Background:Rare diseases are all those diseases that present, in the European Union, a prevalence of less than 5 cases per 10,000 people. The number of rare diseases is estimated at roughly 7,000 but there are also longstanding medical conditions that elude diagnosis and could be identified as rare.Objectives:Demonstrate the importance of international research in orphan diseases.Methods:We report a case of 44 y/o female patient who arrived to our observation in 2006. Short stature, early puberty, ligament laxity, BMI <17. From the age of 29: recurrent diarrhea, pain in the spine, osteolytic lesions in spine and endosteal thickening in long bones, muscle contractures, strength deficit, muscular hypotrophy and hypotonia, cardiac conduction and blood pressure disorders, demyelinating MS-lesions, hyperprolactinaemia, slow wound healing, sicca syndrome, osteoporosis. No familiarity for bone lesions. In 2007 her first son (21y/o) began to complain pain at limbs. The young man presented the same bone lesions as the mother and shortening of the PR, prolactinoma, recurrent diarrhea, short stature, early puberty. Over the years numerous pathologies have been first hypothesized and then excluded: multiple sclerosis, bone metastases, Paget’s disease, celiac disease, McCune Albright, Camurati-Engelmann syndrome, mitochondrial disease. No conclusive diagnosis despite the thousands of kilometers traveled, the numerous experts heard and the countless examinations carried out by the patients.Results:In September 2009, the patients had been investigated at the NIH (Washington D.C.) during the “Undiagnosed Diseases Program” but without results until 2013 when the patients were informed of the detection of an ATP6V1H gene mutation never described before in humans. The gene encodes a vacuolar ATPase, a multimeric enzyme that plays several roles: is involved in endocytosis, intracellular trafficking, and protein degradation and energy production, appears to be a risk factor in the development of dyslipidemias and type II diabetes, has a bone resorption function. Also in the patient’s father were founded the same mutation and asymptomatic bone lesions. In 2016 and 2017 studies have reported mouse models of osteoporosis that were generated by knocking out the ATP6V1H gene.Conclusion:from this case it is possible to understand the difficulty of diagnosing a rare disease, the need of an international collaboration in research. From these studies it can be deduced moreover that the ATP6V1H gene could be an important target for therapeutic interventions aimed at preventing bone resorption and treating osteoporosis; evidence to support exploration of MMP9 and MMP13 as therapeutic targets for patients with ATP6V1H deficiency.This mutation seems to affect only one family, but it is possible that the penetrance of the disease-causing mutation is variable. In literature is reported an enhanced expression of MMP-9 in a variety of autoimmune diseases and neurological pathologies (2) therefore the mutation can be at the basis of other much more common pathologies.References:[1]Zhang Y, Huang H, Zhao G, Yokoyama T, Vega H, Huang Y, Sood R, Bishop K, Maduro V, Accardi J, Toro C, Boerkoel CF, Lyons K, Gahl WA, Duan X, Malicdan MC, Lin S. ATP6V1H Deficiency Impairs Bone Development through Activation of MMP9 and MMP13. PLoS Genet. 2017 Feb 3;13(2):e1006481. doi: 10.1371/journal.pgen.1006481.[2]Ram M, Sherer Y, Shoenfeld Y. Matrix metalloproteinase-9 and autoimmune diseases. J Clin Immunol. 2006 Jul;26(4):299-307. doi: 10.1007/s10875-006-9022-6.Disclosure of Interests:Gilda Sandri: None declared, Lorenza Belletti: None declared, Michele Cavedoni: None declared, Claudio Galluzzo: None declared, stefano bruni Consultant of: Genzyme, Employee of: Genzyme, Maria Teresa Mascia: None declared
X-Linked Emery–Dreifuss Muscular Dystrophy: Study Of X-Chromosome Inactivation and Its Relation with Clinical Phenotypes in Female Carriers