normal copy. they are generally healthy, but there is an increased risk of breast cancer in women. this finding has been confirmed in a variety of different ways, and is the subject of current research. standard surveillance (including monthly breast self-exams and mammography at the usual schedule for age) is recommended, unless additional tests are indicated because the individual has other risk factors (e.g., family history of breast cancer). pathophysiology how loss of the atm protein creates 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 . 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. telangiectasia the cause of telangiectasia 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. diagnosis the diagnosis of a–t is usually suspected by the combination of neurologic clinical features (ataxia, abnormal control of eye movement, and postural instability) with telangiectasia and sometimes increased infections, and confirmed by specific laboratory abnormalities (elevated alpha-fetoprotein levels, increased chromosomal breakage or cell death of white blood cells after exposure to x-rays, absence of atm protein in white blood cells, or mutations in each of the person's atm genes). a variety of laboratory abnormalities occur in most people with a–t, allowing for a tentative diagnosis to be made in the presence of typical clinical features. not all abnormalities are seen in all patients. these abnormalities include: elevated and slowly increasing alpha-fetoprotein levels in serum after 2 years of age immunodeficiency with low levels of immunoglobulins (especially iga, igm, igg, and igg subclasses) and low number of lymphocytes in the blood chromosomal instability (broken pieces of chromosomes) increased sensitivity of cells to x-ray exposure (cells die or develop even more breaks and other damage to chromosomes) cerebellar atrophy on mri scan the diagnosis can be confirmed in the laboratory by finding an absence or deficiency of the atm protein in cultured blood cells, an absence or deficiency of atm function (kinase assay), or mutations in both copies of the cell's atm gene. these more specialized tests are not always needed, but are particularly helpful if a child's symptoms are atypical. differential diagnosis there are several other disorders with similar symptoms or laboratory features that physicians may consider when diagnosing a–t. the three most common disorders that are sometimes confused with a–t are: cerebral palsy friedreich's ataxia cogan oculomotor apraxia each of these can be distinguished from a–t by the neurologic exam and clinical history. cerebral palsy (cp) describes a non-progressive disorder of motor function stemming from malformation or early damage to the brain. cp can manifest in many ways, given the different manner in which the brain can be damaged; in common to all forms is the emergence of signs and symptoms of impairment as the child develops. however, milestones that have been accomplished and neurologic functions that have developed do not deteriorate in cp as they often do in children with a–t in the late pre-school years. most children with ataxia caused by cp do not begin to walk at a normal age, whereas most children with a–t start to walk at a normal age even though they often "wobble" from the start. pure ataxia is a rare manifestation of early brain damage or malformation, however, and the possibility of an occult genetic disorder of brain should be considered and sought for those in whom ataxia is the chief manifestation of cp. children with ataxic cp will not manifest the laboratory abnormalities associated with a–t. cogan occulomotor apraxia is a rare disorder of development. affected children have difficulty moving their eyes only to a new visual target, so they will turn their head past the target to "drag" the eyes to the new object of interest, then turn the head back. this tendency becomes evident in late infancy and toddler years, and mostly improves with time. this contrasts to the oculomotor difficulties evident in children with a–t, which are not evident in early childhood but emerge over time. cogan's oculomotor apraxia is generally an isolated problem, or may be associated with broader developmental delay. friedreich ataxia (fa) is the most common genetic cause of ataxia in children. like a–t, fa is a recessive disease, appearing in families without a history of the disorder. fa is caused by mutation in the frataxin gene, most often an expansion of a naturally occurring repetition of the three nucleotide bases gaa from the usual 5–33 repetitions of this trinucleotide sequence to greater than 65 repeats on each chromosome. most often the ataxia appears between 10 and 15 years of age, and differs from a–t by the absence of telangiectasia and oculomotor apraxia, a normal alpha fetoprotein, and the frequent presence of scoliosis, absent tendon reflexes, and abnormal features on the ekg. individuals with fa manifest difficulty standing in one place that is much enhanced by closure of the eyes (romberg sign) that is not so apparent in those with a–t – even though those with a–t may have greater difficulty standing in one place with their eyes open. there are other rare disorders that can be confused with a–t, either because of similar clinical features, a similarity of some laboratory features, or both. these include: ataxia–oculomotor apraxia type 1 (aoa1) ataxia–oculomotor apraxia type 2 (aoa2 also known as scar1) ataxia–telangiectasia like disorder (atld) nijmegen breakage syndrome (nbs) comparison of clinical and laboratory features of rare genetic disorders than can be confused with a–t ataxia–oculomotor apraxia type 1 (aoa1) is an autosomal recessive disorder similar to a–t in manifesting increasing problems with coordination and oculomotor apraxia, often at a similar age to those having a–t. it is caused by mutation in the gene coding for the protein aprataxin. affected individuals differ from those with a–t by the early appearance of peripheral neuropathy, early in their course manifest difficulty with initiation of gaze shifts, and the absence of ocular telangiectasia, but laboratory features are of key importance in the differentiation of the two. individuals with aoa1 have a normal afp, normal measures of immune function, and after 10–15 years have low serum levels of albumin. genetic testing of the aprataxin gene can confirm the diagnosis. there is no enhanced risk for cancer. ataxia–oculomotor apraxia type 2 (aoa2) is an autosomal recessive disorder also similar to a–t in manifesting increasing problems with coordination and peripheral neuropathy, but oculomotor apraxia is present in only half of affected individuals. ocular telangiectasia do not develop. laboratory abnormalities of aoa2 are like a–t, and unlike aoa1, in having an elevated serum afp level, but like aoa1 and unlike a–t in having normal markers of immune function. genetic testing of the senataxin gene (setx) can confirm the diagnosis. there is no enhanced risk for cancer. ataxia–telangiectasia like disorder (atld) is an extremely rare condition, caused by mutation in the hmre11 gene, that could be considered in the differential diagnosis of a–t. patients with atld are very similar to those with a–t in showing a progressive cerebellar ataxia, hypersensitivity to ionizing radiation and genomic instability. those rare individuals with atld who are well described differ from those with a–t by the absence of telangiectasia, normal immunoglobulin levels, a later onset, and a slower progression of the symptoms. because of its rarity, it is not yet known whether or not atld carries an