Aplastic anemia mainly occurs due to Bonemarrow failure. Failure may be of one cell linei.e. single cytopenia or of all three cell lines(pancytopenia) or quality line fatigue of bonemarrow. Aplastic refers to inability of the stemcells to generate mature blood cells. The diseaseoccurs more frequently in Asia than in the westwith incidence rates 2-3 folds higher.
Aplastic anemia can be caused by exposure tocertain chemicals, drugs, radiation, infection,immune disease; in about half the cases, thecause is unknown. It is not a familial linehereditary condition, nor it is contagious. It canbe acquired due to exposure to other conditionsbut if a person develops the condition, theiroffspring would not develop it by virtue of theirgene connection. Exposure to ionizing radiationfrom radioactive materials or radiation-producingdevices is also associated with the developmentof aplastic anemia. Marie Curie, famous for herpioneering work in the field of radioactivity, diedof aplastic anemia after working unprotectedwith radioactive materials for a long period oftime; the damaging effects of ionizing radiationwere not then known. Aplastic anemia is presentin up to 2% of patients with acute viral hepatitis.One known cause is an autoimmune disorder inwhich white blood cells attack the bone marrow.Short-lived aplastic anemia can also be a resultof parvovirus infection. In humans, the P antigen(also known as globoside), one of the manycellular receptors that contribute to a person'sblood type, is the cellular receptor for parvovirusB19 virus that causes erythema infectiosum (fifthdisease) in children. Because it infects red bloodcells as a result of the affinity for the P antigen,Parvovirus causes complete cessation of redblood cell production. In most cases, this goesunnoticed, as red blood cells live on average120 days, and the drop in production does notsignificantly affect the total number of circulatingred blood cells. In people with conditions wherethe cells die early (such as sickle cell disease),however, parvovirus infection can lead to severeanemia.
The diagnosis can only be confirmed on bonemarrow examination. A patient have had otherblood tests before bone marrow examination tofind diagnostic clues including complete bloodcount, renal function and electrolytes, liverenzymes, thyroid function test, vitamin B12folic acid levels.
Franconi anemia (FA) is an autosomal recessivedisease described as an instability syndromewith cellular hyper immunity to DNA crosslinkingagents. FA cellular phenotype is a highlevel of spontaneous chromosomal breakagewhich is enhanced by exposure of the cells toDNA cross linking agents such as mitomycin C& diepoxybutane. Among those affected themajority develops, most often, and 90% develop(the inability to produce blood cells) by age 40.About 60-75% of people have congenital,commonly, abnormalities of the skin, arms, head,eyes, kidneys, and ears, and developmentaldisabilities. Around 75% of people have someform of endocrine problem, with varying degreesof severity. Fanconi anemia is the most frequentlyreported of the rare inherited bone marrow failuresyndromes (IBMFSs), with approximately 2000 cases reported in the medical literature. In 1927,Guido Fanconi first reported 3 brothers withmacrocytosis, pancytopenia, and physicalabnormalities. Subsequent cases were clinicallydiagnosed because of the combination of aplasticanemia and various characteristic physicalanomalies.
In cultured Fanconi anemia cells, cell cycle arrestin gap 2/mitosis (G2/M) occurs at lowerconcentrations of clastogens than in normal cells.This observation has led to flow cytometry-basedscreening tests used at some centers. The adventof molecular diagnostics has further improvedthe specificity of Fanconi anemia diagnosis.Fanconi anemia accounts for approximately 25%of the cases of aplastic anemia seen at largereferral centers. Approximately 25% of knownpatients with Fanconi anemia do not have majorbirth defects.
The disease has a general, worldwide prevalenceof 1-5 per million and is found in all races andethnic groups, with an estimated heterozygousmutation carrier frequency of between 0.3 and1%. The life expectancy of FA patients is reducedto an average of 20 years (range 0-50 years),primarily because these individuals develop lifethreateningbone marrow failure and aresusceptible to developing malignancies, especiallyacute myeloid leukaemia (AML) and, to a lesserextent, solid tumours, in particular squamouscell carcinomas. The considerable clinicalvariability of the disease is shown by theoccurrence of severe congenital abnormalitiesand death from anaemia or AML in the firstdecade of life at one extreme of the clinicalspectrum, and at the other end of the spectrumby the presentation of mild anaemia (without theother symptoms) and death from oral cancerduring the fifth decade of life. However, theclassical clinical presentation is progressivebone marrow failure, which first manifests aslow platelet counts and which eventually leadsto transfusion-dependent anaemia in the firsttwo decades of life. Treatment is essentiallysupportive, the only chance of a cure for thehaematopoietic aspects of the disease being bonemarrow transplantation. However, those whosurvive these haematological deficiencies mightwell develop solid cancers later in life.
Hereditary diseases, such as FA, xerodermapigmentosum (XP) and hereditary non-polyposiscolorectal cancer (HNPCC), that feature genomicinstability in combination with a strongpredisposition to cancer, are called the'Caretaker-Gene diseases'. Cancer predispositionin these diseases is therefore an indirect resultof the primary genetic defect. The variouscaretaker-gene diseases show fascinatingphenotypes that in some instances can be readilyunderstood from the molecular function of theaffected proteins.
By using linkage analysis, it was possible tomap the FA-A gene to chromosome 16q24.3.This group consists approximately 65-70% oftotal FA patients. However, up to now most ofthe investigations on the sensitivity of FA cellswere focused on chromosomal aberrationsstudies. Chromosome aberrations are cytogeneticend points after un-repaired or mis-repairedDNA damage mainly double strand breaks(DSB). Therefore, these are considered asprocessed DNA damage. Initial DNA damageinduced by chemicals or ionizing radiation atwhole genome level or specific genomic regionmight serve as a diagnostic end point andvaluable tool for studying sensitivity of cellsfrom FA patients to DNA damaging agents.Research on DNA damage induced by agents such as ionizing radiation, environmental toxins,DNA binding substances or therapeutics has beenperformed during the last years with the cometassay.With the combination of the comet-assayand fluorescence in situ hybridization, termedcomet-FISH, specific genomic regions can beexamined in the comet-assay which allowsmeasuring sequence specific DNA fragmentation.This assay is a combination of the comet assaywith fluorescence in situ hybridization. Up tonow, several hybridization procedures includingthose of DNA whole chromosome paintingprobes, gene-specific probes and centromereprobes.
Environmental or occupational exposures toarsenic are associated with numerous chronichealth effects in humans, including increasedrisk of skin, lung, liver, kidney, prostate andurinary bladder cancers. Although arsenic is wellrecognized as a complete carcinogen with tumorpromotingand genotoxic potential, its cocarcinogenicmode of action is becoming morewidely appreciated. Thus, it has been classicallyshown that sub-toxic concentrations of arsenite,the more common environmental form of arsenic,enhance the genotoxicity and carcinogenicityof other DNA-damaging agents, includingpolycyclic aromatic hydrocarbons such asbenzo[a]pyrene, ultraviolet radiation andalkylating compounds by inhibiting DNA repairactivities. Chronic arsenic toxicity due todrinking arsenic contaminated water has beenone of the worst environmental health hazardsaffecting West Bengal.
It is estimated that over 8,00,000 People in WBare chronically exposed to arsenic. We havepreviously found that arsenic acts as apredisposing factor for blood cancer. (Sonalipaul et. al. 2011)
An original article is being published in thisissue on "Morphologically Aplastic anemia casewith Franconi anemia" by Atreyee Dutta andothers from Genetic dept., a collaboration workwith NRS medical college. After diagnosis ofAplastic anemia with bone marrow biopsy theydid stress cytogenetics. 8.16% cases aresuggestive for FA showed positive stress. Inaddition to stress cytogenetics, DNA comet-FISH technique should be performed to confirmthe sequence specific DNA breakage.