How does loss of the ATM protein create a multisystem disorder? Characteristics of the ATM protein A–T has been described as a genome instability syndrome, a DNA repair disorder and a DNA damage response (DDR) syndrome. ATM, the gene responsible for this multi-system disorder, encodes a protein of the same name which coordinates the cellular response to DNA double strand breaks (DSBs). Radiation therapy, chemotherapy that acts like radiation (radiomimetic drugs) and certain biochemical processes and metabolites can cause DSBs. When these breaks occur, ATM stops the cell from making new DNA (cell cycle arrest) and recruits and activates other proteins to repair the damage. Thus, ATM allows the cell to repair its DNA before the completion of cell division. If DNA damage is too severe, ATM will mediate the process of programmed cell death (apoptosis) to eliminate the cell and prevent genomic instability. Cancer and radiosensitivity In the absence of the ATM protein, cell-cycle check-point regulation and programmed cell death in response to DSBs are defective. The result is genomic instability which can lead to the development of cancers. Irradiation and radiomimetic compounds induce DSBs which are unable to be repaired appropriately when ATM is absent. Consequently, such agents can prove especially cytotoxic to A–T cells and people with A–T. Delayed pubertal development (gonadal dysgenesis) Infertility is often described as a characteristic of A–T. Whereas this is certainly the case for the mouse model of A–T, in humans it may be more accurate to characterize the reproductive abnormality as gonadal atrophy or dysgenesis characterized by delayed pubertal development. Because programmed DSBs are generated to initiate genetic recombinations involved in the production of sperm and eggs in reproductive organs (a process known as meiosis), meiotic defects and arrest can occur when ATM is not present. Immune system defects and immune-related cancers ATM and the immune system As lymphocytes develop from stem cells in the bone marrow into mature lymphocytes in the periphery, they rearrange special segments of their DNA V(D)J recombination process. This process requires them to make DSBs, which are difficult to repair in the absence of ATM. As a result, most people with A–T have reduced numbers of lymphocytes and some impairment of lymphocyte function (such as an impaired ability to make antibodies in response to vaccines or infections). In addition, broken pieces of DNA in chromosomes involved in the above-mentioned rearrangements have a tendency to recombine with other genes (translocation), making the cells prone to the development of cancer (lymphoma and leukemia). Progeric changes Cells from people with A–T demonstrate genomic instability, slow growth and premature senescence in culture, shortened telomeres and an ongoing, low-level stress response. These factors may contribute to the progeric (signs of early aging) changes of skin and hair sometimes observed in people with A–T. For example, DNA damage and genomic instability cause melanocyte stem cell (MSC) differentiation which produces graying. Thus, ATM may be a “stemness checkpoint” protecting against MSC differentiation and premature graying of the hair.<unk>  The cause of<unk>  or dilated blood vessels in the absence of the ATM protein is not yet known. Increased alpha-fetoprotein (AFP) levels Approximately 95% of people with A–T have elevated serum AFP levels after the age of two, and measured levels of AFP appear to increase slowly over time. AFP levels are very high in the newborn, and normally descend to adult levels over the first year to 18 months. The reason why individuals with A–T have elevated levels of AFP is not yet known. Neurodegeneration A–T is one of several DNA repair disorders that result in neurological abnormalities or degeneration. Arguably some of the most devastating symptoms of A–T are a result of progressive cerebellar degeneration, characterized by the loss of Purkinje cells and, to a lesser extent, granule cells (located exclusively in the cerebellum). The cause of this cell loss is not known, though many hypotheses have been proposed based on experiments performed both in cell culture and in the mouse model of A–T. Current hypotheses explaining the neurodegeneration associated with A–T include the following: * Defective DNA damage response in neurons which can lead to * Failed clearance of genomically damaged neurons during development * Transcription stress and abortive transcription including topoisomerase 1 cleavage complex (TOP1cc) dependent lesions * Aneuploidy * Defective response to oxidative stress characterized by elevated ROS and altered cellular metabolism * Mitochondrial dysfunction * Defects in neuronal function: * Inappropriate cell cycle re-entry of post-mitotic (mature) neurons * Synaptic/vesicular dysregulation * HDAC4 dysregulation * Histone hypermethylation and altered epigenetics * Altered protein turnover These hypotheses may not be mutually exclusive and more than one of these mechanisms may underlie neuronal cell death when there is an absence or deficiency of ATM. Further, cerebellar damage and loss of Purkinje and granule cells do not explain all of the neurologic abnormalities seen in people with A–T. The effects of ATM deficiency on the other areas of the brain outside of the cerebellum are being actively investigated. Radiation exposure People with A–T have an increased sensitivity to ionizing radiation (X-rays and gamma rays). Therefore, X-ray exposure should be limited to times when it is medically necessary, as exposing an A–T patient to ionizing radiation can damage cells in such a way that the body cannot repair them. The cells can cope normally with other forms of radiation, such as ultraviolet light, so there is no need for special precautions from sunlight exposure.
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SAPHO syndrome
Wiskott–Aldrich syndrome
DiGeorge syndrome
Alagille syndrome
Kabuki syndrome
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Severe combined immunodeficiency