ABOUT AUTHOR:
Akshay Rajgaria
Kanak Manjari Institute of Pharmaceutical Sciences
Rourkela, Orissa
akshaykrish2007@gmail.com
ABSTRACT:
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder of the connective tissue characterized by progressive disability as a result of extensive extra skeletal enchondral bone formation and malformed big toes which are often monophalangic. Occasional features include short thumbs, fifth finger clinodactyly, malformed cervical vertebrae and mild mental retardation. Beginning during childhood, FOP progressively immobilizes all the joints through adult life, rendering movement impossible. Currently, there is no effective prevention or cure for this debilitating disease.
REFERENCE ID: PHARMATUTOR-ART-2023
INTRODUCTION:
Fibro dysplasia ossificans progressiva (FOP), sometimes referred to as Stone Man Syndrome, is an extremely rare disease of the connective tissue. A mutation of the body's repair mechanism causes fibrous tissue (including muscle, tendon, and ligament) to be ossified spontaneously or when damaged. In many cases, injuries can cause joints to become permanently frozen in place. Surgical removal of the extra bone growths has been shown to cause the body to "repair" the affected area with more bone.
CAUSES:
FOP is caused by an autosomal dominant allele on chromosome 2q23-24. The allele has variable expressivity, but complete penetrance. Most cases are caused by spontaneous mutation in the gametes; most people with FOP cannot have children. A study has determined that it affects approximately 1 in every 2 million people. A similar but less catastrophic disease is fibrous dysplasia, which is caused by a post-zygotic mutation.A mutation in the gene ACVR1 (also known as activin-like kinase 2 [ALK-2]) is responsible for the disease. ACVR1 encodes activin receptor type-1, a BMP type-1 receptor. The mutation changes codon 206 from arginine to histidine in the ACVR1 protein. This causes endothelial cells to transform to mesenchymal stem cells and then to bone.
SYMPTOM:
The initial symptoms of Fibrodysplasia Ossificans Progressiva generally arise in childhood. The disease makes a progression all through the life of a sufferer. Children who are born with this disease seem to be normal from all aspects. In most cases, the only defect is an abnormality of the big toes. The toes appear to be shorter than usual and consist of a bony lump close to their base. This congenital abnormality of the toe is regarded as a defining feature of the condition that helps in its diagnosis. The progressive symptoms usually begin to arise as the child nears his or her adolescent years. Initially, painful inflammation of the soft tissues is the only symptom. These are aggravated by viral disorders or injuries. Over time, inflammations increase in number. The existent swellings turn harder due to slow transformation of the soft tissues into bone. The joints become stiffer and mobility becomes painful and difficult. Gradually, individuals with this syndrome begin losing mobility with the progression of the disease. Most sufferers require a wheelchair or other support to move about by the time they enter their thirties. The loss of mobility usually starts with the neck and shoulder region of the body and progresses downwards.
TREATMENT:
Unfortunately, there is still an absence of an effective treatment for Fibro dysplasia Ossificans Progressiva. Surgical removal of excess bones is not considered as an option. This is due to the fact that surgery is often found to result in greater bone formation. Bones thus formed fail to go away on their own. Medications used for FOP treatment usually aim at providing relief from its symptoms, such as inflammation and pain. A short course of high-dose corticosteroids, if commenced within a day of a flare-up episode of symptoms, might help in reducing inflammation and acute tissue edema that FOP sufferers experience during the initial stages of the condition. However, corticosteroid usage should be limited to the very early stages of cure of symptoms rapidly flaring up in the major joints, submandibular area or jaw. Corticosteroids should not be used in curing flare-ups that involve regions such as the trunk, back or neck of a person. This is mainly due to the recurring nature and long duration of the flare-ups along with the problems in assessing the real cause of their onset. Researchers believe that specific kinase inhibitors can be developed that will block the aberrant ACVR1 activity, and are actively investigating dorsomorphin and K02288 as lead compounds with the intention of developing effective therapies. For example, the more potent dorsomorphin derivative LDN-193189 reduced ossification in a transgenic mouse model, in which the engineering of adult ACVR1 activity created an inflammation-dependent ossification sensitive to corticosteroid treatment.
DIAGNOSIS:
In most cases, a proper diagnosis of Fibrodysplasia Ossificans Progressiva (FOP) is possible on the basis of the big toe malformation (a characteristic of this condition) in patients as well as the physical observation of the rapidly altering inflammation on the neck, head or back of sufferers.There is a high lack of awareness of FOP among doctors. This explains why the disease is misdiagnosed in an estimated at 80 percent cases or more. The errors in FOP diagnosis have resulted in suffering and pain for patients as well as their families across the world. Misdiagnosis leads to unnecessary invasive methods, such as biopsies. There have also been permanent complications arising from medical interventions, which include loss of movement.
REFERENCES:
- Connor JM, Evans DA (1982). "Genetic aspects of fibrodysplasia ossificans progressiva".
- Shore EM, Xu M, Feldman GJ et al. (2006). "A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva".
- Dinther et al. (2010). "ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation".
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