Osteogenesis Imperfecta:New Insights into Extraskeletal Complications

This thesis aims at expanding our understanding of Osteogenesis Imperfecta (OI), a genetic disorder causing bone fragility and a range of extraskeletal symptoms. The work examines in particular the epidemiology and the extraskeletal comorbidities of the Dutch OI population. Additionally, the thesis sheds light on the genotype-phenotype correlation and the pathophysiology of the respiratory complications associated with OI. The first part of the thesis discusses the prevalence and hospital admission rates of the Dutch OI population, the genotype-phenotype relation of OI, and the health care characteristics of patients with LRP5, PLS3, or WNT1 pathogenic variants. The second part of the thesis focuses on the pulmonary complications of OI patients. A literature review provides an overview of the current knowledge and knowledge gaps surrounding the pathophysiology of respiratory complications in OI. To gain further insight into the cause of pulmonary complications, the lung pathology in patients with OI type II was analyzed, suggesting intrinsic alterations in the OI lung parenchyma. The second part of this thesis concludes by proposing a more patient-friendly lung function assessment and a pulmonary follow-up plan for OI patients for the prevention of serious respiratory complications. Finally, the third part of the thesis provides an overview of collagen regulation in the context of recent gene discoveries and describes two OI patient with new SPARC pathogenic variants

Las prácticas sociales educativas en la FAD-UNCuyo : reflexiones y debates sobre las experiencias realizadas durante 2019-2020

El trabajo que presentamos surge de las tareas desarrolladas por el equipo del Área de Prácticas Sociales de la FAD-UNCuyo, durante el 2019. Dicha Área tiene entre sus principales objetivos detectar las mejores formas de incorporar las PSE a los planes de estudio de las diferentes carreras de la facultad, como así también contribuir a la formación de los diferentes claustros al respecto. En este sentido, durante el 2019 se realizaron una serie de experiencias junto a distintas organizaciones sociales que buscaban dar insumos para pensar las prácticas socio-educativas, y generaron diversos espacios de encuentro y formación dentro de la facultad. La primera parte de nuestra ponencia buscará describir brevemente este proceso. En una segunda parte proponemos una serie de reflexiones acerca de diferentes situaciones surgidas de las PSE realizadas durante el 2019 que, lejos de pretender ser conclusiones, buscan abrir el debate y el intercambio. Algunos de estos aspectos son: a) dificultades detectadas en la receptividad del claustro docente; b) complejidades de la articulación con organizaciones sociales; c) importancia de una revisión completa de los Planes de Estudio a la luz de la incorporación de las PSE a los mismos. Para finalizar, compartimos una serie de preguntas vinculadas al aspecto institucional (y, a su vez, inevitablemente pedagógico): ¿Qué sucede con las PSE en la UNCuyo? ¿Cuáles son las mejores formas de reconocerlas/acreditarlas? ¿Su incorporación representa realmente un cambio pedagógico profundo en la formación de nuestro estudiantado?Fil: Gutiérrez, Silvana. Universidad Nacional de Cuyo. Facultad de Artes y Diseño.Fil: Storoni, Silvia. Universidad Nacional de Cuyo. Facultad de Artes y Diseño.Fil: Tapia Serrano, Martín. Universidad Nacional de Cuyo. Facultad de Artes y Diseño

Collagen transport and related pathways in Osteogenesis Imperfecta

Osteogenesis Imperfecta (OI) comprises a heterogeneous group of patients who share bone fragility and deformities as the main characteristics, albeit with different degrees of severity. Phenotypic variation also exists in other connective tissue aspects of the disease, complicating disease classification and disease course prediction. Although collagen type I defects are long established as the primary cause of the bone pathology, we are still far from comprehending the complete mechanism. In the last years, the advent of next generation sequencing has triggered the discovery of many new genetic causes for OI, helping to draw its molecular landscape. It has become clear that, in addition to collagen type I genes, OI can be caused by multiple proteins connected to different parts of collagen biosynthesis. The production of collagen entails a complex process, starting from the production of the collagen Iα1 and collagen Iα2 chains in the endoplasmic reticulum, during and after which procollagen is subjected to a plethora of posttranslational modifications by chaperones. After reaching the Golgi organelle, procollagen is destined to the extracellular matrix where it forms collagen fibrils. Recently discovered mutations in components of the retrograde transport of chaperones highlight its emerging role as critical contributor of OI development. This review offers an overview of collagen regulation in the context of recent gene discoveries, emphasizing the significance of transport disruptions in the OI mechanism. We aim to motivate exploration of skeletal fragility in OI from the perspective of these pathways to identify regulatory points which can hint to therapeutic targets

Novel pathogenic variants in SPARC as cause of osteogenesis imperfecta: Two case reports.

Pathogenic variants in SPARC cause a rare autosomal recessive form of osteogenesis imperfecta (OI), classified as OI type XVII, which was first reported in 2015. Only six patient cases with this specific form of OI have been reported to date. The SPARC protein plays a crucial role in the calcification of collagen in bone, synthesis of the extracellular matrix, and the regulation of cell shape. In this case report, we describe the phenotype of two patients with SPARC-related OI, including a patient with two novel pathogenic variants in the SPARC gene. Targeted Next Generation Sequencing revealed new compound heterozygous variants (c.484G > A p.(Glu162Lys)) and c.496C > T p.(Arg166Cys)) in one patient and a homozygous nonsense pathogenic variant (c.145C > T p.(Gln49*)) in the other. In line with previously reported cases, the two OI patients presented delayed motor development, muscular weakness, scoliosis, and multiple fractures. Interestingly, our study reports for the first time the occurrence of dentinogenesis imperfecta. The study also reports the effectiveness of bisphosphonate treatment for OI type XVII. This article enhances the genetic, clinical, therapeutic, and radiological understanding of SPARC-related OI

Prevalence and Hospital Admissions in Patients With Osteogenesis Imperfecta in The Netherlands: A Nationwide Registry Study

Osteogenesis Imperfecta (OI) is a complex disease caused by genetic alterations in production of collagen type I, and collagen-related proteins. Bone fragility is the most common patient issue, but extraskeletal complications also present an adverse factor in the quality of life and prognosis of patients with OI. However, still little is known about the morbidity and mortality of these patients. The objective of this paper is to determine and describe to what extent OI impacts patients’ life in terms of hospitalization and complications describing the incidence and prevalence of the Dutch cohort of OI patients and the characteristics of their hospital admissions. Information regarding OI patients and their hospital admission was extracted from the Statistics Netherlands Database and matched to the OI Genetics Database of Amsterdam UMC. Hospital admission data was available for 674 OI patients. This OI nationwide registry study shows that the life expectancy of OI patients is adversely affected by the disease. The median annual incidence risk of OI between 1992 and 2019 was 6.5 per 100,000 live births. Furthermore, patients with OI had a 2.9 times higher hospitalization rate compared to the general Dutch population. The highest hospitalization rate ratio of 8.4 was reported in the patient group between 0 and 19 years old. OI type and severity had impact on extraskeletal manifestations, which play a key role in the numerous hospital admissions. More awareness about the impact of OI on patients’ life is needed to improve and implement prevention and follow-up guidelines

From Genetics to Clinical Implications: A Study of 675 Dutch Osteogenesis Imperfecta Patients

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder that causes bone fragility due to pathogenic variants in genes responsible for the synthesis of type I collagen. Efforts to classify the high clinical variability in OI led to the Sillence classification. However, this classification only partially takes into account extraskeletal manifestations and the high genetic variability. Little is known about the relation between genetic variants and phenotype as of yet. The aim of the study was to create a clinically relevant genetic stratification of a cohort of 675 Dutch OI patients based on their pathogenic variant types and to provide an overview of their respective medical care demands. The clinical records of 675 OI patients were extracted from the Amsterdam UMC Genome Database and matched with the records from Statistics Netherlands (CBS). The patients were categorized based on their harbored pathogenic variant. The information on hospital admissions, outpatient clinic visits, medication, and diagnosis-treatment combinations (DTCs) was compared between the variant groups. OI patients in the Netherlands appear to have a higher number of DTCs, outpatient clinic visits, and hospital admissions when compared to the general Dutch population. Furthermore, medication usage seems higher in the OI cohort in comparison to the general population. The patients with a COL1A1 or COL1A2 dominant negative missense non-glycine substitution appear to have a lower health care need compared to the other groups, and even lower than patients with COL1A1 or COL1A2 haploinsufficiency. It would be useful to include the variant type in addition to the Sillence classification when categorizing a patient’s phenotype

Prevalence and Hospital Admissions in Patients With Osteogenesis Imperfecta in The Netherlands: A Nationwide Registry Study

Osteogenesis Imperfecta (OI) is a complex disease caused by genetic alterations in production of collagen type I, and collagen-related proteins. Bone fragility is the most common patient issue, but extraskeletal complications also present an adverse factor in the quality of life and prognosis of patients with OI. However, still little is known about the morbidity and mortality of these patients. The objective of this paper is to determine and describe to what extent OI impacts patients’ life in terms of hospitalization and complications describing the incidence and prevalence of the Dutch cohort of OI patients and the characteristics of their hospital admissions. Information regarding OI patients and their hospital admission was extracted from the Statistics Netherlands Database and matched to the OI Genetics Database of Amsterdam UMC. Hospital admission data was available for 674 OI patients. This OI nationwide registry study shows that the life expectancy of OI patients is adversely affected by the disease. The median annual incidence risk of OI between 1992 and 2019 was 6.5 per 100,000 live births. Furthermore, patients with OI had a 2.9 times higher hospitalization rate compared to the general Dutch population. The highest hospitalization rate ratio of 8.4 was reported in the patient group between 0 and 19 years old. OI type and severity had impact on extraskeletal manifestations, which play a key role in the numerous hospital admissions. More awareness about the impact of OI on patients’ life is needed to improve and implement prevention and follow-up guidelines

From Genetics to Clinical Implications: A Study of 675 Dutch Osteogenesis Imperfecta Patients

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder that causes bone fragility due to pathogenic variants in genes responsible for the synthesis of type I collagen. Efforts to classify the high clinical variability in OI led to the Sillence classification. However, this classification only partially takes into account extraskeletal manifestations and the high genetic variability. Little is known about the relation between genetic variants and phenotype as of yet. The aim of the study was to create a clinically relevant genetic stratification of a cohort of 675 Dutch OI patients based on their pathogenic variant types and to provide an overview of their respective medical care demands. The clinical records of 675 OI patients were extracted from the Amsterdam UMC Genome Database and matched with the records from Statistics Netherlands (CBS). The patients were categorized based on their harbored pathogenic variant. The information on hospital admissions, outpatient clinic visits, medication, and diagnosis-treatment combinations (DTCs) was compared between the variant groups. OI patients in the Netherlands appear to have a higher number of DTCs, outpatient clinic visits, and hospital admissions when compared to the general Dutch population. Furthermore, medication usage seems higher in the OI cohort in comparison to the general population. The patients with a COL1A1 or COL1A2 dominant negative missense non-glycine substitution appear to have a lower health care need compared to the other groups, and even lower than patients with COL1A1 or COL1A2 haploinsufficiency. It would be useful to include the variant type in addition to the Sillence classification when categorizing a patient’s phenotype

From Genetics to Clinical Implications: A Study of 675 Dutch Osteogenesis Imperfecta Patients

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder that causes bone fragility due to pathogenic variants in genes responsible for the synthesis of type I collagen. Efforts to classify the high clinical variability in OI led to the Sillence classification. However, this classification only partially takes into account extraskeletal manifestations and the high genetic variability. Little is known about the relation between genetic variants and phenotype as of yet. The aim of the study was to create a clinically relevant genetic stratification of a cohort of 675 Dutch OI patients based on their pathogenic variant types and to provide an overview of their respective medical care demands. The clinical records of 675 OI patients were extracted from the Amsterdam UMC Genome Database and matched with the records from Statistics Netherlands (CBS). The patients were categorized based on their harbored pathogenic variant. The information on hospital admissions, outpatient clinic visits, medication, and diagnosis-treatment combinations (DTCs) was compared between the variant groups. OI patients in the Netherlands appear to have a higher number of DTCs, outpatient clinic visits, and hospital admissions when compared to the general Dutch population. Furthermore, medication usage seems higher in the OI cohort in comparison to the general population. The patients with a COL1A1 or COL1A2 dominant negative missense non-glycine substitution appear to have a lower health care need compared to the other groups, and even lower than patients with COL1A1 or COL1A2 haploinsufficiency. It would be useful to include the variant type in addition to the Sillence classification when categorizing a patient’s phenotype