congenital aplastic anemia
Introduction
Introduction to congenital aplastic anemia Congenital aplastic anemia, also known as Fanconi syndrome, is an autosomal recessive hereditary disease characterized by multiple congenital malformations in addition to a reduction in whole blood cells. basic knowledge The proportion of illness: 0.0001212% Susceptible people: young children Mode of infection: non-infectious Complications: heart disease
Cause
Causes of congenital aplastic anemia
(1) Causes of the disease
The patient's blood and bone marrow mononuclear cells were studied to produce BFU-E and CFU-E in vitro. The etiology can be divided into six cases: 1 no erythroid progenitor cell growth, severe myeloid hyperplasia, relying on blood transfusion to maintain life, male Hormone is ineffective, 2 is similar to the upper group, but only BFU-E does not grow, 3BFU-E is reduced, androgen is effective, myelosuppression is reduced or severely reduced, no blood transfusion is required, 4CFU-E and BFU-E are lower than normal, myelosynthesis Reduced, no androgen therapy, no blood transfusion, 5 stable condition, mild anemia and/or thrombocytopenia and/or red erythrocyte enlargement, BFU-E slightly reduced, 6 normal blood, BFU-E and CFU-E Normal or slightly less, no treatment, indicating that the clinical manifestations of FA patients are very inconsistent, between normal and very abnormal.
(two) pathogenesis
Heterogeneity reflects the heterogeneity of hereditary type. After examining the complementarity of DNA damage repair functions of three FA cell lines, it was found that FA can be divided into four groups, namely FA-A, FA-B, FA-C and FA. -D, indicating that there may be four different FA genes, one of which is FA-C has been isolated and cloned, and gene therapy research has begun.
When Nordenson et al added catalase or superoxide dismutase (SOD) to FA cells, it found that FA cells had a decreased level of spontaneous chromosomal aberrations. SOD is a key enzyme in cancer and intracellular antioxidant activity. Many studies have The SOD level of FA erythrocytes decreased by 20%-40%, but the SOD of leukocytes and fibroblasts did not decrease, and the SOD purified from FA cells showed no change, suggesting that the decrease of SOD in FA erythrocytes is due to this cell. The regulation of the line is abnormal. Similarly, catalase, glutathione and glutathione peroxidase, which are involved in the detoxification of superoxide radicals in different periods, are all normal in FA cells, because FA cells do not peroxidize cells. H2O2 and OH- produced by the destruction of substances and peroxides are particularly sensitive, and the results are not unexpected. In addition, in addition to SOD and catalase, there are many antioxidants including L-cysteine in FA cells. Acid, glutathione, vitamin C and deferoxamine all protect FA cells from chromosomal aberrations caused by mitomycin, indicating that there is a difference between FA cell oxygen pressure and spontaneous chromosome aberrations. Relatedly, these materials indicate that FA cells have damage due to oxygen atoms, and suggest that cells produce too many oxygen atoms or cells increase sensitivity to toxic oxygen intermediates, which may be a fundamental defect of FA. This theory also suggests FA. There is a general increase in cellular oxygen damage. However, Seres and Fomace did not find any difference in oxygen dependence between FA cells and normal cells when directly studying the relationship between DNA damage and oxygen pressure. In order to study which oxygen to chromosomal aberrations in FA cells And the generation of defects is more important. Joenje and Gille prove that it may be single oxygen. Single-line oxygen is a highly active compound, which may be especially important for FA because it can cause DNA and protein cross-linking (cross- Linking).
The fibroblasts and primordial lymphocytes of FA grow poorly during culture. Due to defects in the G2 phase of the FA cell cycle, including the slow transition of the phase transition, or even complete, the defects are improved when the FA cells grow in a hypoxic state. Similar abnormalities were observed when normal cells were cultured under high oxygen conditions. It is strange that the cross-linking agent could not induce this abnormality, suggesting that FA defects are not directly related to DNA repair.
Regarding FA cell DNA repair: FAD is reduced in FA cells, and NAD metabolism required for DNA repair is also abnormal. Some authors have found that FA cells have defects in poly(ADP) ribosyltransferase, which plays an important role in understanding DNA damage. Induced by DNA single-strand breaks, the branched ADF ribose multimer is added to the damaged DNA using NAD as a substrate to provide a putative target signal for DNA repair enzyme to achieve DNA damage repair. The report shows that the transferase activity is different between FA cells and normal cells. However, Scovassi et al. did not find that the basal level of this enzyme activity of FA is different from that induced by mutants after detailed analysis. FA cell DNA ligase The same is true for levels, and the importance of these enzymes is difficult to recognize because FA cells are not sensitive to the repair of single-stranded DNA breaks.
The sensitivity of FA cells to bifunctionality rather than monofunctional alkylating agents to produce intra- and inter-bond crosslinks, along with heritable chromosomal instability, strongly supports the fundamental drawbacks of FA in certain aspects of DNA repair. In contrast to the repair of DNA damage in FA cells and normal cells, it was found that the induction of cross-linking occurred at the same level, however, there may be differences in the proficiency of repair, and it is the FA cells that cut off the cross-linking in this less skilled case. Some FA cell lines are completely lacking in endoscopic repair, which is considered to be the initial stage of excision repair, while others have only a reduction in the level of endonuclear repair. On the contrary, the more sensitive alkylating agent removal technology used by Fornace has not been found. There is a difference between FA cells and normal cells. Moustacchi et al studied the correlation between genetic heterogeneity and proficiency of FA-A and non-FA-A, and the recovery rate of DNA damage induced by 8-Mop+UVA was judged. In terms of repair capacity, they found that the recovery rate of three non-FA-A cell lines was similar to that of normal cell lines, while the recovery rate of the three FA-A cell lines was very low, and this recovery was only in cell comparison. After the time incubation, the alkylating agent scavenging and direct electron microscopy showed that the FA-A cell scavenging alkylating agent was not only slow but also had fewer end-cutting chains, while the non-FA-A cells were in normal and FA-A. Between cells, Digweed et al confirmed these results and pointed out that this may be a relatively simple method for classifying patients with FA. However, Matsumoto et al. demonstrated that the other two non-FA-A, FA-B and FA-D, were cut in. The ability to connect is different.
The heterogeneity of FA cell cross-linking may also be due to genetic heterogeneity. However, the sensitivity of normal cells to mutagens and the ability of cross-linking are also different. FA lesions may be within the normal range. Sogrier et al. have quantitatively analyzed the cell passage-dependent defects in the cross-linking repair of two FA cell lines. There is a direct relationship between the sensitivity of cells of many FA cell lines to DNA damage and cross-linking defects, but Determining whether cell survival depends on cross-linking is difficult.
The basic defect of FA is the repair of DNA, and some of the understanding comes from the faithful study of the repair process itself. Papadopoudo et al. demonstrated that the 8-Mop+UVA-induced mutation rate of FA-A and FA-D is lower than that of FA-A and FA-D. In normal controls, this low mutation in FA is also observed at various doses of mono- and di-functional alkylating agents, and is more pronounced in the case of mutation rates as a dose effect or cell survival indicator, occurring at the HPRT site. Detailed examination of the mutations revealed that the major damage of FA cells was large deletions and rearrangements; in normal cells, point mutations dominated, while large deletions only occurred when a small number of mutations recovered. One explanation was that FA cells could not pass normal The road is used to repair the cross-linking. Under normal circumstances, the cells undergo mismatch repair or repeated repair or both of the damage during DNA replication. Coppey et al found FA in a model system for repairing HSV DNA after cross-linking after transfection. Cells are more effective than normal under conditions of multiple infections, and there is almost no error in this process. These results are consistent with the theory that FA cells have a bug in repairing bypass defects because Multiple reactions depend on normal recombinant repair.
In combination with DNA repair abnormalities and O2 metabolic disorders, Joenje et al. suggested that FA cells have a group of proteins involved in the normal repair of cross-linked DNA that are particularly sensitive to oxide damage. FA mutations may either make the repair mechanism oversensitive to oxide damage or cause Oxidative damage is temporarily increased, and the repair mechanism is inherently sensitive to this damage.
Cytogenetic studies found that 66% of patients had normal karyotypes, 34% had clonal abnormalities, and were mostly similar to MDS or treatment-related ANLL chromosomal abnormalities. Except for chromosome 15, all chromosomes including X and Y chromosomes were found abnormal. Older patients are prone to chromosomal abnormalities. BFU-E and CFU-E do not grow or decrease in progenitor cell culture. Occasionally, the number of progenitor cells is consistent with clinical severity.
Prevention
Congenital aplastic anemia prevention
Establish genetic counseling, strict premarital screening, and strengthen prenatal diagnosis to reduce the birth of children.
Complication
Congenital aplastic anemia complications Complications
Long-term anemia can be combined with anemia.
Symptom
Congenital aplastic anemia symptoms Common symptoms Reticular pigmentation plaque Whole blood cell reduction Skeletal stop development Hematopoietic dysfunction Small head Small eyeball intelligence Reduced bone marrow changes
Patients with low mental retardation, poor physical development, and gradual developmental stagnation with age, patients with significant multiple congenital malformations, such as skin pigmentation, kidney and spleen atrophy, thumb or tibia is not developed or absent or more Refers to genital hypoplasia, small head, small eyeballs, mental retardation and so on.
1. Anemia occurs in childhood, the clinical manifestations are consistent with aplastic anemia, no cirrhosis and splenomegaly.
2. At the same time, there are congenital malformations, the most common of the thumb and ulnar skeletal deformities, skin pigmentation, mental retardation.
3. The laboratory has complete blood cell reduction, low bone marrow hyperplasia, and chromosome aberrations.
Examine
Examination of congenital aplastic anemia
1. Peripheral blood: It shows that the whole blood cells are reduced, the absolute value of reticulocytes is reduced, the anemia is positive cells or slightly large cell, and the young red blood cells or immature white blood cells are occasionally seen in the blood.
2. Red blood cell life is shortened and hemoglobin F is increased.
3. Bone marrow: The proliferation of the three lines of bone marrow is reduced, but it can also proliferate actively in the early stage of the disease, and the plasma cells and tissue basophils increase.
4. Chromosomal aberrations.
According to the condition, clinical manifestations, symptoms, signs, choose ECG, B-ultrasound, X-ray, biochemical examination.
Diagnosis
Diagnosis and diagnosis of congenital aplastic anemia
Diagnosis is based on clinical performance and examination.
Mainly differentiated from other types of aplastic anemia, it is not difficult to distinguish according to laboratory tests.
