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Osteogenesis imperfecta (OI), also known as Brittle Bone Disease, is a heritable disorder of connective tissue. Its hallmark feature is bone fragility, with a tendency to fracture from minimal trauma or from the work of bearing weight against gravity. In the more severe forms of the disorder, the bones are deformed as well as fragile. Most individuals with OI have significant physical handicaps. Affected persons also exhibit an array of associated features, including short stature, macrocephaly, blue sclerae, dentinogenesis imperfecta, hearing loss and neurological and pulmonary complications. There is no preferential distribution of osteogenesis imperfecta by gender, race, or ethnic group.

Osteogenesis imperfecta is a paradigm for the clinical management and genetic analysis of a dominant disorder of a structural protein. OI developed as a paradigm for a dominant disorder of structural protein because it is not rare and its etiology of type I collagen defects has been known for about two decades. The incidence of forms of OI recognizable at birth is 1/16-20,000, with about equal incidence of mild forms that are not recognizable until later in life. (1) OI and Marfan's Syndrome share the distinction of being the most common heritable connective tissue disorders.

CLINICAL CLASSIFICATION AND PHENOTYPE

David Sillence formulated the classification currently in common use for osteogenesis imperfecta in 1979. (2) Since type I collagen defects were not known to cause OI at that time, the Sillence Classification is an artificial grouping based on clinical and radiographic features. The clinical spectrum of OI ranges from perinatal lethal to a mild form that can present in middle aged adults as premature osteoporosis. All types of OI have autosomal dominant inheritance. (3) Some severe cases were thought to be autosomal recessive at the time the Sillence Classification was formulated, but are now known to be autosomal dominant with parental mosaicism (See Parental Mosaicism, below). Autosomal recessive cases with type I collagen defects are possible, although quite rare. There have been three documented cases, one of which is quite similar to the oim murine model for OI.

Type II OI is the perinatal lethal form. Infants may be stillborn; if they survive birth, they usually die in the first two months of life. (4) Some infants with type II OI may live for as long as a year, but eventually do succumb to multiple pneumonias or respiratory insufficiency. The limbs, especially the legs, are short with severe bowing deformities. Most often the legs are abducted into the classic "frog leg position". The cranium is relatively large for the trunk and is very poorly ossified. The anterior fontanelle is large, and often extends frontally to forehead and laterally along the sagittal suture. The posterior fontanelle is often open as well. The presence of two enlarged fontanelles frequently results in ossification only along the lateral plates and for a fingertip breadth at the crown. The infants tend to have flat triangular facies with a small beaked nose and dark blue-gray sclerae. The thorax is usually deformed with a narrow apex. Radiographic examination reveals multiple in utero fractures in various stages of healing. There may be beads of callus on the ribs, which are quite gracile. The long bones are very osteoporotic with minimal to no cortex. Upper extremity long bone morphology is better than that of the lower extremities. The lower long bones are crumpled as well as fractured and are abnormally modeled, with a cylindrical shape. Thus, the defect in type I collagen affects the development as well as the mineralization of the skeleton.

Type III OI, also known as the Progressive Deforming type (1), is the most severe form of OI compatible with survival beyond infancy and is severely handicapping. Individuals with type III OI can have a full life span, however, a significant proportion succumb to respiratory or neurological complications, either during childhood or in early to middle adult years. The long bones of individuals with type III OI are soft as well as fragile and can have bowing deformities of 70-90°, caused either by the tension of normal muscle on the bone, or from angulated healing of fractures. Long bones have a cylindrical shape with more modeling of the metaphysis than in type II; by late childhood there is often exaggerated metaphyseal flaring accompanied by a slender diaphysis. (5) Fractures can occur from activities of daily living; there may be hundreds of fractures in a lifetime. DEXA z-scores are in the range of -5 to -7 SD. Body proportions are better preserved than in type II OI, with less shortening of the extremities relative to the trunk. The calvarium is almost always relatively macrocephalic for the body and frequently measures greater than 95% for age, though occasionally children will have a normal or smaller than average HC for age. The midface is flat with frontal bossing. Children with type III OI almost always develop chest wall abnormalities; pectus carinatum is more frequent and less detrimental to pulmonary status than pectus excavatum. Virtually all children with OI type III will also develop significant scolisis. Without aggressive intervention, these individuals will be wheelchair bound.

Type IV OI is the moderately severe type. The skeletons of these individuals are brittle, not soft. On average, people with type IV OI have dozens of fractures. Most fractures occur either prior to puberty or beyond middle age, with the intervening years relatively protected by sex steroids. Individuals are significantly osteoporotic, with DEXA z-scores in the range of -3 to -5 SD. With medical intervention these individuals can expect to be community ambulators and have an essentially normal life span. Body proportions approach normal, although the legs are still short for the trunk and the cranium is relatively macrocephalic. Individuals are divided into types A and B by the Sillence classification, based on the presence or absence of dentinogenesis imperfecta. (6) Vertebral compressions in childhood and laxity of paraspinal muscles may lead to significant scoliosis.

In conjunction with discussion of type IV OI, it is appropriate to consider the recent proposals for types V and VI OI. Although these types continue the numerical system of the Sillence classification, they have a different basis. These individuals fall within the phenotypic range of type IV OI, as defined by the Sillence classification, but are primarily distinguished from patients with type IV OI by iliac crest histomorphometry. In type V, the distinctive histology is irregular arrangement or a meshlike appearance of the lamellae. Patients also have hypertrophic callus, dense metaphyseal bands and ossification of the interosseus membranes of the forearm. Though individuals initially were distinguished on histologic grounds, the presence of unique phenotypic features suggests that this may be a distinct subgroup within the current OI classification. The type I collagen protein of these patients has normal electrophoretic mobility, and no mutations have been detected at the gene level. (7) Therefore, the cause of type V OI may be defects in a molecule other than type I collagen. The proposed type VI OI is distinguished solely on histology criteria. (8) Since it has no distinctive phenotype within the OI spectrum, it may be premature to split these patients off from type IV OI.

Patients with type I OI have a distinctly milder form of the disease, which is generally not detectable at birth. Patients with type I OI tend to present with early osteoporosis; DEXA z-scores range from -1 to -3. Patients may have their first fracture in the pre-school years, for example when attaining ambulation. They may also have a series of fractures in the pre-pubertal years due to mild trauma. Fractures generally decrease dramatically in the post-pubertal years. Patients with type I OI have normally modeled bone and may have mild bowing of long bones and minimal central vertebral compressions. They are often a few inches shorter than same gender relatives. Leg length may be disproportionately short. Like type IV, type I is divided into A and B subtypes based on the presence or absence of dentinogenesis imperfecta. (6) Blue scleral hue is a defining feature in the Sillence classification, though in actuality it may be present or absent. These patients are expected to be spontaneous ambulators, but may have some mild delay of gross motor skills. They can be expected to have a full life span, limited only by greater vulnerability to accidental trauma.

SECONDARY FEATURES OF OI

Scleral hue

Scleral hue is a defining feature of the Sillence classification, with blue sclerae in type I OI, white sclerae in type IV. This resulted in the grouping of children with inconsistent skeletal features. We consider scleral hue a secondary, not a defining, feature. Most people with type I OI have blue sclerae, but some will have white sclerae. Many persons with types III and IV OI will have blue sclerae.
The bluish tinge may result from decreased scleral thickness. (9) However, it can also occur with normal thickness. In this case, tissues with different proteoglycan compositions, and therefore different hydration, may cause the blue tinge by their reflection of wavelengths of color.

Growth

Short stature is the most prevalent secondary feature of OI. Children with types III and IV OI fall off normal growth curves by one year of age, entering a plateau phase with flat or slow growth which lasts until age 4-5 years. After age five years, children with type IV OI often grow either parallel to the normal growth curve or with a moderately decreased slope. However, they cannot make up for the loss of height incurred during the plateau phase, so final stature approximates that of an early teenager. Children with type III OI have increased growth rates after the plateau phase, but the slope is always less than that of the normal curve. Final adult stature is typically in the range of a prepubertal child and can be that of a 5-7 yr old. (10) Individuals with type I OI grow parallel to the normal growth curve and final height is usually a few inches shorter than same gender relatives.
The cause of short stature in OI is not clear, since OI is an osteodystrophy rather than a chondrodystrophy. Short stature is not caused by fractures or premature closure of growth plates. It may be related to cell-matrix signaling, but further specifics remain elusive.

Hearing Loss

A majority of adults with osteogenesis imperfecta have functionally significant hearing loss related to combined conductive and sensorineural deficits. (11) In most cases, deficits are detectable only on audiology examination in childhood and the teen years; functional loss does not occur until the twenties. A study of hearing loss in Finnish children with OI reported an incidence of 6.7% with loss greater than 20 dB (12); this is comparable to the 7.7% detected in the NIH pediatric OI population. (personal experience) Most pediatric hearing loss is detected between ages 5-9 years; some children may require hearing aids. For adults, the hearing deficits are very similar to those found in otosclerosis. Surgical intervention with stapedectomy can give satisfactory long-term results when hearing loss exceeds the compensation of hearing aids. However, this surgery should not be undertaken routinely. The fragility of the small bones of the ear results in a significant percentage of unsatisfactory long term hearing restoration, even in experienced hands. (13)

Pulmonary Complications

Cardiopulmonary complications of osteogenesis imperfecta are the major cause of mortality directly related to the disorder. Infants with type II OI die of respiratory insufficiency or pneumonias. Children with type III OI develop vertebral collapse and kyphoscoliosis, which contribute to restrictive lung disease. These skeletal features, as well as the inactivity associated with wheelchair mobility, predispose them to multiple pneumonias. Lung disease may progress to cor pulmonale in middle age. Pulmonary function should be evaluated every few years, starting in childhood, for early management with bronchodilators. The need for chronic oxygen may arise as early as adolescence but most frequently occurs in the forties and fifties.

Neurological Complications

Osteogenesis imperfecta is frequently associated with either relative or absolute macrocephaly. Between ages 2-3 years, the child's head circumference may rapidly cross percentile lines for age. Prominence of sulci and ventriculomegaly are not associated with intellectual deficit. There is a high frequency of basilar invagination (BI) in patients with severe osteogenesis imperfecta. BI generally progresses slowly in childhood; radiologic evidence for BI may be present for years before symptoms are present. Children should be screened by CT every 2-3 yrs, and followed annually by MRI if radiographic signs of BI develop. Favorable outcomes have been obtained by delaying surgical intervention until the patient experiences severe headaches as well as long tract signs. As patients become symptomatic they should be followed in centers (University of Iowa, Johns Hopkins) with experience in performing suboccipital craniectomy with occipitocervical fusion in OI patients. (14)

DIAGNOSTIC WORK-UP AND DIFFERENTIAL DIAGNOSIS

Crucial elements of the diagnostic work-up focus on the skeletal system. The physical exam includes measurements of length and head circumference, as well as notations on body proportions, including upper segment:lower segment ratio and arm span. In addition, the segmental lengths of each limb are measured to detect asymmetry. Individuals with OI frequently have relatively long arm span for length and a shortened lower segment (pubis to floor). Sclerae may be blue or blue-gray and teeth may have dentinogenesis imperfecta, with opalescent or yellow-brown enamel. In the thorax, the spine should be examined for scoliosis and the rib cage for flare and/or pectus carinatum or excavatum. In an infant, the size of the fontanelles should be noted. Also essential is a careful family pedigree, with inquiries about fractures, hearing loss, dentinogenesis imperfecta and adult height.

Radiographic examination consists of a selective skeletal survey. AP and lateral views of the long bones are examined for significant osteoporosis, bowing, healing fractures, metaphyseal flare and the sharpness of the growth plate. AP and lateral views of the spine are examined for scoliosis, vertebral compressions, and sharpness of the vertebral endplates. A lateral view of the skull should also be obtained to detect wormian bones.

It is essential to obtain a DEXA of the lumbar vertebral bodies for a relatively quantitative assessment of the individual's osteoporosis. Since the bone matrix in types II, III, and IV OI is qualitatively abnormal, the DEXA z-score reflects the structural arrangement of the mineral as well as the quantity and therefore is not a straightforward quantitative measurement.

Differential diagnosis varies with the severity of OI and age of the patient. On prenatal ultrasound, severe OI may be confused with thanatophoric dysplasia, achondrogenesis type I, or campomelic dysplasia, all of which demonstrate relatively large heads and short limbs. Type III OI may need to be distinguished from infantile hypophosphatasia, which presents with severe osteoporosis and micromelia. Hypophosphatasia results in low serum alkaline phosphatase and increased inorganic pyrophosphate, while in OI, serum alkaline phosphatase is normal or increased. Type IV and more severe type I OI may be confused with primary juvenile osteoporosis or other secondary causes of osteoporosis in childhood, such as hypogonadism of malignancy. Some cases may require collagen studies or bone histology to make a definitive diagnosis. The major differential diagnosis with type I OI is child abuse. Collagen studies can complement decreased BMD and other skeletal features of OI, as necessary.

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COLLAGEN MUTATIONS AND GENOTYPE-PHENOTYPE CORRELATION

The full phenotypic range of OI is caused by mutations in the two chains that comprise type I collagen, the major protein of the extracellular matrix of bone, skin and tendon. (3) It is a heterotrimer composed of two copies of the a1 chain, encoded by the COL1A1 gene on chromosome 17, and one copy of the a2 chain, encoded by COL1A2 on chromosome 7. The two alpha chains are similar in sequence organization; they are composed of 338 uninterrupted repeats of the sequence Gly-X-Y, where gly is glycine, X is often proline and Y is often hydroxyproline. A glycine residue in every third position along the chain is crucial for helix formation; glycine's small size allows it to be tucked into the sterically constricted internal aspect of the helix. The collagen genes are organized with each exon coding for the helical region beginning with a glycine codon and ending with codon for a Y position; therefore the skipping of a helical exon does not cause a frameshift in the collagen transcript.

Over 250 mutations in both chains of type I collagen have been described in OI patients. One general correlation between genotype and phenotype has emerged. Type I OI, the mild form, is caused by quantitative defects in collagen. Only half the normal amount of collagen is produced but all the collagen produced is structurally normal. This is almost always due to a null allele of COL1A1. (15) On the other hand, types II, III and IV OI, the clinically significant forms, are caused by structural defects in either of the type I collagen chains. About 85% of these structural mutations cause the substitution of another amino acid, with a charged, polar or bulky side chain, for one of the obligatory glycine residues occurring in every third position along the chain. Glycine substitution mutations temporarily block helix formation and cause overmodification (glycosylation) of the chains of the trimer. About 12% of structural mutations are single exon skipping defects, which are incorporated into the trimer because the frame of the transcript remains intact. (16) Essentially all OI-causing mutations are dominant negative mutations. They exert their effects by being secreted and incorporated into the matrix, causing a weakened higher order structure.

For structural mutations of type I collagen, the relationship between genotype and phenotype has been elusive. A lethal mutation is more likely to be located in the a1 chain, in which about half of known glycine substitutions cause lethal OI, than in the a2 chain, in which only 1/3 are lethal. Nonetheless, both chains contain substantial numbers of mutations causing the full range of the OI phenotype. The two chains have different patterns of lethal and non-lethal mutations along the helical region, supporting different roles for the two chains in matrix. Lethal and non-lethal clusters alternate along the a2(I) chain. The clusters are quite evenly spaced, suggesting that they may play a role in regularly repeating interactions of collagen with non-collagenous matrix molecules. This Regional Model empirically predicts the lethality of 92% of mutations along the a2(I) chain, but binding data supporting the functional role of the regions has yet to be presented. In the a1(I) chain, the mutations may disrupt the stability of the collagen helix itself. (17)

The phenotype-genotype relationship in OI is complicated by multiple examples of variable expression. Individuals with the same genotype have a different phenotype, an interesting feature of many dominant disorders. In the a1(I) chain, there are currently about 10 (18, 19) examples of extreme variable expression of the same mutation; these glycine substitutions are found in both lethal and non-lethal forms of OI. A more frequent occurrence in both chains is substantial variation in severity between family members or unrelated individuals with the same mutation. For example, phenotype can range from type III to IV OI. One explanation for this interesting feature may be the existence of discrete modifying genes. Understanding modifying factors may provide new approaches to treatment.

Recently generated mouse models will shed new light on the pathophysiology of OI as well as on modifying factors. The brittle mouse (Brtl) is a knock-in model for type IV OI. (20) It contains a classic glycine substitution at a1(I)G349C, which causes dominant negative OI. The Brtl mouse reproduces the phenotype, histology, biochemistry and biomechanics of the disorder. It also has variable phenotypic expression, which may lead to an understanding of modifying factors. In addition, there is a naturally occurring mouse model for type III OI, the oim mouse. (21) This mouse is atypical of OI in that it has recessive inheritance. The collagen defect is a mutation in the a2(I) chain that prevents incorporation into heterotrimer and leads to the production of an a1(I) homotrimer.

GENETIC COUNSELING AND RATIONALE FOR COLLAGEN STUDIES

Approximately 90% of the collagen mutations that cause OI occur de novo. The parents of a child with a de novo mutation are at no increased risk of recurrence compared to the general population. Affected offspring will have a 50% risk of transmission of OI to their children.

Parental Mosaicism

In some families, clinically unaffected parents will have more than one child with dominant OI. This occurs because one parent is a mosaic carrier of the mutation. Presumably, the mutation occurred during the parent's fetal development; that parent then has both a normal and a mutant cell population. The proportion of mutant cells and their distribution in somatic and germline tissues depends on the timing of the mutation and the distribution of cells arising from the first mutant cell. (22) The frequency of occurrence of mosaic parents is relatively high in OI. Empirically, 5-10% of unaffected couples whose child has OI will be at risk of recurrence. For those couples in which one member is a mosaic carrier the recurrence risk may be as high as 50%, equivalent to the fully heterozygous state. To date, all mosaic parents have been detectable by examination of leukocyte DNA for the mutation present in their child. The mutation may also be detectable in skin cell, hair bulb and germ cells.

Prenatal Diagnosis

For the first case of moderate to severe OI in a family, prenatal diagnosis will probably occur during ultrasound at 18 to 24 weeks' gestation. (23) Detecting recurrence of OI prenatally is easiest if the exact collagen mutation in the affected child is known. In that case, a potential mutation in the current pregnancy can be detected early and with confidence. Cultured CVS cells can be used for DNA or RNA extraction and detection by either PCR and restriction enzyme digestion or sequencing. CVS can also be used for biochemical analysis if the known mutation causes significant collagen protein overmodification. (22) Amniocentesis is only appropriate for molecular diagnosis via RNA or DNA analysis. Biochemical analysis of amniocytes is complicated by the overproduction of a1(I) chains; the excess chains form homotrimers, which are overmodified and co-migrate with overmodified heterotrimers, potentially causing a false-positive test result. (22)

Collagen analysis is also useful when the diagnosis is equivocal. A positive collagen study can counteract charges of child abuse in mild cases, although the absence of a positive study still leaves a 5-10% chance of a false negative. A positive collagen analysis can also settle subtle distinctions between type IV OI and idiopathic juvenile osteoporosis.

From a research standpoint, each new collagen mutation delineated in OI provides information about genotype-phenotype relationships either directly or by making the cells containing that particular mutation available for studies of mechanism at the level of bone matrix. Further, mutations may vary in response to different therapeutic approaches. Determination of mutations that cause OI may allow investigators to understand which drugs or therapies will be helpful for different individuals.

THERAPEUTIC APPROACHES

Conventional

Conventional management of osteogenesis imperfecta involves intensive physical rehabilitation, supplemented with orthopedic intervention as needed. Many parents and physicians place undue importance on the number of fractures sustained by children with OI. Fracture number may not be as important in judging the severity of the disorder as the degree of trauma needed to cause a fracture. In general, children with type III OI sustain fractures from more trivial trauma than those with type IV OI. In addition, they tend to have more fractures in arms and ribs than occur in type IV. Fractures, in addition to long bone deformity, can lead to significant physical handicap.

The goal of physical rehabilitation for children with OI is to promote and maintain optimal functioning in all aspects of life. This is best accomplished by a program combining early intervention, muscle strengthening and aerobic conditioning. Early intervention should include correct positioning of the infant. Proper head support to help avoid torticollis and neutral alignment of the femora are essential. (24) Custom molded seats can help with lower extremity alignment as well as head and spine positioning. (24) Gross motor skills are delayed in OI, mostly because of muscle weakness. This can be addressed with isotonic strengthening exercises of the deltoids and biceps in the upper extremity and the gluteus maximus and medius and trunk extensors in the lower extremity. Strengthening of these muscle groups will ensure that children are able to lift their limbs against gravity and transfer independently. (25)

In patients with potential, protected ambulation should be initiated as early as possible. This may require a combination of bracing, surgical correction and physical therapy. Long leg braces provide support for weak muscles, control joint alignment and improve upright balance. Stabilizing the pelvic girdle and controlling the knees helps facilitate independent movement. Braces do not provide protection per se against fractures. Instead, bracing support promotes increased independent activity that may actually put the child at risk of incurring additional fractures. However, the advantages of increased independence and higher functional level tend to outweigh any increased fracture risk.

Individuals with OI should be under the care of an orthopedic surgeon with experience in the management of this disorder. Fractures should be evaluated with standard x-rays and should be managed with reduction and realignment, as needed, to prevent loss of function. Cast immobilization should be monitored to minimize any worsening of osteoporosis and muscle weakness. The decision to intervene surgically must take into account functional as well as skeletal status. Appropriate goals for surgery are to correct bowing to enhance ambulation potential and to interrupt a cycle of fracturing and refracturing. The classical surgical procedure was developed by Sofield and Millar, with multiple osteotomies, realignment of the long bone sections and fixation with intramedullary rods. Indications for this procedure include long bone angulation of greater than 40°, functional valgus or varus deformity which interferes with gait, or more than two fractures in the same bone in a 6-month period. Both elongating (Bailey-Dubow) and non-elongating (Rush) rods are currently used for intramedullary fixation. Elongating rods have the advantage of extension with growth, but have a high rate of migration from OI bone. (26) Rush rods have less migration potential but need revision as the child outgrows them. In general, intramedullary rods induce significant cortical atrophy through mechanical unloading, especially in the diaphysis. The least stiff and smallest diameter rod possible should be utilized.

Significant scoliosis is a feature of most type III and some type IV OI. Severe scoliosis does not correlate with number of collapsed vertebrae; however, it may be related to ligamentous laxity. Since resultant thoracic deformities can lead to pulmonary compromise, routine attention to the OI spine is warranted. (27) Scoliosis in OI does not respond to management with Milwaukee bracing. Spinal fusion with Harrington rod placement can provide stabilization and some correction to prevent pulmonary complications, but will not fully correct the curve. For best results, corrective surgery should occur when the curvature is less than 60°.

Pharmacological Therapy

Recently, the potential of bisphosphonate treatment has caused great excitement in the OI patient community. These drugs are synthetic analogs of pyrophosphate; their mechanism of action involves the inhibition of bone resorption. Bisphosphonates are deposited on the bone surface and are ingested by osteoclasts, inducing apoptosis. Because they inhibit bone resorption, these drugs have been used to treat malignancies with bony metastases. In this context, their ability to decrease bone pain has been notable. There is also extensive experience with these compounds in treatment of post-menopausal osteoporosis. Only limited knowledge about treatment of patients with structurally abnormal bone matrix has been gathered.

When used in patients with OI, bisphosphonates would presumably not affect the deposition of abnormal collagen into matrix. Thus, patients might have quantitatively more bone after treatment, but it would not be more structurally normal than before drug administration. Uncontrolled studies of pamidronate use in children and teenagers (28) and infants (29) with OI have been published. These studies reported increased BMD and vertebral height, as well as decreased fractures, less bone pain, and improved ambulation status. Anecdotal use of the drug has been widely associated with decreased bone pain, especially in the spine, and increased endurance. Controlled trials are essential to determine if increased bone density is associated with stronger bone, or if increased density correlates with increased brittleness. Also, these compounds may be helpful for the trabecular bone of the vertebral bodies, but not beneficial to the cortical bone of long bones.

The use of growth hormone to ameliorate the cardinal feature of short stature in types III and IV OI is still under active investigation. Approximately half of the children studied to this point have achieved a sustained increase in linear growth of 50% or more over baseline growth rate. (personal experience) Most responders (about 70%) had moderate type IV OI, and higher baseline PICP values. In addition, responders had increased bone formation and density. Trials of growth hormone in children with severe OI and short stature are therefore warranted in an effort to increase final adult stature.

Gene therapy

Gene therapy of a dominant negative disorder such as osteogenesis imperfecta will not be amenable to the replacement approach being employed for recessive enzyme disorders. Dominant negative disorders are disorders of commission; the mutant protein is synthesized, secreted from the cell and incorporated into matrix, where it actively participates in weakening the structure.

Two potential approaches to gene therapy in OI are indicated by nature's lessons. The first example is type I OI, in which individuals have a null allele, make half the normal amount of collagen, and have very mild disease. Approaches attempting to suppress expression of mutant collagen are modeled on this example. If expression of the mutant allele can be specifically suppressed, for example, by hammerhead ribozymes, the recipient will be biochemically transformed from type II, III or IV OI into type I. (30)

The second natural example is that of mosaic carriers, who have a substantial proportion of cells heterozygous for the collagen mutation but are clinically normal. They demonstrate that the presence of a substantial burden of mutant cells is possible before reaching the threshold of clinical disease. Approaches aimed at cell replacement by donated bone cell progenitors are modeled on this example. (31) Engraftment of only 1-2% of mesenchymal stem cells has been demonstrated after bone marrow transplant; therefore, this approach remains highly experimental.