Clinically, hematological abnormalities are the most serious symptoms in<unk> . By the age of 40, 98% of<unk>  patients will have developed some type of hematological abnormality. However, a few cases have occurred in which older patients have died without ever developing them. Symptoms appear progressively, and often lead to complete bone marrow<unk> ilure. While at birth, blood count is usually normal, macrocytosis/megaloblastic anemia, defined as unusually large red blood cells, is the first detected abnormality, often within the first decade of life (median age of onset is 7 years). Within the next 10 years, over 50% of patients presenting haematological abnormalities will have developed pancytopenia, defined as abnormalities in two or more blood cell lineages. This is in contrast to Diamond–Blackfan anemia, which affects only erythrocytes, and Shwachman–Diamond syndrome, which primarily causes neutropenia. Most commonly, a low platelet count (thrombocytopenia) precedes a low neutrophil count (neutropenia), with both appearing with relative equal frequencies. The deficiencies cause increased risk of hemorrhage and recurrent infections, respectively. As<unk>  is now known to affect DNA repair, specifically homologous recombination, and given the current knowledge about dynamic cell division in the bone marrow, patients are consequently more likely to develop bone marrow<unk> ilure, myelodysplastic syndromes, and acute myeloid leukemia (AML). Myelodysplastic syndromes MDSs, formerly known as preleukemia, are a group of bone marrow neoplastic diseases that share many of the morphologic features of AML, with some important differences. First, the percentage of undifferentiated progenitor cells, blast cells, is always less than 20%, with considerably more dysplasia, defined as cytoplasmic and nuclear morphologic changes in erythroid, granulocytic, and megakaryocytic precursors, than what is usually seen in cases of AML. These changes reflect delayed apoptosis or a<unk> ilure of programmed cell death. When left untreated, MDS can lead to AML in about 30% of cases. Due to the nature of the<unk>  pathology, MDS diagnosis cannot be made solely through cytogenetic analysis of the marrow. Indeed, it is only when morphologic analysis of marrow cells is performed, that a diagnosis of MDS can be ascertained. Upon examination, MDS-afflicted<unk>  patients will show many clonal variations, appearing either prior or subsequent to the MDS. Furthermore, cells will show chromosomal aberrations, the most frequent being monosomy 7 and partial trisomies of chromosome 3q 15. Observation of monosomy 7 within the marrow is well correlated with an increased risk of developing AML and with a very poor prognosis, death generally ensuing within 2 years (unless prompt allogeneic hematopoietic progenitor cell transplant is an option). Acute myeloid leukemia<unk>  patients are at elevated risk for the development of AML defined as presence of 20% or more of myeloid blasts in the marrow or 5 to 20% myeloid blasts in the blood. All of the subtypes of AML can occur in<unk>  with the exception of promyelocytic. However, myelomonocytic and acute monocytic are the most common subtypes observed. Many MDS patients' diseases evolve into AML if they survive long enough. Furthermore, the risk of developing AML increases with the onset of bone-marrow<unk> ilure. Although risk of developing either MDS or AML before the age of 20 is only 27%, this risk increases to 43% by the age of 30 and 52% by the age of 40. Historically, even with a marrow transplant, about a quarter of<unk>  patients diagnosed with MDS/ALS have died from MDS/ALS-related causes within two years, although more recent published evidence suggests that earlier allogeneic hematopoietic progenitor cell transplantation in children with<unk>  is leading to better outcomes over time. Bone marrow<unk> ilure The last major haematological complication associated with<unk>  is bone marrow<unk> ilure, defined as inadequate blood cell production. Several types of<unk> ilure are observed in<unk>  patients, and generally precede MDS and AML. Detection of decreasing blood count is generally the first sign used to assess necessity of treatment and possible transplant. While most<unk>  patients are initially responsive to androgen therapy and haemopoietic growth<unk> ctors, these have been shown to promote leukemia, especially in patients with clonal cytogenetic abnormalities, and have severe side effects, including hepatic adenomas and adenocarcinomas. The only treatment left would be bone marrow transplant; however, such an operation has a relatively low success rate in<unk>  patients when the donor is unrelated (30% 5-year survival). It is, therefore, imperative to transplant from an HLA-identical sibling. Furthermore, due to the increased susceptibility of<unk>  patients to chromosomal damage, pretransplant conditioning cannot include high doses of radiation or immunosuppressants, thus increased chances of patients developing graft-versus-host disease. If all precautions are taken, and the marrow transplant is performed within the first decade of life, two-year probability of survival can be as high as 89%. However, if the transplant is performed at ages older than 10, two-year survival rates drop to 54%. A recent report by Zhang et al. investigates the mechanism of bone marrow<unk> ilure in<unk> NCC-/- cells. They hypothesize and successfully demonstrate that continuous cycles of hypoxia-reoxygenation, such as those seen by haemopoietic and progenitor cells as they migrate between hyperoxic blood and hypoxic marrow tissues, leads to premature cellular senescence and therefore inhibition of haemopoietic function. Senescence, together with apoptosis, may constitute a major mechanism of haemopoietic cell depletion occurred in bone marrow<unk> ilure. Molecular basis ATM (ATM) is a protein kinase that is recruited and activated by DNA double-strand breaks. DNA double-strand damages also activate the<unk>  core complex <unk> NCA/B/C/E/F/G/L/M). The<unk>  core complex monoubiquitinates the downstream targets<unk> NCD2 and<unk> NCI. ATM activates (phosphorylates) CHEK2 and<unk> NCD2 CHEK2 phosphorylates BRCA1. Ubiquinated<unk> NCD2 complexes with BRCA1 and RAD51. The PALB2 protein acts as a hub, bringing together BRCA1, BRCA2 and RAD51 at the site of a DNA double-strand break, and also binds to RAD51C, a member of the RAD51 paralog complex RAD51B-RAD51C-RAD51D-XRCC2 (BCDX2). The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites. RAD51 plays a major role in homologous recombinational repair of DNA during double strand break repair. In this process, an ATP dependent DNA strand exchange takes place in which a single strand invades base-paired strands of homologous DNA molecules. RAD51 is involved in the search for homology and strand pairing stages of the process. There are 19 genes responsible for<unk> , one of them being the breast-cancer susceptibility gene BRCA2. They are involved in the recognition and repair of damaged DNA; genetic defects leave them unable to repair DNA. The<unk>  core complex of 8 proteins is normally activated when DNA stops replicating because of damage. The core complex adds ubiquitin, a small protein that combines with BRCA2 in another cluster to repair DNA (see Figure Recombinational repair of DNA double-strand damage). At the end of the process, ubiquitin is removed. Recent studies have shown that eight of these proteins,<unk> NCA, -B, -C, -E, -F, -G, -L and -M, assemble to form a core protein complex in the nucleus. According to current models, the complex moves from the cytoplasm into the nucleus following nuclear localization signals on<unk> NCA and<unk> NCE. Assembly is activated by replicative stress, particularly DNA damage caused by cross-linking agents (such as mitomycin C or cisplatin) or reactive oxygen species (ROS) that is detected by the<unk> NCM protein. Following assembly, the protein core complex activates<unk> NCL protein which acts as an E3 ubiquitin-ligase and monoubiquitinates<unk> NCD2. Monoubiquitinated<unk> NCD2, also known as<unk> NCD2-L, then goes on to interact with a BRCA1/BRCA2 complex (see Figure Recombinational repair of DNA double-strand damage). Details are not known, but similar complexes are involved in genome surveillance and associated with a variety of proteins implicated in DNA repair and chromosomal stability. With a crippling mutation in any<unk>  protein in the complex, DNA repair is much less effective, as shown by its response to damage caused by cross-linking agents such as cisplatin, diepoxybutane and Mitomycin C. Bone marrow is particularly sensitive to this defect. In another pathway responding to ionizing radiation,<unk> NCD2 is thought to be phosphorylated by protein complex ATM/ATR activated by double-strand DNA breaks, and takes part in S-phase checkpoint control. This pathway was proven by the presence of radioresistant DNA synthesis, the hallmark of a defect in the S phase checkpoint, in patients with<unk> -D1 or<unk> -D2. Such a defect readily leads to uncontrollable replication of cells and might also explain the increase frequency of AML in these patients. Spermatogenesis In humans, infertility is one of the characteristics of individuals with mutational defects in the<unk> NC genes. In mice, spermatogonia, preleptotene spermatocytes, and spermatocytes in the meiotic stages of leptotene, zygotene and early pachytene are enriched for<unk> NC proteins. This finding suggests that recombinational repair processes mediated by the<unk> NC proteins are active during germ cell development, particularly during meiosis, and that defects in this activity can lead to infertility. Neural stem cell homeostasis Microphthalmia and microcephaly are frequent congenital defects in<unk>  patients. The loss of<unk> NCA and<unk> NCG in mice causes neural progenitor apoptosis both during early developmental neurogenesis and later during adult neurogenesis. This leads to depletion of the neural stem cell pool with aging. Much of the<unk> nconi
Fanconi anemia
Diamond–Blackfan anemia
XMEN disease
Beta thalassemia
Delta-beta thalassemia
Hemoglobin Lepore syndrome
Sick cell syndrome
Hereditary spherocytosis