LEARNING ABOUT FANCONI ANEMIA

Transcription

1 opyr LEARNING ABOUT FANCONI ANEMIA *Jacqueline Rosenberg *Justin Mark Artwork By: Jacqueline Rosenberg 00 Posters. Ccted. F1000

2 OVERVIEW Fanconi Anemia (FA) is a rare disease of the blood that leads to failure of the bone marrow as well as other organs and tissues This genetic disorder may be prevalent in all races and ethnicities. However, it is most common in Ashkenazi Jews and Native South Africans 1 Each year, 1 out of 360,000 people are born with the disorder: 1 out of 30,000 are Jews 1 out of 22,000 are South Africans opyr 1 out of 300 people are carriers for the disease: 1 out of 90 Jews 1 out of 77 South Africans The disease is caused by mutations of various genes: In 99% of cases, an autosomal recessive pattern is shown The remaining 1% displays an X-linked recessive inheritance 2 Although the child is born with the disease, symptoms may not present until ages 2 to 15 and a diagnosis is typically made at this time 3 00 Posters. Ccted. F1000

3 CAUSES Genetic analysis indicates a mutation in 1 of 15 genes as the etiology for FA An inheritance of any mutation in the BRCA1, RAD51, FANCA, B, C, E, F, G, I, J, L, M or N gene may result in the disease 2 Mechanism of action 4 : Genes FANCD2 and FANCI become ubiquitylated, which disrupts various DNA repair mechanisms and destabilizes the genome This eventually causes malfunction of the bone marrow as well as increased susceptibility to cancer Various theories indicate 3 : -Hematopoietic stem cells may become damaged -Mutated cells have increased sensitivity to free radicals -The cell cycle becomes deregulated opyr 00 Posters. Ccted. F1000

4 HISTORY In 1927, Guido Fanconi was the first to discover the disease in three brothers These brothers presented with pancytopenia, aplastic anemia, and physical abnormalities 5 opyr 00 Posters. Ccted. F1000

5 SYMPTOMS The major symptoms of FA are 6 : Aplastic Anemia Bone Marrow Defects opyr Patients with FA show a high incidence of Acute Myeloid Leukemia (AML) 00 Posters. Ccted. F1000

6 SYMPTOMS More physical symptoms include 7 : Thumb and arm anomalies Abnormalities of the hips, spine or ribs Kidney problems. Skin discoloration opyr Small head or eyes Mental retardation or learning disabilities Low birth weight Gastrointestinal difficulties Small reproductive organs in males Defects in tissues separating chambers of the heart 00 Posters. Ccted. F1000

7 SUBTYPES OF FA The subtypes of FA refer to which gene the mutation is present Type C is the form that is most common in Ashkenazi Jews opyr 00 Posters. Ccted. F1000

8 DIAGNOSTIC PROCEDURES FA is most reliably diagnosed by using genetic testing: Chromosome Breakage Test 8 Blood cells are extracted and the DNA is tested using crosslinking chemicals, such as Diepoxybutane and Mitomycin C Normal DNA are able to repair these newly formed linkages opyr FA- induced damaged DNA more likely to show chromosome breakages This test may be performed prenatally by testing either the amniotic fluid or the chorionic villi 00 Posters. Ccted. F1000

9 OTHER DIAGNOSTIC PROCEDURES Flow Cytometry 9 Upon treatment with nitrogen mustard, damaged DNA shows a characteristic pattern in the cell cycle compared to normal DNA Studies show that DNA damaged from FA are more likely to be arrested in the G2/M phase opyr 00 Posters. Ccted. F1000

10 PROGNOSIS 10 The median survival age of FA patients is 20 years old, with an increase to 30 years within the last 10 years Bone marrow failure serves as the major cause of fatalities from the disease opyr Myelodysplastic disorders, Leukemia, Cancers of the head, neck, and esophagus and solid tumors in the liver frequently develop Undergoing a successful bone marrow transplant has shown an increase in survival rate 00 Posters. Ccted. F1000

11 MEDICINAL TREATMENT OF FA- ASSOCIATED APLASTIC ANEMIA There are four main categories of drugs used to counteract aplastic anemia 11 : Androgenic agents stimulate the production of erythropoietin in the kidneys with damaged bone marrow or erythropoiesis due to the lack of red blood cells Anadrol- 50 (Oxymetholone) is a testosterone derivative that increases the above processes opyr Antifibrinolytic agents decrease bleeding by protecting blood clots Amicar (aminocaproic acid) inhibits the conversion of fibrinogen to fibrin, a protein that degrades blood clots Hematopoietic growth factors help stimulate the proliferation, differentiation and activation of various blood cells G-CSF, Neupogen (Filgrastim ) helps produce functional neutrophils Epogen, Procrit (Epoetin alfa) helps in the differentiation of erythroid progenitor cells Glucocorticoids help counteract the growth effects from androgens. They may also help reduce bleeding Prednisone is used for anti-inflammatory purposes and suppression of the immune system 00 Posters. Ccted. F1000

12 TREATMENT OF OTHER FA-ASSOCIATED ABNORMALITIES A bone marrow transplant or other types of hematopoietic stem cell treatment is necessary and is the only current cure of the aplastic anemia The appropriate surgical care can be used to address the multitude of physical symptoms opyr i.e. Cardiovascular, Orthopedic, Plastic, GI or Oncological Surgeries 00 Posters. Ccted. F1000

13 CLINICAL TRIALS Gene Therapy Trials in Mice 12 Scientists have used the Lentivirus for the transduction of normal FANCA and FANCC genes into mice These genes were able to be incorporated into the genome of the mice and were properly expressed Hematopoietic progenitors were adequately repaired to stimulate precursor cell proliferation opyr Bone marrow damage was corrected The mice DNA was protected against the cross-linking chemicals Thus, these trials have shown a great deal of promise with FA gene viral transduction in humans 00 Posters. Ccted. F1000

14 CLINICAL TRIALS Bone marrow tissue, hematopoietic progenitor cells, and DNA samples are constantly being obtained and analyzed in order to gain new knowledge on the disease opyr PCR, Western Blotting, Gel Electrophoresis, Chromatography, and Microarray analysis techniques used 00 Posters. Ccted. F1000

15 SCIENTISTS/ CLINICIANS Swiss Pediatrician Dr. Guido Fanconi was the first to describe the disease Presently, a few of the major researchers on the disease include: Dr. Markus Grompe, M.D.- Professor at Oregon Health & Science University opyr Dr. Agata Smogorzewska, M.D., Ph.D, Dr. Arleen Auerbach, Ph.D, Dr. Elizabeth Garner, Postdoctoral Associate- The Rockefeller University Dr. Andre Rogatko, Ph.D- Professor at Emery University and Researcher at Samuel Oschin Comprehensive Cancer Institute and Cedars Sinai Medical Center 00 Posters. Ccted. F1000

16 RODENT MODELS Scientists have reproduced various FA gene mutations in mice to experimentally determine any functional differences FANCA and FANCC mutations studies in mice have concluded no known differences These genes are part of the FA pathway that act together in response to DNA damage, proliferate hematopoietic precursors and ensure the survival of germ cells 13 opyr This is merely one rodent model of FA, as many studies have indicated the mechanism of action of the disease 00 Posters. Ccted. F1000

17 AGENCIES, SOCIETIES, SUPPORT, CONFERENCES opyr FANCONI Phone: National Heart, Lung, Blood Institute 00 Posters. Ccted. F1000

18 FAMOUS PATIENTS Since the disease is quite rare, there have yet to be any famous cases of FA. opyr 00 Posters. Ccted. F1000

19 CONCLUSIONS Fanconi Anemia is a rare autosomal recessive disease that occurs because of damage to one or more genes of the FA pathway. This pathway is responsible for DNA repair and the proliferation of hematopoietic progenitor cells. Any mutation in an FA gene will lead to aplastic anemia and failure of the bone marrow, as well as physical abnormalities and a high likely hood for a form of cancer. Research has shown promise in the survival rate of the disease both because of more reliable bone marrow transplants and advanced knowledge of the pathway in both rodents and humans. opyr 00 Posters. Ccted. F1000

20 REFERENCES 1 "Fanconi Anemia in Ashkenazi Jews and Afrikaners." National Heart, Lung and Blood Institute. Web. 06 June < 2 Alter, MD, MPH, FAAP, Blanche P. "Fanconi Anemia Etiology." Medscape Reference. Ed. Jeffery M. Lipton, MD, PhD and Max J. Coppes, MD, PhD, MBA Web. 6 June < overview#aw2aab6b2b2aa>. 3 "Fanconi Anemia Diagnosis, Genetic Testing." National Heart, Lung and Blood Institute. Web. 06 June < 4 Garner, E., and A. Smogorzewska. "Ubiquitylation and the Fanconi Anemia Pathway." Federation of the Biochemistry Society Letters (2011). PubMed. Elsevier B.V, 19 May Web. 06 June < 5 Alter, MD, MPH, FAAP, Blanche P. "Fanconi Anemia Background." Medscape Reference. Ed. Jeffery M. Lipton, MD, PhD and Max J. Coppes, MD, PhD, MBA Web. 6 June < opyr 6 "Fanconi Anemia Symptoms." National Heart, Lung and Blood Institute. Web. 06 June < 7 "FA Fact Sheet." Home Fanconi Anemia Research Fund. Fanconi Anemia Research Fund, Inc. Web. 06 June < 8 Auerbach, AD, A. Rogatko, and TM Schroeder-Kurth. "International Fanconi Anemia Registry: Relation of Clinical Symptoms to Diepoxybutane Sensitivity." Blood 73.2 (1989): PubMed. Web. 11 June < 9 Berger, R., M. Le Coniat, and MC Gendron. "Fanconi Anemia. Chromosome Breakage and Cell Cycle Studies." Cancer Genetics and Cytogenetics 69.1 (1993): PubMed. 20 Jan Web. 11 June < 10 Alter, MD, MPH, FAAP, Blanche P. "Fanconi Anemia Prognosis." Medscape Reference. Ed. Jeffery M. Lipton, MD, PhD and Max J. Coppes, MD, PhD, MBA Web. 6 June < overview#aw2aab6b2b4aa> 11 Alter, MD, MPH, FAAP, Blanche P. "Fanconi Anemia Medication." Medscape Reference. Ed. Jeffery M. Lipton, MD, PhD and Max J. Coppes, MD, PhD, MBA Web. 6 June < medication#5> 00 Posters. Ccted. F1000

21 REFERENCES 12 Galimi, F., M. Noll, Y. Kanazawa, T. Lax, C. Chen, M. Grompe, and IM Verma. "Gene Therapy of Fanconi Anemia: Preclinical Efficacy Using Lentiviral Vectors." Blood (2002): PubMed. 21 June Web. 11 June < 13 Noll, M., KP Battaile, R. Bateman, TP Lax, K. Rathbun, C. Reifsteck, G. Bagby, M. Finegold, S. Olsen, and M. Grompe. "Fanconi Anemia Group A and C Double-mutant Mice: Functional Evidence for a Multi-protein Fanconi Anemia Complex." Experimental Hematology 30.7 (2002): PubMed. 16 Apr Web. 11 June < A special thanks to Dr. Rosalind Silverman, Dr. Lorelei Silverman, and the Models of Human Disease Conference at the University of Toronto opyr 00 Posters. Ccted. F1000