Ataxia-Telangiectasia 

Updated: Apr 22, 2019
Author: Camila K Janniger, MD; Chief Editor: Dirk M Elston, MD 

Overview

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 (see image below), 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.[1]

Face of a boy with ataxia-telangiectasia. Apparent Face of a boy with ataxia-telangiectasia. Apparent ocular telangiectasia.

The clinical and immunological presentation of ataxia-telangiectasia may differ even within the same family, as described by Soresina et al.[2]

Syllaba and Henner first published descriptions of patients with ataxia-telangiectasia in 1926.[3] 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.[4] The syndrome subsequently received the name of Louis-Bar. Ataxia-telangiectasia was not described as a distinct clinical entity for another 16 years until Boder and Sedgwick[5] in 1957 and Biemond[6] in 1957, with the aid of autopsies, reported organ developmental abnormalities; neurologic manifestations; and a third major feature of the disease, recurrent sinopulmonary infection.

Ataxia-telangiectasia 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.

Ataxia-telangiectasia can also be classified among the neurocutaneous syndromes, although not among the phakomatoses as originally proposed, because the vascular and cutaneous lesions of ataxia-telangiectasia are not congenital nevi but develop in the course of the disease as a progeric manifestation. Ataxia-telangiectasia 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.

Elevated immunoglobulin M (IgM) occurs in only 60% of patients, challenging this finding as a probable diagnosis criterion.[7]

Also see Ataxia-Telangiectasia in Ophthalmology.

Pathophysiology

The ATM gene encodes the protein kinase ATM, which is the key regulator of cellular response to double-strand breaks (DSB) in DNA. Therefore, ataxia-telangiectasia symptoms include all the possible consequences of the perturbations in DNA damage response (DDR).[8, 9, 10]

One basic defect associated with the malady is the abnormal sensitivity of ataxia-telangiectasia 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, ataxia-telangiectasia 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.[11] The authors analyzed the production of antibodies to polysaccharide antigens in patients with ataxia-telangiectasia 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 ataxia-telangiectasia families have consistently reported an increased risk of breast cancer in women with one mutated ATM gene,[12] but, to date, an increased frequency of ATM mutations has not been found in women with breast cancer.[13]

ATM mutations are poor prognostic factor in patients with lung cancer.[14]

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.[15, 16] ATM has been shown to be pivotal for neurodevelopment, especially for stem cell differentiation, as well as for elimination of damaged postmitotic cells.[17] Frappart and McKinnon showed that the ATM protein has a proapoptotic function in the developing mouse CNS, acting in cooperation with another key proapoptotic factor—Bax protein.[18] ATM-dependent apoptosis occurred only in postmitotic populations of neurons after irradiation.

These results suggest that ATM may serve to eliminate neurons with excessive DNA damage during CNS development. 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.

Research suggests that ataxia-telangiectasia 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 ataxia-telangiectasia cell genomic stability and viability and activate ATM-dependent cellular events in normal cells, Edwin Shackelford et al suggested that pharmacological manipulation of ATM activity via iron chelation might have clinical efficacy in Parkinson disease treatment.[19]  Targeted next-generation sequencing is a rapid cost-effective method that identified five disease-causing variants in three Chinese probands in one study.[20]

Etiology

The ataxia-telangiectasia 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. The discovery of this gene has also led to phenotypic spectrum expansion.[21]  Also see Laboratory Studies.

Epidemiology

Frequency

Ataxia-telangiectasia is reported in all regions of the world. The probable incidence of ataxia-telangiectasia is about 1 case in 100,000 births.[22] The frequency of ataxia-telangiectasia mutant allele heterozygosity was reported to be 1.4-2% of the general population.[22, 23] The incidence of ataxia-telangiectasia was significantly higher in the highly consanguineous Bedouin population than in the relatively nonconsanguineous Jewish population of southern Israel.[24]

Race

Ataxia-telangiectasia is reported in all races, although the mortality ratios differ between the ethnic groups.

Sex

Ataxia-telangiectasia 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. Trimis et al reported a 6-year-old girl without any neurological symptoms.[25]

Oculocutaneous telangiectasia, the second diagnostic hallmark of ataxia-telangiectasia, usually has a later onset than the ataxia, typically at age 3-6 years.

The progression of the disease is apparent in subsequent years.

Prognosis

The neurologic features of ataxia-telangiectasia 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.

Gene therapy holds promise for the future.[26]

A 20-month-old girl with T-cell acute lymphoblastic leukemia and ataxia-telangiectasia was apparently cured after only 7 weeks of antileukemic therapy, as she was reported in remission for 8 years.[27]

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.[23] To date, the longest reported survival is 34 years.[28] In a retrospective study in the United States, mortality from all causes in ataxia-telangiectasia was 50- and 147-fold higher for white and black patients with ataxia-telangiectasia, respectively, than expected based on overall US mortality rates.[29]

Boder 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.[30]

The lifetime risk of cancer among patients with ataxia-telangiectasia has been estimated to be 10-38%,[31, 32, 33] which is about 100-fold more than the population rate[29] ; however, in the absence of chronic bronchopulmonary disease and lymphoreticular malignancy, ataxia-telangiectasia is consistent with survival into the fifth or sixth decade.

Ataxia-telangiectasia heterozygotes present an excess risk of death (they die 7-8 y earlier than the normal population), mostly from ischemic heart disease (ataxia-telangiectasia carriers die 11 y younger than noncarriers) or cancer (ataxia-telangiectasia carriers die 4 y younger than noncarriers).[23]

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 ataxia-telangiectasia to malignant neoplasms and to the importance of regular examinations for early cancer detection.

 

Presentation

History

Even in classic ataxia-telangiectasia 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 ataxia-telangiectasia 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 ataxia-telangiectasia 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 ataxia-telangiectasia.

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 Examination

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

Face of a boy with ataxia-telangiectasia. Apparent Face of a boy with ataxia-telangiectasia. Apparent ocular telangiectasia.
Close-up view of advanced telangiectasia of the bu Close-up view of advanced telangiectasia of the bulbar conjunctiva.

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 ataxia-telangiectasia.

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 ataxia-telangiectasia, 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 ataxia-telangiectasia 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 ataxia-telangiectasia 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 ataxia-telangiectasia 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 ataxia-telangiectasia.

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. Rarely, it may be the pivotal symptom.[34]

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 ataxia-telangiectasia, 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 ataxia-telangiectasia 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 ataxia-telangiectasia 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 ataxia-telangiectasia.

About 30% of patients have mild mental retardation. Mental retardation is not a characteristic feature of ataxia-telangiectasia; 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 ataxia-telangiectasia 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 ataxia-telangiectasia, 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. Refer to the image below.

Close-up view of advanced telangiectasia of the bu Close-up view of advanced telangiectasia of the bulbar conjunctiva.

Telangiectatic vessels of ataxia-telangiectasia 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 ataxia-telangiectasia.

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.

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.[35]

Other skin changes include the following:

  • Café au lait spots, usually single rather than multiple

  • Frequent hyperpigmented macules resembling large freckles

  • Occasional vitiligo

  • Cutaneous granulomas: These noninfectious findings may precede the diagnosis of this immunodeficiency disorder and two others—combined variable immunodeficiency and severe combined immunodeficiency.[36, 37] These granulomas were evident clinically as red-brownish nodules and infiltrated ulcerative plaques, often evident on the face and limbs.[38] These granulomas have been linked with rubella as a complicating infection.[39]

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 ataxia-telangiectasia 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 ataxia-telangiectasia, solid tumors are more frequent.[23]

Lymphoid malignancies in ataxia-telangiectasia 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 ataxia-telangiectasia is worse than in the general population due to advanced disease stage, coexisting chronic lung disease, or frequent application of insufficient doses of chemotherapy.[40] 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 ataxia-telangiectasia 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.

Hecht and Hecht, in an analysis of 108 patients with ataxia-telangiectasia with 119 neoplasms, reported that 31 (26%) of these were solid tumors varying in the type and the location.[41] Solid tumors include stomach cancer, breast cancer, medulloblastoma, basal-cell carcinoma, ovarian dysgerminoma, hepatoma, uterine leiomyoma, parotid gland cancer, and thyroid cancer.[42, 43] Brain tumors reported in ataxia-telangiectasia patients include medulloblastomas, multiform glioblastomas, and pilocytic astrocytomas.[44] Determination of subsequent risk in patients with ataxia-telangiectasia 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, 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.[45]

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 ataxia-telangiectasia achieves somatic growth at the 50th percentile or beyond. Patients with ataxia-telangiectasia 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 ataxia-telangiectasia and the thymic dysplasia. Endocrine studies performed on a number of patients give no evidence of hypothyroidism or hypopituitarism.

Other likely unrelated cutaneous disorders, including acneiform eruptions, may occur in affected children.[46]

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.

 

DDx

Diagnostic Considerations

Also consider the following:

  • 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

Differential Diagnoses

 

Workup

Laboratory Studies

Laboratory markers are important for both diagnosis and prognosis. The most constant markers are elevated levels of alpha-fetoprotein (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 ataxia-telangiectasia includes an absent or low level of immunoglobulin A (IgA), including secretory IgA; a normal or low level of immunoglobulin G (IgG); and an elevated or normal level of immunoglobulin M (IgM). Elevated IgM is evident in only 60% of patients.[7] 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.

Genetic testing

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 ataxia-telangiectasia 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.

Identification of the disease gene for ataxia-telangiectasia 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 ataxia-telangiectasia 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 ataxia-telangiectasia heterozygotes with ATM of both normal size and reduced size.

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 MRIs progresses with age, starting from early childhood.[47] Cerebral white matter dysmyelination or demyelination, microhemorrhages and teleangiectases also are reported.[44] See image shown below.

Chest MRI showing a hyperintense lesion in the rig Chest MRI showing a hyperintense lesion in the right mediastinum corresponding to lymphoma.

Radiologic findings of decreased or absent adenoidal tissue in the nasopharynx on lateral skull radiographs are so typical in ataxia-telangiectasia 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 ataxia-telangiectasia 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 ataxia-telangiectasia and differentiating ataxia-telangiectasia from Friedreich ataxia.

Histologic Findings

The major pathological marker of ataxia-telangiectasia 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 ataxia-telangiectasia 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. Histologically, cutaneous granulomas with this primary immunodeficiency disorder may be sarcoidal, tuberculoid, palisaded, or undefined, with several different granulomatous patterns sometimes evident in the same biopsy specimen.[38]

 

Treatment

Medical Care

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

The life span of patients with ataxia-telangiectasia 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 ataxia-telangiectasia with lymphoid malignancies,[40, 48] whereas others advise reduced doses, especially for alkylating agents.[49] 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.[31, 43, 50] 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.[50]

Desferrioxamine has been shown to increase genomic stability of ataxia-telangiectasia cells and, therefore, may present a promising tool in ataxia-telangiectasia treatment.[51]

Concerning the role of increased oxidative stress in ataxia-telangiectasia pathophysiology, several clinical trials based on antioxidants in ataxia-telangiectasia patients have been constructed and are currently underway.[52]

Consultations

Provide genetic counseling to all patients with ataxia-telangiectasia 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.

Long-Term Monitoring

Patients with ataxia-telangiectasia should undergo regular examinations for early cancer detection.

 

Questions & Answers

Overview

What is ataxia-telangiectasia (A-T)?

What is the pathophysiology of ataxia-telangiectasia (A-T)?

What causes ataxia-telangiectasia (A-T)?

What is the prevalence of ataxia-telangiectasia (A-T)?

What are the racial predilections of ataxia-telangiectasia (A-T)?

What are the sexual predilections of ataxia-telangiectasia (A-T)?

At what age does ataxia-telangiectasia (A-T) typically present?

What is the prognosis of ataxia-telangiectasia (A-T)?

What is included in patient education about ataxia-telangiectasia (A-T)?

Presentation

Which clinical history findings are characteristic of ataxia-telangiectasia (A-T)?

Which physical findings are characteristic of ataxia-telangiectasia (A-T)?

What are the possible complications of ataxia-telangiectasia (A-T)?

DDX

Which conditions are included in the differential diagnoses of ataxia-telangiectasia (A-T)?

What are the differential diagnoses for Ataxia-Telangiectasia?

Workup

What is the role of lab tests in the workup of ataxia-telangiectasia (A-T)?

What is the role of genetic testing in the workup of ataxia-telangiectasia (A-T)?

What is the role of imaging studies in the workup of ataxia-telangiectasia (A-T)?

What is the role of EMG in the workup of ataxia-telangiectasia (A-T)?

Which histologic findings are characteristic of ataxia-telangiectasia (A-T)?

Treatment

How is ataxia-telangiectasia (A-T) treated?

Which specialist consultations are beneficial to patients with ataxia-telangiectasia (A-T)?

Which activity modifications are used in the treatment of ataxia-telangiectasia (A-T)?

What is included in the long-term monitoring of ataxia-telangiectasia (A-T)?