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Calcified Tissue International Mar 2024Osteogenesis imperfecta (OI) is a rare genetic disorder caused by abnormal collagen type I production. While OI is primarily characterized by bone fragility and... (Review)
Review
Osteogenesis imperfecta (OI) is a rare genetic disorder caused by abnormal collagen type I production. While OI is primarily characterized by bone fragility and deformities, patients also have extraskeletal manifestations, including an increased risk of cardiovascular disease. This review provides a comprehensive overview of the literature on cardiovascular diseases in OI patients in order to raise awareness of this understudied clinical aspect of OI and support clinical guidelines. In accordance with the PRISMA guidelines, a systematic literature search in PubMed, Embase, Web of Science and Scopus was conducted that included articles from the inception of these databases to April 2023. Valvular disease, heart failure, atrial fibrillation, and hypertension appear to be more prevalent in OI than in control individuals. Moreover, a larger aortic root was observed in OI compared to controls. Various cardiovascular diseases appear to be more prevalent in OI than in controls. These cardiovascular abnormalities are observed in all types of OI and at all ages, including young children. As there are insufficient longitudinal studies, it is unknown whether these abnormalities are progressive in nature in OI patients. Based on these findings, we would recommend referring individuals with OI to a cardiologist with a low-threshold.
Topics: Child; Humans; Child, Preschool; Osteogenesis Imperfecta; Cardiovascular Diseases; Cardiovascular Abnormalities; Collagen Type I; Longitudinal Studies
PubMed: 38243143
DOI: 10.1007/s00223-023-01171-3 -
Archives of Osteoporosis Nov 2023In a cross-sectional study assessing the experiences of individuals with osteogenesis imperfecta accessing care during the COVID-19 pandemic, participants reported high...
UNLABELLED
In a cross-sectional study assessing the experiences of individuals with osteogenesis imperfecta accessing care during the COVID-19 pandemic, participants reported high rates of delays in accessing medical care and high utilization of telehealth. Considering the needs of individuals with complex medical conditions is important when improving access to care.
PURPOSE
Individuals with osteogenesis imperfecta (OI) often have complex care needs requiring that they see a variety of specialists. The onset of the COVID-19 pandemic in March 2020 led to delays in medical care for many health conditions. The goal of this study was to describe the experiences of individuals with OI accessing medical care during this time.
METHODS
Responses to an electronic survey distributed via the OI Foundation mailing list were collected from August 2020 until February 2021. Participants were instructed to compare their experiences in the months since the start of the pandemic with their experiences prior to this date. Data were analyzed using descriptive statistics and were compared across demographic groups using logistic regression and chi-squared tests.
RESULTS
Surveys were completed by 110 participants. Most participants (72%) reported experiencing delays in accessing at least one care provider. The majority of participants reported less or similar amounts of bone pain (74.3%) and less or the same rate of fracture (88.6%) as before the start of the pandemic.
CONCLUSION
While most study participants experienced delays in care, they did not report an increase in symptoms associated with OI. They also frequently utilized telehealth as a tool to see their providers. Future research should focus on the impact of changes in telehealth legislation on patients' ability to access care. As methods for care delivery evolve, the needs of people with OI and other rare diseases should be considered and prioritized.
Topics: Humans; Osteogenesis Imperfecta; COVID-19; Pandemics; Cross-Sectional Studies; Health Services Accessibility
PubMed: 38015270
DOI: 10.1007/s11657-023-01355-2 -
Frontiers in Medicine 2023Respiratory insufficiency is a leading cause of death in individuals with osteogenesis imperfecta (OI). However, evaluating pulmonary function in OI presents challenges....
INTRODUCTION
Respiratory insufficiency is a leading cause of death in individuals with osteogenesis imperfecta (OI). However, evaluating pulmonary function in OI presents challenges. Commonly used pulmonary function tests such as spirometry and body plethysmography are sometimes difficult to perform for OI patients, and reference intervals are not always applicable. The forced oscillation technique (FOT) is a patient-friendly method for detecting respiratory abnormalities that requires no effort from the patient.
OBJECTIVE
This study investigates the feasibility of FOT in the evaluation of respiratory function in the clinical management of OI patients.
METHODS
Twelve OI patients, comprising eight with Sillence OI I, two with OI IV, and two with OI III, underwent spirometry, body plethysmography, and FOT, both pre-and post-administration of salbutamol.
RESULTS
FOT measurements exhibited consistent trends that aligned with spirometry and body plethysmography findings. The resistance at 8 Hz decreased after the administration of salbutamol, indicating that FOT is able to detect bronchial obstruction and its alleviation by medication ( < 0.05). The resonant frequency during expiration was higher than during inspiration in nearly all patients, suggesting obstructive disease. The technique gives insight into both inspiratory and expiratory impairment of pulmonary ventilation. The main FOT parameters showed a relatively high repeatability in duplicate measurements.
CONCLUSION
Bronchial obstruction can be detected by FOT in patients with OI during quiet breathing, making it an easily executable alternative to other lung function measurements. The technique can detect the bronchodilator effect of sympathomimetic medication. It has the potential to provide information on expiratory flow limitation, pulmonary restriction, and reduced lung compliance.
PubMed: 38179272
DOI: 10.3389/fmed.2023.1301873 -
International Journal of Molecular... Nov 2023Osteogenesis imperfecta (OI) is a rare congenital bone dysplasia generally caused by a mutation of one of the type I collagen genes and characterized by low bone mass,...
Osteogenesis imperfecta (OI) is a rare congenital bone dysplasia generally caused by a mutation of one of the type I collagen genes and characterized by low bone mass, numerous fractures, and bone deformities. The collagen organization and osteocyte lacuna arrangement were investigated in the long bones of 17-week-old wildtype (WT, n = 17) and osteogenesis imperfecta mice (OIM, n = 16) that is a validated model of severe human OI in order to assess their possible role in bone fragility. Fractures were counted after in vivo scanning at weeks 5, 11, and 17. Humerus, femur, and tibia diaphyses from both groups were analyzed ex vivo with pQCT, polarized and ordinary light histology, and Nano-CT. The fractures observed in the OIM were more numerous in the humerus and femur than in the tibia, whereas the quantitative bone parameters were altered in different ways among these bones. Collagen fiber organization appeared disrupted, with a lower birefringence in OIM than WT bones, whereas the osteocyte lacunae were more numerous, more spherical, and not aligned in a lamellar pattern. These modifications, which are typical of immature and less mechanically competent bone, attest to the reciprocal alteration of collagen matrix and osteocyte lacuna organization in the OIM, thereby contributing to bone fragility.
Topics: Animals; Humans; Mice; Bone and Bones; Collagen; Disease Models, Animal; Fractures, Bone; Mutation; Osteogenesis; Osteogenesis Imperfecta
PubMed: 38069332
DOI: 10.3390/ijms242317010 -
Genetics, Selection, Evolution : GSE May 2024Nine male and eight female calves born to a Normande artificial insemination bull named "Ly" were referred to the French National Observatory of Bovine Abnormalities for...
BACKGROUND
Nine male and eight female calves born to a Normande artificial insemination bull named "Ly" were referred to the French National Observatory of Bovine Abnormalities for multiple fractures, shortened gestation, and stillbirth or perinatal mortality.
RESULTS
Using Illumina BovineSNP50 array genotypes from affected calves and 84 half-sib controls, the associated locus was mapped to a 6.5-Mb interval on chromosome 19, assuming autosomal inheritance with germline mosaicism. Subsequent comparison of the whole-genome sequences of one case and 5116 control genomes, followed by genotyping in the affected pedigree, identified a de novo missense substitution within the NC1 domain of the COL1A1 gene (Chr19 g.36,473,965G > A; p.D1412N) as unique candidate variant. Interestingly, the affected residue was completely conserved among 243 vertebrate orthologs, and the same substitution in humans has been reported to cause type II osteogenesis imperfecta (OI), a connective tissue disorder that is characterized primarily by bone deformity and fragility. Moreover, three COL1A1 mutations have been described to cause the same syndrome in cattle. Necropsy, computed tomography, radiology, and histology confirmed the diagnosis of type II OI, further supporting the causality of this variant. In addition, a detailed analysis of gestation length and perinatal mortality in 1387 offspring of Ly and more than 160,000 progeny of 63 control bulls allowed us to statistically confirm in a large pedigree the association between type II OI and preterm delivery, which is probably due to premature rupture of fetal membranes and has been reported in several isolated cases of type II OI in humans and cattle. Finally, analysis of perinatal mortality rates and segregation distortion supported a low level of germ cell mosaicism in Ly, with an estimate of 4.5% to 7.7% of mutant sperm and thus 63 to 107 affected calves born. These numbers contrast with the 17 cases reported and raise concerns about the underreporting of congenital defects to heredo-surveillance platforms, even for textbook genetic syndromes.
CONCLUSIONS
In conclusion, we describe a large animal model for a recurrent substitution in COL1A1 that is responsible for type II OI in humans. More generally, this study highlights the utility of such datasets and large half-sib families available in livestock species to characterize sporadic genetic defects.
Topics: Animals; Cattle; Mutation, Missense; Osteogenesis Imperfecta; Collagen Type I; Male; Female; Collagen Type I, alpha 1 Chain; Cattle Diseases; Premature Birth; Pedigree; Pregnancy
PubMed: 38773368
DOI: 10.1186/s12711-024-00909-3 -
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 -
JBMR Plus Dec 2023The skeletal dysplasias are a heterogeneous group of genetic conditions caused by abnormalities of growth, development, and maintenance of bone and cartilage. Little is...
The skeletal dysplasias are a heterogeneous group of genetic conditions caused by abnormalities of growth, development, and maintenance of bone and cartilage. Little is known about the roles that cytokines play in the inflammatory and non-inflammatory pathophysiology of skeletal dysplasia. We sought to test our hypothesis that cytokines would be differentially expressed in children with skeletal dysplasia as compared to typically growing controls. Cytokine levels were analyzed using the Cytokine Human Magnetic 25-Plex Panel (Invitrogen, Waltham, MA, USA); 136 growing individuals with skeletal dysplasia and compared to a cohort of 275 healthy pediatric control subjects. We focused on the expression of 12 cytokines across nine dysplasia cohorts. The most common skeletal dysplasia diagnoses were: achondroplasia (58), osteogenesis imperfecta (19), type II collagenopathies (11), multiple epiphyseal dysplasia (MED: 9), diastrophic dysplasia (8), metatropic dysplasia (8), and microcephalic osteodysplastic primordial dwarfism type II (MOPDII: 8). Of the 108 specific observations made, 45 (41.7%) demonstrated statistically significant differences of expression between controls and individuals with skeletal dysplasia. Four of the 12 analyzed cytokines demonstrated elevated expression above control levels in all of the dysplasia cohorts (interleukin 12 [IL-12], IL-13, interferon γ-induced protein 10 kDa [IP-10], regulated on activation, normal T cell expressed and secreted [RANTES]) and two demonstrated expression below control levels across all dysplasia cohorts (monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein-1β [MIP-1β]). The highest levels of overexpression were seen in MOPDII, with expression levels of IP-10 being increased 3.8-fold ( < 0.0001). The lowest statistically significant levels of expressions were in type II collagenopathies, with expression levels of MCP-1 being expressed 0.43-fold lower ( < 0.005). With this data, we hope to lay the groundwork for future directions in dysplasia research that will enhance our understanding of these complex signaling pathways. Looking forward, validating these early trends in cytokine expression, and associating the observed variations with trends in the progression of dysplasia may offer new candidates for clinical biomarkers or even new therapeutics. © 2023 The Authors. published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
PubMed: 38130766
DOI: 10.1002/jbm4.10816 -
Annals of Medicine and Surgery (2012) Nov 2023Acalvaria is a rare congenital malformation in which the flat bones of the cranial vault, dura mater, and associated muscles are absent while the central nervous system...
INTRODUCTION AND IMPORTANCE
Acalvaria is a rare congenital malformation in which the flat bones of the cranial vault, dura mater, and associated muscles are absent while the central nervous system usually remains unaffected. It is an extremely rare congenital anomaly with only a handful of cases being reported in literature.
CASE PRESENTATION
The authors report a case of a 2-month-old male infant with acalvaria who was delivered at home and brought to our centre with the complaint of an abnormally soft skull. He was evaluated in a primary centre in rural Nepal. Parietal bones were missing bilaterally but no other abnormalities were found during the physical examination and investigations. Major differential diagnoses like anencephaly, cephalocele, osteogenesis imperfecta type II, and hypophosphatasia were ruled out with the help of history, physical examination, and available investigations and the case was diagnosed as acalvaria.
CLINICAL DISCUSSION
Acalvaria is a post-neurulation defect which is associated with anomalies of various organ systems. Radiological diagnosis, with supportive laboratory investigations, is the most reliable method of antenatal diagnosis.
CONCLUSION
Acalvaria is known to have a dismal prognosis and all the living cases with long-term follow-up are mentally retarded and physically disabled. Early and reliable antenatal diagnosis can reduce the economic, physical, and psychological burden associated with this fatal disease, especially in low-income countries.
PubMed: 37915700
DOI: 10.1097/MS9.0000000000001339 -
The Journal of Clinical Endocrinology... Jun 2024The comparative effectiveness of denosumab and zoledronic acid for adult patients with osteogenesis imperfecta (OI) has not been established. (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
CONTEXT
The comparative effectiveness of denosumab and zoledronic acid for adult patients with osteogenesis imperfecta (OI) has not been established.
OBJECTIVE
To evaluate the efficacy and safety of denosumab and zoledronic acid in adult patients with OI.
METHODS
This was a prospective, open-label study. Patients were randomized to receive denosumab 60 mg every 6 months or zoledronic acid 5 mg once for 12 months. Pathogenic mutations of OI were identified by next-generation sequencing and confirmed by Sanger sequencing. Percentage changes in the areal bone mineral density (aBMD), trabecular bone score (TBS), and bone turnover biomarkers (BTMs) from baseline to 6 and 12 months of treatment, as well as safety, were evaluated.
RESULTS
A total of 51 adults with OI (denosumab: 25, zoledronic acid: 26) were included, of whom 49 patients had identified pathogenic mutations. At 12 months, aBMD at the lumbar spine and total hip significantly increased by 4.34% (P = .005) and 1.45% (P = .023) in the denosumab group and by 4.92% (P = .006) and 2.02% (P = .016) in the zoledronic acid group, respectively. TBS showed an increasing trend by 1.39% and 2.70% in denosumab and zoledronic acid groups, respectively. Serum levels of β-isomerized carboxy-telopeptide of type I collagen and alkaline phosphatase markedly decreased after denosumab treatment. Percentage changes in aBMD, TBS, and BTMs during the treatment were similar between the 2 groups. Patients with OI with milder phenotypes showed a significantly higher increase in the TBS after 12 months of denosumab treatment than those with more severe phenotypes (P = .030). During the study period, the denosumab group had fewer adverse events than the zoledronic acid group.
CONCLUSION
Denosumab effectively increases aBMD in adults with OI, with similar efficacy to zoledronic acid. Long-term and large-sample studies are needed to confirm the antifracture efficacy and safety of denosumab in adult patients with OI.
Topics: Humans; Denosumab; Zoledronic Acid; Female; Male; Adult; Bone Density Conservation Agents; Osteogenesis Imperfecta; Bone Density; Prospective Studies; Treatment Outcome; Bone Remodeling; Young Adult; Middle Aged
PubMed: 38181430
DOI: 10.1210/clinem/dgae012 -
Molecular Therapy. Nucleic Acids Mar 2024Osteogenesis imperfecta (OI) is a genetic disorder characterized by bone fragility, low bone mass, fractures, and extraskeletal manifestations. Since OI is commonly...
Osteogenesis imperfecta (OI) is a genetic disorder characterized by bone fragility, low bone mass, fractures, and extraskeletal manifestations. Since OI is commonly caused by single-nucleotide mutation(s) in the or genes encoding type I collagens, we developed a genome-editing strategy to correct a mutation in an OIM mouse model resembling a severe dominant form of human type III OI. Using a recombinant adeno-associated virus (rAAV), we delivered CRISPR-Cas9 to bone-forming osteoblast-lineage cells in the skeleton. Homology-directed repair (HDR)-mediated gene editing efficiency in these cells was improved when CRISPR-Cas9 was coupled with a donor AAV vector containing a promoterless partial mouse complementary DNA sequence. This approach effectively reversed the dysregulation of osteogenic differentiation by a mutation . Furthermore, systemic administration of dual rAAVs in OIM mice lowered bone matrix turnover rates by reducing osteoblast and osteoclast development while improving the cellular network of mechano-sensing osteocytes embedded in the bone matrix. This strategy significantly improved bone architecture/mass/mineralization, skeletal deformities, grip strength, and spontaneous fractures. Our study is the first demonstration that HDR-mediated gene editing via AAV-mediated delivery effectively corrects a collagen mutation in OI osteoblasts and reverses skeletal phenotypes in OIM mice.
PubMed: 38261950
DOI: 10.1016/j.omtn.2023.102111