144 results on '"Ferreira, CR"'
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2. OUTCOMES, PROGNOSTIC FACTORS, PREDICTORS FOR TRANSFORMATION TO HIGH-GRADE B-CELL LYMPHOMA, AND THERAPEUTIC MANAGEMENT IN FOLLICULAR LYMPHOMA: REAL-WORLD EVIDENCE FROM A LARGE AND LONG-TERM LATIN-AMERICAN COHORT
- Author
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Nogueira, DS, primary, Lage, LAPC, additional, Reichert, CO, additional, Culler, HF, additional, Freitas, FA, additional, Ferreira, CR, additional, Costa, RO, additional, Rocha, V, additional, Levy, D, additional, and Pereira, J, additional
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- 2023
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3. TRANSFORMED MYCOSIS FUNGOIDES RELAPSED AT CENTRAL NERVOUS SYSTEM AFTER ALLOGENEIC BONE MARROW TRANSPLANT
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Santanna, PVH, primary, Cortez, AC, additional, Costa, AD, additional, Correa, APR, additional, Ferreira, CR, additional, Costa, FD, additional, Silveira, TB, additional, and Fischer, T, additional
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- 2021
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4. 22q11.2 Deletion Syndrome in Diverse Populations
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Muthukumarasamy, P, Muenke, M, Linguraru, MG, Kruszka, P, Addissie, YA, McGinn, DE, Porras, AR, Biggs, E, Share, M, Crowley, TB, Kaplan, JD, Chung, BHY, Abdul-Rahman, OA, Uwineza, A, Mok, TKG, MAK, CCY, Mutesa, L, Moresco, A, Obregon, MG, Richieri-Costa, A, Zackai, EH, Summar, M, McDonald-McGinn, DM, Adeyemo, AA, Gil-da-Silva-Lopes, VL, Thong, MK, Siriseria, ND, Dissanayake, VHW, Paththinige, CS, Prabodha, LBL, Mishra, R, Shotelersuk, V, Ekure, EN, Sokunbi, OJ, Kalu, N, Ferreira, CR, Duncan, JM, Patil, SJ, and Jones, KL
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Adult ,Heart Defects, Congenital ,Male ,Adolescent ,Learning Disabilities ,Chromosomes, Human, Pair 22 ,Infant, Newborn ,Black People ,Facies ,Infant ,Hispanic or Latino ,Article ,White People ,Phenotype ,Asian People ,Biometric Identification ,Child, Preschool ,Image Interpretation, Computer-Assisted ,DiGeorge Syndrome ,Humans ,Female ,Child ,human activities ,In Situ Hybridization, Fluorescence - Abstract
22q11.2 deletion syndrome (22q11.2 DS) is the most common microdeletion syndrome and is underdiagnosed in diverse populations. This syndrome has a variable phenotype and affects multiple systems, making early recognition imperative. In this study, individuals from diverse populations with 22q11.2 DS were evaluated clinically and by facial analysis technology. Clinical information from 106 individuals and images from 101 were collected from individuals with 22q11.2 DS from 11 countries; average age was 11.7 and 47% were male. Individuals were grouped into categories of African descent (African), Asian, and Latin American. We found that the phenotype of 22q11.2 DS varied across population groups. Only two findings, congenital heart disease and learning problems, were found in greater than 50% of participants. When comparing the clinical features of 22q11.2 DS in each population, the proportion of individuals within each clinical category was statistically different except for learning problems and ear anomalies (P 0.05). However, when Africans were removed from analysis, six additional clinical features were found to be independent of ethnicity (P ≥ 0.05). Using facial analysis technology, we compared 156 Caucasians, Africans, Asians, and Latin American individuals with 22q11.2 DS with 156 age and gender matched controls and found that sensitivity and specificity were greater than 96% for all populations. In summary, we present the varied findings from global populations with 22q11.2 DS and demonstrate how facial analysis technology can assist clinicians in making accurate 22q11.2 DS diagnoses. This work will assist in earlier detection and in increasing recognition of 22q11.2 DS throughout the world.
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- 2017
5. L'Homme-Bus
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Ferreira, Cristina, Maugué, Ludovic, and Maulini, Sandrine
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Psychiatrie ,privation de liberté à des fins d'assistance ,Internements administratifs ,Histoire Suisse - Abstract
Le 10 janvier 1986, un jeune homme est escorté par la police à l’hôpital psychiatrique de Cery situé dans la périphérie de Lausanne. Connu pour arpenter la ville au volant de charrettes transformées en trolleybus, l’Homme-bus se trouve au centre des attentions médiatiques. Explorant des sources archivistiques, journalistiques et littéraires, ce livre situe ce cas singulier dans un contexte marqué par des controverses intenses sur la psychiatrie (1960-1980). Droits de l’homme et lois d’internement, psychiatrie punitive en URSS, fermeture des asiles en Italie, activisme des associations militantes en Suisse romande : ce moment historique est reconstitué à partir des débats sur la privation de liberté à des fins d’assistance de l’Homme-bus.
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- 2020
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6. Relevance of the Iron Distribution in Natural Smectite Clays for the Thermal Stability of PMMA-Clay Nanocomposites.
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Ferreira CR, Santilli CV, Briois V, and Pulcinelli SH
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Polymer-clay nanocomposites have greater thermal stability compared to the pristine polymer matrix. This can be attributed to the physical barrier provided by the inclusion of 2D clay nanoparticles (especially of the smectite group), together with radical trapping related to the distribution of specific 3d atoms in the inorganic phase. To elucidate the relevance of the Fe
3+ distribution in this synergic effect, the iron atoms present in octahedral sheets of natural nontronite clay (Non, 5.6 wt % Fe) or in maghemite (M) nanoparticles (γ-Fe2 O3 ) were incorporated in a poly(methyl methacrylate) (PMMA) matrix. Na-laponite (Lap) clay was used to evaluate the contribution of the diffusion barrier effect to the increased thermal stability of a PMMA-Lap nanocomposite, as evidenced by the upshift of the thermogravimetric (TGA) curve compared to that for PMMA. The contribution of radical trapping to the thermal stability of the PMMA-Non nanocomposite was evidenced by a significant shift of the Fe K-edge rising edge position by -4.5 eV after iron reduction by heating in N2 , while similar treatment of pristine nontronite did not lead to a significant rising edge shift in the X-ray absorption spectra (XAS). This downshift demonstrated the reduction of Fe3+ to Fe0 , induced by the sequestration of radicals formed by PMMA depolymerization. Raman spectroscopy analysis evidenced the formation of graphitic char deposits above 400 °C, further improving the thermal stability of PMMA-Non by providing an additional physical barrier to mass transport. A fourth contribution of well-dispersed iron was the abstraction of carbon from the char by the iron carburization reaction, which hindered CO2 formation by oxidative coking. In contrast, no relevant contribution of graphitic layer deposition was observed for the PMMA-M-Lap nanocomposite, where its improved thermal stability was only due to the combined contributions of the gas diffusion barrier effect and radical trapping by iron atoms. The maghemite effectively captured the radicals confined by the clay sheets, resulting in significant stabilization of the nanocomposite, with a shift of the mass loss of the PMMA-M-Lap nanocomposite compared to PMMA-Lap., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)- Published
- 2024
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7. Ocular findings in Jansen metaphyseal chondrodysplasia.
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Obiezu F, Magone De Quadros Costa MT, Huryn LA, Pan K, Almpani K, Ninan A, Roszko KL, Weinstein LS, Gafni RI, Ferreira CR, Lee J, Collins MT, and Jha S
- Abstract
Jansen metaphyseal chondrodysplasia (JMC) is an ultra-rare disorder caused by germline heterozygous PTHR1 variants resulting in constitutive activation of parathyroid hormone type 1 receptor. A description of ocular manifestations of the disease is lacking. Six patients with JMC underwent a detailed ophthalmic evaluation, spectral-domain optical coherence tomography (OCT), visual field testing, and craniofacial CT scans. Five of 6 patients had good visual acuity. All patients had widely spaced eyes; 5/6 had downslanted palpebral fissures. One patient had proptosis, and another had bilateral ptosis. Two patients had incomplete closure of the eyelids (lagophthalmos), one had a history of progressive right facial nerve palsy with profuse epiphora, while the second had advanced optic nerve atrophy with corresponding retinal nerve fiber layer (RNFL) thinning on OCT and significant bilateral optic canal narrowing on CT scan. Additionally, this patient also had central visual field defects and abnormal color vision. A third patient had normal visual acuity, subtle temporal pallor of the optic nerve head, normal average RNFL, but decreased temporal RNFL and retinal ganglion cell layer analysis (GCA) on OCT. GCA was decreased in 4/6 patients indicating a subclinical optic nerve atrophic process. None of the patients had glaucoma or high myopia. These data represent the first comprehensive report of ophthalmic findings in JMC. Patients with JMC have significant eye findings associated with optic canal narrowing due to extensive skull base dysplastic bone overgrowth that appear to be more prevalent and pronounced with age. Progressive optic neuropathy from optic canal narrowing may be a feature of JMC, and OCT GCA can serve as a useful biomarker for progression in the setting of optic canal narrowing. We suggest that patients with JMC should undergo regular ophthalmic examination including color vision, OCT, visual field testing, orbital, and craniofacial imaging., Competing Interests: No conflicting relationship exists for any author., (Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research 2024.)
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- 2024
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8. Rumen-protected methionine supplementation alters lipid profile of preimplantation embryo and endometrial tissue of Holstein cows.
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Stella SL, Guadagnin AR, Velasco-Acosta DA, Ferreira CR, Rubessa M, Wheeler MB, Luchini D, and Cardoso FC
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Our objective is to evaluate the effects of feeding rumen-protected Met (RPM) throughout the transition period and early lactation on the lipid profile of the preimplantation embryos and the endometrial tissue of Holstein cows. Treatments consisted of feeding a total mixed ration with top-dressed RPM (Smartamine
® M, Adisseo, Alpharetta, GA, United States; MET; n = 11; RPM at a rate of 0.08% of DM: Lys:Met = 2.8:1) or not (CON; n = 9, Lys:Met = 3.5:1). Endometrial biopsies were performed at 15, 30, and 73 days in milk (DIM). Prior to the endometrial biopsy at 73 DIM, preimplantation embryos were harvested via flushing. Endometrial lipid profiles were analyzed using multiple reaction monitoring-profiling and lipid profiles of embryos were acquired using matrix assisted laser desorption/ionization mass spectrometry. Relative intensities levels were used for principal component analysis. Embryos from cows in MET had greater concentration of polyunsaturated lipids than embryos from cows in CON. The endometrial tissue samples from cows in MET had lesser concentrations of unsaturated and monounsaturated lipids at 15 DIM, and greater concentration of saturated, unsaturated (specifically diacylglycerol), and monounsaturated (primarily ceramides) lipids at 30 DIM than the endometrial tissue samples from cows in CON. In conclusion, feeding RPM during the transition period and early lactation altered specific lipid classes and lipid unsaturation level of preimplantation embryos and endometrial tissue., Competing Interests: DL from Adisseo had input in the experimental design and had no influence in performing the experiment and analyzing the data. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Stella, Guadagnin, Velasco-Acosta, Ferreira, Rubessa, Wheeler, Luchini and Cardoso.)- Published
- 2024
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9. Imipramine Treatment Alters Sphingomyelin, Cholesterol, and Glycerophospholipid Metabolism in Isolated Macrophage Lysosomes.
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Albright JM, Sydor MJ, Shannahan J, Ferreira CR, and Holian A
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- Humans, Cholesterol metabolism, Macrophages metabolism, Lysosomes metabolism, Inflammation metabolism, Lipid Metabolism, Glycerophospholipids metabolism, Sphingomyelins metabolism, Imipramine pharmacology
- Abstract
Lysosomes are degradative organelles that facilitate the removal and recycling of potentially cytotoxic materials and mediate a variety of other cellular processes, such as nutrient sensing, intracellular signaling, and lipid metabolism. Due to these central roles, lysosome dysfunction can lead to deleterious outcomes, including the accumulation of cytotoxic material, inflammation, and cell death. We previously reported that cationic amphiphilic drugs, such as imipramine, alter pH and lipid metabolism within macrophage lysosomes. Therefore, the ability for imipramine to induce changes to the lipid content of isolated macrophage lysosomes was investigated, focusing on sphingomyelin, cholesterol, and glycerophospholipid metabolism as these lipid classes have important roles in inflammation and disease. The lysosomes were isolated from control and imipramine-treated macrophages using density gradient ultracentrifugation, and mass spectrometry was used to measure the changes in their lipid composition. An unsupervised hierarchical cluster analysis revealed a clear differentiation between the imipramine-treated and control lysosomes. There was a significant overall increase in the abundance of specific lipids mostly composed of cholesterol esters, sphingomyelins, and phosphatidylcholines, while lysophosphatidylcholines and ceramides were overall decreased. These results support the conclusion that imipramine's ability to change the lysosomal pH inhibits multiple pH-sensitive enzymes in macrophage lysosomes.
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- 2023
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10. Deep phenotyping of the neuroimaging and skeletal features in KBG syndrome: a study of 53 patients and review of the literature.
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Peluso F, Caraffi SG, Contrò G, Valeri L, Napoli M, Carboni G, Seth A, Zuntini R, Coccia E, Astrea G, Bisgaard AM, Ivanovski I, Maitz S, Brischoux-Boucher E, Carter MT, Dentici ML, Devriendt K, Bellini M, Digilio MC, Doja A, Dyment DA, Farholt S, Ferreira CR, Wolfe LA, Gahl WA, Gnazzo M, Goel H, Grønborg SW, Hammer T, Iughetti L, Kleefstra T, Koolen DA, Lepri FR, Lemire G, Louro P, McCullagh G, Madeo SF, Milone A, Milone R, Nielsen JEK, Novelli A, Ockeloen CW, Pascarella R, Pippucci T, Ricca I, Robertson SP, Sawyer S, Falkenberg Smeland M, Stegmann S, Stumpel CT, Goel A, Taylor JM, Barbuti D, Soresina A, Bedeschi MF, Battini R, Cavalli A, Fusco C, Iascone M, Van Maldergem L, Venkateswaran S, Zuffardi O, Vergano S, Garavelli L, and Bayat A
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- Humans, Facies, Phenotype, Repressor Proteins genetics, Transcription Factors, Neuroimaging, Intellectual Disability diagnosis, Intellectual Disability genetics, Abnormalities, Multiple diagnosis, Abnormalities, Multiple genetics, Bone Diseases, Developmental diagnostic imaging, Bone Diseases, Developmental genetics, Tooth Abnormalities diagnostic imaging, Tooth Abnormalities genetics
- Abstract
Background: KBG syndrome is caused by haploinsufficiency of ANKRD11 and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined., Methods: CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network. We evaluated the original imaging and compared our results with data in the literature., Results: We identified 53 individuals, 44 with CNS and 40 with skeletal imaging. Common CNS findings included incomplete hippocampal inversion and posterior fossa malformations; these were significantly more common than previously reported (63.4% and 65.9% vs 1.1% and 24.7%, respectively). Additional features included patulous internal auditory canal, never described before in KBG syndrome, and the recurrence of ventriculomegaly, encephalic cysts, empty sella and low-lying conus medullaris. We found no correlation between these structural anomalies and epilepsy or intellectual disability. Prevalent skeletal findings comprised abnormalities of the spine including scoliosis, coccygeal anomalies and cervical ribs. Hand X-rays revealed frequent abnormalities of carpal bone morphology and maturation, including a greater delay in ossification compared with metacarpal/phalanx bones., Conclusion: This cohort enabled us to describe the prevalence of very heterogeneous neuroradiological and skeletal anomalies in KBG syndrome. Knowledge of the spectrum of such anomalies will aid diagnostic accuracy, improve patient care and provide a reference for future research on the effects of ANKRD11 variants in skeletal and brain development., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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11. Immunoexpression of Autophagy-Related Proteins in Salivary Gland Tumors: An Exploratory Study.
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Pires EG, Ferreira CR, Cavalcante RB, de Aguiar MCF, Mesquita RA, Alves PM, and Nonaka CFW
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- Humans, Autophagy-Related Proteins, Immunohistochemistry, Salivary Glands metabolism, Biomarkers, Tumor metabolism, Salivary Gland Neoplasms pathology, Adenoma, Pleomorphic pathology, Carcinoma, Adenoid Cystic pathology, Adenocarcinoma pathology, Carcinoma, Mucoepidermoid pathology
- Abstract
Background: Autophagy is a cellular survival mechanism involved in several human diseases, but its participation in the development of salivary gland tumors is not fully understood. This study investigated the immunoexpression of autophagy-related proteins (autophagy-related 7 [Atg7], microtubule-associated protein 1 light chain 3A [LC3A], microtubule-associated protein 1 light chain 3B [LC3B], protein p62 [p62], and phosphorylated mammalian target of rapamycin [p-mTOR]) in pleomorphic adenoma (PA), polymorphous adenocarcinoma (PAC), mucoepidermoid carcinoma (MEC), and adenoid cystic carcinoma (ACC) of salivary glands., Methods: Twenty PAs, 20 PACs, 20 MECs, and 14 ACCs were selected. The percentages of cytoplasmic and nuclear positivity for autophagy-related proteins in neoplastic cells were assessed and correlated with histopathological parameters., Results: Cytoplasmic immunoexpression of Atg7 was observed in all groups, with high median percentages of positivity. Regarding LC3A and LC3B, cytoplasmic immunoexpression was found in most PACs (95%) and in all cases of PA, MEC and ACC, with the highest percentages of positivity in PACs and PAs (p < 0.005). ACCs exhibited lower cytoplasmic immunoexpression of p-mTOR (p < 0.005) and lower nuclear expression of p62 (p < 0.05) when compared to PAs, PACs and MECs. Low nuclear immunoexpression of Atg7, LC3A and p-mTOR and absence of nuclear staining for LC3B were observed in all groups. Regarding histopathological parameters of PAs, MECs and ACCs, there were no significant differences in the expression of autophagy-related proteins. In all groups, positive correlations were observed between the immunoexpression of some autophagy-related proteins (p < 0.05)., Conclusions: The results suggest the participation of autophagy in the pathogenesis of PA, PAC, MEC, and ACC of salivary glands. Upregulation of autophagy and reduced nuclear translocation of p62 may contribute to the aggressive biological behavior of salivary gland ACC., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2023
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12. Vascular stiffness and healthy arterial aging in older patients with optimal blood pressure.
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Jiticovski AFM, Souza DF, Freitas EGB, Ferreira CR, Pereira CS, Galvão RDV, Santos WAM, Oliveira EP, and Ferreira Filho SR
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- Humans, Aged, Blood Pressure physiology, Antihypertensive Agents therapeutic use, Pulse Wave Analysis, Aging, Vascular Stiffness physiology
- Abstract
Introduction: Pulse wave velocity is used to diagnose central arterial stiffness (CAS) and quantify healthy vascular aging (HVA)., Objective: To evaluate the CAS and HVA in elderly patients with systemic blood pressure levels classified as optimal/normal., Methods: A total of 102 patients without comorbidities and with systolic pressure (SP) < 120 mmHg and diastolic pressure (DP) < 80 mmHg were selected from the EVOPIU database (Pulse Wave Velocity of Elderly Individuals in an Urban area of Brazil). The carotid-femoral pulse wave velocity (c-fPWV) and the central and peripheral pressures were evaluated in all patients. The patients were divided into four groups: G1: (n = 19, with c-fPWV < 7.6 m/s, without medication), G2 (n = 26, c-fPWV ≥ 7.6 m/s; without medication), G3 (n = 25, c-fPWV < 7.6 m/s with antihypertensive medication), and G4 (n = 32, c-fPWV ≥ 7.6 m/s with antihypertensive medication)., Results: In our sample, 56.7% of patients had c-fPWV ≥ 7.6 m/s. The central systolic pressure in G1 [99 (10) mmHg] was lower than that found in the other three groups [vs. 112 (14) mmHg, 111 (15), 112 (20) mmHg; P < 0.05)]., Conclusion: Older people with optimal arterial blood pressure do not necessarily have HVA and could have c-fPWV values close to the limits established for CAS diagnosis.
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- 2023
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13. Step-by-Step Approach to Build Multiple Reaction Monitoring (MRM) Profiling Instrument Acquisition Methods for Class-based Lipid Exploratory Analysis by Mass Spectrometry.
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Reis LG, Casey TM, Sobreira TJP, Cooper BR, and Ferreira CR
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- Mass Spectrometry, Databases, Factual, Isomerism, Carbon, Fatty Acids
- Abstract
Multiple reaction monitoring (MRM) profiling is a strategy for the exploratory analysis of small molecules and lipids by direct sample injection, ie, without the use of chromatographic separation. It is based on instrument methods that comprise a list of ion transitions (MRMs), in which the precursor ion is the expected ionized m/z of the lipid at its species level, ie, the description of lipid class and number of carbon and double bonds in the fatty acid chain(s), and the product ion is a fragment expected for the lipid class or for the fatty acid neutral loss. The Lipid Maps database is expanding constantly, and therefore the MRM-profiling methods associated with this database need to be continuously updated. Here, we provide a comprehensive overview and the key references for the MRM-profiling methodology and workflow, followed by a step-by-step approach to build MRM-profiling instrument acquisition methods for class-based lipid exploratory analysis based on the Lipid Maps database. The detailed workflow includes (1) importing the list of lipids from the database; (2) for a given class, combining isomeric lipids described at full structural level into 1 entry to obtain the neutral mass at species level; (3) attributing the standard Lipid Maps abbreviated nomenclature for the lipid at its species level; (4) predicting the ionized precursor ions; and (5) adding the expected product ion. We also describe how to simulate the precursor ion for the suspect screening of modified lipids using lipid oxidation and their expected product ions as an example. After determining the MRMs, information about collision energy, dwell time, and other instrument parameters are added to finalize the acquisition method. As an example of final method output, we describe the format for Agilent MassHunter v.B.06 and provide the parameters in which optimization can be performed by lipid class using one or more lipid standards., Competing Interests: Conflict of Interest Disclosures: The authors declare no conflicts of interest., (Copyright © 2023 Association of Biomolecular Resource Facilities. All rights reserved.)
- Published
- 2023
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14. Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study.
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Loong L, Tardivo A, Knaus A, Hashim M, Pagnamenta AT, Alt K, Böhrer-Rabel H, Caro-Llopis A, Cole T, Distelmaier F, Edery P, Ferreira CR, Jezela-Stanek A, Kerr B, Kluger G, Krawitz PM, Kuhn M, Lemke JR, Lesca G, Lynch SA, Martinez F, Maxton C, Mierzewska H, Monfort S, Nicolai J, Orellana C, Pal DK, Płoski R, Quarrell OW, Rosello M, Rydzanicz M, Sabir A, Śmigiel R, Stegmann APA, Stewart H, Stumpel C, Szczepanik E, Tzschach A, Wolfe L, Taylor JC, Murakami Y, Kinoshita T, Bayat A, and Kini U
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- Pregnancy, Female, Humans, Muscle Hypotonia genetics, Seizures genetics, Phenotype, Genetic Association Studies, Syndrome, Epilepsy genetics, Abnormalities, Multiple genetics, Hernia, Diaphragmatic genetics, Congenital Disorders of Glycosylation
- Abstract
Purpose: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported., Methods: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp)., Results: Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period., Conclusion: We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. All rights reserved.)
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- 2023
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15. Repeat expansions nested within tandem CNVs: a unique structural change in GLS exemplifies the diagnostic challenges of non-coding pathogenic variation.
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Fazal S, Danzi MC, van Kuilenburg ABP, Reich S, Traschütz A, Bender B, Leen R, Toro C, Usdin K, Hayward B, Adams DR, van Karnebeek CDM, Ferreira CR, D'Sousa P, Network UD, Tekin M, Züchner S, and Synofzik M
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- Humans, 5' Untranslated Regions, Ataxia diagnosis, Ataxia genetics, Glutaminase genetics
- Abstract
Glutaminase deficiency has recently been associated with ataxia and developmental delay due to repeat expansions in the 5'UTR of the glutaminase (GLS) gene. Patients with the described GLS repeat expansion may indeed remain undiagnosed due to the rarity of this variant, the challenge of its detection and the recency of its discovery. In this study, we combined advanced bioinformatics screening of ~3000 genomes and ~1500 exomes with optical genome mapping and long-read sequencing for confirmation studies. We identified two GLS families, previously intensely and unsuccessfully analyzed. One family carries an unusual and complex structural change involving a homozygous repeat expansion nested within a quadruplication event in the 5'UTR of GLS. Glutaminase deficiency and its metabolic consequences were validated by in-depth biochemical analysis. The identified GLS patients showed progressive early-onset ataxia, cognitive deficits, pyramidal tract damage and optic atrophy, thus demonstrating susceptibility of several specific neuron populations to glutaminase deficiency. This large-scale screening study demonstrates the ability of bioinformatics analysis-validated by latest state-of-the-art technologies (optical genome mapping and long-read sequencing)-to effectively flag complex repeat expansions using short-read datasets and thus facilitate diagnosis of ultra-rare disorders., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2023
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16. Estimation of ENPP1 deficiency genetic prevalence using a comprehensive literature review and population databases.
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Chunn LM, Bissonnette J, Heinrich SV, Mercurio SA, Kiel MJ, Rutsch F, and Ferreira CR
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- Animals, Female, Pregnancy, Humans, Prevalence, Asian People, Databases, Factual, Familial Hypophosphatemic Rickets, Rickets, Hypophosphatemic
- Abstract
Background: ENPP1 Deficiency-caused by biallelic variants in ENPP1-leads to widespread arterial calcification in early life (Generalized Arterial Calcification of Infancy, GACI) or hypophosphatemic rickets in later life (Autosomal Recessive Hypophosphatemic Rickets type 2, ARHR2). A prior study using the Exome Aggregation Consortium (ExAC)-a database of exomes obtained from approximately 60,000 individuals-estimated the genetic prevalence at approximately 1 in 200,000 pregnancies., Methods: We estimated the genetic prevalence of ENPP1 Deficiency by evaluating allele frequencies from a population database, assuming Hardy-Weinberg equilibrium. This estimate benefitted from a comprehensive literature review using Mastermind ( https://mastermind.genomenon.com/ ), which uncovered additional variants and supporting evidence, a larger population database with approximately 140,000 individuals, and improved interpretation of variants as per current clinical guidelines., Results: We estimate a genetic prevalence of approximately 1 in 64,000 pregnancies, thus more than tripling the prior estimate. In addition, the carrier frequency of ENPP1 variants was found to be highest in East Asian populations, albeit based on a small sample., Conclusion: These results indicate that a significant number of patients with ENPP1 Deficiency remain undiagnosed. Efforts to increase disease awareness as well as expand genetic testing, particularly in non-European populations are warranted, especially now that clinical trials for enzyme replacement therapy, which proved successful in animal models, are underway., (© 2022. The Author(s).)
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- 2022
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17. Determination of FGF23 Levels for the Diagnosis of FGF23-Mediated Hypophosphatemia.
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Hartley IR, Gafni RI, Roszko KL, Brown SM, de Castro LF, Saikali A, Ferreira CR, Gahl WA, Pacak K, Blau JE, Boyce AM, Salusky IB, Collins MT, and Florenzano P
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- Humans, Phosphates, Familial Hypophosphatemic Rickets diagnosis, Fibroblast Growth Factors blood, Hypophosphatemia diagnosis, Osteomalacia diagnosis
- Abstract
Fibroblast growth factor-23 (FGF23) measurement is a critical tool in the evaluation of patients with disordered phosphate homeostasis. Available laboratory reference ranges for blood FGF23 were developed using samples from normophosphatemic individuals. Reliance on such values can lead to misdiagnosis in patients with FGF23-mediated hypophosphatemia, such as X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO), in whom pathology-driving FGF23 levels can be in the "normal range." To determine FGF23 levels that are diagnostic for the identification of patients with FGF23-mediated hypophosphatemic disorders, we studied 149 patients with various disorders of FGF23-mediated and FGF23-independent hypophosphatemia and defined cut-off levels for both intact FGF23 (iFGF23) and C-terminal FGF23 (cFGF23) that can accurately distinguish between FGF23-mediated and FGF23-independent hypophosphatemia. In addition, to demonstrate the relationship between FGF23 and phosphate across the spectrum of human physiology, we assessed blood levels of FGF23 and phosphate in 434 patients with various forms of hypophosphatemia, hyperphosphatemia, and normophosphatemia. An intact FGF23 cut point of 27 pg/mL was 100% sensitive and specific in distinguishing FGF23-mediated from FGF23-independent hypophosphatemia, and a cFGF23 cut point of 90 RU/mL was 100% sensitive and specific in distinguishing specifically TIO from FGF23-independent hypophosphatemia. There was overlap in the cFGF23 range of 45-90 RU/mL between genetic forms of FGF23 excess and FGF23-independent hypophosphatemia, substantiating the superiority of iFGF23 over cFGF23 in making the diagnosis of FGF23-mediated hypophosphatemia. In this cohort, using the laboratory upper limit of normal for cFGF23 (180 RU/mL) would result in a misdiagnosis in more than half of patients with FGF23-mediated hypophosphatemia. In this, the largest study of FGF23 in chronic hypophosphatemia to date, we established iFGF23 and cFGF23 cut-off values to assist in the evaluation and diagnosis of hypophosphatemic conditions. © 2022 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA., (© 2022 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.)
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- 2022
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18. Ovarian cancer cell fate regulation by the dynamics between saturated and unsaturated fatty acids.
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Zhao G, Tan Y, Cardenas H, Vayngart D, Wang Y, Huang H, Keathley R, Wei JJ, Ferreira CR, Orsulic S, Cheng JX, and Matei D
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- Disease Progression, Fatty Acid Desaturases, Fatty Acids pharmacology, Female, Humans, Phospholipids, Protein Serine-Threonine Kinases, Stearoyl-CoA Desaturase metabolism, Cell Survival, Endoribonucleases, Fatty Acids, Unsaturated pharmacology, Ovarian Neoplasms
- Abstract
Fatty acids are an important source of energy and a key component of phospholipids in membranes and organelles. Saturated fatty acids (SFAs) are converted into unsaturated fatty acids (UFAs) by stearoyl Co-A desaturase (SCD), an enzyme active in cancer. Here, we studied how the dynamics between SFAs and UFAs regulated by SCD impacts ovarian cancer cell survival and tumor progression. SCD depletion or inhibition caused lower levels of UFAs vs. SFAs and altered fatty acyl chain plasticity, as demonstrated by lipidomics and stimulated Raman scattering (SRS) microscopy. Further, increased levels of SFAs resulting from SCD knockdown triggered endoplasmic reticulum (ER) stress response with brisk activation of IRE1α/XBP1 and PERK/eIF2α/ATF4 axes. Disorganized ER membrane was visualized by electron microscopy and SRS imaging in ovarian cancer cells in which SCD was knocked down. The induction of long-term mild ER stress or short-time severe ER stress by the increased levels of SFAs and loss of UFAs led to cell death. However, ER stress and apoptosis could be readily rescued by supplementation with UFAs and reequilibration of SFA/UFA levels. The effects of SCD knockdown or inhibition observed in vitro translated into suppression of intraperitoneal tumor growth in ovarian cancer xenograft models. Furthermore, a combined intervention using an SCD inhibitor and an SFA-enriched diet initiated ER stress in tumors growing in vivo and potently blocked their dissemination. In all, our data support SCD as a key regulator of the cancer cell fate under metabolic stress and point to treatment strategies targeting the lipid balance.
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- 2022
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19. Genetics of non-isolated hemivertebra: A systematic review of fetal, neonatal, and infant cases.
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Powel JE, Sham CE, Spiliopoulos M, Ferreira CR, Rosenthal E, Sinkovskaya ES, Brown S, Jelin AC, and Al-Kouatly HB
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- Female, Genetic Counseling, Humans, Infant, Infant, Newborn, Karyotyping, Pregnancy, Retrospective Studies, Spine abnormalities, Ultrasonography, Prenatal, Fetus abnormalities, Musculoskeletal Abnormalities
- Abstract
Hemivertebra is a congenital vertebral malformation caused by unilateral failure of formation during embryogenesis that may be associated with additional abnormalities. A systematic review was conducted to investigate genetic etiologies of non-isolated hemivertebra identified in the fetal, neonatal, and infant periods using PubMed, Cochrane database, Ovid Medline, and ClinicalTrials.gov from inception through May 2022 (PROSPERO ID CRD42021229576). The Human Phenotype Ontology database was accessed May 2022. Studies were deemed eligible for inclusion if they addressed non-isolated hemivertebra or genetic causes of non-isolated hemivertebra identified in the fetal, neonatal, or infant periods. Cases diagnosed clinically without molecular confirmation were included. Systematic review identified 23 cases of non-isolated hemivertebra with karyotypic abnormalities, 2 cases due to microdeletions, 59 cases attributed to single gene disorders, 18 syndromic cases without known genetic etiology, and 14 cases without a known syndromic association. The Human Phenotype Ontology search identified 49 genes associated with hemivertebra. Non-isolated hemivertebra is associated with a diverse spectrum of cytogenetic abnormalities and single gene disorders. Genetic syndromes were notably common. Frequently affected organ systems include musculoskeletal, cardiovascular, central nervous system, genitourinary, gastrointestinal, and facial dysmorphisms. When non-isolated hemivertebra is identified on prenatal ultrasound, the fetus must be assessed for associated anomalies and genetic counseling is recommended., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2022
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20. Characterisation of institutionalised Portuguese older adult fallers: is there a place for pharmacist intervention? A preliminary study.
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Ferreira CR, Mascarenhas-Melo F, Rodrigues AR, Lima MJR, Pinheiro JP, Chaves C, Teixeira-Lemos E, and Bell V
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Background: Falls are a major public health issue, given their prevalence and social impact. Older adults living in long-term care facilities (LTCF) are at greater risk of injury resulting from a fall due to multiple factors, such as nutritional, functional/cognitive impairment, postural instability, polypharmacy, and the presence of potentially inappropriate medications (PIMs). Medication management in LTCF is complex and often sub-optimal and might be crucial for falls. Pharmacist intervention is important, since they have a unique knowledge of medication. However, studies mapping the impact of pharmaceutical activities in Portuguese LTC settings are scarce., Objective: This study aims to assess the characteristics of older adult fallers living in LTFCs and examine the relationship between falling and several factors in this population. We also intend to explore the prevalence of PIMs and their relationship with the occurrence of falls., Methods: The study was conducted in two long-term care facilities for elderly people, in the central region of Portugal. We included patients aged 65 and older with no reduced mobility or physical weakness and with the ability to understand spoken and written Portuguese. The following information was assessed: sociodemographic characteristics, comorbidities, polypharmacy, fear of falling, functional, nutritional and cognitive status. PIMs were evaluated according to the Beers criteria (2019)., Results: A total of 69 institutionalised older adults, 45 women and 24 men, with a mean age of 83.14 ± 8.87 years were included. The prevalence of falls was 21.74% Out of these, 46.67% (n=7) fell once, 13.33% (n=2) fell twice, and 40% (n=6) fell 3 or more times. Fallers were mainly women, had lower levels of education, were well nourished, had moderate to severe levels of dependence, and displayed moderate cognitive impairment. All adult fallers had a fear of falling. The main comorbidities of this population were related to the cardiovascular system. Polypharmacy was present in every patient, and at least one PIM was identified in 88.41% of the subjects. Fear of falling (FOF) and cognitive impairment (in subjects with 1 to 11 years of education) showed statistically significant associations with the occurrence of falls (p=0.005 and p=0.05, respectively). No significant differences were found between fallers and non-fallers for any other factors., Conclusions: This present study is a preliminary contribution to characterise a group of older adult fallers living in Portuguese LTCFs and demonstrated that fear of falling and cognitive impairment are associated with the occurrence of falls in this population. The high prevalence of polypharmacy and PIMs emphasises the need for tailored interventions featuring the collaboration of a pharmacist to optimise medication management in this population., (Copyright: © Pharmacy Practice.)
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- 2022
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21. Characterization of hearing-impairment in Generalized Arterial Calcification of Infancy (GACI).
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Theng EH, Brewer CC, Oheim R, Zalewski CK, King KA, Delsmann MM, Rolvien T, Gafni RI, Braddock DT, Jeffrey Kim H, and Ferreira CR
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- Animals, Cross-Sectional Studies, Hearing, Humans, Mice, Vascular Calcification, Hearing Loss diagnosis, Hearing Loss genetics, Otitis Media complications
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Background and Importance: Hearing loss (HL) has been sporadically described, but not well characterized, in Generalized Arterial Calcification of Infancy (GACI), a rare disease in which pathological calcification typically presents in infancy., Objectives: This study aims to describe the clinical audiologic and otologic features and potential etiology of hearing impairment in GACI and gain pathophysiological insight from a murine model of GACI., Design: Cross-sectional cohort study of individuals with GACI. Murine ossicle micromorphology of the ENPP1
asj/asj mutant compared to wild-type., Setting: Clinical research hospital; basic science laboratory., Participants: Nineteen individuals with GACI who met clinical, biochemical, and genetic criteria for diagnosis., Main Outcomes and Measures: Clinical, biochemical, and radiologic features associated with hearing status., Results: Pure-tone thresholds could be established in 15 (n = 30 ears) of the 19 patients who underwent audiological assessments. The prevalence of HL was 50% (15/30) of ears, with conductive HL in 80% and sensorineural HL in 20%. In terms of patients with HL (n = 8), seven patients had bilateral HL and one patient had unilateral HL. Degree of HL was mild to moderate for 87% of the 15 ears with hearing loss. Of those patients with sufficient pure-tone and middle ear function data, 80% (8/10) had audiometric configurations suggestive of ossicular chain dysfunction (OCD). Recurrent episodes of otitis media (ROM) requiring pressure-equalizing tube placement were common. In patients who underwent cranial CT, 54.5% (6/11) had auricular calcification. Quantitative backscattered electron imaging (qBEI) of murine ossicles supports an OCD component of auditory dysfunction in GACI, suggesting loss of ossicular osteocytes without initiation of bone remodeling., Conclusions and Relevance: Hearing loss is common in GACI; it is most often conductive, and mild to moderate in severity. The etiology of HL is likely multifactorial, involving dysfunction of the ossicular chain and/or recurrent otitis media. Clinically, this study highlights the importance of early audiologic and otologic evaluation in persons with GACI. Novel findings of high rates of OCD and ROM may inform management, and in cases of unclear HL etiology, dedicated temporal bone imaging should be considered., (© 2022. The Author(s).)- Published
- 2022
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22. Modulation of Pulmonary Toxicity in Metabolic Syndrome Due to Variations in Iron Oxide Nanoparticle-Biocorona Composition.
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Xia L, Alqahtani S, Ferreira CR, Aryal UK, Biggs K, and Shannahan JH
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Nanoparticles (NPs) interact with biomolecules by forming a biocorona (BC) on their surface after introduction into the body and alter cell interactions and toxicity. Metabolic syndrome (MetS) is a prevalent condition and enhances susceptibility to inhaled exposures. We hypothesize that distinct NP-biomolecule interactions occur in the lungs due to MetS resulting in the formation of unique NP-BCs contributing to enhanced toxicity. Bronchoalveolar lavage fluid (BALF) was collected from healthy and MetS mouse models and used to evaluate variations in the BC formation on 20 nm iron oxide (Fe
3 O4 ) NPs. Fe3 O4 NPs without or with BCs were characterized for hydrodynamic size and zeta potential. Unique and differentially associated proteins and lipids with the Fe3 O4 NPs were identified through proteomic and lipidomic analyses to evaluate BC alterations based on disease state. A mouse macrophage cell line was utilized to examine alterations in cell interactions and toxicity due to BCs. Exposures to 6.25, 12.5, 25, and 50 μg/mL of Fe3 O4 NPs with BCs for 1 h or 24 h did not demonstrate overt cytotoxicity. Macrophages increasingly associated Fe3 O4 NPs following addition of the MetS BC compared to the healthy BC. Macrophages exposed to Fe3 O4 NPs with a MetS-BC for 1 h or 24 h at a concentration of 25 μg/mL demonstrated enhanced gene expression of inflammatory markers: CCL2 , IL-6 , and TNF -α compared to Fe3 O4 NPs with a healthy BC. Western blot analysis revealed activation of STAT3, NF-κB, and ERK pathways due to the MetS-BC. Specifically, the Jak/Stat pathway was the most upregulated inflammatory pathway following exposure to NPs with a MetS BC. Overall, our study suggests the formation of distinct BCs due to NP exposure in MetS, which may contribute to exacerbated inflammatory effects and susceptibility.- Published
- 2022
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23. 2022 Overview of Metabolic Epilepsies.
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Tumiene B, Ferreira CR, and van Karnebeek CDM
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- Energy Metabolism, Glycosylation, Humans, Seizures diagnosis, Seizures genetics, Epilepsy diagnosis, Epilepsy genetics, Metabolic Diseases diagnosis, Metabolic Diseases genetics
- Abstract
Understanding the genetic architecture of metabolic epilepsies is of paramount importance, both to current clinical practice and for the identification of further research directions. The main goals of our study were to identify the scope of metabolic epilepsies and to investigate their clinical presentation, diagnostic approaches and treatments. The International Classification of Inherited Metabolic Disorders and IEMbase were used as a basis for the identification and classification of metabolic epilepsies. Six hundred metabolic epilepsies have been identified, accounting for as much as 37% of all currently described inherited metabolic diseases (IMD). Epilepsy is a particularly common symptom in disorders of energy metabolism, congenital disorders of glycosylation, neurotransmitter disorders, disorders of the synaptic vesicle cycle and some other IMDs. Seizures in metabolic epilepsies may present variably, and most of these disorders are complex and multisystem. Abnormalities in routine laboratory tests and/or metabolic testing may be identified in 70% of all metabolic epilepsies, but in many cases they are non-specific. In total, 111 metabolic epilepsies (18% of all) have specific treatments that may significantly change health outcomes if diagnosed in time. Although metabolic epilepsies comprise an important and significant group of disorders, their real scope and frequency may have been underestimated.
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- 2022
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24. DDX58 (RIG-I)-related disease is associated with tissue-specific interferon pathway activation.
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Prasov L, Bohnsack BL, El Husny AS, Tsoi LC, Guan B, Kahlenberg JM, Almeida E, Wang H, Cowen EW, De Jesus AA, Jani P, Billi AC, Moroi SE, Wasikowski R, Almeida I, Almeida LN, Kok F, Garnai SJ, Mian SI, Chen MY, Warner BM, Ferreira CR, Goldbach-Mansky R, Hur S, Brooks BP, Richards JE, Hufnagel RB, and Gudjonsson JE
- Subjects
- DEAD Box Protein 58 genetics, Humans, Interferons genetics, Metacarpus pathology, Receptors, Immunologic, Exanthema pathology, Glaucoma, Open-Angle pathology, Odontodysplasia genetics, Odontodysplasia pathology
- Abstract
Background: Singleton-Merten syndrome (SGMRT) is a rare immunogenetic disorder that variably features juvenile open-angle glaucoma (JOAG), psoriasiform skin rash, aortic calcifications and skeletal and dental dysplasia. Few families have been described and the genotypic and phenotypic spectrum is poorly defined, with variants in DDX58 (DExD/H-box helicase 58) being one of two identified causes, classified as SGMRT2., Methods: Families underwent deep systemic phenotyping and exome sequencing. Functional characterisation with in vitro luciferase assays and in vivo interferon signature using bulk and single cell RNA sequencing was performed., Results: We have identified a novel DDX58 variant c.1529A>T p.(Glu510Val) that segregates with disease in two families with SGMRT2. Patients in these families have widely variable phenotypic features and different ethnic background, with some being severely affected by systemic features and others solely with glaucoma. JOAG was present in all individuals affected with the syndrome. Furthermore, detailed evaluation of skin rash in one patient revealed sparse inflammatory infiltrates in a unique distribution. Functional analysis showed that the DDX58 variant is a dominant gain-of-function activator of interferon pathways in the absence of exogenous RNA ligands. Single cell RNA sequencing of patient lesional skin revealed a cellular activation of interferon-stimulated gene expression in keratinocytes and fibroblasts but not in neighbouring healthy skin., Conclusions: These results expand the genotypic spectrum of DDX58-associated disease, provide the first detailed description of ocular and dermatological phenotypes, expand our understanding of the molecular pathogenesis of this condition and provide a platform for testing response to therapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2022
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25. Musculoskeletal Comorbidities and Quality of Life in ENPP1-Deficient Adults and the Response of Enthesopathy to Enzyme Replacement Therapy in Murine Models.
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Ferreira CR, Ansh AJ, Nester C, O'Brien C, Stabach PR, Murtada SI, Lester ER, Khursigara G, Molloy L, Carpenter TO, and Braddock DT
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- Adult, Animals, Disease Models, Animal, Enzyme Replacement Therapy, Female, Fibroblast Growth Factors, Humans, Male, Mice, Pain, Phosphoric Diester Hydrolases genetics, Pyrophosphatases genetics, Quality of Life, Enthesopathy drug therapy, Enthesopathy genetics, Familial Hypophosphatemic Rickets genetics, Vascular Calcification genetics
- Abstract
Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) deficiency leads to cardiovascular calcification in infancy, fibroblast growth factor 23 (FGF23)-mediated hypophosphatemic rickets in childhood, and osteomalacia in adulthood. Excessive enthesis mineralization and cervical spine fusion have been previously reported in patients with biallelic ENPP1 deficiency, but their effect on quality of life is unknown. We describe additional musculoskeletal complications in patients with ENPP1 deficiency, namely osteoarthritis and interosseous membrane ossification, and for the first time evaluate health-related quality of life (HRQoL) in patients with this disease, both subjectively via narrative report, and objectively via the Brief Pain Inventory-Short Form, and a Patient Reported Outcome Measurement Information System Physical Function (PROMIS PF) short form. Residual pain, similar in magnitude to that identified in adult patients with X-linked hypophosphatemia, was experienced by the majority of patients despite use of analgesic medications. Impairment in physical function varied from mild to severe. To assess murine ENPP1 deficiency for the presence of enthesopathy, and for the potential response to enzyme replacement therapy, we maintained Enpp1
asj/asj mice on regular chow for 23 weeks and treated cohorts with either vehicle or a long-acting form of recombinant ENPP1. Enpp1asj/asj mice treated with vehicle exhibited robust calcification throughout their Achilles tendons, whereas two-thirds of those treated with ENPP1 enzyme replacement exhibited complete or partial suppression of the Achilles tendon calcification. Our combined results document that musculoskeletal complications are a significant source of morbidity in biallelic ENPP1 deficiency, a phenotype which is closely recapitulated in Enpp1asj/asj mice. Finally, we show that a long-acting form of recombinant ENPP1 prevents the development of enthesis calcification at the relatively modest dose of 0.3 mg/kg per week, suggesting that suppression of enthesopathy may be attainable upon dose escalation. © 2021 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA., (© 2021 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.)- Published
- 2022
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26. Relationship of cow and calf circulating lipidomes with colostrum lipid composition and metabolic status of the cow.
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Klopp RN, Ferreira CR, Casey TM, and Boerman JP
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- Animals, Animals, Newborn, Cattle, Fatty Acids, Nonesterified, Female, Parturition, Pregnancy, Colostrum, Lipidomics
- Abstract
Newborn calves rely on lipids in colostrum for energy and immune function. The lipid concentration in colostrum, however, is highly variable, and little is known about its composition and maternal factors that influence its composition. The first objective was to measure plasma lipid composition of multiparous cows at 35 d before calving (BC; 35 ± 3 d; ± standard deviation) and 7 d BC (7 ± 2 d), their colostrum, and serum lipid composition of calves (24 h after birth) using multiple reaction monitoring profiling, which is an exploratory and highly sensitive lipidomic analysis method that screens lipids based on chemical functionality. Second, data were analyzed to determine if there were relationships between circulating lipids in the cow, colostrum lipids, and calf serum lipids. Third, relationships between markers of metabolic status of the cows and circulating and colostrum lipids were analyzed with correlation analysis. Blood was sampled and plasma prepared from multiparous cows (n = 16) at 35 and 7 d BC. Within 3 h of parturition, colostrum was collected from cows and fed to her calf. Calves received another feeding of colostrum within 12 h after birth and a serum sample was collected from each calf 24 h after the first feeding of colostrum. The metabolic status of cows was evaluated using insulin, glucose, and nonesterified fatty acid area under the curve in response to an intravenous glucose tolerance test performed at 3 wk BC. Lipids were extracted from plasma, colostrum, and calf serum and were analyzed using multiple reaction monitoring profiling. Concentration of lipids were calculated using spiked in standards and expressed as percent of lipids identified. Data were uploaded into MetaboAnalyst 5.0 for multivariate and univariate analysis. Principal component analysis indicated that circulating lipids in the cow and calf were distinct from lipids in colostrum. Phosphatidylglycerol (PG) concentration was greater in colostrum and calf serum than in cow plasma, with 23 of the 24 PG found in colostrum also found in calf serum. In response to intravenous glucose tolerance test in late gestation, nonesterified fatty acid area under the curve was positively related to total triacylglycerols lipids in 7 d BC plasma (r = 0.63) but negatively related to total membrane lipids in colostrum (r = -0.55). Thus, the metabolic status of the dam influences circulating lipids and colostrum lipid content. Moreover, the circulating lipidome of the cow and calf are similar to one another and distinct from the colostrum lipidome, except for PG, where it appears that colostrum serves as the source for PG in the calf's circulation., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)
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- 2022
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27. Langmuir monolayers and proteoliposomes as models of matrix vesicles involved in biomineralization.
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Ramos AP, Bolean M, Cruz MAE, Andrilli LHS, Nogueira LFB, Sebinelli HG, Dos Santos ALN, Favarin BZ, Macedo JMM, Veschi EA, Ferreira CR, Millán JL, Bottini M, and Ciancaglini P
- Abstract
Competing Interests: Conflict of interestThe authors declare no competing interests.
- Published
- 2021
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28. Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies.
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Ferreira CR, Kintzinger K, Hackbarth ME, Botschen U, Nitschke Y, Mughal MZ, Baujat G, Schnabel D, Yuen E, Gahl WA, Gafni RI, Liu Q, Huertas P, Khursigara G, and Rutsch F
- Subjects
- Humans, Infant, Mutation, Familial Hypophosphatemic Rickets diagnostic imaging, Familial Hypophosphatemic Rickets genetics, Multidrug Resistance-Associated Proteins deficiency, Multidrug Resistance-Associated Proteins genetics, Phosphoric Diester Hydrolases deficiency, Phosphoric Diester Hydrolases genetics, Pyrophosphatases deficiency, Pyrophosphatases genetics, Vascular Calcification diagnostic imaging, Vascular Calcification genetics
- Abstract
Generalized arterial calcification of infancy (GACI) is a rare disorder caused by ENPP1 or ABCC6 variants. GACI is characterized by low pyrophosphate, arterial calcification, and high mortality during the first year of life, but the natural course and possible differences between the causative genes remain unknown. In all, 247 individual records for patients with GACI (from birth to 58.3 years of age) across 19 countries were reviewed. Overall mortality was 54.7% (13.4% in utero or stillborn), with a 50.4% probability of death before the age of 6 months (critical period). Contrary to previous publications, we found that bisphosphonate treatment had no survival benefit based on a start-time matched analysis and inconclusive results when initiated within 2 weeks of birth. Despite a similar prevalence of GACI phenotypes between ENPP1 and ABCC6 deficiencies, including arterial calcification (77.2% and 89.5%, respectively), organ calcification (65.8% and 84.2%, respectively), and cardiovascular complications (58.4% and 78.9%, respectively), mortality was higher for ENPP1 versus ABCC6 variants (40.5% versus 10.5%, respectively; p = 0.0157). Higher prevalence of rickets was reported in 70.8% of surviving affected individuals with ENPP1 compared with that of ABCC6 (11.8%; p = 0.0001). Eleven affected individuals presenting with rickets and without a GACI diagnosis, termed autosomal recessive hypophosphatemic rickets type 2 (ARHR2), all had confirmed ENPP1 variants. Approximately 70% of these patients demonstrated evidence of ectopic calcification or complications similar to those seen in individuals with GACI, which shows that ARHR2 is not a distinct condition from GACI but represents part of the spectrum of ENPP1 deficiency. Overall, this study identified an early mortality risk in GACI patients despite attempts to treat with bisphosphonates, high prevalence of rickets almost exclusive to ENPP1 deficiency, and a spectrum of heterogenous calcification and multiple organ complications with both ENPP1 and ABCC6 variants, which suggests an overlapping pathology. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA., (© 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.)
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- 2021
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29. Lysosomal storage disorders as an etiology of nonimmune hydrops fetalis: A systematic review.
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Iyer NS, Gimovsky AC, Ferreira CR, Critchlow E, and Al-Kouatly HB
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- Animals, Biomarkers, Clinical Decision-Making, Disease Management, Female, Genetic Predisposition to Disease, Humans, Hydrops Fetalis diagnosis, Hydrops Fetalis epidemiology, Lysosomal Storage Diseases diagnosis, Lysosomal Storage Diseases etiology, Lysosomal Storage Diseases metabolism, Molecular Diagnostic Techniques, Pregnancy, Disease Susceptibility, Hydrops Fetalis etiology, Lysosomal Storage Diseases complications
- Abstract
We performed a systematic review of the literature to evaluate the incidence and types of lysosomal storage disorders (LSD) in case series of nonimmune hydrops fetalis (NIHF). PubMed, Ovid, and clinicaltrials.gov were reviewed for case series evaluating the workup of NIHF diagnosed in utero or in the neonatal period in human subjects from 1979 to August 2020. Retrospective case series with at least five cases of fetal and/or neonatal NIHF with its workup mentioned were identified. Idiopathic NIHF was defined as NIHF without an apparent cause after initial standard-of-care workup. In total, 22 case series with 2678 total cases of NIHF were identified. The overall incidence of LSD was 6.6% (177/2663) in NIHF cases that were tested for any LSD, and 8.2% (177/2151) in idiopathic NIHF cases. The most common LSD identified in cases of NIHF were mucopolysaccharidosis type VII, galactosialidosis, infantile sialic acid storage disease, Gaucher disease, GM1 gangliosidosis, and sialidosis. More than 40% of the most common LSD causes of NIHF have a potential postnatal treatment. LSD testing for NIHF allows for early diagnosis, better counseling and appropriate management, planning for possible early treatment, and counseling for recurrence risk., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2021
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30. Response to Stern et al.
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Ziegler SG and Ferreira CR
- Published
- 2021
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31. Quantitative analysis of the natural history of prolidase deficiency: description of 17 families and systematic review of published cases.
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Rossignol F, Duarte Moreno MS, Benoist JF, Boehm M, Bourrat E, Cano A, Chabrol B, Cosson C, Díaz JLD, D'Harlingue A, Dimmock D, Freeman AF, García MT, Garganta C, Goerge T, Halbach SS, de Laffolie J, Lam CT, Martin L, Martins E, Meinhardt A, Melki I, Ombrello AK, Pérez N, Quelhas D, Scott A, Slavotinek AM, Soares AR, Stein SL, Süßmuth K, Thies J, Ferreira CR, and Schiff M
- Subjects
- Child, Child, Preschool, Delayed Diagnosis, Humans, Phenotype, Crohn Disease, Leg Ulcer, Prolidase Deficiency diagnosis, Prolidase Deficiency genetics
- Abstract
Purpose: Prolidase deficiency is a rare inborn error of metabolism causing ulcers and other skin disorders, splenomegaly, developmental delay, and recurrent infections. Most of the literature is constituted of isolated case reports. We aim to provide a quantitative description of the natural history of the condition by describing 19 affected individuals and reviewing the literature., Methods: Nineteen patients were phenotyped per local institutional procedures. A systematic review following PRISMA criteria identified 132 articles describing 161 patients. Main outcome analyses were performed for manifestation frequency, diagnostic delay, overall survival, symptom-free survival, and ulcer-free survival., Results: Our cohort presented a wide variability of severity. Autoimmune disorders were found in 6/19, including Crohn disease, systemic lupus erythematosus, and arthritis. Another immune finding was hemophagocytic lymphohistiocytosis (HLH). Half of published patients were symptomatic by age 4 and had a delayed diagnosis (mean delay 11.6 years). Ulcers were present initially in only 30% of cases, with a median age of onset at 12 years old., Conclusion: Prolidase deficiency has a broad range of manifestations. Symptoms at onset may be nonspecific, likely contributing to the diagnostic delay. Testing for this disorder should be considered in any child with unexplained autoimmunity, lower extremity ulcers, splenomegaly, or HLH., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)
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- 2021
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32. IgG4-related Disease: a diagnostic challenge.
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Olmos RD, Rodrigues MAVM, Ferreira CR, Etrusco RCF, and Romagnolli C
- Abstract
Immunoglobulin IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition with a characteristic histopathological appearance that can affect almost any organ. The clinical features result from a focal or diffuse appearance of a tumor-like swelling of the affected organs, identified by physical and/or imaging examination. Herein, we report the case of a 38-year-old male complaining of a worsening chronic right lumbar pain associated with legs and scrotum edema. He also had itchy and erythematous cutaneous lesions on the abdominal wall over the last 8 months, and complained of a diffuse and mild to moderate abdominal discomfort. On examination, the liver was firmly enlarged and tender. His legs had 2+ symmetrical pitting edema extending from his feet to just above the knees. An abdominal computed tomography scan showed a large mass (10 x 8 x 4cm) involving the abdominal infrarenal aorta and the iliac arteries, and compressing the inferior vena cava, with dilated iliac veins, raising the possibility of lymphoproliferative disease. During the initial investigation, the laboratory workup revealed anemia, without other marked changes. A laparoscopic-guided biopsy of the peri-aortic mass was undertaken. The histological report associated with IgG4 immunoglobulin measurement rendered the diagnosis of IgG4-RD. The patient had a favorable outcome after the use of glucocorticoids with the abdominal mass remission., Competing Interests: Conflict of interest: The authors have no conflict of interest to declare., (Copyright: © 2021 The Authors.)
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- 2021
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33. Biomarkers predictive of long-term fertility found in vaginal lipidome of gilts at weaning.
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Mills KM, Ferreira CR, Stevens JG, Stewart KR, and Casey TM
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- Animals, Biomarkers, Female, Fertility, Litter Size, Parity, Pregnancy, Swine, Vagina, Weaning, Lipidomics, Reproduction
- Abstract
A marker indicative of the fertility potential of replacement gilts early in development would decrease culling rates in the sow herd, improve sow herd reproductive efficiency, and reduce production costs. The objective of this study was to determine if vaginal lipid profiles at 21 d postnatal (PN) could predict sow reproductive performance. Vaginal swabs of the anterior vagina were taken at 21 ± 4 d PN from gilts born on a commercial sow production facility for lipidomic analysis. Animals were followed prospectively for 2 yr and assigned to reproductive performance categories based on the observation of estrus or piglets weaned per sow per year (PSY) across two farrowings. Lipids were extracted from cellular material collected with swabs taken from high fertility (HF; n = 28; ≥26 PSY) and infertile (IF; n = 34; no estrus, no pregnancy) animals, and multiple reaction monitoring profiling was used for lipidome analysis. The relative abundance of arachidonic acid (C20:4) and docosahexaenoic acid (C22:6) was lower (P < 0.05) in IF gilts than HF gilts, whereas the abundance of the free fatty acids such as cerotic (C26:0), ximenic (C26:1), and nonadecanoic (C19:0) acids was greater (P < 0.05) in IF gilts. Additionally, eicosapentaenoic acid (C20:5), a precursor of prostaglandins, was higher (P < 0.05) in IF gilts. The perspective of having a panel of lipids captured with vaginal swabs at weaning that can predict the reproductive efficiency of gilts shows promise and warrants future research in this area., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2021
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34. Germline Saturation Mutagenesis Induces Skeletal Phenotypes in Mice.
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Rios JJ, Denton K, Russell J, Kozlitina J, Ferreira CR, Lewanda AF, Mayfield JE, Moresco E, Ludwig S, Tang M, Li X, Lyon S, Khanshour A, Paria N, Khalid A, Li Y, Xie X, Feng JQ, Xu Q, Lu Y, Hammer RE, Wise CA, and Beutler B
- Subjects
- Animals, Ethylnitrosourea, Humans, Mice, Mutation, Phenotype, Phosphotransferases (Alcohol Group Acceptor) genetics, Bone Diseases genetics, Germ Cells, Mutagenesis
- Abstract
Proper embryonic and postnatal skeletal development require coordination of myriad complex molecular mechanisms. Disruption of these processes, through genetic mutation, contributes to variation in skeletal development. We developed a high-throughput N-ethyl-N-nitrosourea (ENU)-induced saturation mutagenesis skeletal screening approach in mice to identify genes required for proper skeletal development. Here, we report initial results from live-animal X-ray and dual-energy X-ray absorptiometry (DXA) imaging of 27,607 G3 mice from 806 pedigrees, testing the effects of 32,198 coding/splicing mutations in 13,020 genes. A total of 39.7% of all autosomal genes were severely damaged or destroyed by mutations tested twice or more in the homozygous state. Results from our study demonstrate the feasibility of in vivo mutagenesis to identify mouse models of skeletal disease. Furthermore, our study demonstrates how ENU mutagenesis provides opportunities to create and characterize putative hypomorphic mutations in developmentally essential genes. Finally, we present a viable mouse model and case report of recessive skeletal disease caused by mutations in FAM20B. Results from this study, including engineered mouse models, are made publicly available via the online Mutagenetix database. © 2021 American Society for Bone and Mineral Research (ASBMR)., (© 2021 American Society for Bone and Mineral Research (ASBMR).)
- Published
- 2021
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35. Lipid profiling suggests species specificity and minimal seasonal variation in Pacific Green and Hawksbill Turtle plasma.
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Clyde-Brockway CE, Ferreira CR, Flaherty EA, and Paladino FV
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- Animals, Climate, Costa Rica, Lipids classification, Lipids genetics, Seasons, Turtles physiology, Lipids blood, Phylogeny, Species Specificity, Turtles genetics
- Abstract
In this study, we applied multiple reaction monitoring (MRM)-profiling to explore the relative ion intensity of lipid classes in plasma samples from sea turtles in order to profile lipids relevant to sea turtle physiology and investigate how dynamic ocean environments affect these profiles. We collected plasma samples from foraging green (Chelonia mydas, n = 28) and hawksbill (Eretmochelys imbricata, n = 16) turtles live captured in North Pacific Costa Rica in 2017. From these samples, we identified 623 MRMs belonging to 10 lipid classes (sphingomyelin, phosphatidylcholine, free fatty acid, cholesteryl ester, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatidylethanolamine, ceramide, and triacylglyceride) and one metabolite group (acyl-carnitine) present in sea turtle plasma. The relative ion intensities of most lipids (80%) were consistent between species, across seasons, and were not correlated to body size or estimated sex. Of the differences we observed, the most pronounced was the differences in relative ion intensity between species. We identified 123 lipids that had species-specific relative ion intensities. While some of this variability is likely due to green and hawksbill turtles consuming different food items, we found indications of a phylogenetic component as well. Of these, we identified 47 lipids that varied by season, most belonging to the structural phospholipid classes. Overall, more lipids (n = 39) had higher relative ion intensity in the upwelling (colder) season compared to the non-upwelling season (n = 8). Further, we found more variability in hawksbill turtles than green turtles. Here, we provide the framework in which to apply future lipid profiling in the assessment of health, physiology, and behavior in endangered sea turtles., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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36. Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice.
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Ferreira CR, Kavanagh D, Oheim R, Zimmerman K, Stürznickel J, Li X, Stabach P, Rettig RL, Calderone L, MacKichan C, Wang A, Hutchinson HA, Nelson T, Tommasini SM, von Kroge S, Fiedler IA, Lester ER, Moeckel GW, Busse B, Schinke T, Carpenter TO, Levine MA, Horowitz MC, and Braddock DT
- Subjects
- Adolescent, Animals, Dietary Supplements, Humans, Mice, Phenotype, Phosphoric Diester Hydrolases genetics, Pyrophosphatases, Enzyme Replacement Therapy, Phosphates
- Abstract
Inactivating mutations in human ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) may result in early-onset osteoporosis (EOOP) in haploinsufficiency and autosomal recessive hypophosphatemic rickets (ARHR2) in homozygous deficiency. ARHR2 patients are frequently treated with phosphate supplementation to ameliorate the rachitic phenotype, but elevating plasma phosphorus concentrations in ARHR2 patients may increase the risk of ectopic calcification without increasing bone mass. To assess the risks and efficacy of conventional ARHR2 therapy, we performed comprehensive evaluations of ARHR2 patients at two academic medical centers and compared their skeletal and renal phenotypes with ENPP1-deficient Enpp1
asj/asj mice on an acceleration diet containing high phosphate treated with recombinant murine Enpp1-Fc. ARHR2 patients treated with conventional therapy demonstrated improvements in rickets, but all adults and one adolescent analyzed continued to exhibit low bone mineral density (BMD). In addition, conventional therapy was associated with the development of medullary nephrocalcinosis in half of the treated patients. Similar to Enpp1asj/asj mice on normal chow and to patients with mono- and biallelic ENPP1 mutations, 5-week-old Enpp1asj/asj mice on the high-phosphate diet exhibited lower trabecular bone mass, reduced cortical bone mass, and greater bone fragility. Treating the Enpp1asj/asj mice with recombinant Enpp1-Fc protein between weeks 2 and 5 normalized trabecular bone mass, normalized or improved bone biomechanical properties, and prevented the development of nephrocalcinosis and renal failure. The data suggest that conventional ARHR2 therapy does not address low BMD inherent in ENPP1 deficiency, and that ENPP1 enzyme replacement may be effective for correcting low bone mass in ARHR2 patients without increasing the risk of nephrocalcinosis. © 2021 American Society for Bone and Mineral Research (ASBMR)., (© 2021 American Society for Bone and Mineral Research (ASBMR).)- Published
- 2021
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37. Treatable inherited metabolic disorders causing intellectual disability: 2021 review and digital app.
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Hoytema van Konijnenburg EMM, Wortmann SB, Koelewijn MJ, Tseng LA, Houben R, Stöckler-Ipsiroglu S, Ferreira CR, and van Karnebeek CDM
- Subjects
- Humans, Rare Diseases, Intellectual Disability diagnosis, Metabolic Diseases, Metabolism, Inborn Errors, Mobile Applications
- Abstract
Background: The Treatable ID App was created in 2012 as digital tool to improve early recognition and intervention for treatable inherited metabolic disorders (IMDs) presenting with global developmental delay and intellectual disability (collectively 'treatable IDs'). Our aim is to update the 2012 review on treatable IDs and App to capture the advances made in the identification of new IMDs along with increased pathophysiological insights catalyzing therapeutic development and implementation., Methods: Two independent reviewers queried PubMed, OMIM and Orphanet databases to reassess all previously included disorders and therapies and to identify all reports on Treatable IDs published between 2012 and 2021. These were included if listed in the International Classification of IMDs (ICIMD) and presenting with ID as a major feature, and if published evidence for a therapeutic intervention improving ID primary and/or secondary outcomes is available. Data on clinical symptoms, diagnostic testing, treatment strategies, effects on outcomes, and evidence levels were extracted and evaluated by the reviewers and external experts. The generated knowledge was translated into a diagnostic algorithm and updated version of the App with novel features., Results: Our review identified 116 treatable IDs (139 genes), of which 44 newly identified, belonging to 17 ICIMD categories. The most frequent therapeutic interventions were nutritional, pharmacological and vitamin and trace element supplementation. Evidence level varied from 1 to 3 (trials, cohort studies, case-control studies) for 19% and 4-5 (case-report, expert opinion) for 81% of treatments. Reported effects included improvement of clinical deterioration in 62%, neurological manifestations in 47% and development in 37%., Conclusion: The number of treatable IDs identified by our literature review increased by more than one-third in eight years. Although there has been much attention to gene-based and enzyme replacement therapy, the majority of effective treatments are nutritional, which are relatively affordable, widely available and (often) surprisingly effective. We present a diagnostic algorithm (adjustable to local resources and expertise) and the updated App to facilitate a swift and accurate workup, prioritizing treatable IDs. Our digital tool is freely available as Native and Web App (www.treatable-id.org) with several novel features. Our Treatable ID endeavor contributes to the Treatabolome and International Rare Diseases Research Consortium goals, enabling clinicians to deliver rapid evidence-based interventions to our rare disease patients.
- Published
- 2021
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38. The low excretor phenotype of glutaric acidemia type I is a source of false negative newborn screening results and challenging diagnoses.
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Guenzel AJ, Hall PL, Scott AI, Lam C, Chang IJ, Thies J, Ferreira CR, Pichurin P, Laxen W, Raymond K, Gavrilov DK, Oglesbee D, Rinaldo P, Matern D, and Tortorelli S
- Abstract
Background: Glutaric acidemia type I (GA1) is an organic acidemia that is often unrecognized in the newborn period until patients suffer an acute encephalopathic crisis, which can be mistaken for nonaccidental trauma. Presymptomatic identification of GA1 patients is possible by newborn screening (NBS). However, the biochemical "low-excretor" (LE) phenotype with nearly normal levels of disease metabolites can be overlooked, which may result in untreated disease and irreversible neurological sequelae. The LE phenotype is also a potential source of false negative (FN) NBS results that merits further investigation., Methods: Samples from six LE GA1 patients were analyzed by biochemical and molecular methods and newborn screen outcomes were retrospectively investigated., Results: Five LE GA1 patients were identified that had normal NBS results and three of these presented clinically with GA1 symptoms. One additional symptomatic patient was identified who did not undergo screening. Semiquantitative urine organic acid analysis was consistent with a GA1 diagnosis in two (33%) of the six patients, while plasma glutarylcarnitine was elevated in four (67%) of the six and urine glutarylcarnitine was elevated in four (80%) of five patients. Five GCDH variants were identified in these patients; three of which have not been previously linked to the biochemical LE phenotype., Conclusions: The data presented here raise awareness of potential FN NBS results for LE GA1 patients. The LE phenotype is not protective against adverse clinical outcomes, and the possibility of FN NBS results calls for high vigilance amongst clinicians, even in the setting of a normal NBS result., Competing Interests: The authors declare no potential conflict of interest., (© 2021 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)
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- 2021
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39. A novel experimental workflow to determine the impact of storage parameters on the mass spectrometric profiling and assessment of representative phosphatidylethanolamine lipids in mouse tissues.
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Kobos L, Ferreira CR, Sobreira TJP, Rajwa B, and Shannahan J
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- Animals, Brain metabolism, Lipids blood, Lung metabolism, Mice, Mice, Inbred C57BL, Multivariate Analysis, Myocardium metabolism, Phospholipids chemistry, Principal Component Analysis, Reproducibility of Results, Solvents chemistry, Temperature, Tissue Distribution, Ions, Lipids chemistry, Phosphatidylethanolamines chemistry, Workflow
- Abstract
Evaluation of signaling lipids is essential for measuring biological processes. There is a lack of experimental data regarding the proper storage of extracts for signaling lipid analysis, potentially impacting the procedures that can lead to accurate and reproducible evaluation. In this study, the importance of pre-analytical conditions for analyzing ion transitions for phosphatidylethanolamines (PEs), an abundant signaling phospholipid, was systematically assessed. A novel workflow was utilized involving an MRM-based experimental approach followed by statistical analysis. Specifically, lipids were extracted from the brain, heart, lungs, and serum of C57BL/6 mice. Extract subsets were resuspended in organic solvents prior to storage in various temperature conditions. Mass spectrometry analysis by multiple reaction monitoring (MRM) profiling was performed at four time points (1 day, 2 weeks, 2 months, or 6 months) to measure relative amounts of PEs in distinct lipid extract aliquots. We introduce an innovative statistical workflow to measure the changes in relative amounts of PEs in the profiles over time to determine lipid extract storage conditions in which fewer profile changes occur. Results demonstrated that time is the most significant factor affecting the changes in lipid samples, with temperature and solvent having comparatively minor effects. We conclude that for lipid extracts obtained by Bligh & Dyer extraction, storage at - 80.0 °C without solvent for less than 2 weeks before analysis is ideal. By considering the data generated by this study, lipid extract storage practices may be optimized and standardized, enhancing the validity and reproducibility of lipid assessments.
- Published
- 2021
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40. Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI).
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Ferreira CR, Hackbarth ME, Ziegler SG, Pan KS, Roberts MS, Rosing DR, Whelpley MS, Bryant JC, Macnamara EF, Wang S, Müller K, Hartley IR, Chew EY, Corden TE, Jacobsen CM, Holm IA, Rutsch F, Dikoglu E, Chen MY, Mughal MZ, Levine MA, Gafni RI, and Gahl WA
- Subjects
- Adolescent, Adult, Female, Fibroblast Growth Factor-23, Humans, Mutation, Pregnancy, Prospective Studies, Survivors, Vascular Calcification, Phosphoric Diester Hydrolases genetics, Pyrophosphatases genetics
- Abstract
Purpose: Generalized arterial calcification of infancy (GACI), characterized by vascular calcifications that are often fatal shortly after birth, is usually caused by deficiency of ENPP1. A small fraction of GACI cases result from deficiency of ABCC6, a membrane transporter. The natural history of GACI survivors has not been established in a prospective fashion., Methods: We performed deep phenotyping of 20 GACI survivors., Results: Sixteen of 20 subjects presented with arterial calcifications, but only 5 had residual involvement at the time of evaluation. Individuals with ENPP1 deficiency either had hypophosphatemic rickets or were predicted to develop it by 14 years of age; 14/16 had elevated intact FGF23 levels (iFGF23). Blood phosphate levels correlated inversely with iFGF23. For ENPP1-deficient individuals, the lifetime risk of cervical spine fusion was 25%, that of hearing loss was 75%, and the main morbidity in adults was related to enthesis calcification. Four ENPP1-deficient individuals manifested classic skin or retinal findings of PXE. We estimated the minimal incidence of ENPP1 deficiency at ~1 in 200,000 pregnancies., Conclusion: GACI appears to be more common than previously thought, with an expanding spectrum of overlapping phenotypes. The relationships among decreased ENPP1, increased iFGF23, and rickets could inform future therapies.
- Published
- 2021
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41. DYRK1A pathogenic variants in two patients with syndromic intellectual disability and a review of the literature.
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Meissner LE, Macnamara EF, D'Souza P, Yang J, Vezina G, Ferreira CR, Zein WM, Tifft CJ, and Adams DR
- Subjects
- Child, Child, Preschool, Eye Abnormalities pathology, Female, Humans, Intellectual Disability pathology, Microcephaly pathology, Mutation, Phenotype, Syndrome, Dyrk Kinases, Eye Abnormalities genetics, Intellectual Disability genetics, Microcephaly genetics, Protein Serine-Threonine Kinases genetics, Protein-Tyrosine Kinases genetics
- Abstract
Background: DYRK1A-Related Intellectual Disability Syndrome is a rare autosomal dominant condition characterized by intellectual disability, speech and language delays, microcephaly, facial dysmorphism, and feeding difficulties. Affected individuals represent simplex cases that result from de novo heterozygous pathogenic variants in DYRK1A (OMIM 614104), or chromosomal structural rearrangements involving the DYRK1A locus. Due to the rarity of DYRK1A-Related Intellectual Disability Syndrome, the spectrum of symptoms associated with this disease has not been completely defined., Methods and Results: We present two unrelated cases of DYRK1A-Related Intellectual Disability Syndrome resulting from variants in DYRK1A. Both probands presented to the National Institutes of Health (NIH) with multiple dysmorphic facial features, primary microcephaly, absent or minimal speech, feeding difficulties, and cognitive impairment; features that have been previously reported in individuals with DYRK1A. During NIH evaluation, additional features of enlarged cerebral subarachnoid spaces, retinal vascular tortuosity, and bilateral anomalous large optic discs with increased cup-to-disc ratio were identified in the first proband and multiple ophthalmologic abnormalities and sensorineural hearing loss were identified in the second proband., Conclusion: We recommend that the workup of future of patients include a comprehensive eye exam. Early establishment of physical, occupational, and speech therapy may help in the management of ataxia, hypertonia, and speech impairments common in these patients., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)
- Published
- 2020
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42. Loss of Muscle Carnitine Palmitoyltransferase 2 Prevents Diet-Induced Obesity and Insulin Resistance despite Long-Chain Acylcarnitine Accumulation.
- Author
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Pereyra AS, Rajan A, Ferreira CR, and Ellis JM
- Subjects
- Animals, Carnitine metabolism, Female, Humans, Mice, Obesity drug therapy, Carnitine analogs & derivatives, Carnitine O-Palmitoyltransferase metabolism, Insulin Resistance physiology, Obesity prevention & control
- Abstract
To assess the effects of acylcarnitine accumulation on muscle insulin sensitivity, a model of muscle acylcarnitine accumulation was generated by deleting carnitine palmitoyltransferase 2 (CPT2) specifically from skeletal muscle (Cpt2
Sk-/- mice). CPT2 is an irreplaceable enzyme for mitochondrial long-chain fatty acid oxidation, converting matrix acylcarnitines to acyl-CoAs. Compared with controls, Cpt2Sk-/- muscles do not accumulate anabolic lipids but do accumulate ∼22-fold more long-chain acylcarnitines. High-fat-fed Cpt2Sk-/- mice resist weight gain, adiposity, glucose intolerance, insulin resistance, and impairments in insulin-induced Akt phosphorylation. Obesity resistance of Cpt2Sk-/- mice could be attributed to increases in lipid excretion via feces, GFD15 production, and energy expenditure. L-carnitine supplement intervention lowers acylcarnitines and improves insulin sensitivity independent of muscle mitochondrial fatty acid oxidative capacity. The loss of muscle CPT2 results in a high degree of long-chain acylcarnitine accumulation, simultaneously protecting against diet-induced obesity and insulin resistance., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2020
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43. Fourteen-year follow-up of a child with acroscyphodysplasia with emphasis on the need for multidisciplinary management: a case report.
- Author
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Kartalias K, Gillies AP, Peña MT, Estrada A, Bulas DI, Ferreira CR, and Tosi LL
- Subjects
- Bone and Bones abnormalities, Bone and Bones diagnostic imaging, Bone and Bones metabolism, Cyclic AMP-Dependent Protein Kinase RIalpha Subunit genetics, Cyclic Nucleotide Phosphodiesterases, Type 4 genetics, Dysostoses diagnosis, Dysostoses genetics, Follow-Up Studies, Genetic Predisposition to Disease genetics, Intellectual Disability diagnosis, Intellectual Disability genetics, Osteochondrodysplasias diagnosis, Osteochondrodysplasias genetics, Pseudohypoparathyroidism diagnosis, Pseudohypoparathyroidism genetics, Radiography methods, Time Factors, Dysostoses therapy, Intellectual Disability therapy, Interdisciplinary Communication, Osteochondrodysplasias therapy, Patient Care Team, Pseudohypoparathyroidism therapy
- Abstract
Background: Acroscyphodysplasia has been described as a phenotypic variant of acrodysostosis type 2 and pseudohypoparathyroidism. In acrodysostosis, skeletal features can include brachydactyly, facial hypoplasia, cone-shaped epiphyses, short stature, and advanced bone age. To date, reports on this disorder have focused on phenotypic findings, endocrine changes, and genetic variation. We present a 14-year overview of a patient, from birth to skeletal maturity, with acroscyphodysplasia, noting the significant orthopaedic challenges and the need for a multidisciplinary team, including specialists in genetics, orthopaedics, endocrinology, and otolaryngology, to optimize long-term outcomes., Case Presentation: The patient presented as a newborn with dysmorphic facial features, including severe midface hypoplasia, malar flattening, nasal stenosis, and feeding difficulties. Radiologic findings were initially subtle, and a skeletal survey performed at age 7 months was initially considered normal. Genetic evaluation revealed a variant in PDE4D and subsequent pseudohypoparathyroidism. The patient presented to the department of orthopaedics, at age 2 years 9 months with a leg length discrepancy, right knee contracture, and severely crouched gait. Radiographs demonstrated cone-shaped epiphyses of the right distal femur and proximal tibia, but no evidence of growth plate changes in the left leg. The child developed early posterior epiphyseal arrest on the right side and required multiple surgical interventions to achieve neutral extension. Her left distal femur developed late posterior physeal arrest and secondary contracture without evidence of schypho deformity, which improved with anterior screw epiphysiodesis. The child required numerous orthopaedic surgical interventions to achieve full knee extension bilaterally. At age 13 years 11 months, she was an independent ambulator with erect posture. The child underwent numerous otolaryngology procedures and will require significant ongoing care. She has moderate intellectual disability., Discussion and Conclusions: Key challenges in the management of this case included the subtle changes on initial skeletal survey and the marked asymmetry of her deformity. While cone-shaped epiphyses are a hallmark of acrodysostosis, posterior tethering/growth arrest of the posterior distal femur has not been previously reported. Correction of the secondary knee contracture was essential to improve ambulation. Children with acroscyphodysplasia require a multidisciplinary approach, including radiology, genetics, orthopaedics, otolaryngology, and endocrinology specialties.
- Published
- 2020
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44. A homozygous missense variant of SUMF1 in the Bedouin population extends the clinical spectrum in ultrarare neonatal multiple sulfatase deficiency.
- Author
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Staretz-Chacham O, Schlotawa L, Wormser O, Golan-Tripto I, Birk OS, Ferreira CR, Dierks T, and Radhakrishnan K
- Subjects
- Cell Line, Tumor, Child, Preschool, Enzyme Stability, Homozygote, Humans, Infant, Male, Multiple Sulfatase Deficiency Disease pathology, Oxidoreductases Acting on Sulfur Group Donors metabolism, Multiple Sulfatase Deficiency Disease genetics, Mutation, Missense, Oxidoreductases Acting on Sulfur Group Donors genetics, Phenotype
- Abstract
Background: Multiple sulfatase deficiency (MSD, MIM #272200) is an ultrarare congenital disorder caused by SUMF1 mutation and often misdiagnosed due to its complex clinical presentation. Impeded by a lack of natural history, knowledge gained from individual case studies forms the source for a reliable diagnosis and consultation of patients and parents., Methods: We collected clinical records as well as genetic and metabolic test results from two MSD patients. The functional properties of a novel SUMF1 variant were analyzed after expression in a cell culture model., Results: We report on two MSD patients-the first neonatal type reported in Israel-both presenting with this most severe manifestation of MSD. Our patients showed uniform clinical symptoms with persistent pulmonary hypertension, hypotonia, and dysmorphism at birth. Both patients were homozygous for the same novel SUMF1 mutation (c.1043C>T, p.A348V). Functional analysis revealed that the SUMF1-encoded variant of formylglycine-generating enzyme is highly instable and lacks catalytic function., Conclusion: The obtained results confirm genotype-phenotype correlation in MSD, expand the spectrum of clinical presentation and are relevant for diagnosis including the extremely rare neonatal severe type of MSD., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)
- Published
- 2020
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45. Nephropathic Cystinosis: A Distinct Form of CKD-Mineral and Bone Disorder that Provides Novel Insights into the Regulation of FGF23.
- Author
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Florenzano P, Jimenez M, Ferreira CR, Nesterova G, Roberts MS, Tella SH, Fernandez de Castro L, Gafni RI, Wolf M, Jüppner H, Gales B, Wesseling-Perry K, Markovich D, Gahl WA, Salusky IB, and Collins MT
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Female, Fibroblast Growth Factor-23, Homeostasis, Humans, Male, Phosphates metabolism, Vitamin D blood, Young Adult, Chronic Kidney Disease-Mineral and Bone Disorder metabolism, Cystinosis metabolism, Fibroblast Growth Factors blood
- Abstract
Background: The rare lysosomal storage disease nephropathic cystinosis presents with renal Fanconi syndrome that evolves in time to CKD. Although biochemical abnormalities in common causes of CKD-mineral and bone disorder have been defined, it is unknown if persistent phosphate wasting in nephropathic cystinosis is associated with a biochemical mineral pattern distinct from that typically observed in CKD-mineral and bone disorder., Methods: We assessed and compared determinants of mineral homeostasis in patients with nephropathic cystinosis across the predialysis CKD spectrum to these determinants in age- and CKD stage-matched patients, with causes of CKD other than nephropathic cystinosis., Results: The study included 50 patients with nephropathic cystinosis-related CDK and 97 with CKD from other causes. All major aspects of mineral homeostasis were differentially effected in patients with CKD stemming from nephropathic cystinosis versus other causes. Patients with nephropathic cystinosis had significantly lower percent tubular reabsorption of phosphate and fibroblast growth factor-23 (FGF23) at all CKD stages, and lower blood phosphate in CKD stages 3-5. Linear regression analyses demonstrated lower FGF23 levels in nephropathic cystinosis participants at all CKD stages when corrected for eGFR and age, but not when adjusted for serum phosphate., Conclusions: Nephropathic cystinosis CKD patients have mineral abnormalities that are distinct from those in CKD stemming from other causes. Persistently increased urinary phosphate excretion maintains serum phosphate levels within the normal range, thus protecting patients with nephropathic cystinosis from elevations of FGF23 during early CKD stages. These findings support the notion that phosphate is a significant driver of increased FGF23 levels in CKD and that mineral abnormalities associated with CKD are likely to vary depending on the underlying renal disease., (Copyright © 2020 by the American Society of Nephrology.)
- Published
- 2020
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46. Lipidomic Profiling of the Epidermis in a Mouse Model of Dermatitis Reveals Sexual Dimorphism and Changes in Lipid Composition before the Onset of Clinical Disease.
- Author
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Franco J, Rajwa B, Ferreira CR, Sundberg JP, and HogenEsch H
- Abstract
Atopic dermatitis (AD) is a multifactorial disease associated with alterations in lipid composition and organization in the epidermis. Multiple variants of AD exist with different outcomes in response to therapies. The evaluation of disease progression and response to treatment are observational assessments with poor inter-observer agreement highlighting the need for molecular markers. SHARPIN-deficient mice ( Sharpin
cpdm ) spontaneously develop chronic proliferative dermatitis with features similar to AD in humans. To study the changes in the epidermal lipid-content during disease progression, we tested 72 epidermis samples from three groups (5-, 7-, and 10-weeks old) of cpdm mice and their WT littermates. An agnostic mass-spectrometry strategy for biomarker discovery termed multiple-reaction monitoring (MRM)-profiling was used to detect and monitor 1,030 lipid ions present in the epidermis samples. In order to select the most relevant ions, we utilized a two-tiered filter/wrapper feature-selection strategy. Lipid categories were compressed, and an elastic-net classifier was used to rank and identify the most predictive lipid categories for sex, phenotype, and disease stages of cpdm mice. The model accurately classified the samples based on phospholipids, cholesteryl esters, acylcarnitines, and sphingolipids, demonstrating that disease progression cannot be defined by one single lipid or lipid category.- Published
- 2020
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47. Characterization of the in Vitro Osteogenic Response to Submicron TiO 2 Particles of Varying Structure and Crystallinity.
- Author
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Tovani CB, Ferreira CR, Simão AMS, Bolean M, Coppeta L, Rosato N, Bottini M, Ciancaglini P, and Ramos AP
- Abstract
Titanium oxide (TiO
2 ) nano-/microparticles have been widely used in orthopedic and dental sciences because of their excellent mechanical properties, chemical stability, and ability to promote the osseointegration of implants. However, how the structure and crystallinity of TiO2 particles may affect their osteogenic activity remains elusive. Herein, we evaluated the osteogenic response to submicron amorphous, anatase, and rutile TiO2 particles with controlled size and morphology. First, the ability of TiO2 particles to precipitate apatite was assessed in an acellular medium by using a simulated body fluid (SBF). Three days after the addition to SBF, anatase and rutile TiO2 particles induced the precipitation of aggregates of nanoparticles with a platelike morphology, typical for biomimetic apatite. Conversely, amorphous TiO2 particles induced the precipitation of particles with poor Ca/P atomic ratio only after 14 days of exposure to SBF. Next, the osteogenic response to TiO2 particles was assessed in vitro by incubating MC3T3-E1 preosteoblasts with the particles. The viability and mineralization efficiency of osteoblastic cells were maintained in the presence of all the tested TiO2 particles despite the differences in the induction of apatite precipitation in SBF by TiO2 particles with different structures. Analysis of the particles' surface charge and of the proteins adsorbed onto the particles from the culture media suggested that all the tested TiO2 particles acquired a similar biological identity in the culture media. We posited that this phenomenon attenuated potential differences in osteoblast response to amorphous, anatase, and rutile particles. Our study provides an important insight into the complex relationship between the physicochemical properties and function of TiO2 particles and sheds light on their safe use in medicine., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)- Published
- 2020
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48. Estimated birth prevalence of Menkes disease and ATP7A-related disorders based on the Genome Aggregation Database (gnomAD).
- Author
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Kaler SG, Ferreira CR, and Yam LS
- Abstract
Background: Previous estimates of the prevalence of Menkes disease, a lethal X-linked recessive disorder of copper metabolism, were based on confirmed clinical cases ascertained from specific populations and varied from 1 in 40,000 to 1 in 354,507. With newly available population-based allelic frequencies of DNA sequence variants, the expected birth prevalence of Menkes disease and other ATP7A -related phenotypes can be reconsidered using Hardy-Weinberg theoretical principles., Methods: We reviewed the canonical ATP7A transcript in the current version of gnomAD (v2.1.1) to evaluate frequency of complete loss-of-function alleles in a diverse normal control population. As a comparator, we used the DMD locus, associated with Duchenne and Becker Muscular Dystrophy, another X-linked recessive trait. We applied Hardy-Weinberg theory and PolyPhen-2 in silico plus REVEL and CADD ensemble analyses to calculate estimated frequencies of normal and predicted deleterious ATP7A alleles., Results: We identified 1106 total ATP7A variants out of 205,523 alleles in gnomAD, with missense variants most common (43.4%). Complete loss-of-function variants were found in four ATP7A alleles (frequency = 0.0000194), including three frameshift/nonsense mutations and one canonical splice donor site defect. Assuming Harvey-Weinberg equilibrium, this frequency of pathogenic alleles predicts 1 in 34,810 live male births with Menkes disease or other ATP7A-related disorders each year in the US. The same analysis for DMD loss-of-function variants predicted 1 in 7246 newborn males with Duchenne (or Becker) muscular dystrophy. We also identified nine ATP7A missense variants in gnomAD predicted as deleterious by PolyPhen-2 and stringent REVEL/CADD criteria, comprising 12 more disease-causing alleles and raising the estimated birth prevalence to 1 in 8664 and predicting 225 newborns with Menkes disease or other ATP7A-related disorders per year in the US alone., Conclusions: Assuming Harvey-Weinberg equilibrium, the allelic frequency of deleterious ATP7A variants in a genomic database from a large diverse population predicts a birth prevalence of Menkes disease or ATP7A-related disorders as high as 1 in 8664 live male births. This genome-driven ascertainment of deleterious ATP7A alleles in the population implies a higher birth prevalence of Menkes disease and ATP7A-related conditions than previously appreciated. A population-based newborn screening pilot study for Menkes disease will be instrumental in confirming the prediction., Competing Interests: Dr. Kaler's NIH laboratory received research funding from a Collaborative Research and Development Award (CRADA) between NIH and Cyprium Therapeutics, Inc., New York, NY in 2017. Cyprium is focused on development of novel therapies for the treatment of Menkes disease and related copper metabolism disorders. Dr. Yam is an officer and employee of Cyprium., (© 2020 The Authors.)
- Published
- 2020
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49. B4GALT1-congenital disorders of glycosylation: Expansion of the phenotypic and molecular spectrum and review of the literature.
- Author
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Staretz-Chacham O, Noyman I, Wormser O, Abu Quider A, Hazan G, Morag I, Hadar N, Raymond K, Birk OS, Ferreira CR, and Koifman A
- Subjects
- Cholestasis genetics, Cholestasis pathology, Congenital Disorders of Glycosylation pathology, Glycosylation, Homozygote, Humans, Hypertension, Pulmonary genetics, Hypertension, Pulmonary pathology, Infant, Infant, Newborn, Intellectual Disability pathology, Male, Mutation genetics, Nephrotic Syndrome pathology, Pedigree, Seizures genetics, Seizures pathology, Thrombocytopenia genetics, Thrombocytopenia pathology, Congenital Disorders of Glycosylation genetics, Galactosyltransferases genetics, Intellectual Disability genetics, Nephrotic Syndrome genetics
- Abstract
A congenital disorder of glycosylation due to biallelic mutations in B4GALT1 has been previously reported in only three patients with two different mutations. Through homozygosity mapping followed by segregation analysis in an extended pedigree, we identified three additional patients homozygous for a novel mutation in B4GALT1, expanding the phenotypic spectrum of the disease. The patients showed a uniform clinical presentation with intellectual disability, marked pancytopenia requiring chronic management, and novel features including pulmonary hypertension and nephrotic syndrome. Notably, affected individuals exhibited a moderate elevation of Man3GlcNAc4Fuc1 on serum N-glycan analysis, yet two of the patients had a normal pattern of transferrin glycosylation in repeated analysis. The novel mutation is the third disease-causing variant described in B4GALT1, and the first one within its transmembrane domain., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2020
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50. Lessons learned from 40 novel PIGA patients and a review of the literature.
- Author
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Bayat A, Knaus A, Pendziwiat M, Afenjar A, Barakat TS, Bosch F, Callewaert B, Calvas P, Ceulemans B, Chassaing N, Depienne C, Endziniene M, Ferreira CR, Moura de Souza CF, Freihuber C, Ganesan S, Gataullina S, Guerrini R, Guerrot AM, Hansen L, Jezela-Stanek A, Karsenty C, Kievit A, Kooy FR, Korff CM, Kragh Hansen J, Larsen M, Layet V, Lesca G, McBride KL, Meuwissen M, Mignot C, Montomoli M, Moore H, Naudion S, Nava C, Nougues MC, Parrini E, Pastore M, Schelhaas JH, Skinner S, Szczałuba K, Thomas A, Thomassen M, Tranebjaerg L, van Slegtenhorst M, Wolfe LA, Lal D, Gardella E, Bomme Ousager L, Brünger T, Helbig I, Krawitz P, and Møller RS
- Subjects
- Adult, Amino Acid Sequence, Child, Cohort Studies, Electroencephalography methods, Facies, Hernia, Diaphragmatic physiopathology, Humans, Infant, Newborn, Limb Deformities, Congenital physiopathology, Magnetic Resonance Imaging methods, Male, Genetic Variation genetics, Hernia, Diaphragmatic diagnostic imaging, Hernia, Diaphragmatic genetics, Limb Deformities, Congenital diagnostic imaging, Limb Deformities, Congenital genetics, Membrane Proteins genetics
- Abstract
Objective: To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations., Methods: Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches., Results: Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein., Significance: Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA., (© 2020 International League Against Epilepsy.)
- Published
- 2020
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