar growth. © 2012 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 09/2012; 158A(11):2733-42. · 2.30 Impact Factor
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    ABSTRACT: Achondroplasia and hypochondroplasia are two of the most common forms of skeletal dysplasia. They are both caused by activating mutations in FGFR3 and are inherited in an autosomal dominant manner. Our patient was born to parents with presumed achondroplasia, and found on prenatal testing to have p.G380R and p.N540K FGFR3 mutations. In addition to having typical problems associated with both achondroplasia and hypochondroplasia, our patient had several atypical findings including: abnormal lobulation of the lungs with respiratory insufficiency, C1 stenosis, and hypoglycemia following a Nissen fundoplication. After his reflux and aspiration were treated, the persistence of the tachypnea and increased respiratory effort indicated this was not the primary source of the respiratory distress. Our subsequent hypothesis was that primary restrictive lung disease was the cause of his respiratory distress. A closer examination of his chest circumference did not support this conclusion either. Following his death, an autopsy found the right lung had 2 lobes while the left lung had 3 lobes. A literature review demonstrates that other children with achondroplasia-hypochondroplasia complex have been described with abnormal pulmonary function and infants with thanatophoric dysplasia have similar abnormal pulmonary anatomy. We hypothesize that there may be a primary pulmonary phenotype associated with FGFR3-opathies, unrelated to chest size which leads to the consistent finding of increased respiratory signs and symptoms in these children. Further observation of respiratory status, combined with the macroscopic and microscopic analysis of pulmonary branching anatomy and alveolar structure in this patient population will be important to explore this hypothesis.
    American Journal of Medical Genetics Part A 08/2012; 158A(9):2336-41. · 2.30 Impact Factor
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    ABSTRACT: Microcephalic primordial dwarfism (MPD) is a class of disorders characterized by intrauterine growth restriction (IUGR), impaired postnatal growth and microcephaly. Majewski osteodysplastic primordial dwarfism type II (MOPD II) is one of the more common conditions within this group. MOPD II is caused by truncating mutations in pericentrin (PCNT) and is inherited in an autosomal recessive manner. Detailed growth curves for length, weight, and OFC are presented here and derived from retrospective data from 26 individuals with MOPD II confirmed by molecular or functional studies. Severe pre- and postnatal growth failure is evident in MOPD II patients. The length, weight, and OFC at term (when corrected for gestational age) were -7.0, -3.9, and -4.6 standard deviation (SD) below the population mean and equivalent to the 50th centile of a 28-29-, 31-32-, and 30-31-week neonate, respectively. While at skeletal maturity, the height, weight, and OFC were -10.3, -14.3, and -8.5 SD below the population mean and equivalent to the size of 3-year 10- to 11-month-old, a 5-year 2- to 3-month-old, and 5- to 6-month-old, respectively. During childhood, MOPD II patients grow with slowed, but fairly constant growth velocities and show no evidence of any pubertal growth spurt. Treatment with human growth hormone (n = 11) did not lead to any significant improvement in final stature. The growth charts presented here will be of assistance with diagnosis and management of MOPD II, and should have particular utility in nutritional management of MOPD II during infancy. © 2012 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 07/2012; 158A(11):2719-25. · 2.30 Impact Factor
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    ABSTRACT: The modalities and results of surgical intervention in the lower extremity in children with Morquio syndrome type A [mucopolysaccharidosis-IV (MPS-IVA)] have not been well described. The aims of this study are to define the lower extremity deformities, and describe the results of intervention in MPS-IVA patients. Retrospective chart and radiograph review of 23 MPS-IVA patients with a minimum follow-up of >2 years. Patients were divided into no intervention and surgical groups. Demographic data, surgical details, clinical results, and complications were recorded. Standard lower extremity radiographic measurements made on standing radiographs at initial presentation, preoperatively (in surgical group), and at the final follow-up were used to study the deformities and effects of hip, knee, and ankle surgery. Descriptive statistics were performed. There were 11 boys and 12 girls. The average age at presentation was 6.8±3.4 years and at the last visit was 13.5±5 years with a mean follow-up of 6.7±3.7 years. Progressive hip subluxation, genu valgum, and ankle valgus were observed in all patients without intervention. Twenty patients had a total of 159 lower extremity surgical procedures (average, 8 procedures per patient). There were 61 hip, 78 knee, and 20 ankle procedures. Surgery resulted in improvement of the center edge angle, femoral head coverage, lateral distal femoral angle, medial proximal tibial angle, tibiofemoral angle, and lateral distal tibial angle. Mechanical axis of the lower extremities improved after intervention. Six patients (12 hips) had recurrence of hip subluxation after acetabular osteotomies and/or femoral varus derotation osteotomy, and 8 patients (16 knees) had postoperative genu valgum recurrence requiring subsequent intervention. There was no recurrent hip subluxation after shelf acetabuloplasty. Progressive hip subluxation, genu valgum, and ankle valgus were seen and often needed surgery. After shelf acetabuloplasty and varus derotation osteotomy, there was no recurrent hip subluxation. Recurrence after genu valgum correction was common. Level IV, therapeutic case series.
    Journal of pediatric orthopedics 07/2012; 32(5):534-40. · 1.23 Impact Factor
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    ABSTRACT: We describe a series of seven male patients from six different families with skeletal dysplasia, characteristic facial features, and developmental delay. Skeletal findings include patellar dislocation, short tubular bones, mild metaphyseal changes, brachymetacarpalia with stub thumbs, short femoral necks, shallow acetabular roofs, and platyspondyly. Facial features include: a flattened midface with broad nasal bridge, cleft palate or bifid uvula and synophrys. All of the patients demonstrated pre-school onset of a cognitive developmental delay with a shortened attention span. Some of the cognitive delay was masked by a warm and engaging personality. We posit that these individuals have a newly recognized syndrome characterized by the described features. There is some phenotypic overlap between these patients and Desbuquois dysplasia; however molecular testing demonstrated that this is a distinct disorder. Given the family information available for each patient, we are suspicious that the constellation of findings reported herein could be an X-linked recessive syndrome.
    American Journal of Medical Genetics Part A 06/2012; 158A(8):1815-22. · 2.30 Impact Factor
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    ABSTRACT: Hypophosphatasia results from mutations in the gene for the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). Inorganic pyrophosphate accumulates extracellularly, leading to rickets or osteomalacia. Severely affected babies often die from respiratory insufficiency due to progressive chest deformity or have persistent bone disease. There is no approved medical therapy. ENB-0040 is a bone-targeted, recombinant human TNSALP that prevents the manifestations of hypophosphatasia in Tnsalp knockout mice. We enrolled infants and young children with life-threatening or debilitating perinatal or infantile hypophosphatasia in a multinational, open-label study of treatment with ENB-0040. The primary objective was the healing of rickets, as assessed by means of radiographic scales. Motor and cognitive development, respiratory function, and safety were evaluated, as well as the pharmacokinetics and pharmacodynamics of ENB-0040. Of the 11 patients recruited, 10 completed 6 months of therapy; 9 completed 1 year. Healing of rickets at 6 months in 9 patients was accompanied by improvement in developmental milestones and pulmonary function. Elevated plasma levels of the TNSALP substrates inorganic pyrophosphate and pyridoxal 5'-phosphate diminished. Increases in serum parathyroid hormone accompanied skeletal healing, often necessitating dietary calcium supplementation. There was no evidence of hypocalcemia, ectopic calcification, or definite drug-related serious adverse events. Low titers of anti-ENB-0040 antibodies developed in four patients, with no evident clinical, biochemical, or autoimmune abnormalities at 48 weeks of treatment. ENB-0040, an enzyme-replacement therapy, was associated with improved findings on skeletal radiographs and improved pulmonary and physical function in infants and young children with life-threatening hypophosphatasia. (Funded by Enobia Pharma and Shriners Hospitals for Children; ClinicalTrials.gov number, NCT00744042.).
    New England Journal of Medicine 03/2012; 366(10):904-13. · 54.42 Impact Factor
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    ABSTRACT: Meier-Gorlin syndrome (MGS) is an autosomal recessive disorder characterized by microtia, patellar aplasia/hypoplasia, and short stature. Recently, mutations in five genes from the pre-replication complex (ORC1, ORC4, ORC6, CDT1, and CDC6), crucial in cell-cycle progression and growth, were identified in individuals with MGS. Here, we report on genotype-phenotype studies in 45 individuals with MGS (27 females, 18 males; age 3 months-47 years). Thirty-five individuals had biallelic mutations in one of the five causative pre-replication genes. No homozygous or compound heterozygous null mutations were detected. In 10 individuals, no definitive molecular diagnosis was made. The triad of microtia, absent/hypoplastic patellae, and short stature was observed in 82% of individuals with MGS. Additional frequent clinical features were mammary hypoplasia (100%) and abnormal genitalia (42%; predominantly cryptorchidism and hypoplastic labia minora/majora). One individual with ORC1 mutations only had short stature, emphasizing the highly variable clinical spectrum of MGS. Individuals with ORC1 mutations had significantly shorter stature and smaller head circumferences than individuals from other gene categories. Furthermore, compared with homozygous missense mutations, compound heterozygous mutations appeared to have a more severe effect on phenotype, causing more severe growth retardation in ORC4 and more frequently pulmonary emphysema in CDT1. A lethal phenotype was seen in four individuals with compound heterozygous ORC1 and CDT1 mutations. No other clear genotype-phenotype association was observed. Growth hormone and estrogen treatment may be of some benefit, respectively, to growth retardation and breast hypoplasia, though further studies in this patient group are needed.
    European journal of human genetics: EJHG 02/2012; 20(6):598-606. · 3.56 Impact Factor
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    ABSTRACT: Hypophosphatasia is a rare autosomal recessive disorder caused by deficient activity of tissue nonspecific alkaline phosphatase (TNSALP) and characterized by defective bone mineralization. In the perinatal lethal form, respiratory complications due to rachitic deformities of the thoracic cage and associated hypoplastic lungs are present. ENB-0040 is a bone-targeted human recombinant TNSALP fusion protein that aims to restore skeletal mineralization. The goal of this study was to characterize pulmonary and thoracic cage mechanics in an infant with the perinatal lethal form of hypophosphatasia under enzyme replacement therapy. Pulmonary function testing was performed on a preterm, 8-week-old patient with hypophosphatasia who was mechanically ventilated since birth because of severe chest wall insufficiency. The measurements consisted of respiratory impulse oscillation measurements (resistance and reactance), ventilatory mechanics (compliance and resistance), and thoracoabdominal motion (TAM) analysis. At baseline, chest wall compliance was 50% of normal, and the TAM indicated predominantly abdominal displacement. After 12 weeks of treatment, a consistent decrease in ventilator requirements and improvement in lung function and chest wall mechanics were observed and correlated with thoracic cage radiologic findings. Measurable changes in chest wall dynamics and respiratory mechanics using noninvasive technology were useful for respiratory management and therapeutic guidance of ENB-0040 treatment in this patient.
    Pediatric Pulmonology 02/2012; 47(9):917-22. · 2.38 Impact Factor
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    ABSTRACT: The spliceosome, a ribonucleoprotein complex that includes proteins and small nuclear RNAs (snRNAs), catalyzes RNA splicing through intron excision and exon ligation to produce mature messenger RNAs, which, in turn serve as templates for protein translation. We identified four point mutations in the U4atac snRNA component of the minor spliceosome in patients with brain and bone malformations and unexplained postnatal death [microcephalic osteodysplastic primordial dwarfism type 1 (MOPD 1) or Taybi-Linder syndrome (TALS); Mendelian Inheritance in Man ID no. 210710]. Expression of a subgroup of genes, possibly linked to the disease phenotype, and minor intron splicing were affected in cell lines derived from TALS patients. Our findings demonstrate a crucial role of the minor spliceosome component U4atac snRNA in early human development and postnatal survival.
    Science 04/2011; 332(6026):240-3. · 31.20 Impact Factor
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    ABSTRACT: Studies into disorders of extreme growth failure (for example, Seckel syndrome and Majewski osteodysplastic primordial dwarfism type II) have implicated fundamental cellular processes of DNA damage response signaling and centrosome function in the regulation of human growth. Here we report that mutations in ORC1, encoding a subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. We establish that these mutations disrupt known ORC1 functions including pre-replicative complex formation and origin activation. ORC1 deficiency perturbs S-phase entry and S-phase progression. Additionally, we show that Orc1 depletion in zebrafish is sufficient to markedly reduce body size during rapid embryonic growth. Our data suggest a model in which ORC1 mutations impair replication licensing, slowing cell cycle progression and consequently impeding growth during development, particularly at times of rapid proliferation. These findings establish a novel mechanism for the pathogenesis of microcephalic dwarfism and show a surprising but important developmental impact of impaired origin licensing.
    Nature Genetics 02/2011; 43(4):350-5. · 35.21 Impact Factor

Publication Stats

262 Citations
236.63 Total Impact Points

Institutions

  • 2013
    • The University of Edinburgh
      • Institute of Genetics and Molecular Medicine
      Edinburgh, Scotland, United Kingdom
  • 2011
    • Western General Hospital
      Edinburgh, Scotland, United Kingdom
  • 2010
    • Nemours
      • Department of Pediatrics
      Jacksonville, FL, United States
  • 2009
    • Thomas Jefferson University Hospitals
      • Division of Rheumatology
      Philadelphia, Pennsylvania, United States