The diagnosis of A–T is usually suspected by the combination of neurologic clinical features<unk> , abnormal control of eye movement, and postural instability) with<unk>  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<unk>  * 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<unk>  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<unk>  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<unk>  is the chief manifestation of CP. Children with<unk>  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<unk>  (FA) is the most common genetic cause of<unk>  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<unk>  appears between 10 and 15 years of age, and differs from A–T by the absence of<unk>  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: *<unk> –oculomotor apraxia type 1 (AOA1) *<unk> –oculomotor apraxia type 2 (AOA2 also known as SCAR1) *<unk>  like disorder (ATLD) * Nijmegen breakage syndrome (NBS) Comparison of clinical and laboratory features of rare genetic disorders than can be confused with A–T<unk> –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<unk> , 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.<unk> –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<unk>  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.<unk>  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<unk> , 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<unk> , 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 increased risk to develop cancer. Because those mutations of Mre11 that severely impair the MRE11 protein are incompatible with life, individuals with ATLD all have some partial function of the Mre11 protein, and hence likely all have their own levels of disease severity. Nijmegen breakage syndrome (NBS) is a rare genetic disorder that has similar chromosomal instability to that seen in people with A–T, but the problems experienced are quite different. Children with NBS have significant microcephaly, a distinct facial appearance, short stature, and moderate cognitive impairment, but do not experience any neurologic deterioration over time. Like those with A–T, children with NBS have enhanced sensitivity to radiation, disposition to lymphoma and leukemia, and some laboratory measures of impaired immune function, but do not have ocular<unk>  or an elevated level of AFP. The proteins expressed by the hMre11 (defective in ATLD) and Nbs1 (defective in NBS) genes exist in the cell as a complex, along with a third protein expressed by the hRad50 gene. This complex, known as the MRN complex, plays an important role in DNA damage repair and signaling and is required to recruit ATM to the sites of DNA double strand breaks. Mre11 and Nbs1 are also targets for phosphorylation by the ATM kinase. Thus, the similarity of the three diseases can be explained in part by the fact that the protein products of the three genes mutated in these disorders interact in common pathways in the cell. Differentiation of these disorders is often possible with clinical features and selected laboratory tests. In cases where the distinction is unclear, clinical laboratories can identify genetic abnormalities of ATM, aprataxin and senataxin, and specialty centers can identify abnormality of the proteins of potentially responsible genes, such as ATM, MRE11, nibrin, TDP1, aprataxin and senataxin as well as other proteins important to ATM function such as ATR, DNA-PK, and RAD50.
Ataxia–telangiectasia
SAPHO syndrome
Wiskott–Aldrich syndrome
DiGeorge syndrome
Alagille syndrome
Kabuki syndrome
Chronic granulomatous disease
Severe combined immunodeficiency