**3.5 Other clinical features**

*Neurodevelopment and Neurodevelopmental Disorder*

DDR controlled pathway and vascularization [121, 122].

**3.3 Immunodeficiency and inflammation**

**3.4 Radiosensitivity and increased cancer risk**

**3.2 Telangiectasia**

[117]. Paused RNA polymerase sites activate ATM, which then elicit a response that includes interactions with spliceosome components that may mediate R-loop resolution [118]. In the cerebellum, the combination of high levels of oxidative stress with high demands of transcription may produce an abnormally high amount of paused transcription sites due to DNA damage. In the absence of ATM, R-loops may not be adequately resolved, eventually creating a scenario incompatible with cell life.

The localized abnormal vascular formations that A-T patients show in several parts of their bodies—particularly in the eyes—is one of the most obvious and yet least investigated phenotypes of the disease [119]. Telangiectasia is highly prevalent in A-T, only missing in patients bearing mild ATM mutations that maintain some residual protein function [120]. Very little is known about the molecular mechanism that prompts telangiectasia when ATM is absent or dysfunctional. The current model proposes that oxidative stress caused by a lack of functional ATM may upregulate HIF1A levels, a hypoxia-activated transcription factor that can induce vascularization by increasing the levels of angiogenesis factor VEGF [120]. Intriguingly, SAPS also induces secretion of VEGF, suggesting a link between this

A-T patients can show low levels of at least one type of immunoglobulin, inadequate antibody responses to infections and abnormal T and B lymphocyte counts [123, 124]. These phenotypes can be attributed to the roles that ATM has in regulating NHEJ during V(D)J recombination and class-switch recombination (CSR), two recombination processes required to produce antibody diversity during adaptive immunity. Both V(D)J and CSR involve induction of programmed DSBs followed by ATM-aided NHEJ repair [125]. For instance, during V(D)J ATM localizes to break sites and regulate NHEJ components, while p53BP1 phosphorylation by ATM is a crucial event during CSR. The regulatory roles that ATM exerts on these two processes are likely to be extensive and involve other DDR pathways. In A-T patients with immunodeficiencies, programmed DSBs remain unrepaired, and their persis-

There is growing evidence that the innate immune response may be tightly linked to several clinical manifestations observed in A-T patients. Lack of ATM creates high levels of ROS and oxidative damage, which is known to induce pro-inflammatory cytokines [111, 129, 130]. ATM-deficient cells cannot trigger pexophagy and other forms of autophagy to counteract the negatives effect of oxidative damage, further compounding the problem [91]. Persistent genotoxic stress can, therefore, create chronic inflammation in A-T patients, a condition linked to several A-T symptoms: increased levels of cardiovascular and autoimmune diseases, insulin resistance, and aging. Tellingly, the immune response contributes to neurodegeneration during Alzheimer's disease, possibly suggesting that in A-T patients, chronic inflammation may also contribute to neurodegeneration in cerebellar tissues suffering high levels of genotoxic stress [131].

Several DDR pathways contribute to the increased cancer risk seen in A-T patients. The inability of A-T cells to coordinate DNA repair with other DDR pathways can leave unrepaired genomic injuries and elevate the number of mutations in cells—including perilous DSBs—rendering cells highly sensitive to ionizing

tence can cause severe T and B-cell developmental problems [126–128].

**76**

Both male and female A-T patients show infertility due to abnormal meiosis progression. During meiosis, ATM controls the number of DSBs created by SPO11 and ensures their even distribution in the genome [134]. This is achieved by recruiting ATM to SPO11-generated DSBs, which inhibits the formation of further cuts in the vicinity of break sites. Mice models have shown a meiotic arrest in prophase I, faulty synapsis, and chromosome fragmentation leading to massive germ cell loss [107, 135], suggesting that the loss of ATM's roles during meiosis is the underlying cause of infertility in A-T patients.

A-T patients can suffer from insulin resistance and thus, have a higher risk of developing diabetes, a clinical feature that they share with carriers of the disease. The cause for this phenotype is likely to be multifactorial, but it is well-defined that ATM phosphorylates several targets—e.g., translation regulation 4E-BP1—in response to insulin [25]. Furthermore, a lack of fully functional ATM correlates with an inhibition of IRS1 (insulin receptor substrate 1) and low levels of IGF1-R (insulin-like growth factor1 receptor), suggesting possible mechanisms causing this clinical feature [94, 136, 137].
