Introduction
Congenital aplastic anemiaFanconi syndromeIt is an autosomal recessive hereditary disease characterized by multiple congenital malformations in addition to complete blood cell reduction.
Cause
(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 The hormone is ineffective. 2 is similar to the upper group, but only BFU-E does not grow. 3BFU-E is reduced, androgen is effective, bone marrow hyperplasia is reduced or severely reduced, and no blood transfusion is required. 4CFU-E and BFU-E are lower than normal, bone marrow hyperplasia is reduced, no androgen therapy is needed, and no blood transfusion is needed. 5 stable disease, mild anemia and / or thrombocytopenia and / or red blood cells, BFU-E slightly reduced. 6 blood picture is normal, BFU-E and CFU-E are normal or slightly less, no treatment is needed. The clinical manifestations of FA patients are very inconsistent, between normal and very abnormal.
(two) pathogenesis
Heterogeneity reflects the heterogeneity of heredity. After examining the complementarity of DNA damage repair functions of the 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. Explain that there may be four different FA genes. One of them, 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 the level of spontaneous chromosome aberrations in FA cells decreased. SOD is a key enzyme in cancer and intracellular antioxidant action. Many studies have determined that the level of SOD in FA red blood cells has decreased by 20% to 40%, but the SOD of leukocytes and fibroblasts has not decreased. Moreover, no changes were found in the SOD purified from FA cells, suggesting that the reduction of SOD in FA red blood cells is due to the abnormal regulation of this cell line. Similarly, catalase, glutathione, and glutathione peroxidase, which are involved in the detoxification of superoxide radicals at different times, are all normal in FA cells. Since FA cells are not particularly sensitive to H2O2 and OH- produced by cellular peroxides and peroxide damage, such results are not unexpected. In addition, in addition to SOD and catalase in FA cells, there are many antioxidants including L-cysteine, glutathione, vitamin C andDeferoxamine(deferoxamine) and the like have a role in protecting FA cells from chromosomal aberrations caused by mitomycin, indicating a positive correlation between FA cell oxygen pressure and spontaneous chromosomal aberrations. These materials indicate that FA cells have damage due to oxygen atoms. At the same time, it suggests that the cells produce too many oxygen atoms or the cells increase the sensitivity to toxic oxygen intermediates, which may be the basic defect of FA. This theory also suggests a general increase in oxygen damage in FA cells. However, when Seres and Fomace directly studied the relationship between DNA damage and oxygen pressure, they did not find any difference in oxygen dependence between FA cells and normal cells. In order to study which oxygen is more important for FA cell chromosomal aberrations and defects, Joenje and Gille proved to be single oxygen. Single-line oxygen is a highly active compound that may be particularly important for FA because it causes DNA-protein cross-linking.
FA fibroblasts and primordial lymphocytes grow poorly during culture. Due to defects in the G2 phase of the FA cell cycle, including the slow or even complete cessation of the phase transition, this defect is improved when the FA cells are grown in a hypoxic state, and similar abnormalities are observed when the normal cells are cultured under a high oxygen state. . The strange thing is that this abnormality cannot be induced by a cross-linking agent. It is suggested that FA defects are not directly related to DNA repair.
Regarding FA cell DNA repair: The NAD of FA cells is reduced, and the NAD metabolism required for DNA repair is also abnormal. Some authors have found that FA cells have defects in poly(ADP) ribosyltransferase. This enzyme plays an important role in understanding DNA damage. It is induced by DNA single-strand breaks, which use NAD as a substrate to add branched ADF ribose multimers to damaged DNA, providing a putative target signal for DNA repair enzymes to achieve DNA damage repair. Earlier reports showed different transferase activities between FA cells and normal cells. However, Scovassi et al. did not find that the basal level of this enzymatic activity of FA differed from the level induced by the mutant after a more detailed analysis. The same is true for FA cell DNA ligase levels. The importance of these enzymes is difficult to recognize because FA cells are not sensitive to the repair of single-stranded DNA breaks.
The susceptibility of FA cells to bifunctional rather than monofunctional alkylating agents to produce intra- and inter-bond crosslinks, along with heritable chromosomal instability, etc., strongly supports the fundamental drawback of FA in certain aspects of DNA repair. In contrast to FA cell and normal cell DNA damage repair, it was found that the induction of cross-linking occurred at the same level. However, there may be differences in the proficiency of the repair. It is in this less skilled case that FA cells cut off the crosslinks. Some FA cell lines lack complete endonuclear repair that is considered to be an early stage of excision repair, while others have only a reduction in the level of endontal repair. In contrast, the more sensitive alkylating agent removal technology used by Fornace did not find a difference in the amount of FA cells and normal cells. Moustacchi et al. studied the genetic heterogeneity and proficiency of FA-A and non-FA-A. The recovery rate of DNA damage induced by 8-Mop+UVA was an indicator of cell repair ability. They found that the recovery rate of three non-FA-A cell lines was similar to that of normal cell lines, and the recovery rate of three FA-A cell lines. It is very low, and this recovery is only after the cells have been incubated for a longer period of time. 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-interlacing chains, whereas the non-FA-A cells were between normal and FA-A cells. Digweed et al confirmed these results and pointed out that this may be a relatively simple method of classifying patients with FA. However, Matsumoto et al. demonstrated that the other two non-FA-A, FA-B and FA-D, differ in their intrinsic cross-linking ability.
The heterogeneity of FA cell cross-linking may also be due to genetic heterogeneity. However, it has been found that normal cells have different sensitivities to mutagens and cross-linking ability. FA lesions may be in the normal range. Sogrier et al. have quantitatively analyzed cell passage-dependent defects in 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 it is difficult to determine whether cell survival depends on cross-linking.
The basic flaw of FA is the repair of DNA. Some of the understanding also 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 was lower than that of the normal control. This low mutation of 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. A detailed examination of mutations at the HPRT site revealed that the major lesions in FA cells were large deletions and rearrangements; in normal cells, point mutations dominated, while large deletions only occurred when a small number of mutations recovered. One explanation is that FA cells cannot repair the cross-link through normal bypass. Under normal circumstances, cells undergo mismatch repair or repeated repair or both of the damage during DNA replication. In a model system for repair of cross-linked HSV DNA after transfection, Coppey et al found that FA cells were more effective than normal under conditions of multiple infections, and that there was almost no error in this process. These results are consistent with the theory that FA cells have a bug in repairing defects on the bypass. Because multiple responses depend on normal recombinant repair.
In combination with DNA repair abnormalities and O2 metabolic disorders, Joenje et al. proposed that FA cells have a group of proteins involved in the normal repair of cross-linked DNA that are particularly sensitive to oxide damage. Mutations in FA may either cause the repair mechanism to be overly sensitive to oxide damage or cause a temporary increase in oxidative damage, and the repair mechanism is inherently sensitive to such 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 have been found abnormal. Older patients are prone to chromosomal abnormalities. Progenitor cell culture found that BFU-E, CFU-E did not grow or decreased, and occasionally normal. The number of progenitor cells is consistent with clinical severity.
symptom
The patient has a low mental retardation and poor physical development, and gradually develops stagnation with age. Patients with more common congenital malformations, such as skin pigmentation, kidney and spleen atrophy, thumb or tibia is not developed or absent or multi-finger, genital hypoplasia, small head, small eyeball, mental retardation.
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.
diagnosis
Mainly differentiated from other types of aplastic anemia, it is not difficult to distinguish according to laboratory tests.
complication
Long-term anemia can be combined with anemia.
treatment
(a) treatment
The most important treatment is to use androgens and corticosteroids. Most patients are effective against androgens. Recently, molastin (GM-CSF) (12.5-10 μg/kg for 42 days) and IL-3 (0.5-10 μg/kg) have been tried, which are effective for some patients. From the European and American literature, 23 cases were found to have the same gene bone marrow transplantation, and 1 case was treated with umbilical cord blood stem cells. In addition to 1 case of failure, 22 cases survived after 18 to 67 months of tracing. It is believed that bone marrow transplantation can cure patients.
(two) prognosis
Acute long-term survival of 5% to 10% can occur in acute myeloid leukemia or other malignant tumors.
prevention
Establish genetic counseling, strict premarital screening, and strengthen prenatal diagnosis to reduce the birth of children.
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