ALUND osteogenesis imperfecta rough draft

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1 Osteogenesis Imperfect Article Autumn Lund Grand Canyon University: BIO 457 – WF700 Professor Peientak April 2, 2023

2 Osteogenesis Imperfecta Osteogenesis imperfecta (OI) is an autosomal dominant inherited disease that affects connective tissue within the body by the abnormal synthesis or processing of type I collagen. There are 8 types of osteogenesis imperfecta, for this paper, types I and II will be discussed. Other types of the disease have symptoms that fall between the two that result in differing classification. This disease, depending on the type, can be seen before birth or after birth and is characterized by the susceptibility to bone fractures and the decreased bone density. In this article, a description of the disease, genetic and molecular basis of the disease, as well as the treatment and prognosis of the disease will be discussed (Subramanian & Viswanathan, 2020). Description Osteogenesis imperfecta was first documented by a Professor of Anatomy, Pathological Anatomy, and Zoology at the University of Amsterdam by the name of Willem Vrolik. He described this disease in his Handbook of Pathological Anatomy (1842-1844) about a newborn who had numerous fractures and had lived for three days (Baljet, 2002). This case described would later be reexamined and re-diagnosed as osteogenesis imperfects type II, due to the condition of the bones and the poor mineralization of them. Originally called Vrolik’s syndrome because of his discovery, it was later termed as Osteogenesis imperfecta and often called brittle bones disease in layman terms. Clinical forms of this disease are characterized into eight types; type I is the mildest and most common form of osteogenesis imperfecta and type II is the most severe form. The other six types have symptoms that fall between both of these two types, which then results in the

3 different types to be more precisely diagnosed (U.S. Department of Health and Human Services, 2022). As there are many types of osteogenesis imperfecta, the focus of the article will be around OI type I and OI type II. The OMIM number for osteogenesis imperfecta type I is 166200 (McKusick, 2023). The OMIM number for osteogenesis imperfecta type II is #166210 (McKusick, 2023). Osteogenesis imperfecta is an autosomal dominantly inherited disease characterized by the susceptibility of bone fractures and decreased bone density. Through many resources, the effects of osteogenesis in different regions, among different races, ages, and genders is no different. Osteogenesis imperfecta affects all genders, races, and ethnic groups equally and in the various types of osteogenesis imperfect, it occurs in approximately 1 of 15,000-20,000 births (Forlino et al., 2011). The signs of osteogenesis imperfecta can be seen from birth, sometimes even before birth. A possible exception to this would be the result of deafness, which is usually seen to occur near adulthood. For all people with osteogenesis imperfecta have weak or brittle bones and because of this, some people may only experience a few broken bones throughout their lives while others will experience hundreds of broken bones. Patients with osteogenesis imperfecta type I often have broken bones from mild to moderate trauma, with most of these breaks occurring before puberty (Marini et al., 2017). With osteogenesis imperfecta type I dealing with a lower type I collagen level, bone deformed are mild to none and their teeth strength and color may change as well. For patients with osteogenesis imperfeceta type II, the signs and symptoms are more severe and is more likely to be the cause of death at birth or shortly after. This is due to the inability to breathe because of the underdeveloped lungs and severe bone deformities. It is common for those with osteogenesis imperfecta type II to have numerous broken bones that

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4 develop before birth while they are still in the womb. These causes are due to a mutation within the collagen protein (Marom et al., 2020). Genetic Basis Osteogenesis imperfecta is a result of mutations in the genes involved in the production of type I collagen: COL1A1 and COL1A2. Type I collagen is the most common collagen protein in bone, skin, and connective tissues which provide strength and structure to the body (Marom et al., 2020). The structure of type I collagen is a triple helix which comprises of two alpha-I chains and one alpha-II chain. The COL1A1 gene (collagen type I alpha I chain) is located on the long arm of chromosome 17 in the 17q21.33 region. COL1A1 gene size is that of 51 exons which is the same as about 1464 amino acids. This gene is used to encode the pro-alpha I chains of type I collagen (U.S. National Library of Medicine, 2023). The COL1A2 gene (collagen type I alpha II chain) is located on chromosome 7 in the 7q21.3 region. COL1A2 gene size is 52 exons which are approximately 1366 amino acids. This gene encodes the pro-alpha II chain of type I collagen (U.S. National Library of Medicine, 2023). Mutations of the COL1A1 gene mostly result in a quantitative decrease in the amount of structurally normal type I collagen. Deletion mutation in the COL1A1 gene involves the deletion of segments of DNA from the gene and results in an abnormally shortened pro-alpha I chain. Most common is a missense mutation to the COL1A1 gene. The amino acid sequence is altered in the pro-alpha I chain, and is usually the replacement of the amino acid Glycine with that of a different one. Sometimes these substitutions result in an alteration to one end of the protein chain called C-propeptide (Marom et al., 2020). Deletion mutation in the COL1A2 gene involves the deletion of pieces of the gene resulting in a pro-alpha II chain that is missing critical regions.

5 Same as the COL1A1 gene, the COL1A2 gene can also have missense mutation which can alter one end of the protein chain (Marom et al., 2020). Osteogenesis imperfecta can be inherited as a dominant, recessive, or X0linked disorder, however, most often it is a dominant disease caused by pathogenic variants of either the COL1A1 gene or COL1A2 gene (Marom et al., 2020). The autosomal dominant inheritance pattern is where one copy of the altered gene is in each cell which is sufficient to cause osteogenesis imperfecta. Many who have osteogenesis imperfect type I inherit the mutation from a parent who has the disorder. Infants with a more severe type, osteogenesis imperfects type II, have no history of the condition within their families. In these cases, osteogenesis is caused by new mutations in the COL1A1 or COL1A2 genes (U.S. National Library of Medicine, 2019). Molecular Basis Overall, osteogenesis imperfecta (all types) occur due to a genetic mutation that affects the synthesis and/or processing of type I collagen protein. These changes to type I collagen then affect the bones, skin, and connective tissues of the affected individuals. For osteogenesis imperfecta types I and II, the two genes that have OI as an outcome are COL1A1 and COL1A2 which affect the protein called type I collagen. This is the main protein of focus because it makes up to 90% of the body’s collagen. It is found mostly in the skin, tendons, teeth, bones, ligaments, and between organs. Type I collagen is made up of two alpha-1 (I) chains encoded by COL1A1 and one alpha-2 (I) chain encoded by COL1A2. It is also densely packed and used to provide structure to the body (Gelse et al., 2003). Mutations of the COL1A1 gene are responsible for most osteogenesis imperfecta type I cases. These mutations reduce the production of pro-alpha I chains and with fewer pro-alpha I

6 chains available, cells are only able to make half the normal amount of type I collagen. Through a deletion mutation, the pro-alpha I chain is shortened and results in a delay in the formation of type I collagen. The most common mutation is the missense mutation where glycine is replaced by another amino acid. Glycine is the smallest amino acid which allows for the triple helix structure of type I collagen to be tightly wound and able to withstand stress. Through missense mutation of the COL1A1 gene, Glycine is replaced by a bulkier amino acid which then alters the collagens triple helix structure (Wu et al., 2022). C-propeptide frameshift mutation-dominant is a more severe mutation that results in both wild-type and mutant chains of collagen. Mutations of the COL1A2 gene are responsible for more severe types of osteogenesis imperfecta; OI type II. Through a deletion mutation, the pro-alpha2 I chain loses critical regions and this can then cause the formation of collagen to misfold and be unable to bind to their target proteins and/or be degraded more quickly (Wu et al., 2022). When Glycine is replaced, the structure of type I collagen is altered and in severe cases, a structurally abnormal collagen is found (Nuytinck et al., 2000). In cases where there is normally structured type I collagen, but less than the normal amount produced, many of the phenotypes of osteogenesis imperfecta type I can be explained. Due to the lower amount of type I collagen, the level found within bones is not as high as they should be and this results in the weaker or brittle bones that are more susceptible to fractures. The lower levels of type I collagen could also result in dentinogenesis imperfecta where the teeth may be discolored and weaker than normal. This allows them to be more susceptible to rapid wear, loss, and breakage to both baby and permanent teeth. In cases where there is improperly formed type I collagen, these abnormal forms make their way to the tissues and bones and result in severe forms of osteogenesis imperfects. This causes severe bone deformities in osteogenesis

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7 imperfect type II because the structure of type I collagen is not normal, but abnormal (Krishnamurthy et al., 2020). Treatment Diagnostic Diagnosing osteogenesis imperfecta (moderate/severe types) is most commonly done during a prenatal ultrasound at 18 to 24 weeks. This is mostly due to the fact that in severe cases of osteogenesis imperfecta, OI type II, some bones can already be broken and seen as well as bone deformities. If a parent or sibling has osteogenesis imperfecta, the provider can test the DNA of the fetus to see if there are any osteogenesis imperfecta mutations present. This can be done two ways, the first being amniocentesis. This is where a small amount of fluid from around the sac surrounding the fetus is taken by inserting a thin needle into the uterus through the abdomen. The second way would be by Chorionic villus sampling (CVS), which has a similar procedure to amniocentesis but instead of taking fluid, a sample of tissue from the placenta is taken. If osteogenesis imperfecta is not detected prenatally, it can be diagnosed postnatally through physical exams, medical history, and bone density tests. These tests and questions allow the providers a way to determine if osteogenesis imperfecta is a possibility (Forlino et al., 2011). Current Treatment In treating osteogenesis imperfecta, the main goals are to decrease fracture incidence, improve pain, and promote growth, mobility, and functional independence. Treatment of osteogenesis imperfecta is management of the symptoms which include orthopedics, rehabilitation medicine, and mental health. There is not a set treatment because many are still being studied. However, bisphosphonate therapy is the most common treatment in pediatric

8 patients with osteogenesis imperfecta. Bisphosphonates act by inhibiting osteoclast activity and bone resorption. They have been shown to consistently improve bone mineral density in those with osteogenesis imperfect and to some extent, they have also been able to reduce fracture incidence (Rossi et al.,). They are used for pediatric patients especially because during growth, they have shown a beneficial effect to reshaping the vertebrae what have compression fractures. Progress in Treatment Research Many treatments that are still in the works and being studied involve antibodies as well as hormones. Teriparatide, a PTH analogue, induces anabolism in bone and significantly increases the bone mineral density in adults with osteogenesis imperfecta type I, but not as effective in moderate to severe osteogenesis imperfecta types (Rossi et al., 2019). This treatment is limited to a 24-month period and is still being researched. Denosumab, an anti-RANL antibody, inhibits osteoclast differentiation and function is currently approved for treating osteoporosis and is being studied for osteogenesis imperfecta. It is similar to that of bisphosphonates where it acts on osteoclases to suppress bone resorption and treating with denosumab has shown improved bone mineral density in patients with osteogenesis imperfecta in a few studies (Rossi et al., 2019). Trials rising sclerostin inhibitory antibodies, an anabolic agent designed to target sclerostin (an inhibitor of bone formation), have been expanded to see the efficacy in a larger cohort of adult patients with osteogenesis imperfecta types I, III, and IV (Marom et al., 2020). Finally, progenitor cell therapy, a transplantation of healthy progenitor stem cells, has been proposed to address bone fragility in osteogenesis imperfecta specifically. The theory is that the healthy donor cells will differentiate into osteoblasts and that these osteoblasts will produce collagen. To date, cell therapy has been promising, but is still experimental and due to inconsistent results, ethical and safety concerns are still present (Rossi et al., 2019)

9 Prognosis The effects of osteogenesis imperfecta differ depending on the type of OI a person has. For those who have osteogenesis imperfecta type I, the effects are not severe, but with the decrease level of type I collagen, they are more susceptible to fractures and bruising. For those with osteogenesis type II, due to the abnormal type I collagen, they are more likely to have severe bone deformities which can be life threatening. Unlike osteogenesis type I, those with type II don’t have a decrease level of type I collagen, but an increase in an abnormal type I collagen which results in deformities. As mentioned in the treatment section, there is not exactly a treatment for osteogenesis imperfecta, but there are many ways to manage the symptoms. Overall quality of life for those who manage the symptoms is far greater than those who do not. Patients who have osteogenesis imperfecta type I can have a better quality of life when they maintain physical therapy and rehabilitation which allows them to promote motor development, increase endurance, relieve pain, gain independence, and assist in the recovery of surgical procedures. For those that do not maintain this regiment, they will have a poorer quality of life because of the pain and decreased motor development and use (Steiner & Basel, 2021). This is especially the case for those who have osteogenesis imperfecta type II. Type II is more severe and results in severe bone deformities which need to be surgically moved and trained. With that, there are more surgeries and need to keep up with physical therapy and rehabilitation. Osteogenesis imperfecta is the type of disease that does not affect fertility. With or without treatment, those with osteogenesis imperfecta can still reproduce. One restraint for reproductivity could result in the decrease motor development but besides that aspect, there is nothing holding back those with osteogenesis imperfecta from reproducing.

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10 The life expectancy of someone with osteogenesis imperfecta depends highly on the type they have. Those with moderate type I see no chance in their life expectancy while those with severe type II have a different story. Osteogenesis imperfecta type II babies are born with multiple broken bones and small rib cage with underdeveloped lungs usually die soon after birth (Deguchi et al., 2021). OI continues to trouble those in the medical field as well as plague patients with severe types of OI. Severe types that often result in the end of their lives within the first month or two after birth. Medical professionals are still in search of a true treatment for those with OI and not just management of their symptoms. Although cell therapy is promising, there are many bridges that still need to be crossed in hope of it becoming a true treatment. Research and more development hopefully come in hope of finding ways to save those who suffer from sever OI.

11 References Baljet B. (2002). Aspects of the history of osteogenesis imperfecta (Vrolik's syndrome). Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft , 184 (1), 1–7. https://doi.org/10.1016/S0940-9602(02)80023-1 Deguchi, M., Tsuji, S., Katsura, D., Kasahara, K., Kimura, F., & Murakami, T. (2021). Current Overview of Osteogenesis Imperfecta. Medicina (Kaunas, Lithuania) , 57 (5), 464. https://doi.org/10.3390/medicina57050464 Forlino, A., Cabral, W. A., Barnes, A. M., & Marini, J. C. (2011). New perspectives on osteogenesis imperfecta. Nature reviews. Endocrinology , 7 (9), 540–557. https://doi.org/10.1038/nrendo.2011.81 Gelse, K., Pöschl, E., & Aigner, T. (2003). Collagens--structure, function, and biosynthesis. Advanced drug delivery reviews , 55 (12), 1531–1546. https://doi.org/10.1016/j.addr.2003.08.002 Krishnamurthy, N. H., Chikkanarasaiah, N., Nanjappa, A., & Vathariparambath, N. (2020). Fragile and Brittle Bone Disease or Osteogenesis Imperfecta: A Case Report. International journal of clinical pediatric dentistry , 13 (4), 425–428. https://doi.org/10.5005/jp-journals-10005-1792 Marini, J. C., Forlino, A., Bächinger, H. P., Bishop, N. J., Byers, P. H., Paepe, A., Fassier, F., Fratzl-Zelman, N., Kozloff, K. M., Krakow, D., Montpetit, K., & Semler, O. (2017).

12 Osteogenesis imperfecta. Nature reviews. Disease primers , 3 , 17052. https://doi.org/10.1038/nrdp.2017.52 Marom, R., Rabenhorst, B. M., & Morello, R. (2020). Osteogenesis imperfecta: an update on clinical features and therapies. European journal of endocrinology , 183 (4), R95–R106. https://doi.org/10.1530/EJE-20-0299 McKusick, V. (2023). Entry - #166200 – osteogenesis imperfecta, type I; oi1 – OMIM. https://omim.org/entry/166200 McKusick, V. (2023). Entry - #166210 – osteogenesis imperfecta, type II; oi2 – OMIM. https://omim.org/entry/166210 Nuytinck, L., Tükel, T., Kayserili, H., Apak, M. Y., & De Paepe, A. (2000). Glycine to tryptophan substitution in type I collagen in a patient with OI type III: a unique collagen mutation. Journal of medical genetics , 37 (5), 371–375. https://doi.org/10.1136/jmg.37.5.371 Rossi, V., Lee, B., & Marom, R. (2019). Osteogenesis imperfecta: advancements in genetics and treatment. Current opinion in pediatrics , 31 (6), 708–715. https://doi.org/10.1097/MOP.0000000000000813 Subramanian, S., & Viswanathan, V. K. (2022). Osteogenesis Imperfecta. In StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Steiner, R., Basel, D., (2021). COL1A1/2 Osteogenesis Imperfecta – GeneReviews® - NCBI

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13 Bookshelf. National Library of Medicine. PMID: 20301472 U.S. Department of Health and Human Services. (2022). Osteogenesis imperfecta . National Institute of Arthritis and Musculoskeletal and Skin Diseases. https://www.niams.nih.gov/health-topics/osteogenesis-imperfecta U.S. National Library of Medicine. (2019). COL1A1 gene . MedlinePlus. https://medlineplus.gov/genetics/gene/col1a1/#conditions U.S. National Library of Medicine. (2023). COL1A1 collagen type I alpha 1 chain [Homo Sapiens (human)] - gene - NCBI . National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/gene/1277 U.S. National Library of Medicine. (2023). COL1A2 collagen type I alpha 2 chain [Homo Sapiens (human)] - gene - NCBI . National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/gene/1278 Wu M, Cronin K, Crane JS. (2022). Biochemistry, Collagen Synthesis. In StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing.

ALUND osteogenesis imperfecta rough draft

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