AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Ataxia-telangiectasia (A-T) is an autosomal recessive, complex, multisystem disorder characterized by progressive neurologic impairment, cerebellar ataxia, variable immunodeficiency with susceptibility to sinopulmonary infections, impaired organ maturation, x-ray hypersensitivity, ocular and cutaneous telangiectasia, and a predisposition to malignancy. The disease is heterogeneous, both clinically and genetically, as shown by the existence of 4 complementation groups (A, C, D, E). The responsible gene (ATM gene) has been mapped to band 11q22-23.

Syllaba and Henner first published descriptions of patients with A-T in 1926. They observed progressive choreoathetosis and ocular telangiectasia in 3 members of a single family. A gap of some 15 years occurred before the next report in 1941 by Louis-Bar, who described progressive cerebellar ataxia and cutaneous telangiectasia in a Belgian child. The syndrome subsequently received the name of Louis-Bar. A-T was not described as a distinct clinical entity for another 16 years until Boder and Sedgwick in 1957 and Biemond in 1957, with the aid of autopsies, reported organ developmental abnormalities; neurologic manifestations; and a third major feature of the disease, recurrent sinopulmonary infection.

A-T can best be classified, according to its major clinical and pathologic features, as a predominantly cerebellar form of spinocerebellar degeneration, which is transmitted as an autosomal recessive trait and evolves ultimately to include motor neuron disease, with spinal muscular atrophy and peripheral neuropathy.

A-T can also be classified among the neurocutaneous syndromes, though not among the phakomatoses as originally proposed, because the vascular and cutaneous lesions of A-T are not congenital nevi but develop in the course of the disease as a progeric manifestation. A-T should be considered among the immunodeficiency diseases, cancer-prone genetic disorders, chromosomal instability syndromes, disorders with abnormal radiosensitivity, syndromes with possible DNA-repair/processing defects, and (as is now evident) the progeroid syndromes.

Pathophysiology

One basic defect associated with the malady is the abnormal sensitivity of A-T cells to x-rays and certain radiomimetic chemicals but not to ultraviolet irradiation, which leads to chromosome and chromatid breaks. Breakpoints are randomly distributed, but nonrandom chromosome rearrangements selectively affect chromosomes 7 and 14 at sites that are concerned with T-cell receptors and heavy-chain immunoglobulin coding and with the development of hematologic malignancies. Such disturbances could account for the frequency of infections and neoplasias.

As has been shown by Guerra-Maranhao et al in 2006, A-T patients are at high risk of having impaired responses to infection with pneumococci, which may be one of the causes of recurrent sinopulmonary infections in these patients. The authors analyzed the production of antibodies to polysaccharide antigens in patients with A-T and found that the levels of immunoglobulin G (IgG) antibodies to serotypes 1, 3, 5, 6B, 9V, and 14 of Streptococcus pneumoniae before and after immunization with 23-valent polysaccharide vaccine were significantly lower than in a healthy population.

ATM gene targets include well-known tumor suppressor genes such as TP53 and BRCA1, both of which play an important role in the predisposition to breast cancer. Studies of A-T families have consistently reported an increased risk of breast cancer in women with one mutated ATM gene, but, to date, an increased frequency of ATM mutations has not been found in women with breast cancer.

The mechanisms responsible for neurologic disease, thymus aplasia, telangiectasias, growth retardation, and impaired organ mutation have not been elucidated, but most likely, they are linked to accelerated telomere loss (Senior, 2003; Qi, 2003). Recently, ATM was shown to be pivotal for neurodevelopment, especially for stem cell differentiation, as well as for elimination of damaged postmitotic cells (Lee, 2001). A general disturbance in tissue differentiation accounts for the almost constant elevation of alpha-fetoprotein (AFP), a fetal serum protein of hepatic origin that indicates dedifferentiation of liver cells.

Recent work suggests that A-T may be associated with dysregulation of the immunoglobulin gene superfamily, which includes genes for T-cell receptors. The normal switch from the production of immunoglobulin M (IgM) to IgG, immunoglobulin A (IgA), and immunoglobulin E (IgE) is defective, and the same may apply to the switch from immature T cells that express the gamma/delta rather than the alpha/beta receptors. Conceivably, an absence or a mutation of a single protein coded for by chromosome 11 could explain the immunologic and perhaps even the neurologic features of the disease. The ATM protein apparently controls the cell cycle and plays a major role in the protection of the genome.

The ATM gene product has been shown to be required for cell survival and genomic stability maintenance following exposure to low labile iron concentrations. Because iron chelation agents increase A-T cell genomic stability and viability and activate ATM-dependent cellular events in normal cells, Edwin-Shackelford et al suggested in 2005 that pharmacological manipulation of ATM activity via iron chelation might have clinical efficacy in Parkinson disease treatment.

Frequency

International

A-T is reported in all regions of the world. The probable incidence of A-T is about 1 case in 100,000 births (Swift, 1986). The frequency of A-T mutant allele heterozygosity was reported to be 1.4-2% of the general population (Swift, 1986; Su, 2000).

Mortality/Morbidity

Death typically occurs in early or middle adolescence, usually from bronchopulmonary infection, less frequently from malignancy, or from a combination of both. The median age at death is reported to be approximately 20 years (Su, 2000). In a retrospective study in the United States, mortality from all causes in A-T was 50-fold and 147-fold higher for white and black patients with A-T, respectively, than expected based on overall US mortality rates (Morrell, 1986).

• Boder (1987) reviewed 58 complete autopsy cases: 27 (46%) deaths were caused by pulmonary infection alone, 12 (21%) by malignancy alone, 16 (28%) by a combination of both, and 3 (5%) by other reasons.
• The lifetime risk of cancer among patients with A-T has been estimated to be 10-38% (Morell, 1990; Olsen, 2001; Spector, 1982), which is about 100-fold more than the population rate (Morrell, 1986); however, in the absence of chronic bronchopulmonary disease and lymphoreticular malignancy, A-T is consistent with survival into the fifth or sixth decade.
• A-T heterozygotes present an excess risk of death (they die 7-8 y earlier than the normal population), mostly from ischemic heart disease (A-T carriers die 11 y younger than noncarriers) or cancer (A-T carriers die 4 y younger than noncarriers) (Su, 2000).

Race

A-T is reported in all races, although the mortality ratios differ between the ethnic groups (see Mortality/Morbidity above).

Sex

A-T occurs equally among males and females.

Age

No characteristic features are detectable during very early childhood.

• Ataxia is usually a first diagnostic hallmark, having its onset in the first years of life. Beyond the age of 5 years, the progression of the ataxia becomes increasingly apparent and the child requires a wheelchair by age 10 or 11 years. In 2004, Trimis et al reported a 6-year-old girl without any neurological symptoms.
• Oculocutaneous telangiectasia, the second diagnostic hallmark of A-T, usually has a later onset than the ataxia, typically at age 3-6 years.
• The progression of the disease is apparent in subsequent years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Even in classic A-T with ataxia and telangiectasia, the onset of clinical symptoms and the rate of progression are variable. Several reports describe differences in the age of presentation and the rates of progression.

• Some classify patients in groupings that reflect the clinical heterogeneity.
• • Type I is the classic syndrome with all manifestations described below.
  • Type II lacks some of the typical findings but shows radiosensitivity.
  • Type III has the classic clinical findings but is not radiosensitive.
  • Type IV shows only some clinical features and is not radiosensitive.
• Patients with atypical forms of A-T are uncommon.
• • Some of these patients lack one or the other of the laboratory markers. These forms raise the question of the genetic heterogeneity of the disease, a question that will be solved by identifying the abnormal gene or genes.
  • All biological markers for A-T are absent, and, in several cases, cultured fibroblasts were normally resistant to irradiation.
  • The course is usually more benign and appears to represent a disease distinct from A-T.
• Repeated sinopulmonary infections are present in 48-81% of patients. One study divided the patients into 3 groups with regard to the occurrence of infections.
• • One third of patients had frequent and severe infections with progressive lung disease.
  • One third of patients had infections but no progressive lung disease.
  • The remaining third had only a normal incidence of infections.
  • A good correlation exists between the occurrence of infections and immunodeficiency as assessed by laboratory tests.

Physical

The main abnormalities on physical examination are ocular and cutaneous telangiectasia and neurologic symptoms (mainly ataxia and abnormal eye movements present in virtually all cases) and choreoathetosis (30-90% of patients).

• Ataxia has its onset in infancy, becoming apparent when the child begins to walk (usually from 12-14 mo). From this early stage, ataxia is associated with abnormal head movements and is slowly and steadily progressive; however, the normal development of motor skills between ages 2-5 years tends to mask the progression of ataxia, so that parents may report an actual improvement in gait. At this point, a diagnosis of cerebral palsy, ataxic or athetoid, is frequently made, but children who are affected have a peculiar gait like little clowns; this finding is highly suggestive of A-T.
• • Ataxia is relentlessly progressive, but the pace is variable, even in the same sibship.
  • Beyond age 5 years, the progression of the ataxia becomes increasingly apparent, and misdiagnosis of Friedreich ataxia may be made, particularly if the telangiectasia has not yet appeared.
  • In a study of 70 patients with A-T, the incidence of the onset of symptoms of ataxia was 20% prior to age 1 year, 65% before age 2 years, and 85% by age 4 years.
  • At a typical rate of progression, the child requires a wheelchair by age 10 or 11 years, even when muscular strength continues to be good.
• Dyssynergia and intention tremor of the extremities become prominent features with age.
• Myoclonic jerks of the trunk and the extremities, particularly on intention, occur in some patients with A-T but not before age 9 or 10 years.
• The myoclonus may result in sudden and frequent falling and, in itself, make the child nonambulatory.
• The Romberg sign is negative but is often reported to be positive because of the failure to observe that swaying of the trunk is equally marked with the eyes open or closed.
• Slow initiation and performance of all voluntary activity and muscular hypotonia are characteristic and are also manifestations of cerebellar symptomatology.
• Deep reflexes may be normal in the younger child, but they are usually diminished or absent after age 7 or 8 years; the plantar responses are flexor or equivocal.
• All modalities of sensation are intact, although vibratory and position senses are usually impaired in older patients.
• Intact sensation and a negative Romberg sign are helpful in differentiating the cerebellar ataxia of A-T from Friedreich ataxia, in which the ataxia is predominantly spinal or sensory and the Romberg sign is positive.
• The early absence of spinal signs in younger patients with A-T is consistent with the histopathologic findings that significant spinal cord involvement occurs much later than the devastating early cerebellar degeneration.
• Choreoathetosis is the most prominent extrapyramidal feature in A-T.
• Choreoathetosis is seen more in older children than in younger children, in whom the purely cerebellar picture predominates and may be so marked in some patients as to overshadow or mask the ataxia.
• A dystonic component is also possible.
• Characteristic facies and postural attitudes, observed in all of the children, are part of the cerebellar hypotonia and ataxia.
• The facies is usually relaxed, dull, sad, and seemingly inattentive, which is in sharp contrast to the cheerful, alert appearance when the patient is smiling.
• The hypotonic cerebellar facies, though often described in the literature as masklike, appears so only in older patients with A-T, in whom the facial skin has become atrophic and inelastic.
• Stooping, with the shoulders drooped and the head sunk forward and usually tilted to one side, becomes the characteristic posture, and gives an impression of muscular weakness and fatigue that contributes to an appearance of premature aging.
• Dystonic posturing of the fingers is characteristic.
• Oculomotor signs are diagnostically important because they usually precede the appearance of telangiectasias and are steadily progressive.
• Saccades are slowly initiated and hypometric so that fixation of a target is obtained by head deviation rather than eye deviation, often in association with a head thrust or a forced blinking (as in Cogan ocular motor apraxia) but is present in both horizontal gaze and vertical gaze.
• Eye deviation, when obtained, is saccadic and often halts midway, and optokinetic nystagmus is absent.
• More recently, electrooculographic studies have demonstrated the difficulty in initiating voluntary and involuntary saccades, and the increased reaction time of voluntary and involuntary saccades.
• • The oculomotor signs of A-T differ from those of other cerebellar degenerations in that they combine features of both cerebellar disorders and extrapyramidal disorders.
  • A later electrooculographic study indicated that the oculomotor abnormality of A-T is sufficiently different from that of Friedreich ataxia and was valuable in the differential diagnosis.
• Dysarthria of the cerebellar type, characteristic postures, and a dull facies at rest with a slow-spreading smile contribute to the peculiar appearance of children with A-T.
• About 30% of patients have mild mental retardation. Mental retardation is not a characteristic feature of A-T; however, the results of psychometric testing show wide scatter, and intelligence quotient (IQ) scores may drop below the normal range as the disease progresses.
• Mental deficiency was reported in one third of patients on whom information was available.
• Analysis of serial test results in the early decades of life gives no indication that cognitive function is lost. Rather, the drop in IQ scores that tends to occur as the disease progresses appears to reflect an increasing disparity between the mental age and the chronologic age. It is a leveling off of mental function rather than an actual mental deterioration.
• Some older patients in their 20s and 30s have shown a selective severe loss of short-term memory, suggestive of premature aging.
• Children with A-T are generally socially responsive, appreciative, and undemanding. Parents comment on their children being "easy to take care of" and having "a good sense of humor."
• Telangiectasias are a second major clinical manifestation (nonneurologic) of the disease. They have a later onset than ataxia, first noticed after age 3-6 years and sometimes not until adolescence. They may be absent even later in some cases; however, telangiectasia can be observed considerably earlier, particularly if the clinician suspects A-T, such as in children with a prior family history.
• Dilated conjunctivae vessels, first noticed in the angles of both eyes, spread horizontally in the equatorial region of the conjunctivae toward the corneal limb. They may subtly involve the internal ears, the eyelids, and the cubital and popliteal fossas.
• Patches of telangiectasia elsewhere in the skin are less common.
• Ocular telangiectasias may be mistaken for conjunctivitis, but they can be readily distinguished because they are dilated vessels against a white background, whereas the background is pink in conjunctivitis.
• Telangiectatic vessels of A-T very rarely hemorrhage.
• The telangiectases were originally thought to be arterial in origin, but capillary microscopy indicates that they are predominantly of venous origin and are not arteriovenous fistulas.
• Progeric changes of hair and skin are a cardinal feature of A-T.
• Some gray hairs are usually found, even in young children if carefully looked for; diffuse graying of the hair may continue to increase slightly through adolescence but is no more than normally progressive thereafter.
• The facial skin tends to become atrophic and sclerodermoid in adolescence; atrophic areas resembling large varicella scars may appear.
• The ears tend to become inelastic.
• The wasted face, the scattered gray hairs, the oculocutaneous telangiectasia, and the stooped posture give the older children an appearance of premature aging.
• Chronic seborrheic blepharitis is frequent, stimulating in association with the ocular telangiectasia, a blepharoconjunctivitis.
• Some authors reported a variety of lesions in dermatologic studies.
• Pigmentary changes were frequent, occurring in a mottled pattern of hyperpigmentation and hypopigmentation with cutaneous atrophy and telangiectasia, similar to the poikiloderma seen in scleroderma, advanced actinodermatitis, or radiodermatitis, and in premature aging.
• Other skin changes include the following:
• • Café au lait spots, usually single rather than multiple
  • Frequent hyperpigmented macules resembling large freckles
  • Occasional vitiligo
• Seborrheic dermatitis; keratosis pilaris; common warts; and, in female patients, hirsutism of the arms and the legs are also frequently found.
• Multiple senile keratoses and basal cell carcinomas of the face have been reported in patients in their 20s.
• Patients with A-T have an elevated incidence of cancers, approximately 100-fold in comparison to the general population. In children, more than 85% of neoplasm cases are acute lymphocytic leukemia or lymphoma. In adults with A-T, solid tumors are more frequent (Su, 2000).
• Lymphoid malignancies in A-T are of both B-cell and T-cell origin and include non-Hodgkin lymphoma, Hodgkin lymphoma, and several forms of leukemia. The outcome of Hodgkin disease in patients with A-T is worse than in the general population due to advanced disease stage, coexisting chronic lung disease, or frequent application of insufficient doses of chemotherapy (Sandoval, 2003). At autopsy, non-Hodgkin lymphoma accounted for approximately 40% of neoplasms detected, leukemias about 20%, and Hodgkin lymphomas about 10%. The increased frequency of lymphoid tumors in A-T could possibly be accounted for by a defect in immune surveillance as part of the underlying immunodeficiency; however, the picture is more complex as malignancies are not confined to the lymphoid system.
• In 1990, Hecht and Hecht, in an analysis of 108 patients with A-T with 119 neoplasms, reported that 31 (26%) of these were solid tumors varying in the type and the location. Solid tumors include stomach cancer, breast cancer, medulloblastoma, basal-cell carcinoma, ovarian dysgerminoma, hepatoma, uterine leiomyoma, parotid gland cancer, and thyroid cancer (Sandoval, 2001; Swift, 1991). Determination of subsequent risk in patients with A-T diagnosed with one type of neoplasm revealed that approximately 25% of patients with solid tumors subsequently developed non-Hodgkin lymphoma or leukemia. A very low risk of subsequent neoplasms existed when the first tumor was lymphoid in origin.
• Genetic polymorphism of the ATM gene also plays an important role in the development of lung cancer. As documented by Kim et al in 2006, subjects with the A allele at the site (IVS62+60G>A) have a significantly higher risk of lung cancer than those with the G allele.
• Retardation of somatic growth with significant dwarfing is observed in a large proportion of the patients.
• The heights and weights of children aged 4-7 years are typically at the 10th percentile by adolescence.
• Only an exceptional patient with A-T achieves somatic growth at the 50th percentile or beyond.
• Patients with A-T who develop normal puberty are the ones most likely to achieve somatic growth within the normal range.
• The stunting of growth is not well understood. Chronic sinopulmonary disease may be a contributing factor, but stunting of growth also occurs in its absence. Other factors may include the hypogonadism typical of A-T and the thymic dysplasia. Endocrine studies performed on a number of patients give no evidence of hypothyroidism or hypopituitarism.

Causes

The A-T gene has been localized to band 11q22-23.

• The gene, called ATM (ataxia-telangiectasia mutated), is a member of a family of phosphatidylinositol-3-kinase–related genes involved in cell cycle control, intracellular protein transport, and DNA damage response.
• Little correlation exists between the level of ATM protein and the type of underlying mutation, clinical phenotype, or radiophenotype.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Friedreich disease
Cerebral palsy (cerebellar type)
Familial spinocerebellar atrophies
GM1 and GM2 gangliosidoses
Metachromatic leukodystrophy
Krabbe disease
Maple syrup urine disease
Progressive rubella panencephalitis
Subacute sclerosing panencephalitis
Postinfectious encephalomyelitis
Encephalitis
Other polyneuropathies
Cerebellar tumor

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Laboratory markers are important for both diagnosis and prognosis. The most constant markers are elevated levels of AFP and carcinoembryonic antigen and chromosomal abnormalities, especially inversions and translocations involving chromosomes 7 and 14, though neither of these abnormalities is always found and their demonstration requires specific techniques available in only a few centers.
• • The demonstration of humoral or cellular immunologic defects may also permit an early diagnosis, although such defects are nonspecific and present less frequently.
  • The dysgammaglobulinemia of A-T includes an absent or low level of IgA, including secretory IgA, a normal or low level of IgG, and an elevated or normal level of IgM. IgA deficiency is found in about 70% of patients with ataxia-telangiectasia syndrome.
  • A deficit in IgG2 and IgG4 subclasses has been demonstrated in several patients, and IgE may also be absent or low.
  • Defects of cellular immunity include a low lymphocyte count, a poor response to skin tests to common antigens, low T-lymphocyte proliferation in the presence of mitogens, and deficient antibody production to viral or bacterial antigens.
  • Excessive T-cell suppressor activity and intrinsic B-cell defects have been described in some patients, suggesting disturbances of immunoregulatory mechanisms.
  • The incidence of immunologic abnormalities increases with the age of the patients.
• Increased chromosomal breakage after exposure of cell cultures to ionizing radiation is rapidly increasing diagnostic importance, though not yet a routine procedure. Such tests have been considered for the prenatal diagnosis of A-T but are being supplanted by DNA diagnosis.
• Protein-truncation testing of the entire ATM complementary DNA (cDNA) reveals as much as 66% of truncating mutations in the group with mutant alleles. These rapid assays detected mutations in 76% of Costa Rican patients, 50% of Norwegian patients, 25% of Polish patients, and 14% of Italian patients.

Imaging Studies

• MRI and sporadically made CT scan often show evidence of nonspecific cerebellar atrophy with widened cerebellar sulci and enlargement of the fourth ventricle. According to Tavani et al, cerebellar atrophy found on MRI progresses with age, starting from early childhood (Tavani, 2003).
• Radiologic findings of decreased or absent adenoidal tissue in the nasopharynx on lateral skull radiographs are so typical in A-T that they are of value in confirming the diagnosis.
• • Chest radiographs may show a small or absent thymic shadow, decreased mediastinal lymphoid tissue, and pulmonary changes similar to those seen in cystic fibrosis.
  • Hypoplastic peripheral lymphoid tissue is such a consistent clinical finding in A-T that the appearance of lymphadenopathy or even easily palpable lymph nodes has been highly suggestive of lymphoma.

Other Tests

• Electromyogram (EMG) and nerve conduction velocities are frequently normal in small children. In later stages of the disease, when the anterior horn cells are involved and peripheral neuropathy has occurred, the EMG shows signs of denervation and the nerve conduction velocity is reduced, especially in sensory fibers.
• Electrooculography is valuable in corroborating the characteristic oculomotor abnormality of A-T and differentiating A-T from Friedreich ataxia.

Histologic Findings

The major pathological marker of A-T in the CNS is degeneration of Purkinje and granule cells in the cerebellum. No vascular abnormalities are usually found, except late degenerative gliovascular nodules in the white matter. Lesions of the basal ganglia are found only occasionally. Degeneration of spinal tracts and anterior horn cells is often present in late cases. Nucleocytomegaly is a feature of several cell types throughout the body.

Biopsy specimens have shown that the typical skin changes in A-T are similar to those seen in cumulative actinic damage and, thus, are suggestive of progeric changes. The predilection of both the progeric skin changes and the oculocutaneous telangiectases for sun-exposed areas further suggests increased propensity to actinic damage.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Although no specific treatment is available, several features of A-T are accessible to active therapy. This applies especially to infections.

• The life span of patients with A-T clearly has been prolonged by antibiotic treatment. Prevention of infections by regular injection of immunoglobulins is considered useful. Fetal thymus implants and stimulants of the immunologic system have given inconclusive results.
• Treatment of neurologic manifestations is disappointing. Beta-adrenergic blockers may improve fine motor coordination in some cases.
• The use and doses of radiation therapy and chemotherapy are controversial. Some reports indicate that standard-dose chemotherapy should be given to each patient with A-T with lymphoid malignancies (Sandoval, 1998; Sandoval, 2003), whereas others advise reduced doses, especially for alkylating agents (Seidemann, 2000). According to some references, bleomycin, actinomycin D, and cyclophosphamide should be avoided.
• Regular surveillance of heterozygotes for cancer should be part of family management. ATM heterozygosity was reported to be a risk factor for breast and lung cancers (Olsen, 2001; Swift, 1991; Swift, 1987). ATM carriers are also suggested to be more vulnerable at X-radiation, as in many cases breast cancer occurrence was preceded by x-ray exposure (Swift, 1987).
• Recently, desferrioxamine was shown to increase genomic stability of A-T cells (Shackelford, 2003) and, therefore, may present a promising tool in A-T treatment.

Consultations

• Provide genetic counseling to all patients with A-T and their family members.
• Consult a neurologist, a cardiologist, and an endocrinologist as determined by the patient's history and physical examination.
• Rehabilitation and adequate educative support are always necessary.
• • Physical therapy is useful in maintaining good muscular strength, preventing limb contractures, and learning techniques of falling to avoid injury.
  • Occupational therapy helps to develop functional adaptions in the activities of daily living.
  • Speech therapy may be useful in improving articulation and in increasing voice volume.

Activity

Daily participation (to tolerance) in a structured physical fitness program, which may include swimming, use of a special bicycle, and graduated weight lifting, is useful in maintaining good muscular strength and preventing limb contractures and, thus, may postpone confinement to a wheelchair.

FOLLOW-UP

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Inpatient care is needed if indicated by associated abnormalities or complications.

Further Outpatient Care

• Patients with A-T should undergo regular examinations for early cancer detection.

Complications

• Early death is frequently due to pulmonary disease, but malignancies are also a common cause.
• • The incidence of malignancy is 60-300 times higher than in healthy persons, and, on autopsy report, 49% of cases had malignant tumors.
  • The most common tumors are lymphoreticular malignancies, especially non-Hodgkin lymphomas, but other kinds of tumors also occur.
  • Malignancies are also more common in obligate heterozygotes than in the general population.

Prognosis

• The neurologic features of A-T are relentlessly progressive. In addition to the classic early features, older patients tend to develop other signs of spinocerebellar degeneration (eg, posterior cord involvement with loss of the deep tendon reflexes, spinal muscular atrophy). Most patients are wheelchair dependent by age 10-15 years, but mild forms are not rare.

Patient Education

• Good patient and parental education should include tactful genetic counseling and an explanation of the multisystem nature of the disease.
• Pay special attention to the susceptibility of adult members of families with A-T to malignant neoplasms and to the importance of regular examinations for early cancer detection.

MISCELLANEOUS

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to provide a thorough evaluation to identify any associated anomalies is a pitfall.
• Failure to evaluate the patient's siblings is a pitfall.
• Failure to provide genetic counseling is a pitfall. The need for genetic counseling is implied by the autosomal recessive mode of inheritance.

Special Concerns

• Identification of the disease gene for A-T has opened a number of avenues for research. While further mutation analysis will provide insight into the defect and genotype-phenotype correlations, it is also possible to contemplate correction of the abnormal phenotype by using full-length ATM (A-T, mutated) cDNA transfer. Full-length constructs that have been cloned and introduced into other vectors may allow for the correct radiosensitive phenotype. Insertion of the full-length cDNA into other vectors may allow for correction in vivo. Antibodies against the ATM protein are being used for screening tumor samples for loss of expression. Other approaches, such as the yeast 2-hybrid system, will be used to identify additional cellular proteins that associate with ATM.
• Because A-T heterozygotes appear to be predisposed to a number of tumors, including breast cancer, it may become useful in the future to screen selected at-risk individuals for ATM mutations. Such persons might include members of families with a history of breast cancer or individuals who show an adverse reaction to radiation therapy. The observation that approximately 70% of mutations in the ATM gene known to date appear to encode truncated proteins with premature stop codons will allow for application of such assays as the protein truncation test, which is capable of detecting a single mutated allele. It may also be possible to carry out rapid screening with antibodies to detect A-T heterozygotes with ATM of both normal size and reduced size.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Face of a boy with ataxia-telangiectasia. Apparent ocular telangiectasia.
	View Full Size Image
Media type:  Photo

Media file 2:  Close-up view of advanced telangiectasia of the bulbar conjunctiva.
	View Full Size Image
Media type:  Photo

Media file 3:  Chest MRI showing a hyperintense lesion in the right mediastinum corresponding to lymphoma.
	View Full Size Image
Media type:  MRI

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

• Andrews BF, Kopack FM, Bruton OC. A syndrome of ataxia, oculocutaneous telangiectasia, and sinopulmonary infections. U S Armed Forces Med J. May 1960;11:587-92. [Medline].
• Athma P, Rappaport R, Swift M. Molecular genotyping shows that ataxia-telangiectasia heterozygotes arepredisposed to breast cancer. Cancer Genet Cytogenet. Dec 1996;92(2):130-4. [Medline].
• Baumer A, Bernthaler U, Wolz W, et al. New mutations in the ataxia telangiectasia gene. Hum Genet. Aug 1996;98(2):246-9. [Medline].
• Beamish H, Lavin MF. Radiosensitivity in ataxia-telangiectasia: anomalies in radiation-induced cell cycle delay. Int J Radiat Biol. Feb 1994;65(2):175-84. [Medline].
• Becker-Catania SG, Chen G, Hwang MJ, et al. Ataxia-telangiectasia: phenotype/genotype studies of ATM proteinexpression, mutations, and radiosensitivity. Mol Genet Metab. Jun 2000;70(2):122-33. [Medline].
• Biemond A. Paleocerebellar atrophy with extrapyramidal manifestations in association with bronchiectasis and telangiectasis of the conjunctiva bulbi as a familial syndrome. van Bogaert L, Radermecker J, eds. Proceedings of the First International Congress. 1957;206.
• Boder E. Ataxia-Telangiectasia. In: Gomez MR, ed. Neurocutaneous Diseases: A Practical Approach. Boston, Mass: Butterworth-Heinemann; 1987:. 95-117.
• Borresen AL, Andersen TI, Tretli S, et al. Breast cancer and other cancers in Norwegian families withataxia-telangiectasia. Genes Chromosomes Cancer. Nov 1990;2(4):339-40. [Medline].
• Browne SE, Roberts LJ 2nd, Dennery PA, et al. Treatment with a catalytic antioxidant corrects the neurobehavioral defect in ataxia-telangiectasia mice. Free Radic Biol Med. Apr 1 2004;36(7):938-42. [Medline].
• Centerwall WR, Miller MM. Ataxia, telangiectasia, and sinopulmonary infections; a syndrome of slowly progressive deterioration in childhood. AMA J Dis Child. Apr 1958;95(4):385-96. [Medline].
• Chen P, Imray FP, Kidson C. Gene dosage and complementation analysis of ataxia telangiectasia lymphoblastoid cell lines assayed by induced chromosome aberrations. Mutat Res. Nov 1984;129(2):165-72. [Medline].
• Chen P, Farrell A, Hobson K. Comparative study of radiation-induced G2 phase delay and chromatid damage in families with ataxia-telangiectasia. Cancer Genet Cytogenet. Aug 1994;76(1):43-6. [Medline].
• Chessa L, Petrinelli P, Antonelli A, et al. Heterogeneity in ataxia-telangiectasia: classical phenotype associated with intermediate cellular radiosensitivity. Am J Med Genet. Mar 1 1992;42(5):741-6. [Medline].
• Chun HH, Gatti RA. Ataxia-telangiectasia, an evolving phenotype. DNA Repair (Amst). Aug-Sep 2004;3(8-9):1187-96. [Medline].
• Dulic V, Kaufmann WK, Wilson SJ, et al. p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest. Cell. Mar 25 1994;76(6):1013-23. [Medline].
• Edwin Shackelford R, Manuszak RP, Heard SC, et al. Pharmacological manipulation of ataxia-telangiectasia kinase activity as a treatment for Parkinson's disease. Med Hypotheses. 2005;64(4):736-41. [Medline].
• Enoch T, Norbury C. Cellular responses to DNA damage: cell-cycle checkpoints, apoptosis andthe roles of p53 and ATM. Trends Biochem Sci. Oct 1995;20(10):426-30. [Medline].
• Epstein WL, Fudenberg HH, Reed WB, et al. Immunologic studies in ataxia-telangiectasia. I. Delayed hypersensitivityand serum immune globulin levels in probands and first-degree relatives. Int Arch Allergy Appl Immunol. 1966;30(1):15-29. [Medline].
• Finlan LE, Hupp TR. Epidermal stem cells and cancer stem cells: insights into cancer and potential therapeutic strategies. Eur J Cancer. Jun 2006;42(9):1283-92. [Medline].
• Foray N, Priestley A, Alsbeih G, et al. Hypersensitivity of ataxia telangiectasia fibroblasts to ionizingradiation is associated with a repair deficiency of DNA double-strandbreaks. Int J Radiat Biol. Sep 1997;72(3):271-83. [Medline].
• Gatti RA, Becker-Catania S, Chun HH, et al. The pathogenesis of ataxia-telangiectasia. Learning from a Rosetta Stone. Clin Rev Allergy Immunol. Feb 2001;20(1):87-108. [Medline].
• Gatti RA, Berkel I, Boder E, et al. Localization of an ataxia-telangiectasia gene to chromosome 11q22-23. Nature. Dec 8 1988;336(6199):577-80. [Medline].
• Gatti RA, Boder E, Vinters HV, et al. Ataxia-telangiectasia: an interdisciplinary approach to pathogenesis. Medicine (Baltimore). Mar 1991;70(2):99-117. [Medline].
• Gilad S, Khosravi R, Shkedy D, et al. Predominance of null mutations in ataxia-telangiectasia. Hum Mol Genet. Apr 1996;5(4):433-9. [Medline].
• Guerra-Maranhao MC, Costa-Carvalho BT, Nudelman V, et al. Response to polysaccharide antigens in patients with ataxia-telangiectasia. J Pediatr (Rio J). Mar-Apr 2006;82(2):132-6. [Medline].
• Gueven N, Becherel OJ, Birrell G, et al. Defective p53 response and apoptosis associated with an ataxia-telangiectasia-like phenotype. Cancer Res. Mar 15 2006;66(6):2907-12. [Medline].
• Gutmann L, Lemli L. Ataxia-telangiectasia associated with hypogammaglobulinemia. Arch Neurol. Mar 1963;8:318-27. [Medline].
• Hecht F, Hecht BK. Cancer in ataxia-telangiectasia patients. Cancer Genet Cytogenet. May 1990;46(1):9-19. [Medline].
• Hernandez D, McConville CM, Stacey M, et al. A family showing no evidence of linkage between the ataxia telangiectasiagene and chromosome 11q22-23. J Med Genet. Feb 1993;30(2):135-40. [Medline].
• Innes CL, Heinloth AN, Flores KG, et al. ATM requirement in gene expression responses to ionizing radiation in human lymphoblasts and fibroblasts. Mol Cancer Res. Mar 2006;4(3):197-207. [Medline].
• Jaspers NG, Taalman RD, Baan C. Patients with an inherited syndrome characterized by immunodeficiency, microcephaly, and chromosomal instability: genetic relationship to ataxia telangiectasia. Am J Hum Genet. Jan 1988;42(1):66-73. [Medline].
• Jaspers NG, Gatti RA, Baan C, et al. Genetic complementation analysis of ataxia telangiectasia and Nijmegen breakage syndrome: a survey of 50 patients. Cytogenet Cell Genet. 1988;49(4):259-63. [Medline].
• Kamsler A, Daily D, Hochman A, et al. Increased oxidative stress in ataxia telangiectasia evidenced by alterations in redox state of brains from Atm-deficient mice. Cancer Res. Mar 1 2001;61(5):1849-54. [Medline].
• Kapp LN, Painter RB, Yu LC, et al. Cloning of a candidate gene for ataxia-telangiectasia group D. Am J Hum Genet. Jul 1992;51(1):45-54. [Medline].
• Khanna KK, Lavin MF. Ionizing radiation and UV induction of p53 protein by different pathways in ataxia-telangiectasia cells. Oncogene. Dec 1993;8(12):3307-12. [Medline].
• Khanna KK, Chenevix-Trench G. ATM and genome maintenance: defining its role in breast cancer susceptibility. J Mammary Gland Biol Neoplasia. Jul 2004;9(3):247-62. [Medline].
• Kim JH, Kim H, Lee KY, et al. Genetic polymorphisms of ataxia telangiectasia mutated affect lung cancer risk. Hum Mol Genet. Apr 1 2006;15(7):1181-6. [Medline].
• Kojima K, Konopleva M, McQueen T, et al. Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Mdm2 and Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia. Blood. Mar 16 2006;[Medline].
• Kuljis RO, Xu Y, Aguila MC, Baltimore D. Degeneration of neurons, synapses, and neuropil and glial activation in a murine Atm knockout model of ataxia-telangiectasia. Proc Natl Acad Sci U S A. Nov 11 1997;94(23):12688-93. [Medline].
• Lange E, Borresen AL, Chen X, et al. Localization of an ataxia-telangiectasia gene to an approximately 500- kb interval on chromosome 11q23.1: linkage analysis of 176 families by an international consortium. Am J Hum Genet. Jul 1995;57(1):112-9. [Medline].
• Lavin MF, Khanna KK, Beamish H, et al. Defect in radiation signal transduction in ataxia-telangiectasia. Int J Radiat Biol. Dec 1994;66(6 Suppl):S151-6. [Medline].
• Lee KM, Choi JY, Park SK, et al. Genetic polymorphisms of ataxia telangiectasia mutated and breast cancer risk. Cancer Epidemiol Biomarkers Prev. Apr 2005;14(4):821-5. [Medline].
• Lee Y, Chong MJ, McKinnon PJ. Ataxia telangiectasia mutated-dependent apoptosis after genotoxic stress in the developing nervous system is determined by cellular differentiation status. J Neurosci. Sep 1 2001;21(17):6687-93. [Medline].
• Louis-Bar D. Sur syndrome progressif comprenant des telangiectasies capillaires cutanees et conjonctivales symetriques, a disposition naevoide et de troubles cerebelleux. Confin Neurol (Basel). 1941;4:32-42.
• McConville CM, Stankovic T, Byrd PJ, et al. Mutations associated with variant phenotypes in ataxia-telangiectasia. Am J Hum Genet. Aug 1996;59(2):320-30. [Medline].
• McConville CM, Byrd PJ, Ambrose HJ, Taylor AM. Genetic and physical mapping of the ataxia-telangiectasia locus onchromosome 11q22-q23. Int J Radiat Biol. Dec 1994;66(6 Suppl):S45-56. [Medline].
• McFarlin DE, Strober W, Waldmann TA. Ataxia-telangiectasia. Medicine (Baltimore). Jul 1972;51(4):281-314. [Medline].
• Meyn MS. High spontaneous intrachromosomal recombination rates in ataxia-telangiectasia. Science. May 28 1993;260(5112):1327-30. [Medline].
• Meyn MS. Ataxia-telangiectasia and cellular responses to DNA damage. Cancer Res. Dec 15 1995;55(24):5991-6001. [Medline].
• Mondello C, Faravelli M, Pipitone L, et al. Gene amplification in fibroblasts from ataxia telangiectasia (AT) patientsand in X-ray hypersensitive AT-like Chinese hamster mutants. Carcinogenesis. Jan 2001;22(1):141-5. [Medline].
• Morgan JL, Holcomb TM, Morrissey RW. Radiation reaction in ataxia telangiectasia. Am J Dis Child. Nov 1968;116(5):557-8. [Medline].
• Morrell D, Chase CL, Swift M. Cancers in 44 families with ataxia-telangiectasia. Cancer Genet Cytogenet. Nov 1 1990;50(1):119-23. [Medline].
• Morrell D, Cromartie E, Swift M. Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. J Natl Cancer Inst. Jul 1986;77(1):89-92. [Medline].
• Olsen JH, Hahnemann JM, Børresen-Dale AL, et al. Cancer in patients with ataxia-telangiectasia and in their relatives in the nordic countries. J Natl Cancer Inst. Jan 17 2001;93(2):121-7. [Medline].
• Pietrucha B, Skopczyl H, Nowacka K, et al. Humoral deficiency disorders in ataxia-telangiectasia syndrome. Ped Pol. 1998;73:395-8.
• Qi L, Strong MA, Karim BO, et al. Short telomeres and ataxia-telangiectasia mutated deficiency cooperatively increase telomere dysfunction and suppress tumorigenesis. Cancer Res. Dec 1 2003;63(23):8188-96. [Medline].
• Rotman G, Savitski K, Vanagaite L, et al. Physical and genetic mapping at the ATA/ATC locus on chromosome 11q22-23. Int J Radiat Biol. Dec 1994;66(6 Suppl):S63-6. [Medline].
• Sandoval C, Schantz S, Posey D, Swift M. Parotid and thyroid gland cancers in patients with ataxia-telangiectasia. Pediatr Hematol Oncol. Dec 2001;18(8):485-90. [Medline].
• Sandoval C, Swift M. Hodgkin disease in ataxia-telangiectasia patients with poor outcomes. Med Pediatr Oncol. Mar 2003;40(3):162-6. [Medline].
• Sandoval C, Swift M. Treatment of lymphoid malignancies in patients with ataxia-telangiectasia. Med Pediatr Oncol. Dec 1998;31(6):491-7. [Medline].
• Savitsky K, Platzer M, Uziel T, et al. Ataxia-telangiectasia: structural diversity of untranslated sequences suggests complex post-transcriptional regulation of ATM gene expression. Nucleic Acids Res. May 1 1997;25(9):1678-84. [Medline].
• Sedgwick RP, Boder E. Progressive ataxia in childhood with particular reference to ataxia-telangiectasia. Neurology. Jul 1960;10:705-15. [Medline].
• Seidemann K, Henze G, Beck JD, et al. Non-Hodgkin''s lymphoma in pediatric patients with chromosomal breakage syndromes (AT and NBS): experience from the BFM trials. Ann Oncol. 2000;11 Suppl 1:141-5. [Medline].
• Senior K. DNA damage mechanisms in ataxia telangiectasia. Lancet Neurol. 2003;2 (3):139.
• Shackelford RE, Manuszak RP, Johnson CD, et al. Desferrioxamine treatment increases the genomic stability of Ataxia-telangiectasia cells. DNA Repair (Amst). Sep 18 2003;2(9):971-81. [Medline].
• Shiloh Y. Ataxia-telangiectasia: closer to unraveling the mystery. Eur J Hum Genet. 1995;3(2):116-38. [Medline].
• Shiloh Y, Andegeko Y, Tsarfaty I. In search of drug treatment for genetic defects in the DNA damage response: the example of ataxia-telangiectasia. Semin Cancer Biol. Aug 2004;14(4):295-305. [Medline].
• Shiotani B, Kobayashi M, Watanabe M, et al. Involvement of the ATR- and ATM-dependent checkpoint responses in cell cycle arrest evoked by pierisin-1. Mol Cancer Res. Feb 2006;4(2):125-33. [Medline].
• Spector BD, Filipovich AH, Perry GS, et al. Epidemiology of cancer in ataxia-telangiectasia. In: Bridges BA, Harnden DG, eds. Ataxia-Telangiectasia â€" A Cellular and Molecular Link Between Cancer, Neuropathology, and Immune Deficiency. New York, NY: Wiley; 1982:. 103-37.
• Su Y, Swift M. Mortality rates among carriers of ataxia-telangiectasia mutant alleles. Ann Intern Med. Nov 21 2000;133(10):770-8. [Medline].
• Swift M, Morrell D, Cromartie E, et al. The incidence and gene frequency of ataxia-telangiectasia in the UnitedStates. Am J Hum Genet. Nov 1986;39(5):573-83. [Medline].
• Swift M, Morrell D, Massey RB, Chase CL. Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med. Dec 26 1991;325(26):1831-6. [Medline].
• Swift M, Reitnauer PJ, Morrell D, Chase CL. Breast and other cancers in families with ataxia-telangiectasia. N Engl J Med. May 21 1987;316(21):1289-94. [Medline].
• Syllaba L, Henner K. Contribution a l'independance de l'athetose double idiopathique et congenitale. Rev Neurol (Paris). 1926;1:541-562.
• Tavani F, Zimmerman RA, Berry GT, et al. Ataxia-telangiectasia: the pattern of cerebellar atrophy on MRI. Neuroradiology. May 2003;45(5):315-9. [Medline].
• Telatar M, Teraoka S, Wang Z, et al. Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. Am J Hum Genet. Jan 1998;62(1):86-97. [Medline].
• Telatar M, Wang Z, Udar N, et al. Ataxia-telangiectasia: mutations in ATM cDNA detected byprotein-truncation screening. Am J Hum Genet. Jul 1996;59(1):40-4. [Medline].
• Teraoka SN, Telatar M, Becker-Catania S, et al. Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences. Am J Hum Genet. Jun 1999;64(6):1617-31. [Medline].
• Trimis GG, Athanassaki CK, Kanariou MM, Giannoulia-Karantana AA. Unusual absence of neurologic symptoms in a six-year old girl with ataxia-telangiectasia. J Postgrad Med. Oct-Dec 2004;50(4):270-1. [Medline].
• Vanagaite L, James MR, Rotman G, et al. A high-density microsatellite map of the ataxia-telangiectasia locus. Hum Genet. Apr 1995;95(4):451-4. [Medline].
• Watters D, Khanna KK, Beamish H, et al. Cellular localisation of the ataxia-telangiectasia (ATM) gene product and discrimination between mutated and normal forms. Oncogene. Apr 24 1997;14(16):1911-21. [Medline].
• Woods CG, Taylor AM. Ataxia telangiectasia in the British Isles: the clinical and laboratoryfeatures of 70 affected individuals. Q J Med. Feb 1992;82(298):169-79. [Medline].
• Woods CG, Bundey SE, Taylor AM. Unusual features in the inheritance of ataxia telangiectasia. Hum Genet. May 1990;84(6):555-62. [Medline].
• Wright J, Teraoka S, Onengut S, et al. A high frequency of distinct ATM gene mutations in ataxia-telangiectasia. Am J Hum Genet. Oct 1996;59(4):839-46. [Medline].
• Wu X, Shell SM, Yang Z, Zou Y. Phosphorylation of nucleotide excision repair factor xeroderma pigmentosum group A by ataxia telangiectasia mutated and Rad3-related-dependent checkpoint pathway promotes cell survival in response to UV irradiation. Cancer Res. Mar 15 2006;66(6):2997-3005. [Medline].
• Wu ZH, Shi Y, Tibbetts RS, Miyamoto S. Molecular linkage between the kinase ATM and NF-kappaB signaling in response to genotoxic stimuli. Science. Feb 24 2006;311(5764):1141-6. [Medline].
• Xu Y, Ashley T, Brainerd EE, et al. Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev. Oct 1 1996;10(19):2411-22. [Medline].
• Yang Y, Herrup K. Loss of neuronal cell cycle control in ataxia-telangiectasia: a unified disease mechanism. J Neurosci. Mar 9 2005;25(10):2522-9. [Medline].
• Yih LH, Lee TC. Arsenite induces p53 accumulation through an ATM-dependent pathway inhuman fibroblasts. Cancer Res. Nov 15 2000;60(22):6346-52. [Medline].
• Zhang J, Lahti JM, Bruce A, et al. Identification of an ataxia telangiectasia-mutated protein mediated surveillance system to regulate Bcl-2 overexpression. Oncogene. Apr 24 2006;[Medline].
• Zhang N, Chen P, Khanna KK, et al. Isolation of full-length ATM cDNA and correction of theataxia-telangiectasia cellular phenotype. Proc Natl Acad Sci U S A. Jul 22 1997;94(15):8021-6. [Medline].
• Zhou J, Lim CU, Li JJ, et al. The role of NBS1 in the modulation of PIKK family proteins ATM and ATR in the cellular response to DNA damage. Cancer Lett. Mar 9 2006;[Medline].
• Ziv Y, Rotman G, Frydman M, et al. The ATC (ataxia-telangiectasia complementation group C) locus localizes to11q22-q23. Genomics. Feb 1991;9(2):373-5. [Medline].
• Ziv Y, Bar-Shira A, Pecker I, et al. Recombinant ATM protein complements the cellular A-T phenotype. Oncogene. Jul 10 1997;15(2):159-67. [Medline].

Article Last Updated: Jul 20, 2006