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Orphanet Journal of Rare Diseases Mar 2024Osteogenesis imperfecta (OI) is a rare, heritable connective tissue disorder associated with a variety of symptoms, that affect individuals' quality of life (QoL) and...
BACKGROUND
Osteogenesis imperfecta (OI) is a rare, heritable connective tissue disorder associated with a variety of symptoms, that affect individuals' quality of life (QoL) and can be associated with increased healthcare resource use. While some aspects of OI are well studied, others remain poorly understood. Therefore, the IMPACT survey aimed to elucidate the humanistic, clinical and economic burden of OI on individuals with OI, their families, caregivers and wider society.
METHODS
We developed an international mixed methods online survey in eight languages (fielded July-September 2021), aimed at adults (aged ≥ 18 years) or adolescents (aged ≥ 12-17 years) with OI, caregivers (with or without OI) of individuals with OI and other close relatives. All respondents provided data on themselves; caregivers additionally provided data on individuals in their care by proxy. Data were cleaned, coded, and analysed using the pandas Python software package and Excel.
RESULTS
IMPACT collected 2208 eligible questionnaires (covering 2988 individuals of whom 2312 had OI) including 1290 non-caregiver adults with OI, 92 adolescents with OI, 150 caregiver adults with OI, 560 caregivers for individuals with OI, 116 close relatives and 780 proxy care-recipients with OI. Most individuals with OI (direct or proxy) described their OI as moderate (41-52% across populations) and reported OI type 1 (33-38%). Pain (72-82%) was the most reported clinical condition experienced in the past 12 months and was also most frequently rated as severely or moderately impactful. Further, among adults, 67% reported fatigue, 47% scoliosis, and 46% sleep disturbance; in adolescents, fatigue affected 65%, scoliosis and other bone problems 60%, and mental health problems 46%; in children, fractures were common in 67%, fatigue in 47%, and dental problems in 46%.
CONCLUSION
IMPACT has generated an extensive dataset on the experience of individuals with OI, their caregivers and relatives. We found that, irrespective of age, individuals with OI experience numerous and evolving symptoms that affect their QoL; however, pain and fatigue are consistently present. Upcoming analyses will provide further insights into the economic impact, healthcare journey and caregiver wellbeing, aiming to contribute to improved treatment and care for the OI community.
Topics: Adult; Child; Humans; Adolescent; Osteogenesis Imperfecta; Quality of Life; Caregivers; Scoliosis; Pain; Fatigue
PubMed: 38515144
DOI: 10.1186/s13023-024-03126-9 -
Biomedicine & Pharmacotherapy =... Jun 2024Qualitative alterations in type I collagen due to pathogenic variants in the COL1A1 or COL1A2 genes, result in moderate and severe Osteogenesis Imperfecta (OI), a rare...
Qualitative alterations in type I collagen due to pathogenic variants in the COL1A1 or COL1A2 genes, result in moderate and severe Osteogenesis Imperfecta (OI), a rare disease characterized by bone fragility. The TGF-β signaling pathway is overactive in OI patients and certain OI mouse models, and inhibition of TGF-β through anti-TGF-β monoclonal antibody therapy in phase I clinical trials in OI adults is rendering encouraging results. However, the impact of TGF-β inhibition on osteogenic differentiation of mesenchymal stem cells from OI patients (OI-MSCs) is unknown. The following study demonstrates that pediatric skeletal OI-MSCs have imbalanced osteogenesis favoring the osteogenic commitment. Galunisertib, a small molecule inhibitor (SMI) that targets the TGF-β receptor I (TβRI), favored the final osteogenic maturation of OI-MSCs. Mechanistically, galunisertib downregulated type I collagen expression in OI-MSCs, with greater impact on mutant type I collagen, and concomitantly, modulated the expression of unfolded protein response (UPR) and autophagy markers. In vivo, galunisertib improved trabecular bone parameters only in female oim/oim mice. These results further suggest that type I collagen is a tunable target within the bone ECM that deserves investigation and that the SMI, galunisertib, is a promising new candidate for the anti-TGF-β targeting for the treatment of OI.
Topics: Osteogenesis Imperfecta; Osteogenesis; Animals; Humans; Mesenchymal Stem Cells; Down-Regulation; Collagen Type I; Female; Quinolines; Mice; Child; Pyrazoles; Male; Cell Differentiation; Mutation; Disease Models, Animal; Receptor, Transforming Growth Factor-beta Type I; Child, Preschool; Cells, Cultured; Transforming Growth Factor beta; Unfolded Protein Response; Signal Transduction
PubMed: 38744219
DOI: 10.1016/j.biopha.2024.116725 -
Endocrine Journal Jul 2023Osteogenesis imperfecta (OI) is an inherited disease characterized by bone fragility due to impaired type I collagen. Although orthopedic management is improving, other... (Review)
Review
Osteogenesis imperfecta (OI) is an inherited disease characterized by bone fragility due to impaired type I collagen. Although orthopedic management is improving, other complications are poorly understood. We describe three patients with OI with unruptured intracranial aneurysm (IA) detected by magnetic resonance angiography (MRA) screening of 14 patients. Case 1 was a 73-year-old woman with type 1 OI with blue sclera, vertebral compression fractures, and impaired hearing. Lumbar spine bone mineral density (BMD) was preserved (young adult mean (YAM): 86%). MRA revealed an IA in the right internal carotid artery. Case 2 was a 43-year-old man with type 4 OI and leg-length discrepancy due to left femoral neck fracture. Lumbar spine BMD was decreased (YAM: 61%). MRA showed an IA in the left anterior cerebral artery. Case 3 was a 35-year-old woman with type 3 OI with blue sclera, dentinogenesis imperfecta, deformity of the long bones, and severe scoliosis. She had undergone spine surgery and needed wheelchair assistance. The YAM of the femoral neck BMD was 71%. MRA indicated an IA in the right posterior communicating artery. The prevalence of IA in our series of patients with OI was 21%, which is higher than the reported prevalence of unruptured IA in the Japanese general population (2.2%), suggesting that IA may be a complication of OI. Our literature review revealed no cases of OI with unruptured IA, but 11 cases of OI with subarachnoid hemorrhage. IA seems unrelated to OI type, sex, or age. We recommend MRA of adults with OI.
Topics: Male; Female; Young Adult; Humans; Aged; Adult; Osteogenesis Imperfecta; Intracranial Aneurysm; Fractures, Compression; Spinal Fractures; Collagen Type I; Bone Density
PubMed: 37164684
DOI: 10.1507/endocrj.EJ22-0620 -
Medicine Sep 2023Despite the growing body of research on chronic pain in adults with osteogenesis imperfecta (OI), there is still a lack of comprehensive understanding of the influence...
Despite the growing body of research on chronic pain in adults with osteogenesis imperfecta (OI), there is still a lack of comprehensive understanding of the influence of psychological factors on pain experienced by individuals with this condition. This study aims to delve into the correlation between personality traits and various aspects of pain, such as frequency, intensity, appraisal, and coping mechanisms, in a significant sample of adults with OI. Additionally, the investigation seeks to identify whether certain personality profiles may be more susceptible to chronic pain within this specific population. A descriptive cross-sectional study was conducted on a sample of 418 adults diagnosed with OI. Participants completed an online survey that assessed sociodemographic and clinical variables, pain parameters, personality traits, pain appraisal, and coping strategies. Subsequently, descriptive, correlational, cluster and comparative analyses were performed. Up to 83% of the participants reported experiencing pain on a regular basis. Regarding personality dimensions, moderate scores were obtained, with no significant differences compared to the general population. Neuroticism emerged as the trait showing the most robust relationships with the evaluated variables. It positively correlated with pain intensity, frequency, and the perception of pain as threatening (P < .001). Conversely, higher levels of extraversion were associated with a reduction in pain and its threatening perception (P < .001). Finally, the cluster analysis revealed a personality profile that showed greater vulnerability in pain adaptation, characterized by high levels of neuroticism and low levels of extraversion, agreeableness, and conscientiousness. Chronic pain is prevalent in adults with OI. Personality dimensions maintain a significant relationship with this pain, acting as vulnerability or protective factors. Consequently, specific personality profiles are associated with poorer adaptation. Understanding these profiles would allow for a deeper comprehension of the pain experience in adults with OI.
Topics: Humans; Adult; Chronic Pain; Cross-Sectional Studies; Osteogenesis Imperfecta; Personality; Neuroticism
PubMed: 37773867
DOI: 10.1097/MD.0000000000035352 -
Orphanet Journal of Rare Diseases Jun 2024The IMPACT survey aimed to elucidate the humanistic, clinical and economic burden of osteogenesis imperfecta (OI) on individuals with OI, their families, caregivers and...
BACKGROUND
The IMPACT survey aimed to elucidate the humanistic, clinical and economic burden of osteogenesis imperfecta (OI) on individuals with OI, their families, caregivers and wider society. Research methodology, demographics and initial insights from the survey have been previously reported. The cost of illness (healthcare resource use, productivity loss, out-of-pocket spending) and drivers of the economic impact of OI are reported here.
METHODS
IMPACT was an international mixed-methods online survey in eight languages (fielded July-September 2021) targeting adults (aged ≥ 18 years) or adolescents (aged ≥ 12-17 years) with OI, caregivers with or without OI and other close relatives. Survey domains included demographics, socioeconomic factors, clinical characteristics, treatment patterns, quality of life and health economics. The health economic domain for adults, which included questions on healthcare resource use, productivity loss and out-of-pocket spending, was summarised. Regression and pairwise analyses were conducted to identify independent drivers and associations with respondent characteristics.
RESULTS
Overall, 1,440 adults with OI responded to the survey. Respondents were mostly female (70%) and from Europe (63%) with a median age of 43 years. Within a 12-month period, adults with OI reported visiting a wide range of healthcare professionals. Two-thirds (66%) of adults visited a hospital, and one-third (33%) visited the emergency department. The mean total number of diagnostic tests undergone by adults within these 12 months was 8.0. Adults had undergone a mean total of 11.8 surgeries up to the time point of the survey. The proportions of adults using queried consumables or services over 12 months ranged from 18-82%, depending on the type of consumable or service. Most adults (58%) were in paid employment, of which nearly one-third (29%) reported missing a workday. Of the queried expenses, the mean total out-of-pocket spending in 4 weeks was €191. Respondent characteristics such as female sex, more severe self-reported OI and the experience of fractures were often associated with increased economic burden.
CONCLUSION
IMPACT provides novel insights into the substantial cost of illness associated with OI on individuals, healthcare systems and society at large. Future analyses will provide insights into country-specific economic impact, humanistic impact and the healthcare journey of individuals with OI.
Topics: Humans; Osteogenesis Imperfecta; Adult; Female; Male; Surveys and Questionnaires; Cost of Illness; Adolescent; Middle Aged; Young Adult; Quality of Life; Child; Health Expenditures
PubMed: 38831282
DOI: 10.1186/s13023-024-03218-6 -
Journal of Community Genetics Dec 2023Caregivers caring for a child with a genetic condition may experience psychosocial distress, which may be compounded by the context in which the caring takes place. Few...
Caregivers caring for a child with a genetic condition may experience psychosocial distress, which may be compounded by the context in which the caring takes place. Few studies have examined psychosocial distress and support among caregivers caring for a child with a genetic disorder in low-middle-income countries such as Ghana. The purpose of the current study was to investigate the psychosocial impacts of caring for a child with a genetic disorder in an urban setting in Ghana's capital, Accra. We conducted individual interviews among 17 caregivers who were taking care of children with various genetic disorders including, albinism, Edward's syndrome, osteogenesis imperfecta, sickle cell disease, and spondyloepiphyseal dysplasia congenita. Thematic analysis of the data revealed three main themes on the psychosocial impacts, including: (1) self-blame, guilt, and shame; (2) sleep and mood disturbances; and (3) discrimination and stigmatization. We observed three themes about support: (1) psychological support; (2) family and community support; and (3) institutional support. Participants reported limited support from professionals such as psychologists. Discussion focuses on the supportive care needs of caregivers and implications for genetic counselling awareness, advocacy, and training.
PubMed: 37581869
DOI: 10.1007/s12687-023-00662-y -
Journal of Endocrinological... Jan 2024Lipocalin 2 (LCN2) is a newly recognized bone-derived factor that is important in regulation of energy metabolism. We investigated the correlation of serum LCN2 levels...
PURPOSE
Lipocalin 2 (LCN2) is a newly recognized bone-derived factor that is important in regulation of energy metabolism. We investigated the correlation of serum LCN2 levels and glycolipid metabolism, and body composition in a large cohort of patients with osteogenesis imperfecta (OI).
METHODS
A total of 204 children with OI and 66 age- and gender-matched healthy children were included. Circulating levels of LCN2 and osteocalcin were measured by enzyme-linked immunosorbent assay. Serum levels of fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), and low- and high-density lipoprotein cholesterol (LDL-C, HDL-C) were measured by automated chemical analyzers. The body composition was measured by dual-energy X-ray absorptiometry. Grip strength and timed-up-and-go (TUG) were tested to evaluate the muscle function.
RESULTS
Serum LCN2 levels were 37.65 ± 23.48 ng/ml in OI children, which was significantly lower than those in healthy control (69.18 ± 35.43 ng/ml, P < 0.001). Body mass index (BMI) and serum FBG level were significantly higher and HDL-C levels were lower in OI children than healthy control (all P < 0.01). Grip strength was significantly lower (P < 0.05), and the TUG was significantly longer in OI patients than healthy control (P < 0.05). Serum LCN2 level was negatively correlated to BMI, FBG, HOMA-IR, HOMA-β, total body, and trunk fat mass percentage, and positively correlated to total body and appendicular lean mass percentage (all P < 0.05).
CONCLUSIONS
Insulin resistance, hyperglycemia, obesity, and muscle dysfunction are common in OI patients. As a novel osteogenic cytokine, LCN2 deficiency may be relevant to disorders of glucose and lipid metabolism, and dysfunction of muscle in OI patients.
Topics: Child; Humans; Osteogenesis Imperfecta; Lipocalin-2; Body Composition; Insulin Resistance; Cholesterol, HDL; Lipid Metabolism; Glycolipids
PubMed: 37326909
DOI: 10.1007/s40618-023-02121-4 -
Journal of Pediatric Nursing Mar 2024To describe the level of risk perception for fractures among family caregivers of children diagnosed with osteogenesis imperfecta, and explore the related factors.
PURPOSE
To describe the level of risk perception for fractures among family caregivers of children diagnosed with osteogenesis imperfecta, and explore the related factors.
DESIGN AND METHODS
This was a cross-sectional survey study. A self-administered questionnaire on family caregivers' perception of fracture risk of underage patients with osteogenesis imperfecta was used. The study was performed in mainland China from May to December 2022, with 127 family caregivers of patients aged 3-17. Stepwise backwards multivariable linear regression analysis was undertaken to examine risk factors for caregivers' risk perception of fractures.
RESULTS
A total of 16.54% of caregivers had a higher level of risk perception for fractures of patients. The caregiver's educational level, the family members, the patient's self-care ability, fracture times in the past year, and whether or not they had received community services were associated with the caregiver's risk perception for fracture.
CONCLUSIONS
Patients with osteogenesis imperfecta will eventually leave the medical system and receive more support from themselves or family caregivers instead of health personnel. These findings should be incorporated into the prevention and health education of fractures in caregivers of underage patients with osteogenesis imperfecta to help develop effective risk communication strategies and induce caregivers to implement appropriate protective behaviors.
PRACTICE IMPLICATIONS
It is important to evaluate the risk perception for fractures and its related factors among family caregivers of underage patients with osteogenesis imperfecta. Identifying these factors can help healthcare providers to screen caregivers with high perceived level of fracture risk in a quicker and earlier way. This study provides evidence for the establishment of interventions to balance caregivers' risk perception and patient socialization.
PubMed: 38484687
DOI: 10.1016/j.pedn.2024.03.003 -
International Journal of Medical... 2024CREB3 subfamily belongs to the bZIP transcription factor family and comprises five members. Normally they are located on the endoplasmic reticulum (ER) membranes and... (Review)
Review
CREB3 subfamily belongs to the bZIP transcription factor family and comprises five members. Normally they are located on the endoplasmic reticulum (ER) membranes and proteolytically activated through RIP (regulated intramembrane proteolysis) on Golgi apparatus to liberate the N-terminus to serve as transcription factors. CREB3L1 acting as one of them transcriptionally regulates the expressions of target genes and exhibits distinct functions from the other members of CREB3 family in eukaryotes. Physiologically, CREB3L1 involves in the regulation of bone morphogenesis, neurogenesis, neuroendocrine, secretory cell differentiation, and angiogenesis. Pathologically, CREB3L1 implicates in the modulation of osteogenesis imperfecta, low grade fibro myxoid sarcoma (LGFMS), sclerosing epithelioid fibrosarcoma (SEF), glioma, breast cancer, thyroid cancer, and tissue fibrosis. This review summarizes the upstream and downstream regulatory network of CREB3L1 and thoroughly presents our current understanding of CREB3L1 research progress in both physiological and pathological conditions with special focus on the novel findings of CREB3L1 in cancers.
Topics: Humans; Fibrosarcoma; Basic-Leucine Zipper Transcription Factors; Biomarkers, Tumor; Nerve Tissue Proteins; Cyclic AMP Response Element-Binding Protein
PubMed: 38164349
DOI: 10.7150/ijms.90189 -
Journal of Medical Genetics Nov 2023Pulmonary disease is the major cause of morbidity and mortality in osteogenesis imperfecta (OI). We investigated the contribution of intrinsic lung factors to impaired...
PURPOSE
Pulmonary disease is the major cause of morbidity and mortality in osteogenesis imperfecta (OI). We investigated the contribution of intrinsic lung factors to impaired pulmonary function in children and young adults with OI types III, IV, VI.
METHODS
Patients with type III (n=8), IV (n=21), VI (n=5), VII (n=2) or XIV (n=1) OI (mean age 23.6 years) prospectively underwent pulmonary function tests (PFTs) and thoracic CT and radiographs.
RESULTS
PFT results were similar using arm span or ulnar length as height surrogates. PFTs were significantly lower in type III than type IV or VI OI. All patients with type III and half of type IV OI had lung restriction; 90% of patients with OI had reduced gas exchange. Patients with variants had significantly lower forced expiratory flow (FEF)25%-75% compared with those with variants. PFTs correlated negatively with Cobb angle or age. CT scans revealed small airways bronchial thickening (100%, 86%, 100%), atelectasis (88%, 43%, 40%), reticulations (50%, 29%, 20%), ground glass opacities (75%, 5%, 0%), pleural thickening (63%, 48%, 20%) or emphysema (13%, 19%, 20%) in type III, IV or VI OI, respectively.
CONCLUSION
Both lung intrinsic and extrinsic skeletal abnormalities contribute to OI pulmonary dysfunction. Most young adult patients have restrictive disease and abnormal gas exchange; impairment is greater in type III than type IV OI. Decreased FEF25%-75% and thickening of small bronchi walls indicate a critical role for small airways. Lung parenchymal abnormalities (atelectasis, reticulations) and pleural thickening were also detected. Clinical interventions to mitigate these impairments are warranted.
TRIAL REGISTRATION NUMBER
NCT03575221.
Topics: Humans; Osteogenesis Imperfecta; Male; Female; Respiratory Function Tests; Adolescent; Young Adult; Adult; Child; Lung; Tomography, X-Ray Computed; Lung Diseases; Child, Preschool; Collagen Type I
PubMed: 37197785
DOI: 10.1136/jmg-2022-109009