-
Clinical Rehabilitation May 2024The aim of the study was to assess the muscoloskeletal system and spatiotemporal gait parameters of patients in three types of osteogenesis imperfecta.
OBJECTIVES
The aim of the study was to assess the muscoloskeletal system and spatiotemporal gait parameters of patients in three types of osteogenesis imperfecta.
DESIGN STUDY
Retrospective observational study.
SETTINGS
The Department of Rehabilitation, Children's Memorial Health Institute in Warsaw, Poland.
PARTICIPANTS
This study investigated individuals with various types of osteogenesis imperfecta: 33 with osteogenesis imperfecta I (aged 13.9), 16 with osteogenesis imperfecta III (aged 10.4), and 14 with osteogenesis imperfecta IV (aged, 15.8), as well as a reference group of 400 healthy individuals.
MAIN MEASURES
The musculoskeletal assessment included: medical record review, clinical evaluation, functional tests, long bone deformity assessment via clinical and X-ray examination, and objective gait analysis with the Vicon Motion Systems (Ltd, Oxford, UK).
RESULTS
The study revealed notable differences in clinical presentation, deformities within the musculoskeletal system, gait parameters across the various types of osteogenesis imperfecta (p < 0.001). The most affected gait parameters were: cadence, gait speed and step length. The greatest deformities of lower limbs and spine were presented in patients with osteogenesis imperfecta type III.
CONCLUSIONS
These findings are significant for understanding gait abnormalities in osteogenesis imperfecta patients and designing customized physiotherapy programs to help them participate fully in daily life. Improvement of muscle strength is one of the key for easier engagement in activities like walking or stair-climbing.
PubMed: 38767090
DOI: 10.1177/02692155241254661 -
Oral Diseases Sep 2023This review aimed to summarize recent progress on syndromic dentin defects, promoting a better understanding of systemic diseases with dentin malformations, the... (Review)
Review
OBJECTIVE
This review aimed to summarize recent progress on syndromic dentin defects, promoting a better understanding of systemic diseases with dentin malformations, the molecules involved, and related mechanisms.
SUBJECTS AND METHODS
References on genetic diseases with dentin malformations were obtained from various sources, including PubMed, OMIM, NCBI, and other websites. The clinical phenotypes and genetic backgrounds of these diseases were then summarized, analyzed, and compared.
RESULTS
Over 10 systemic diseases, including osteogenesis imperfecta, hypophosphatemic rickets, vitamin D-dependent rickets, familial tumoral calcinosis, Ehlers-Danlos syndrome, Schimke immuno-osseous dysplasia, hypophosphatasia, Elsahy-Waters syndrome, Singleton-Merten syndrome, odontochondrodysplasia, and microcephalic osteodysplastic primordial dwarfism type II were examined. Most of these are bone disorders, and their pathogenic genes may regulate both dentin and bone development, involving extracellular matrix, cell differentiation, and metabolism of calcium, phosphorus, and vitamin D. The phenotypes of these syndromic dentin defects various with the involved genes, part of them are similar to dentinogenesis imperfecta or dentin dysplasia, while others only present one or two types of dentin abnormalities such as discoloration, irregular enlarged or obliterated pulp and canal, or root malformation.
CONCLUSION
Some specific dentin defects associated with systemic diseases may serve as important phenotypes for dentists to diagnose. Furthermore, mechanistic studies on syndromic dentin defects may provide valuable insights into isolated dentin defects and general dentin development or mineralization.
Topics: Humans; Dentinogenesis Imperfecta; Odontodysplasia; Osteogenesis Imperfecta; Dentin; Vitamin D
PubMed: 37094075
DOI: 10.1111/odi.14589 -
Osteogenesis imperfecta type 10 and the cellular scaffolds underlying common immunological diseases.Genes and Immunity May 2024Osteogenesis imperfecta type 10 (OI10) is caused by loss of function codon variants in the gene SERPINH1 that encodes heat shock protein 47 (HSP47), rather than in a... (Review)
Review
Osteogenesis imperfecta type 10 (OI10) is caused by loss of function codon variants in the gene SERPINH1 that encodes heat shock protein 47 (HSP47), rather than in a gene specifying bone formation. The HSP47 variants disrupt the folding of both collagen and the endonuclease IRE1α (inositol-requiring enzyme 1α) that splices X-Box Binding Protein 1 (XBP1) mRNA. Besides impairing bone development, variants likely affect osteoclast differentiation. Three distinct biochemical scaffold play key roles in the differentiation and regulated cell death of osteoclasts. These scaffolds consist of non-templated protein modifications, ordered lipid arrays, and protein filaments. The scaffold components are specified genetically, but assemble in response to extracellular perturbagens, pathogens, and left-handed Z-RNA helices encoded genomically by flipons. The outcomes depend on interactions between RIPK1, RIPK3, TRIF, and ZBP1 through short interaction motifs called RHIMs. The causal HSP47 nonsynonymous substitutions occur in a novel variant leucine repeat region (vLRR) that are distantly related to RHIMs. Other vLRR protein variants are causal for a variety of different mendelian diseases. The same scaffolds that drive mendelian pathology are associated with many other complex disease outcomes. Their assembly is triggered dynamically by flipons and other context-specific switches rather than by causal, mendelian, codon variants.
PubMed: 38811682
DOI: 10.1038/s41435-024-00277-4 -
Journal of Clinical Medicine Feb 2024(1) Background: Osteogenesis imperfecta (OI) is a rare skeletal dysplasia characterized as a heterogeneous disorder group with well-defined phenotypic and genetic... (Review)
Review
(1) Background: Osteogenesis imperfecta (OI) is a rare skeletal dysplasia characterized as a heterogeneous disorder group with well-defined phenotypic and genetic features that share uncommon bone fragility. The current treatment options, medical and orthopedic, are limited and not efficient enough to improve the low bone density, bone fragility, growth, and mobility of the affected individuals, creating the need for alternative therapeutic agents. (2) Methods: We searched the medical database to find papers regarding treatments for OI other than conventional ones. We included 45 publications. (3) Results: In reviewing the literature, eight new potential therapies for OI were identified, proving promising results in cells and animal models or in human practice, but further research is still needed. Bone marrow transplantation is a promising therapy in mice, adults, and children, decreasing the fracture rate with a beneficial effect on structural bone proprieties. Anti-RANKL antibodies generated controversial results related to the therapy schedule, from no change in the fracture rate to improvement in the bone mineral density resorption markers and bone formation, but with adverse effects related to hypercalcemia. Sclerostin inhibitors in murine models demonstrated an increase in the bone formation rate and trabecular cortical bone mass, and a few human studies showed an increase in biomarkers and BMD and the downregulation of resorption markers. Recombinant human parathormone and TGF-β generated good results in human studies by increasing BMD, depending on the type of OI. Gene therapy, 4-phenylbutiric acid, and inhibition of eIF2α phosphatase enzymes have only been studied in cell cultures and animal models, with promising results. (4) Conclusions: This paper focuses on eight potential therapies for OI, but there is not yet enough data for a new, generally accepted treatment. Most of them showed promising results, but further research is needed, especially in the pediatric field.
PubMed: 38398378
DOI: 10.3390/jcm13041065 -
Osteoporosis International : a Journal... Jul 2024The epidemiological data on osteogenesis imperfecta (OI) in Asia is limited. This study, representing the first comprehensive epidemiological investigation on OI in...
UNLABELLED
The epidemiological data on osteogenesis imperfecta (OI) in Asia is limited. This study, representing the first comprehensive epidemiological investigation on OI in Taiwan, reveals high medical resource utilization and underscores the importance of early diagnosis to enhance care quality.
INTRODUCTION
This study examines osteogenesis imperfecta, a hereditary connective tissue disorder causing pediatric fractures and limb deformities, using a nationwide database from Taiwan to analyze clinical features and medical burden.
METHODS
The study identified validated OI patients from the Catastrophic Illness Registry in the National Health Insurance Research Database from 2008 to 2019. Demographic data and medical resource utilization were analyzed. A multivariate Cox model assessed the influence of sex, validation age, and comorbidities.
RESULTS
319 OI patients (M/F = 153/166) were identified, with 58% validated before age 20. Prevalence and incidence were 0.8-1.3/100,000 and 0.02-0.09/100,000, respectively, with higher rates in the pediatric demographic. In the study period, 69.6% of the patients had admission history, primarily to pediatric and orthopedic wards. The median admission number was 3, with a median length of stay of 12 days and a median inpatient cost of approximately 3,163 USD during the period. Lower limb fractures were the main reason for hospitalization. 57% of OI patients received bisphosphonate treatment. The leading causes of mortality were OI-related deaths, neurovascular disease, and cardiovascular disease. The median age of validation in the non-survival group was significantly higher compared to the survival group (33 vs. 14 years), and patients validated during childhood required more inpatient fracture surgeries than those validated during adulthood.
CONCLUSION
This study provides comprehensive real-world evidence on the clinical characteristics and high medical resource utilization of OI patients in a low prevalence region like Taiwan. Early diagnosis is crucial for improving care quality and enhancing health outcomes.
Topics: Humans; Osteogenesis Imperfecta; Male; Female; Child; Adolescent; Child, Preschool; Taiwan; Young Adult; Databases, Factual; Infant; Adult; Prevalence; Incidence; Cost of Illness; Middle Aged; Hospitalization; Comorbidity; Age Distribution; Registries; Infant, Newborn; Sex Distribution; Length of Stay
PubMed: 38563961
DOI: 10.1007/s00198-024-07051-2 -
ACS Pharmacology & Translational Science Jan 2024Osteogenesis imperfecta (OI) is an uncommon genetic disorder characterized by shortness of stature, hearing loss, poor bone mass, recurrent fractures, and skeletal... (Review)
Review
Osteogenesis imperfecta (OI) is an uncommon genetic disorder characterized by shortness of stature, hearing loss, poor bone mass, recurrent fractures, and skeletal abnormalities. Pathogenic variations have been found in over 20 distinct genes that are involved in the pathophysiology of OI, contributing to the disorder's clinical and genetic variability. Although medications, surgical procedures, and other interventions can partially alleviate certain symptoms, there is still no known cure for OI. In this Review, we provide a comprehensive overview of genetic pathogenesis, existing treatment modalities, and new developments in biotechnologies such as gene editing, stem cell reprogramming, functional differentiation, and transplantation for potential future OI therapy.
PubMed: 38230285
DOI: 10.1021/acsptsci.3c00324 -
European Journal of Medical Genetics Nov 2023Osteogenesis imperfecta (OI) and hypophosphatasia (HPP) are rare skeletal disorders caused by mutations in the genes encoding collagen type I (COL1A, COL1A2) and...
Combination of osteogenesis imperfecta and hypophosphatasia in three children with multiple fractures, low bone mass and severe osteomalacia, a challenge for therapeutic management.
Osteogenesis imperfecta (OI) and hypophosphatasia (HPP) are rare skeletal disorders caused by mutations in the genes encoding collagen type I (COL1A, COL1A2) and tissue-non-specific isoenzyme of alkaline phosphatase (ALPL), respectively. Both conditions result in skeletal deformities and bone fragility although bone tissue abnormalities differ considerably. Children with OI have low bone mass and hypermineralized matrix, whereas HPP children develop rickets and osteomalacia. We report a family, father and three children, affected with growth retardation, low bone mass and recurrent fractures. None of them had rickets, blue sclera or dentinogenesis imperfecta. ALP serum levels were low and genetics revealed in the four probands heterozygous pathogenic mutations in COL1A2 c.838G > A (p.Gly280Ser) and in ALPL c.1333T > C (p.Ser445Pro). After multidisciplinary meeting, a diagnostic transiliac bone biopsy was indicated for each sibling for therapeutic decision. Bone histology and histomorphometry, as compared to reference values of children with OI type I as well as, to a control pediatric patient harboring the same COL1A2 mutation, revealed similarly decreased trabecular bone volume, increased osteocyte lacunae, but additionally severe osteomalacia. Quantitative backscattered electron imaging demonstrated that bone matrix mineralization was not as decreased as expected for osteomalacia. In summary, we observed within each biopsy samples classical features of OI and classical features of HPP. The apparent nearly normal bone mineralization density distribution results presumably from divergent effects of OI and HPP on matrix mineralization. A combination therapy was initiated with ALP enzyme-replacement and one month later with bisphosphonates. The ongoing treatment led to improved skeletal growth, increased BMD and markedly reduced fracture incidence.
Topics: Child; Humans; Osteogenesis Imperfecta; Hypophosphatasia; Osteomalacia; Fractures, Multiple; Mutation; Alkaline Phosphatase; Calcinosis; Rickets
PubMed: 37758163
DOI: 10.1016/j.ejmg.2023.104856 -
Biochemical Pharmacology Jul 2023Osteogenesis imperfecta (OI) is a genetically heterogeneous connective tissue disorder characterized by bone fragility and different extra-skeletal manifestations. The... (Review)
Review
Osteogenesis imperfecta (OI) is a genetically heterogeneous connective tissue disorder characterized by bone fragility and different extra-skeletal manifestations. The severity of these manifestations makes it possible to classify OI into different subtypes based on the main clinical features. This review aims to outline and describe the current pharmacological alternatives for treating OI, grounded on clinical and preclinical reports, such as antiresorptive agents, anabolic agents, growth hormone, and anti-TGFβ antibody, among other less used agents. The different options and their pharmacokinetic and pharmacodynamic properties will be reviewed and discussed, focusing on the variability of their response and the molecular mechanisms involved to attain the main clinical goals, which include decreasing fracture incidence, improving pain, and promoting growth, mobility, and functional independence.
Topics: Humans; Osteogenesis Imperfecta; Fractures, Bone; Bone Density Conservation Agents
PubMed: 37148979
DOI: 10.1016/j.bcp.2023.115584 -
EMBO Molecular Medicine Jul 2023Osteogenesis imperfecta (OI) is a hereditary skeletal disorder primarily affecting collagen type I structure and function, causing bone fragility and occasionally...
Osteogenesis imperfecta (OI) is a hereditary skeletal disorder primarily affecting collagen type I structure and function, causing bone fragility and occasionally versatile extraskeletal symptoms. This study expands the spectrum of OI-causing TAPT1 mutations and links extracellular matrix changes to signaling regulation.
Topics: Humans; Osteogenesis Imperfecta; Collagen Type I; Extracellular Matrix; Mutation; Signal Transduction
PubMed: 37292039
DOI: 10.15252/emmm.202317528 -
Frontiers in Endocrinology 2023Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous skeletal disorder. The majority of affected cases are attributed to autosomal dominant...
INTRODUCTION
Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous skeletal disorder. The majority of affected cases are attributed to autosomal dominant pathogenic variants (PVs) found in the and genes, which encode type I collagen. However, PVs in other genes involved in collagen posttranslational modification, processing, crosslinking, osteoblast differentiation, and bone mineralization have also been associated with OI.
METHODS
In this study, we present the results of next-generation sequencing (NGS) analysis using a custom panel of 11 genes known to be associated with OI. This clinical study enrolled a total of 10 patients, comprising 7 male and 3 female patients from 7 families, all from the Puglia Region in South Italy, providing a detailed overview of their age, gender, family history, OI type, and non-skeletal features.
RESULTS
The genetic analysis revealed 5 PVs in the gene and 2 PVs in the gene. Importantly, three of these PVs have not been previously reported in the literature. These include two novel heterozygous frameshift PVs in (c.2890_2893del and c.3887del) and one novel heterozygous missense PV in (c.596G>T).
DISCUSSION
The identification of these previously unreported PVs expands the variant spectrum of the and genes and may have implications for accurate diagnosis, genetic counselling, and potential therapeutic interventions in affected individuals and their families.
Topics: Humans; Male; Female; Collagen Type I; Osteogenesis Imperfecta; Collagen Type I, alpha 1 Chain; Mutation
PubMed: 37929041
DOI: 10.3389/fendo.2023.1254695