复旦大学：《医学遗传学 Medical Genetics》课程教学资源（学习报告）Fibrodysplasia_Ossificans_Progressiva_Review_Samantha_He.doc_大学文库

Fibrodysplasia Ossificans Progressiva: The present and future of understand ing and treatment Samantha He January 15, 2009 Med ical Genetics. Prof. liu MBBS, Fudan University ABSTRACT Fibrodysplasia ossificans progressiva(FOP)is a disabling d isease that is caused by episod ic heterotopic ossification(HO)and advances in a pattern similar to embryonic development. The molecular pathway that causes the disease has been identified to involve bone morphogenic proteins and the associated activin type I receptor. A heterozygous point mutation in the type 1 receptor of FoP patients has been identified Currently there are no specific treatments to prevent or reduce HO growth, although experimental drugs were tested with favorable results, such the signal transduction inhibitor LD-193189. However, the battle against FOP is far from over as there are still questions related to FoP disease progression that remains unanswered INTRODUCTION One of the most catastrophic cond itions known to man kind, fibrodysplasia ossificans progressiva(FOP)has been a puzzle to doctors and researchers since the first recorded description some 250 years ago by John Ferke [41 below. The disease is characterized by heterotopic ossification(HO) of muscles, connective tissue, joints, aponeuroses, ligaments and fascia[4]. Although the bone morphogenic protein(BMP) pathway was identified, the genetics of the disease remained a mystery. In 2006,a heterozygous point mutation in FOP patients was found in several stud ies done in different countries. This mutation causes the activin type I receptor(ACVRI) to be constitutively active [6, 7]. Knowing the genetic makeup of the disease is important for an early diagnosis, espec ially for FoP because the misd iagnosis rates can be as high as 90%[5]. Although the genetic advancements are to be applauded, there are still many mysteries that remain unsolved regarding FOP CLINICAL FEATURES FOP has one of the highest misd iagnosis rates. The reason is the rarity of the disease and how the disease progresses. A FOP patient will look normal upon birth, except for malformed big toes that most doctors without prior experience with FOP

Fibrodysplasia Ossificans Progressiva: The present and future of understanding and treatment Samantha He January 15, 2009 Medical Genetics, Prof. Liu MBBS, Fudan University ABSTRACT Fibrodysplasia ossificans progressiva (FOP) is a disabling disease that is caused by episodic heterotopic ossification (HO) and advances in a pattern similar to embryonic development. The molecular pathway that causes the disease has been identified to involve bone morphogenic proteins and the associated activin type I receptor. A heterozygous point mutation in the type 1 receptor of FOP patients has been identified. Currently there are no specific treatments to prevent or reduce HO growth, although experimental drugs were tested with favorable results, such the signal transduction inhibitor LD-193189. However, the battle against FOP is far from over as there are still questions related to FOP disease progression that remains unanswered. INTRODUCTION One of the most catastrophic conditions known to man kind, fibrodysplasia ossificans progressiva (FOP) has been a puzzle to doctors and researchers since the first recorded description some 250 years ago by John Ferke [4]1 below. The disease is characterized by heterotopic ossification (HO) of muscles, connective tissue, joints, aponeuroses, ligaments and fascia [4]. Although the bone morphogenic protein (BMP) pathway was identified, the genetics of the disease remained a mystery. In 2006, a heterozygous point mutation in FOP patients was found in several studies done in different countries. This mutation causes the activin type I receptor (ACVR1) to be constitutively active [6,7]. Knowing the genetic makeup of the disease is important for an early diagnosis, especially for FOP because the misdiagnosis rates can be as high as 90% [5]. Although the genetic advancements are to be applauded, there are still many mysteries that remain unsolved regarding FOP. CLINICAL FEATURES FOP has one of the highest misdiagnosis rates. The reason is the rarity of the disease and how the disease progresses. A FOP patient will look normal upon birth, except for malformed big toes that most doctors without prior experience with FOP

would perceive as congenital big toe malformations [5, 6]. Generally within the first year, FOP patients will experience their first HO flare up. An HO flare up is like an inflammation of an area that produce tumor like swellings [5]. However, unlike a normal nflammation that subsides, the swellings would eventually turn to bone after receding The HO flare ups are episodic in nature but follow an anatomical pattern generally similar with embryonic development [8]. In addition to episod ic flare ups, if the patient is injured the inflammatory response and subsequent heal ing mechanism could also cause HO of the affected area. FOP swellings are usually misdiagnosed to be cancer or juvenile fibromatosis [5] because just by examining with the naked eye, the diagnosis would need to be confirmed usually by biopsy. Such biopsies would cause more flare ups and ossification of the affected area. Thus to be able to d iagnose the d isease without invasive procedures is a milestone. Before the discovery of the FOP gene, the only ev idence for FOP is HO and the malformed big toe, but by then the patient would have already gone through diagnostic procedures or have lived in a way that unnecessarily caused HO Thus an early diagnosis is crucial for managing the disease BMP PATHWAY Accumulative research showed considerable evidence that the BMP pathway is a suspect for causing FOP symptoms [3]. BMP is a large family of proteins that functions as growth factors first described in relation to cartilage and bone growth [1. BMP signals are mediated by several types of transmembrane receptors, type 1 being acvrI Once bmp binds with aCvRl. signal transduction utilizing downstream molecules such as Smad occurs. Ultimately the goal is to transcribe genes, for example, in chondrocytes causes differentiation and maturation [1]. This process in FOP is disrupted by mutate ACVRI receptor that is constitutively signally downstream molecules, thus heterotopic ossification results ACVRI GENE The gene is located on chromosome 2, q23-q24 [7, 10]. The point mutation changes guanine to adenine, which causes a missense mutation R206H in the glycine- serine(GS) rich domain of the ACVRI protein. The mutation is heritable in an autosomal dominant pattern with complete penetrance. In many studies done around the world, the majority of the FOP pat ients have this type of mutation. However,newer stud ies have shown that other novel mutations such as r202i in gs domain and g 328I in kinase domain also occur [7]. Each of these mutations results in atypical features not observed in typical patients with R206H mutation. This could suggest that FOP has of the most specific disease causing mutations [5]. If that is the case treating FOP gene therapy in the future might be possible due to the specificity of the mutation TREATMENT As of now there are no drugs that target HO. Drugs used are mostly to control inflammations and to make the patient more comfortable during a flare up. The patient needs to take non-steroidal anti-inflammatory drugs throughout his or her life. In addition, if inflammations of major joints occur, a heavy course of cortical steroids are prescribed. The purpose is just to reduce the inflammation in hopes that Ho does not

would perceive as congenital big toe malformations [5,6]. Generally within the first year, FOP patients will experience their first HO flare up. An HO flare up is like an inflammation of an area that produce tumor like swellings [5]. However, unlike a normal inflammation that subsides, the swellings would eventually turn to bone after receding. The HO flare ups are episodic in nature but follow an anatomical pattern generally similar with embryonic development [8]. In addition to episodic flare ups, if the patient is injured the inflammatory response and subsequent healing mechanism could also cause HO of the affected area. FOP swellings are usually misdiagnosed to be cancer or juvenile fibromatosis [5] because just by examining with the naked eye, the diagnosis would need to be confirmed usually by biopsy. Such biopsies would cause more flare ups and ossification of the affected area. Thus to be able to diagnose the disease without invasive procedures is a milestone. Before the discovery of the FOP gene, the only evidence for FOP is HO and the malformed big toe, but by then the patient would have already gone through diagnostic procedures or have lived in a way that unnecessarily caused HO. Thus an early diagnosis is crucial for managing the disease. BMP PATHWAY Accumulative research showed considerable evidence that the BMP pathway is a suspect for causing FOP symptoms [3]. BMP is a large family of proteins that functions as growth factors first described in relation to cartilage and bone growth [1]. BMP signals are mediated by several types of transmembrane receptors, type 1 being ACVR1. Once BMP binds with ACVR1, signal transduction utilizing downstream molecules such as Smad occurs. Ultimately the goal is to transcribe genes, for example, in chondrocytes causes differentiation and maturation [1]. This process in FOP is disrupted by mutated ACVR1 receptor that is constitutively signally downstream molecules, thus heterotopic ossification results. ACVR1 GENE The gene is located on chromosome 2, q23-q24 [7,10]. The point mutation changes guanine to adenine, which causes a missense mutation R206H in the glycineserine (GS) rich domain of the ACVR1 protein. The mutation is heritable in an autosomal dominant pattern with complete penetrance. In many studies done around the world, the majority of the FOP patients have this type of mutation. However, newer studies have shown that other novel mutations such as R202I in GS domain and G328I in kinase domain also occur [7]. Each of these mutations results in atypical features not observed in typical patients with R206H mutation. This could suggest that FOP has one of the most specific disease causing mutations [5]. If that is the case treating FOP with gene therapy in the future might be possible due to the specificity of the mutation. TREATMENT As of now there are no drugs that target HO. Drugs used are mostly to control inflammations and to make the patient more comfortable during a flare up. The patient needs to take non-steroidal anti-inflammatory drugs throughout his or her life. In addition, if inflammations of major joints occur, a heavy course of cortical steroids are prescribed. The purpose is just to reduce the inflammation in hopes that HO does not

completely disable the joint. The drug, however, does not stop HO from occurring in the long run. In addition to drugs, the patient must change their live style to avoid unnecessary injury. Hopefully in the future there will be a drug that could reduce HO by nhibiting BMP pathway. Such experiments have been done on mice with positive results such as LDN-193189, a chemical that prevents activation of Smads [9]. Transgenic mice displaying HO was treated with LDN-193189 at the affected joint. The results showed treated mice had less joint ossification when compared to the same type of HO mice without injection. Also the drug has no affect on wild type mice [9]. Although a the model for treatment is still far away from clinical trials, these results give hope that signal transduction inhibitors does lessen the symptoms THE FUTURE OF FOP Over the years, the mystery of FOP seemed to have been solved with the discovery of the pathway and the related gene. However, many questions that puzzle clinicians to this day still remain. One of which is the variability in onset age. In a study done in korea, the patients all have the aCvRi gene mutation but their onset age varies [6]. For such a mutation spec ific disease, FOPs phenotype variability is puzzling Another puzzle is the mystery of the triggers of HO. Not all swellings during an episodic flare up will become bone and not all injuries lead to HO. The reason why Ho in FOP is unpred ictable remains to be explained. These factors could relate to certain pathways or mutations that are und iscovered yet CONCLUSION Many advances in understand ing FoP has been made by research teams around he world. From knowing nothing to pin pointing the mutation, FOP research had come a long way. The bMP pathway gave insight to FOP on a molecular level, which also paved a way to the discovery of the acvri gene mutation. Yet there is more work to be done regarding FOP research. A FOP specif ic drug is yet to be discovered and plenty of unanswered questions remain. The future for FOP research, however, is not only wider but also hopeful

completely disable the joint. The drug, however, does not stop HO from occurring in the long run. In addition to drugs, the patient must change their live style to avoid unnecessary injury. Hopefully in the future there will be a drug that could reduce HO by inhibiting BMP pathway. Such experiments have been done on mice with positive results such as LDN-193189, a chemical that prevents activation of Smads [9]. Transgenic mice displaying HO was treated with LDN-193189 at the affected joint. The results showed treated mice had less joint ossification when compared to the same type of HO mice without injection. Also the drug has no affect on wild type mice [9]. Although a the model for treatment is still far away from clinical trials, these results give hope that signal transduction inhibitors does lessen the symptoms. THE FUTURE OF FOP Over the years, the mystery of FOP seemed to have been solved with the discovery of the pathway and the related gene. However, many questions that puzzle clinicians to this day still remain. One of which is the variability in onset age. In a study done in korea, the patients all have the ACVR1 gene mutation but their onset age varies [6]. For such a mutation specific disease, FOP’s phenotype variability is puzzling. Another puzzle is the mystery of the triggers of HO. Not all swellings during an episodic flare up will become bone and not all injuries lead to HO. The reason why HO in FOP is unpredictable remains to be explained. These factors could relate to certain pathways or mutations that are undiscovered yet. CONCLUSION Many advances in understanding FOP has been made by research teams around the world. From knowing nothing to pin pointing the mutation, FOP research had come a long way. The BMP pathway gave insight to FOP on a molecular level, which also paved a way to the discovery of the ACVR1 gene mutation. Yet there is more work to be done regarding FOP research. A FOP specific drug is yet to be discovered and plenty of unanswered questions remain. The future for FOP research, however, is not only wider but also hopeful