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PubMed2001

Results of stapes surgery on patients with osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a heterogeneous group of connective tissue disorders. The classic triad of blue sclerae, spontaneous fractures and hearing loss is known as the Van der Hoeve and De Kleyn syndrome. Between 1989 and 2000, six patients with OI presented with conductive hearing loss. Five of them proceeded to stapedotomy. All the patients who had surgery had significant hearing gain. None of the patients had any complications. This study presents a higher incidence of spontaneous fractured crura as the cause of the conductive hearing loss than previously reported, and that the presence of a fractured crura with mobile footplate can be anticipated by the presence of a large conductive hearing loss. The pre- and postoperative results are presented and support the view that stapes surgery in OI can have encouraging results, provided the operator anticipates the possibility of a fractured crura and a mobile footplate.

Adult↗

PubMed1976

Psychosocial factors in low-incidence genetic disease: the case of osteogenesis imperfecta.

Osteogenesis imperfecta (OI), a dominant genetic disorder, was examined in an exploratory case study of psychosocial implications. The cross-sectional survey sample consisted of 13 OI-affected adults and 21 families with an OI-affected child who were interviewed. Findings revealed numerous psychosocial concerns and problems in addition to their complex and lifelong medical problems. Specific problem areas differed according to the severity of the disease, type, and mode of genetic inheritance. The results indicate the need for local as well as national policy changes through legislation and extensions of existing services for low-incidence disease groups such as OI-affected persons. Implications for social work practice interventions call for greater involvement with genetic diseases, more aggressive approaches in case identification and service coordination, and performing longer-range monitoring functions than is usually the case.

Adult↗

PubMed1992

Hyperplastic callus formation in osteogenesis imperfecta.

Osteogenesis imperfecta, an inherited disorder of connective tissues, affects roughly (OI) 4000 people in Germany (11). The main clinical symptoms are fragile bones, progressing skeletal deformities, generalized osteoporosis and short stature. Incidentally, the clinical manifestations can range from perinatal lethal forms to phenotypical normal adults. In many instances the underlying causes of the disease are mutations in gene coding for collagen I, the predominant protein in most connective tissues. Fracture healing is usually not impaired, although in a unique group of OI-patients, a tumor-like hyperplastic callus occurs with excessive deposition of extracellular matrix constituents. Biochemical analysis of the callus is reminiscent of bone from early stages of human development and normal fracture healing (e.g. collagen type composition, degree of posttranslational modification). This underlines that, besides collagen mutations, the regulation of collagen synthesis and their posttranslational processing might be disturbed in patients with hyperplastic callus formation.

Bony Callus↗

PubMed2003

COL1A1 mutation analysis in Lithuanian patients with osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a generalised disorder of connective tissue characterised by an increased fragility of bones and also manifested in other tissues containing collagen type I, by blue sclera, hearing loss, dentinogenesis imperfecta, hyperextensible joints, hernias and easy bruising. OI is dominantly inherited and results in >90% OI cases, caused by mutations in one of the two genes COL1A1 or COL1A2 coding for type I procollagen. The Lithuanian OI database comprises 147 case records covering the period of 1980 - 2001. Clinical and genealogical analysis of OI cases/families from Lithuania available for examination revealed 18 familial cases of OI type I and 22 sporadic cases: OI type II (3 cases), OI type III (11 cases) and OI type I (8 cases). As a result of their molecular genetic investigation, 11 mutations were identified in the COL1A1 gene in 13 unrelated patients. Of them, nine mutations (E500X, G481A, c.2046insCTCTCTAG, c.1668delT, c.1667insC, c.4337insC, IVS19+1G > A, IVS20-2A > G, IVS22-1G > T) appeared to be novel, i.e. not yet registered in the Human Type I and Type III Collagen Mutations Database (http://www.le.ac.uk/genetics/collagen).

Collagen↗

PubMed2005

Molecular findings in Brazilian patients with osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a genetic disorder of increased bone fragility and low bone mass. Severity varies widely, ranging from intrauterine fractures and perinatal lethality to very mild forms without fractures. Most patients with a clinical diagnosis of OI have a mutation in the COL1A1 or COL1A2 genes that encode the a chains of type I procollagen, the major protein in bones. Hence, the aim of the present study was to identify mutations in the COL1A1 gene in 13 unrelated Brazilian OI patients. This is the first molecular study of OI in Brazil. We found 6 mutations, 4 of them novel (c.1885delG, p.P239A, p.G592S, p.G649D) and 2 previously described (p.R237X and p.G382S). Thus, the findings show that there are no prevalent mutations in our sample, and that their distribution is similar to that reported by other authors, with preponderance of substitutions for glycine in the triple helix domain, causing OI types II, III and IV.

Brazil↗

PubMed1995

The bone cell biology of osteogenesis imperfecta.

Osteogenesis Imperfecta (OI) has been defined as a heritable connective tissue disorder with variable severity of clinical expression. OI is a type I collagen based disease. Consequently, much research has focused on identifying specific mutations in the pro-alpha (I) genes. Our interest in OI lies in the metabolism of the non-collagenous proteins (NCPs) of the bone matrix. Although type I collagen is the most abundant protein in bone extracellular matrix, it is the NCPs which bind to, modify and have the potential to regulate that collagen matrix. Our approach has been to determine the levels of the NCPs for both OI and age-matched controls. Most recently, we have utilized an in vitro human osteoblast system to study normal and OI NCP metabolism (Fedarko et al. J. Bone Min. Res. 7, 921-930, 1992). It is our hypothesis that the altered stoichiometry of collagen and NCPs is, in part, responsible for the phenotypic variation of the disease.

Animals↗

PubMed2005

Unexpected ultrastructral changes in bone osteiod collagens in osteogenesis imperfecta.

Osteogenesis Imperfecta (OI) is a heterogeneous, inherited bone disorder usually resulting from a defect in collagen synthesis or function. The Sillence classification recognises four OI subtypes of which type III is the severe, progressively deforming form. Here, we report distinctive ultrastructural abnormalities of bone osteoid collagen fibrils from three patients with OI type III and compared with normal controls. Collagen biochemistry of these patients showed normal alpha1(I) and alpha2(I) chains, despite the structurally abnormal collagen fibrils. The expected lamellar organisation of normal osteoid was absent in the bone biopsies of these patients. In addition their collagen fibrils had frayed edges and no periodicity was observed in most of these fibrils. These collagen fibrils were also flower like, twisted, spiralled and sparsely distributed throughout a very thick osteoid with patchy mineralisation. These structurally abnormal collagens may not be able to provide the nucleating and scaffolding sites for normal mineralisation and may lead to the bone fragility observed in OI.

Bone Density↗

PubMed2005

[Mutation detection of COL1A1 gene in a pedigree with osteogenesis imperfecta].

Osteogenesis imperfecta (OI) is heritable bone fragility,which is inherited as an autosomal dominant trait clinical presentation. Clinical symptom, in general, is dominantly inherited OI with blue sclerae, hearing loss and mild-moderate skeletal deformity. Genetic loci of OI have been mapped to17q21.31-q22 and 7q22.1, in which COL1A1 and COL1A2 are known to be the causal genes. In this work,we performed linkage analysis in a kindred with autosomal dominant hereditary OI. A tight linkage to the markers on chromosome 17q21.31-q22 (maximum two-point lod score: 9.31 at theta = .00) was observed. Sequence analysis of COL1A1 revealed a single-base mutation that converted the consensus sequence at the 5' end of intron 26 from GT to AT to form an abnormal splicing site leading to OI.

Adolescent↗

PubMed1993

Communicating hydrocephalus, basilar invagination, and other neurologic features in osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is anecdotally associated with macrocephaly, hydrocephalus, basilar invagination, and cerebral atrophy, but the frequency and the spectrum of neurologic features of this condition are poorly defined. We report our experience with 76 patients with OI seen at NIH. Neuroimaging studies demonstrated sulcal prominence and ventriculomegaly consistent with communicating hydrocephalus in 17 patients. Eight individuals with severe OI types displayed basilar invagination, causing brainstem compression in three patients. Head circumference growth showed abnormal kinetics with percentile crossing after fontanelle closure in 13 patients, and absolute macrocephaly was present in 11 patients. Additional neurologic complications included skull fracture (10 individuals); seizure disorders (five); transient, unexplained long tract signs (three); and spinal compression and pontine, cervical, and thoracic syringohydromyelia (one patient each). The clinically important neurologic complications appear to be brainstem compression from basilar invagination, skull fracture, and seizure disorders. Neurologic evaluation should be part of a team approach in the management of patients with severe OI types.

Adolescent↗

PubMedDate not supplied

A morphometric analysis of osteoid collagen fibril diameter in osteogenesis imperfecta.

Osteogenesis imperfecta is a genetic disorder of connective tissue characterised by frequent bone fracture following minimal trauma. Mutations of type I procollagen genes have been widely reported as the cause of OI and such mutations have been shown to introduce kinks into the collagen molecule. A study was performed to examine type I collagen fibrils at the ultrastructural level in the transmission electron microscope (TEM). Type I collagen fibrils from the bone osteoid of OI patients and age- and site-matched normal control bone were photographed in the electron microscope. A histomorphometric analysis of the diameters of collagen fibrils photographed in the TEM indicated that type I collagen in OI bone was larger in diameter compared with normal bone. This increase in diameter of type I collagen fibrils may represent an alteration in the quaternary structure of the collagen fibril as a consequence of kinked, poorly packed collagen molecules. Such alteration in the collagen fibrils may affect the formation and stability of bone mineral associated with it.

Adolescent↗

PubMed1996

An ultrastructural and immunogold localization study of proteoglycans associated with the osteocytes of fetal bone in osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a rare, heterogeneous, inherited connective tissue disorder frequently caused by abnormalities of type I collagen. It is characterized by bone fragility, osteopenia, and progressive skeletal deformities. Electron microscopy of three OI type II fetal bone samples revealed numerous large osteocyte lacunae. In addition, there was a perilacunar osteoid-like band of collagen surrounding the osteocytes, which was unmineralized and morphologically unusual. Furthermore, large osteocyte lacunae contained fine particles and filamentous material similar to the expected ultrastructural appearance of proteoglycans. More detailed examination was carried out using histochemical and immunogold localization of proteoglycans at light and ultrastructural levels. These tests and the use of electron probe X-ray microanalysis confirmed that the material in the osteocyte lacunae was proteoglycan. In contrast, in the age- and site-matched normal fetal bone, all the osteocyte lacunae appeared negative for proteoglycan. Proteoglycans are regarded as inhibitors of calcification. Our observation of substantial amounts of proteoglycan in abnormally enlarged osteocytic lacunae of some OI fetal bone suggests association with the abnormal bone of this particular subtype of OI type II.

Bone and Bones↗

PubMed1997

Recent progress in diagnosis and treatment of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is an inheritable disorder characterized by bone fragility with various symptoms of connective tissue disorders. OI is commonly classified by Sillence's classification into four types according to the clinical features. The cardinal symptom is pathologic fracture, which is often recognized before birth, is frequent during infancy and childhood, then decreases at puberty. Bone mineral density is markedly decreased in OI, especially of the lumbar spine. Bone deformities are frequently observed in the long bones of the extremities, and spinal deformities and compression fractures are also common. Growth retardation is extremely severe, especially in type III. Calcitonin has been the most common therapy for OI. Recently, bisphosphonates have been found to be potent drugs that increase bone mass in OI patients. To prevent further fracture or bone deformity, appropriate orthopedic managements, including intramedullary rodding, are critically important. Growth hormone is effective in stimulating bone growth during childhood. The pathogenesis of OI is quantitative or qualitative abnormalities of type I collagen. The clinical features of each type usually correspond to the type of mutation. Several possibilities for gene therapy have been proposed.

Adolescent↗

PubMed2001

Delivery of a hammerhead ribozyme specifically downregulates mutant type I collagen mRNA in a murine model of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a systemic heritable disorder of connective tissue, caused by a mutation in one of the genes for type I collagen, whose cardinal manifestation is bone fragility. Several studies have identified two molecular mechanisms of collagen type I defects. In chain exclusion, the mutant chain is not incorporated into the collagen triple helix, whereas in chain nonexclusion, it is. The dominant-negative effect of nonexcluded mutations must be taken into account in all strategies aimed at correcting the collagen defects in individuals affected with moderate or several OI. Herein, we describe the application of hammerhead ribozymes to selectively target the mutant minigene transcript expressed in a murine calvarial osteoblast cell line. Active and control inactive ribozymes were tested in vitro on both mutant and normal targets and in the minigene-expressing cell line. Active ribozyme cleaved its target with high efficiency and specificity in both a time-dependent and dose-dependent manner. After delivery of a ribozyme expression construct, intracellular ribozyme was detected, along with a relative reduction in mutant transcript level.

3T3 Cells↗

PubMed1996

Nuclear retention of COL1A1 messenger RNA identifies null alleles causing mild osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder characterized by bone fragility. Most cases of severe OI result from mutations in the coding region of the COL1A1 or COL1A2 genes yielding an abnormal collagen alpha chain. In contrast, many patients with mild OI show evidence of a null allele due to a premature stop mutation in the mutant RNA transcript. We have previously described a null allele arising from a splice donor mutation where the transcript containing the included intron was sequestered in the nucleus. Here we demonstrate that transcripts from null alleles arising from premature stop mutations are also present in the nucleus and absent in the cytoplasm. Using reverse transcriptase-PCR and single-strand conformational polymorphism of COL1A1 mRNA from patients with mild OI, we describe three patients with distinct null producing mutations identified from the mutant transcript within the nuclear compartment. A fourth patient with a Gly--->Arg expressed point mutation exhibits the mutant transcript in both compartments. Defining the distribution of allelic variants of COL1A1 mRNA in the nuclear and cytoplasmic compartments gives further insight into cell biology of OI and provides a strategy for investigating potential causes of a null allele.

Adult↗

PubMed2003

Modern approach to children with osteogenesis imperfecta.

Osteogenesis Imperfecta (OI) is characterized by bone fragility. At least seven discrete types have been described ranging from mild disease to a lethal form. In a large number of cases, mutations in one of the two genes encoding type I collagen have been found. In forms recently described (types V, VI, VII), such mutations have been excluded. In two other forms, (Bruck, and osteoporosis - pseudoglioma syndromes) defects in other proteins have been characterized. In OI, bone fragility stems from: decreased bone mass, disturbed organization of bone tissue, and altered bone geometry (size and shape). Histologic studies have shown that increased bone turnover is the rule in OI bone. This justifies using bisphosphonates in order to reduce osteoclast mediated bone resorption. Initial results are encouraging. Cyclical intravenous pamidronate administration reduces bone pain and fracture incidence, and increases bone density and level of ambulation, with minimal side effects. Effects on bone include increase in size of vertebral bodies and thickening of cortical bone. These results allow for more efficacious corrective surgery using intramedullary rodding of the long bones and paravertegral instrumentation. Specific occupational and physiotherapy programs are integral parts of the treatment protocol. This multidisciplinary approach will prevail until strategies aiming at the correction of the basic defect(s) will have come to fruition.

Biopsy, Needle↗

PubMed2004

Gene therapy approaches for osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a heterogeneous group of genetic disorders that affect connective tissue integrity. The hallmark of OI is bone fragility, although other manifestations, which include osteoporosis, dentigenesis imperfecta, blue sclera, easy bruising, joint laxity and scoliosis, are also common among OI patients. The severity of OI ranges from prenatal death to mild osteopenia without limb deformity. Most forms of OI result from mutations in the genes that encode either the proalpha1or proalpha2 polypeptide chains that comprise type I collagen molecules, the major structural protein of bone. Treatment depends mainly on the severity of the disease with the primary goal to minimize fractures and maximize function. Current treatments include surgical intervention with intramedullarly stabilization and the use of prostheses. Pharmacological agents have also been attempted with limited success with the exception of recent use of bisphosphonates, which have been to shown to have some effect. Since OI is a genetic disease, these agents are not expected to alter the course of the collagen mutations. Cell and gene therapies as potential treatments for OI are therefore currently being actively investigated. The design of gene therapies for OI is however complicated by the genetic heterogeneity of the disease and by the factor that most of the OI mutations are dominant negative where the mutant allele product interferes with the function of the normal allele. The present review will discuss the molecular changes seen in OI, the current treatment options and the gene therapy approaches being investigated as potential future treatments for OI.

Collagen Type I↗

PubMed1988

A cysteine for glycine substitution at position 1017 in an alpha 1(I) chain of type I collagen in a patient with mild dominantly inherited osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a heterogeneous group of inherited diseases of connective tissue manifested primarily by excessive fracturing of bone but associated with other abnormalities such as blue sclera, thin skin, herniae, ligamentous laxity, reduced stature and hearing loss. We report here molecular studies on a patient with the mild, dominantly inherited, variety of OI (OI type I) previously shown (Nicholls et al., 1984) to be heterozygous for an abnormal alpha 1(I) chain of type I collagen which contained cysteine near the carboxyl terminus (Steinmann et al., 1986). The cognate alpha 1(I) mRNA region was selected for generation of cDNAs which were subsequently amplified by the polymerase chain reaction (PCR), cloned and sequenced. Two sequences were obtained, one of which corresponded to the normal allele, and the other of which harbored a G to T transversion and resulted in a cysteine for glycine substitution. This is the first single amino acid substitution found in type I OI. Surprisingly, the mutation occurs just outside the triple-helical region of the alpha 1(I) chain, a result that accounts for the strikingly different phenotypic and molecular consequences of this mutation as compared with similar cysteine for glycine substitutions within the same region. The PCR appears to be a useful approach for elucidation of structural mutations in collagen chains.

Adolescent↗

PubMed1993

Defective splicing of mRNA from one COL1A1 allele of type I collagen in nondeforming (type I) osteogenesis imperfecta.

Osteogenesis imperfecta (OI) type I is the mildest form of heritable bone fragility resulting from mutations within the COL1A1 gene. We studied fibroblasts established from a child with OI type I and demonstrated underproduction of alpha 1 (I) collagen chains and alpha 1 (I) mRNA. Indirect RNase protection suggested two species of alpha 1 (I) mRNA, one of which was not collinear with fully spliced alpha 1 (I) mRNA. The noncollinear population was confined to the nuclear compartment of the cell, and contained the entire sequence of intron 26 and a G-->A transition in the first position of the intron donor site. The G-->A transition was also identified in the genomic DNA. The retained intron contained an in-frame stop codon and introduced an out-of-frame insertion within the collagen mRNA producing stop codons downstream of the insertion. These changes probably account for the failure of the mutant RNA to appear in the cytoplasm. Unlike other splice site mutations within collagen mRNA that resulted in exon skipping and a truncated but inframe RNA transcript, this mutation did not result in production of a defective collagen pro alpha 1 (I) chain. Instead, the mild nature of the disease in this case reflects failure to process the defective mRNA and thus the absence of a protein product from the mutant allele.

Adolescent↗