Ataxia-telangiectasia …

David T Hsieh MD

General Child Neurology

Updated 01.22.2024
Released 07.12.1994
Expires For CME 01.22.2027

Ataxia-telangiectasia

Author: David T Hsieh MD

See Contributor Disclosures

Editor: Ann Tilton MD

Ataxia-telangiectasia

In This Article

Quick Link

Introduction

Overview

Ataxia-telangiectasia is an autosomal recessive condition of genomic instability that clinically presents in childhood as progressive ataxia and incoordination, dilated blood vessels of skin and conjunctiva, frequent sinus and pulmonary infections due to immune deficiencies, and an increased risk of certain malignancies. Elevated serum alpha-fetoprotein is seen in over 90% of patients; molecular testing of the ataxia telangiectasia mutated (ATM) gene is clinically available. Measurement of serum IgA may predict lower lymphocyte counts and reduced survival prognosis.

Key points

	• Ataxia-telangiectasia is an autosomal recessive condition characterized by progressive childhood ataxia, oculomotor apraxia, some degree of immunodeficiency, an increased risk for certain malignancies, and telangiectasias of the skin and conjunctiva.
	• Elevated serum alpha-fetoprotein is an important biochemical marker because the hallmark telangiectasias do not appear until later in the clinical course.
	• The principal defect is in the ataxia-telangiectasia mutated (ATM) gene, whose end product is a protein kinase involved in cell cycle regulation.
	• Patients are at an increased risk for certain malignancies, primarily leukemias and lymphomas, and are hypersensitive to ionizing radiation.
	• Patients with variant ataxia-telangiectasia may present initially with extrapyramidal movement disorders but are also at an increased risk for malignancy and hypersensitivity to ionizing radiation.

Historical note and terminology

In 1926, Syllaba and Henner first described the association of oculocutaneous telangiectasias with choreoathetosis. Louis-Bar reported the combination of oculocutaneous telangiectasias with progressive cerebellar ataxia in 1941. In 1958, Boder and Sedgwick studied eight cases from five unrelated families, including six familial cases. They emphasized the heredofamilial nature of the disease and the susceptibility of these patients to sinopulmonary infections. They named this syndrome ataxia-telangiectasia (07). Ataxia-telangiectasia is now recognized as one of a group of recessive hereditary genomic instability disorders and is characterized by progressive neurodegeneration, immunodeficiency, and cancer susceptibility.

Clinical manifestations

Presentation and course

	• Ataxia is the core neurologic feature but often presents after cutaneous and immunologic features. Dysarthria, oculomotor apraxia, and extrapyramidal signs are also frequent neurologic manifestations.
	• The cutaneous manifestations are telangiectasias, often present by mid-childhood.
	• Recurrent sinopulmonary infections are often present also starting in childhood.
	• The tendency to develop lymphoreticular malignancies is important to recognize as a prominent cause of morbidity and mortality, and to include a sensitivity to ionizing radiation.

Ataxia-telangiectasia is characterized by progressive cerebellar ataxia, telangiectasias of the skin and bulbar conjunctiva, progressive apraxia of eye movements, choreoathetosis, and increased susceptibility to sinopulmonary infections, lymphoreticular malignancies, and other malignant tumors. Median survival is estimated to be 25 years (17).

Neurologic features. Ataxia is the earliest clinical manifestation of ataxia-telangiectasia. The onset is insidious and is not apparent at birth or early infancy. Early motor development is usually normal. Ataxia is initially truncal and may manifest earlier than 2 years of age as postural instability with motor impersistence (32). The gait is unusual: clumsy but with a narrow base initially, and a tendency to improve with speed. Truncal ataxia is present in the majority (43 of 68 patients) by 3 years of age (80). With the rapid development of choreoathetosis, ambulation is lost by adolescence. The advancement of neurologic disease, however, may progress in a nonlinear fashion in the individual patient (27). An adult-onset form has been described that features prominent distal spinal muscular atrophy in the setting of mild cerebellar signs (25).

Facial features and speech are often characteristic: a mask-like facies with excessive drooling and dysarthria. Dysarthria is common and can manifest with uncontrolled, ataxic, or involuntary movements, resulting in monotonous, unstable, slow, or hypernasal speech (74). Abnormalities of articulation and bulbar function develop early. Progressive disorders of chewing and swallowing as well as silent aspiration become increasingly important and, often, are unrecognized. Furthermore, a small head circumference (61%) and microcephaly (17%), both acquired after the second year of life, have been recognized as a major clinical feature (43).

Ocular abnormalities are an early and progressive feature of ataxia-telangiectasia and include oculomotor apraxia, deficient accommodation, impaired smooth pursuit, hypometric saccades, nystagmus, absence of optokinetic nystagmus, frequent blinking, and photophobia (52). These features, especially eye movements, are important diagnostically (03). The combination of oculomotor apraxia and failure to suppress the vestibulo-ocular reflex (which is often the earliest ocular finding) is characteristic. Oculomotor apraxia involves difficulty in fixating smoothly on an object. In an attempt to visually fix on an object, the head is turned rapidly toward and past the object, often with a head thrust, causing the eyes to reach the target by means of the vestibulo-ocular reflex. Next, while maintaining fixation, the head is moved back to the target. Blinking before gaze changing can be identified before the age of 2 years (32). The head-turning technique, by engaging the vestibulo-ocular reflex, allows the patient to compensate for the difficulty in initiating voluntary refixation eye movements (saccades). This unique head-turning technique for visual fixation may not be seen in all subsets of patients, however (52). Patients will develop impairment of pursuits by school age. Increased saccadic latency, saccadic hypometria, and saccadic intrusions are also seen. Visual acuity, pupillary response, and funduscopic examination are usually normal. Poor accommodation and abnormal eye movements may lead to the reading difficulties often reported in patients with ataxia-telangiectasia (19).

The motor unit is often affected in ataxia-telangiectasia. There is wasting of distal muscles with hypotonia. Many young children have normal deep tendon reflexes that diminish by 7 to 8 years of age, with loss of the ankle jerks in later childhood. Usually no sensory abnormalities are present in the younger patient. However, beyond adolescence, there is variable distal sensory loss of vibratory and position senses.

Extrapyramidal movement abnormalities are the most variable feature; they may be seen in young patients, but they increase with age. Although rare, patients are sometimes diagnosed with ataxia-telangiectasia as adults due to referrals for movement disorders. Movement disorders can present as choreiform movements, tremor, dystonia, subcortical myoclonus, and resting tremor (38). Many patients in their teens, 20s, and 30s develop progressive spinal muscular atrophy of the hands and feet, but some individuals develop severe anterior horn cell degeneration (31). Within families, the age of onset and progression of symptoms is often similar among affected relatives (80; 65).

Neuropsychological difficulties can also be present starting in childhood (26). Earlier in the course, children with ataxia-telangiectasia can show impairments in verbal intelligence, vocabulary and comprehension, processing speed, visuospatial processing, and working memory. Additionally, impairments in attention and abstract reasoning can present later. These neuropsychological impairments can often be overlooked, but they constitute an important area of necessary support.

Cutaneous manifestations. Telangiectasias are characteristic and usually noted in mid-childhood, often by 5 years or even as late as 14 years of age (36). Because of the later appearance of telangiectasias as compared to movement disorders, the correct diagnosis can be mistakenly excluded or may not be considered when a young child has ataxia (13). This is especially important because ataxia-telangiectasia is the most common cause of progressive ataxia of childhood. In the absence of telangiectasias, ataxia-telangiectasia can be suspected when either choreoathetosis or oculomotor apraxia accompanies the ataxia (especially when lymphoid tissue is hypoplastic). The telangiectasias are found on the bulbar conjunctiva and later spread to involve the rest of the conjunctiva.

Telangiectasia of the conjunctiva

(Contributed by Dr. Sudhir Kothari.)

Other affected areas are the bridge of the nose, ears, neck, antecubital fossae, and popliteal exposed areas of the skin along with areas of friction. The cutaneous telangiectasias originally were thought to be arterial in origin. Capillary microscopy has now shown that both ocular and cutaneous telangiectasias arise from the venous system (51).

Other cutaneous manifestations of ataxia-telangiectasia include hyperpigmentation, hypopigmentation, cutaneous atrophy, partial albinism, and premature graying of hair. Seborrheic dermatitis, follicular keratosis, dry skin, and sclerodermatous changes may also be seen (51). Cutaneous granulomatosis, seen rarely in children with primary immunodeficiencies, have also been described in children with ataxia-telangiectasia (20).

Immune system deficiencies. No single, consistent abnormality of the immune system has been identified in ataxia-telangiectasia patients. Even affected siblings can differ in the degree and profile of their immunodeficiencies. However, most ataxia-telangiectasia homozygotes manifest some degree of IgA, IgE, or IgG2 deficiency. Serum levels of IgM, IgG1, and IgG3 are usually normal (47). It should be noted, however, that 10% of patients can have elevated IgM concentrations in addition to decreased IgG and IgA levels (46). Thus, ataxia-telangiectasia should be considered in the differential diagnosis of patients presenting with hyper-IgM syndrome (45; 48). Cellular immunity may also be affected. Recurrent sinopulmonary infection is common, often occurring within the first 2 years of life and preceding neurologic manifestations (08), and often results in chronic bronchitis and bronchiectasis. Pneumococcal antibodies are especially low in these patients. One investigation reports potential value in using PCV7 to trigger and PPV23 to booster the immune response and possibly to prevent severe pneumococcal disease (62).

Pulmonary manifestations. Pulmonary complications observed in ataxia-telangiectasia are a significant source of morbidity and mortality. Three general categories of lung disease include recurrent sinopulmonary disease and bronchiectasis, interstitial lung disease and pulmonary fibrosis, and lung disease associated with neuromuscular and bulbar abnormalities (37). Although there are no specific guidelines for the medical management of pulmonary complications, McGrath and colleagues have published a synopsis of the 2009 multidisciplinary workshop on “Pulmonary Disease in Ataxia-Telangiectasia.” Based on available evidence and expert opinion, they highlight the need for early referral to a pulmonologist to obtain baseline pulmonary function tests and monitor for progressive lung disease, screen for sleep-associated comorbidities, and medically maximize lung function. Management is complicated due to a lack of prospective data regarding common infectious agents and colonization over time. However, reversible obstructive lung disease is common in patients with ataxia-telangiectasia, and treatment with bronchodilators and steroids may be beneficial (05). Other pulmonary complications include pneumothorax and hemoptysis.

Cancer susceptibility. The tendency to develop malignancies is well-known, with homozygotes for ataxia-telangiectasia having a risk of cancer more than 100 times that of controls. Among patients with ataxia telangiectasia, lymphoreticular malignancies, namely Hodgkin disease, leukemia, and lymphomas, are most commonly seen, especially with onset in childhood, but there is an absence of myeloid tumors (68). Solid tumors include breast carcinoma, adenocarcinoma of the stomach, basal cell carcinoma, and tumors of the pancreas, ovary, and bladder (24).

There is also an increased susceptibility for early death in heterozygote carriers of the ATM gene (about 1% of the population). In a careful analysis, heterozygote carriers had an increased mortality rate in the ages of 20 through 79 years, with mortality rates increasing with age. The increased mortality was due to cancer, particularly breast cancer, and ischemic heart disease. On average, carriers died 7 to 8 years earlier than noncarriers (64). Exposure to ionizing radiation causes an increased risk for cancer among heterozygotes, particularly female breast cancer (28). Heterozygotes who have missense mutations of the ATM gene may be at greater risk for cancer (39). In the rare T-cell prolymphocytic leukemia, the ATM gene functions as a tumor suppressor (70).

Endocrine dysfunction. Endocrine manifestations include growth failure, hypogonadism, and insulin-resistant diabetes mellitus (06). Growth failure is more likely a primary manifestation of ataxia-telangiectasia rather than a nutritional impairment (44).

Variant ataxia-telangiectasia. It has long been recognized that varying phenotypes of ataxia-telangiectasia exist. Patients with variant ataxia-telangiectasia tend to have a milder phenotype and tend to possess missense mutations in which some residual ATM protein activity is present. Patients with variant ataxia-telangiectasia tend to present initially with extrapyramidal movement disorders, often mimicking forms of primary torsion dystonias, such as dopa-responsive cervical dystonia (14), with the development of ataxia occurring later in life. Six different trajectories have been described, with initial symptoms in childhood starting with extrapyramidal features or cerebellar features; childhood to adolescent-onset with dystonia or cerebellar features; childhood to adult-onset with initial muscle weakness; or adult-onset with initial extrapyramidal symptoms (72).

The mean age of onset of dystonia in patients with variant ataxia-telangiectasia is 12 years old (56); the median age of ataxia onset is 27 years old (75). Diagnostic delay is not uncommon in patients with variant ataxia-telangiectasia: over 10 years in 68% and over 20 years in 33% (58). Many of these patients have either minimal or no ocular telangiectasias, the cutaneous hallmark of classic ataxia-telangiectasia. Although dystonia is the usual predominating movement disorder in patients with variant ataxia-telangiectasia, rarely some patients will have myoclonus as their predominant movement disorder (69). Thus, ataxia-telangiectasia should be considered in patients with an otherwise unexplained movement disorder (even in the absence of ataxia and telangiectasias), starting with screening with a serum alpha-fetoprotein level. The importance of early diagnosis is accentuated by the fact that these patients are also at higher risk for malignancy, as well as the side effects from radiation hypersensitivity, just as patients with classic ataxia-telangiectasia.

Prognosis and complications

This insidiously progressive disorder, with its onset in early childhood, results in the patient being wheelchair-bound by adolescence. The mean age at loss of walking is 10 years (80). Intellectual function is normal early in life and gradually deteriorates. Long-term survival in ataxia-telangiectasia is often accompanied by an increase in physical symptoms spanning different organ systems, but especially neurologic pain due to contractures and psychosocial problems, such as mood disorders (73). Death occurs typically in early or mid-adolescence due to malignancy or bronchopulmonary infection, but rare patients reach adulthood (02). Diagnosis of extranodal lymphomas, particularly pulmonary, is sometimes delayed because of confusion with bronchopulmonary infections (41).

Clinical vignette

An 8-year-old boy with a history of frequent sinopulmonary infections was evaluated for chronic and progressive gait difficulties and dysarthria. The patient had been previously evaluated, with reportedly normal brain imaging and normal genetic and metabolic testing. The patient had prominent gait ataxia, more so than appendicular ataxia, oculomotor apraxia, palatal dysarthria, and a new finding of ocular telangiectasias. Serum alpha-fetoprotein was elevated, and a diagnosis of ataxia-telangiectasia was confirmed with genetic testing. The patient’s younger brother was subsequently diagnosed with ataxia-telangiectasia at 2 years of age, which was suspected due to delays in walking, and he subsequently developed ocular telangiectasias and progressive ataxia. Both brothers were wheelchair-bound by 10 years of age due to their progressive ataxia. Measurement of serum IgA may predict lower lymphocyte counts and reduced survival prognosis, which may guide patient selection for newer treatments as they are developed (83).

Biological basis

Etiology and pathogenesis

Ataxia-telangiectasia is inherited in an autosomal recessive fashion. The gene for ataxia-telangiectasia is on the long arm of chromosome 11 (11 q22.23) (21). The defective gene, designated ATM (AT mutated), has a transcript of 12 kilobases (57). The ATM gene product is a protein kinase with homology to phosphoinositol-3-kinase.

The ATM gene is expressed in a ubiquitous fashion and posited to be an important component of cell cycle surveillance and, thus, maintenance of genomic stability. ATM protein kinase is activated in the presence of DNA double-strand breaks. The subsequent cascade of phosphorylation modulates numerous signaling pathways that delay cell cycle progression allowing repair of the genome and prevention of deleterious genetic information to be passed to cell progeny (57; 70; 33; 60; 61). The ATM-deficient transgenic mouse model has typical cellular abnormalities but lacks typical neurodegeneration (16; 70). Genotypes such as truncating mutations resulting in a total absence of ATM kinase activity are associated with a classical earlier-onset phenotypic presentation with its associated higher morbidity and mortality, whereas a milder phenotype with a later onset of ataxia is associated with missense or splice site mutations resulting in the expression of ATM with some residual kinase activity (70; 40; 76). Although genotype-phenotype correlation can often be predicted, rarely mutations among family members have varying clinical manifestations (35).

Ataxia-telangiectasia homozygotes have spontaneous chromosomal instability resulting in a high in vivo occurrence of translocation involving both the small and long arm of chromosome 7 and the long arm of chromosome 14 (79). In vitro, the cells derived from these patients have defective DNA repair capability when exposed to irradiation. Serum immunoglobulins, especially IgA and IgE, are decreased. There is a reduction in T-cell numbers with reduced proliferative responses to mitogens. This is thought to be secondary to defective calcium-dependent signal transduction in the T lymphocyte (30).

The pathologic findings of ataxia-telangiectasia, as distinguished from the atrophic thymus and lymphoid hypoplasia and from the infections and various tumors to which ataxia-telangiectasia patients are susceptible, are concentrated in the cerebellum. Macroscopically, the cerebellum is usually grossly atrophic (22). This atrophy is most prominent throughout the vermis. In some patients who survive until the fourth decade, small vascular malformations are occasionally accompanied by glial proliferation to produce gliovascular nodules. Microscopically, atrophy affects all layers of the cerebellar cortex, as evidenced by marked thinning of the molecular layer, diminution in the number of Purkinje cells, and thinning of the underlying granule cell layer (18). Neuropathologic abnormalities also include thalamic and cortical hamartomas, nerve cell loss and spheroids in brainstem nuclei (mesencephalic and trigeminal nuclei), nerve cell loss and astrocytic hypertrophy of the substantia nigra, spinal cord atrophy (especially posterior funiculi) with demyelination, gliosis and hypertrophic glial cells, dystrophic dorsal root ganglia, anterior horn cell degeneration, and neurogenic amyotrophy of striated muscles (18; 31).

A pattern of cerebellar atrophy on MRI is also described in patients with ataxia-telangiectasia. Patient disability well correlated with the degree of cerebellar atrophy. The lateral cerebellum and superior vermis showed the earliest atrophic changes (67).

Differential diagnosis

Confusing conditions

Several conditions with ataxia can be considered in the differential diagnosis of ataxia-telangiectasia, but the most common misdiagnosis is cerebral palsy (13). By contrast, seizures or corticospinal tract dysfunction, which are common accompaniments of cerebral palsy, rarely occur in ataxia-telangiectasia and should lead to a reevaluation of the diagnosis. Another form of familial spinocerebellar ataxia must be considered. It has features that overlap ataxia telangiectasia (including elevated alpha fetoprotein level), Friedreich ataxia, and ataxia with isolated vitamin E deficiency (77). In Friedreich ataxia, there is nystagmus, alteration of reflexes, plantar extensor responses, sensory loss, kyphoscoliosis, and high-arched feet. EKG abnormalities (T-wave inversion and ventricular hypertrophy) are common. Abetalipoproteinemia (Bassen-Kornzweig disease), an autosomal recessive syndrome, has ataxia, areflexia, and proprioceptive loss in the second decade of life. Pigmentary retinopathy is found in most patients. These patients have steatorrhea and severe malabsorption of fat soluble vitamins A, D, E, and K associated with low levels of cholesterol and serum vitamin E. The Marinesco-Sjögren syndrome comprises ataxia, cataracts, mental retardation, short stature, and delayed sexual development. The syndrome of ataxia-ocular motor apraxia shares many features with ataxia-telangiectasia (01). It is a slowly progressive syndrome with ataxia, choreoathetosis, and oculomotor apraxia in the horizontal and vertical planes. Though the neurologic signs are similar to ataxia-telangiectasia, these patients have no telangiectasias, no evidence of multisystem involvement, and no tendency to develop infections. Serum immunoglobulins, serum alpha-fetoprotein, T and B lymphocyte markers, and chromosomal analysis are normal. Cogan congenital oculomotor apraxia lacks athetosis. Progressive ataxia is a frequent feature of mitochondrial encephalomyopathies, which usually have additional manifestations such as myoclonic seizures, retinitis pigmentosa, basal ganglia abnormalities on MRI, lactic acidosis, neurosensory deafness, or ragged-red fiber myopathies. In addition, ataxia and other extrapyramidal symptoms occur with many of the other progressive genetic encephalopathies of childhood, particularly, metachromatic leukodystrophy, Niemann-Pick disease, GM2 gangliosidoses, and Krabbe disease.

Diagnostic workup

• Clinical suspicion should result in serum alpha-fetoprotein screening with further genetic testing to confirm the diagnosis.

The diagnosis is difficult only in the progressively ataxic young child of 2 to 6 years who has not developed telangiectasias. In this situation, an elevated serum alpha-fetoprotein is especially useful to confirm the diagnosis (13). After telangiectasias have developed at 5 years or older, the illness has such a characteristic clinical picture that a correct diagnosis is usually not difficult. When the diagnosis is ambiguous, further testing to support the diagnosis can include: (1) immunoblotting for ATM protein (15) and (2) the postirradiation pattern of thymidine incorporation that is typical of ataxia-telangiectasia lymphocytes. In addition, molecular genetic testing is clinically available and can include (1) sequence analysis, which can detect over 90% of ATM mutations or (2) genetic linkage studies if multiple family members are available.

Serum alpha-fetoprotein is elevated in at least 90% of patients with ataxia-telangiectasia (80), and levels tend to increase with age (63). With the exception of children younger than 1 year (when it is normally elevated) and a new spinocerebellar disorder described in a single Japanese family (77), the values do not overlap with any clinically similar disorder. Another common biochemical marker is carcinoembryonic antigen. Several cellular and humoral immunologic defects may occur. Two-thirds or more of patients with ataxia-telangiectasia have an immunoglobulin deficiency (80). Serum levels of IgA, IgE, or IgG2 are usually absent or low. Serum IgM is normal or elevated. Total IgG isotypes are normal or decreased. There is peripheral lymphopenia and decreased responsiveness to skin antigens. Cytogenetic studies reveal an excess of spontaneous chromosomal breaks and rearrangements. The chest x-ray may show a small or absent thymic shadow. The sinus x-ray often shows sinusitis. Typically, there is decreased or hypoplastic lymphoid tissue in the nasopharynx, as seen in a lateral skull x-ray. MRI of the brain has revealed vermian atrophy and enlargement of the fourth ventricle and cisterna magna (55), and asymptomatic supratentorial vascular abnormalities (34).

Management

	• Treatment is supportive and should include a multidisciplinary team.
	• Live-virus vaccines and ionizing radiation should be avoided.

The treatment of patients with ataxia-telangiectasia requires coordinated multidisciplinary care but is essentially supportive. Practical guidelines in the areas of neurology, immunology, pulmonology, perioperative care, oncology, endocrinology, and nutrition have been published (71). Systemic bacterial infections, severe viral infections, and opportunistic infections are uncommon in ataxia-telangiectasia (46). However, the presence of laboratory immunologic abnormalities warrant close observation. Seven-valent pneumococcal conjugated vaccine may be protective in ataxia-telangiectasia patients; however, multiple doses of conjugated vaccine may be required (53; 59). Infections are treated with antibiotics. Intercurrent infections can be prevented with the use of intravenous gammaglobulin therapy and postural drainage (16). For malignancies, conventional doses of radiation therapy are contraindicated because these patients are hypersensitive to ionizing radiation (22). However, lymphomas should be treated with standard-course chemotherapy while remaining alert to hemorrhagic cystitis or pulmonary complications (54). Live-virus vaccines should not be used after the diagnosis of ataxia-telangiectasia (49).

No effective therapy exists for halting the progression of the ataxia. Studies suggesting that ataxia-telangiectasia cells may be in a constant state of increased oxidative stress make it likely that most antioxidants or free-radical scavengers might counteract some of the progressive neurologic deterioration of patients with ataxia-telangiectasia (78). At least one ataxia-telangiectasia mouse model study suggests that treatment with catalytic antioxidants appear to positively impact neurobehavioral deficits (10). Vitamin E has been recommended for a number of years; alpha-lipoic acid and coenzyme Q10 may also be helpful. Folic acid theoretically minimizes chromosomal fragility and the formation of double-strand DNA breaks. One adult patient had improvement in his gait ataxia with treatment with the GABA-ergic medications pregabalin and tiagabine (23). Acetyl-DL-Leucine may improve ataxia and ocular stability (11). There is also open-label evidence that restoring cellular NAD+ levels using nicotinamide precursors, such as nicotinamide riboside, is well tolerated and may improve coordination and eye movements, but further study is required (50).

Some improvement (76% responder rate, defined as at least 20% improvement in the summation of the three scales used) in movement disorders has been reported with the use of amantadine sulfate (42). The successful treatment of dystonia in a patient with ataxia-telangiectasia has also been reported with trihexyphenidyl (82).

One case report cites short-term improvement of neurologic deficits using steroids (12). Unfortunately, improvement was temporary and typical side effects associated with exogenous steroid use were seen. A follow-up study found similar positive results with clear improvement of neurologic symptoms in five of six patients treated for 10 days with oral betamethasone (09). They found improvement not only in younger patients but also in older patients many years after onset of symptoms. They also found that the clinical benefit was inversely correlated with the degree of cerebellar atrophy. Furthermore, in a multicenter, double-blind, randomized, placebo-controlled trial, oral betamethasone reduced ataxia as measured by standardized ataxia scales (81). However, the long-term safety and effectiveness of oral steroid therapy is still being evaluated.

References

01: Aicardi J. Ataxia-ocular motor apraxia: a syndrome mimicking ataxia-telangiectasia. Ann Neurol 1988;24:497-502. PMID 3239952
02: Amromin GD, Boder E, Teplitz R. Ataxia-telangiectasia with a 32-year survival. J Neuropathol Exp Neurol 1979;38:621-43. PMID 533861
03: Baloh RW, Yee RD, Boder E. Eye movements in ataxia-telangiectasia. Neurology 1978;28:1099-104. PMID 568727
04: Barmettler S, Coffey K, Smith MJ, et al. Functional confirmation of DNA repair defect in ataxia-telangiectasia (AT) infants identified by newborn screening for severe combined immunodeficiency (NBS SCID). J Allergy Clin Immunol Pract 2021;9(2):723-32. PMID 32818697
05: Berkun Y, Vilozni D, Levi Y, et al. Reversible airway obstruction in children with ataxia telangiectasia. Pediatr Pulmonol 2010;45:230-5. PMID 20146367
06: Blevins LS Jr, Gebhart SS. Insulin-resistant diabetes mellitus in a black woman with ataxia-telangiectasia. South Med J 1996;89:619-21. PMID 8638204
07: Boder E, Sedgwick RP. Ataxia-telangiectasia: a familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection. Pediatrics 1958;21:526-54. PMID 13542097
08: Bott L, Lebreton JP, Thumerelle C, et al. Lung disease in ataxia-telangiectasia. Acta Paediatr 2007;96:1021-4. PMID 17524020
09: Broccoletti T, Del Giudice E, Amorosi S. Steroid-induced improvement of neurological signs in ataxia-telangiectasia patients. Eur J Neurol 2008;15:223-8. PMID 18290844
10: 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 2004;36(7):938-42. PMID 15019978
11: Brueggemann A, Bicvic A, Goeldlin M, et al. Effects of Acetyl-DL-Leucine on ataxia and downbeat-nystagmus in six patients with ataxia telangiectasia. J Child Neurol 2022;37(1):20-7. PMID 34620022
12: Buoini S, Zannolli R, Sorrentino L, Fois A. Betamethasone and improvement of neurological symptoms in ataxia-telangiectasia. Arch Neurol 2006;63(10):1479-82. PMID 17030666
13: Cabana MD, Crawford TO, Winkelstein JA, Christensen JR, Lederman HM. Consequences of the delayed diagnosis of ataxia-telangiectasia. Pediatrics 1998;102:98-100. PMID 9651420
14: Charlesworth G, Mohire MD, Schneider SA, Stamelou M, Wood NW, Bhatia KP. Ataxia telangiectasia presenting as dopa-responsive cervical dystonia. Neurology 2013;81(13):1148-51. PMID 23946315
15: Chun HH, Sun X, Nahas SA, et al. Improved diagnostic testing for ataxia-telangiectasia by immunoblotting of nuclear lysates for ATM protein expression. Mol Genet Metab 2003;80(4):437-43. PMID 14654357
16: Crawford TO. Ataxia telangiectasia. [Review]. Semin Pediatr Neurol 1998;5:28794. PMID 9874856
17: Crawford TO, Skolasky RL, et al. Survival probability in ataxia telangiectasia. Arch Dis Child 2006;91(7):610-1. PMID 16790721
18: De Leon GA, Grover WD, Huff DS. Neuropathologic changes in ataxia telangiectasia. Neurology 1976;26:947-51. PMID 986586
19: Farr AK, Shalev B, Crawford TO, Lederman HM, Winkelstein JA, Repka MX. Ocular manifestations of ataxia-telangiectasia. Am J Ophthalmol 2002;134(6):891-6. PMID 12470759
20: Folgori L, Scarselli A, Angelino G, et al. Cutaneous granulomatosis and combined immunodeficiency revealing ataxia-telangiectasia: a case report. Ital J Pediatr 2010;36:29. PMID 20380744
21: Gatti RA, Berkel I, Boder E, et al. Localization of an ataxia telangiectasia gene to chromosome 11q22-23. Nature 1988;336:577-80. PMID 3200306
22: Gatti RA, Boder E, Vinters HV, Sparkes RS, Norman A, Lange K. Ataxia telangiectasia: an interdisciplinary approach to pathogenesis [review]. Medicine 1991;70:99-117. PMID 2005780
23: Gazulla J, Benavente I, Sarasa M. New therapies for ataxia-telangiectasia. Arch Neurol 2007;64:607-8. PMID 17420328
24: Hecht F, Hecht BK. Cancer in ataxia telangiectasia patients. Cancer Genet Cytogenet 1990;46(1):9-19. PMID 2184934
25: Heil JA, van Engelen BG. Distal spinal muscular atrophy as a major feature in adult-onset ataxia telangiectasia. Neurology 2006;67(2):346-9. PMID 16864838
26: Hoche F, Frankenberg E, Rambow J, et al. Cognitive phenotype in ataxia-telangiectasia. Pediatr Neurol 2014;51(3):297-310. PMID 25037873
27: Jackson TJ, Chow G, Suri M, Byrd P, Taylor MR, Whitehouse WP. Longitudinal analysis of the neurological features of ataxia-telangiectasia. Dev Med Child Neurol 2016;58(7):690-7. PMID 26896183
28: Janin N, Andrieu N, Ossian K, et al. Breast cancer risk in ataxia telangiectasia (AT) heterozygotes: haplotype study in French AT families. Br J Cancer 1999;80:1042-5. PMID 10362113
29: Kleijer WJ, Van der Kraan M, Los FJ, Jaspers NG. Prenatal diagnosis of ataxia-telangiectasia and Nijmegen Breakage syndrome by the assay of radioresistant DNA synthesis. Int J Radiat Biol 1994;66:S167-74. PMID 7836844
30: Kondo N, Inoue R, Nishimura S, et al. Defective calcium-dependent signal transduction in T lymphocytes of ataxia telangiectasia. Scand J Immunol 1993;38(1):45-8. PMID 8327858
31: Larnaout A, Belal S, Ben Hamida C, Ben Hamida M, Hentati F. Atypical ataxia telangiectasia with early childhood lower motor neuron degeneration: a clinicopathological observation in three siblings. J Neurol 1998;245:231-5. PMID 9591225
32: Leuzzi V, Elli R, Antonelli A, et al. Neurological and cytogenetic study in early-onset ataxia-telangiectasia patients. Eur J Pediatr 1993;152:609-12. PMID 7689057
33: Levitt NC, Hickson ID. Caretaker tumour suppressor genes that defend genome integrity. Trends Mol Med 2002;8(4):179-86. PMID 11927276
34: Lin DD, Barker PB, Lederman HM, Crawford TO. Cerebral abnormalities in adults with ataxia-telangiectasia. AJNR Am J Neuroradiol 2014;35(1):119-23. PMID 23886747
35: Lohmann E, Kruger S, Hauser A, et al. Clinical variability in ataxia-telangiectasia. J Neurol 2015;262(7):1724-7. PMID 25957637
36: McFarlin DE, Struber W, Waldman TA. Ataxia telangiectasia. Medicine 1972;51:281-314. PMID 5033506
37: McGrath-Morrow SA, Gower WA, Rothblum-Oviatt C, et al. Evaluation and management of pulmonary disease in ataxia-telangiectasia. Pediatr Pulmonol 2010;45:847-59. PMID 20583220
38: Meneret A, Ahmar-Beaugendre Y, Rieunier G, et al. The pleiotropic movement disorders phenotype of adult ataxia-telangiectasia. Neurology 2014;83(12):1087-95. PMID 25122203
39: Meyn MS. Ataxia-telangiectasia, cancer and the pathobiology of the ATM gene. [Review]. Clin Genet 1999;55:289-304. PMID 10422797
40: Micol R, Ben Slama L, Suarez F, et al. Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype. J Allergy Clin Immunol 2011;128(2):382-9.e1. PMID 21665257
41: Murphy RC, Berdon WE, Ruzal-Shapiro C, et al. Malignancies in pediatric patients with ataxia telangiectasia. Pediatr Radiol 1999;29:225-30. PMID 10199897
42: Nissenkorn A, Hassin-Baer S, Lerman SF, Banet Levi Y, Tzadok M, Ben-Zeev B. Movement disorder in ataxia-telangiectasia: treatment with amantadine sulfate. J Child Neurol 2013;28(2):155-60. PMID 22550086
43: Nissenkorn A, Levi YB, Vilozni D, et al. Neurologic presentation in children with ataxia-telangiectasia: is small head circumference a hallmark of the disease. J Pediatr 2011;159(3):466-71.e1. PMID 21429505
44: Nissenkorn A, Levy-Shraga Y, Banet-Levi Y, Lahad A, Sarouk I, Modan-Moses D. Endocrine abnormalities in ataxia-telangiectasia: findings from a national cohort. Pediatr Res 2016;79(6):889-94. PMID 26891003
45: Noordzij JG, Wulffraat NM, Haraldsson A, et al. Ataxia-telangiectasia patients presenting with hyper-IgM syndrome. Arch Dis Child 2009;94(6):448-9. PMID 19224889
46: Nowak-Wegrzyn A, Crawford TO, Winkelstein JA, Carson KA, Lederman HM. Immunodeficiency and infections in ataxia-telangiectasia. J Pediatr 2004;144(4):505-11. PMID 15069401
47: Peterson RD, Kelly WD, Good RA. Ataxia-telangiectasia: its association with a defective thymus, immunological-deficiency disease, and malignancy. Lancet 1964;1:1189. PMID 14132657
48: Pietrucha BM, Heropolitanska-Pliszka E, Wakulinska A, Skopczynska H, Gatti RA, Bernatowska E. Ataxia-telangiectasia with hyper-IgM and Wilms tumor: fatal reaction to irradiation. J Pediatr Hematol Oncol 2010;32(1):e28-30. PMID 20051774
49: Pohl KR, Farley JD, Jan JE, Junker AK. Ataxia telangiectasia in a child with vaccine-associated paralytic poliomyelitis. J Pediatr 1992;121:405-7. PMID 1517916
50: Presterud E, Deng WH, Wennerstrom AB, et al. Long-term nicotinamide riboside use improves coordination and eye movements in ataxia telangiectasia. Mov Disord 2023. [Epub ahead of print] PMID 37899683
51: Reed WB, Epstein WL, Boder E, Sedgwick R. Cutaneous manifestations of ataxia-telangiectasia. JAMA 1966;195:746-53. PMID 5951880
52: Riise R, Ygge J, Lindman C, et al. Ocular findings in Norwegian patients with ataxia-telangiectasia: a 5 year prospective cohort study. Acta Ophthalmol Scand 2007;85:557-62. PMID 17376192
53: Sanal O, Ersoy F, Tezcan I, et al. Antibody response to a seven-valent pneumococcal conjugated vaccine in patients with ataxia-telangiectasia. J Clin Immunol 2004;24(4):411-7. PMID 15163897
54: Sandoval C, Swift M. Treatment of lymphoid malignancies in patients with ataxia-telangiectasia. Med Pediatr Oncol 1998;31:491-7. PMID 9835901
55: Sardanelli F, Parodi RC, Ottonello C, et al. Cranial MRI in ataxia-telangiectasia. Neuroradiology 1995;37:77-82. PMID 7708196
56: Saunders-Pullman R, Raymond D, Stoessl AJ, et al. Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites. Neurology 2012;78(9):649-57. PMID 22345219
57: Savitsky K, Bar-Shira A, Gilad S, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 1995;268:1749-53. PMID 7792600
58: Schon K, van Os NJ, Oscroft N, et al. Genotype, extrapyramidal features, and severity of variant ataxia-telangiectasia. Ann Neurol 2019;85(2):170-80. PMID 30549301
59: Schubert R, Reichenbach J, Rose M, Zielen S. Immunogenicity of the seven valent pneumococcal conjugate vaccine in patients with ataxia-telangiectasia. Pediatr Infect Dis J 2004;23(3):269-70. PMID 15014308
60: Shiloh Y. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 2003;3(3):155-68. PMID 12612651
61: Shiloh Y. The ATM-mediated DNA-damage response: taking shape. Trends Biochem Sci 2006;31(7):402-10. PMID 16774833
62: Stray-Pedersen A, Aaberge IS, Fruh A, Abrahamsen TG. Pneumococcal conjugate vaccine followed by pneumococcal polysaccharide vaccine; immunogenicity in patients with ataxia-telangiectasia. Clin Exp Immunol 2005;140(3):507-16. PMID 15932512
63: Stray-Pederson A, Borresen-Dale AL, Paus E, et al. Alpha fetoprotein is increasing with age in ataxia-telangiectasia. Eur J Paediatr Neurol 2007;11:375-80. PMID 17540590
64: Su Y, Swift M. Mortality rates among carriers of ataxia-telangiectasia mutant alleles. Ann Int Med 2000;133(10):770-8. PMID 11085839
65: Swift M, Heim RA, Lench NJ. Genetic aspects of ataxia telangiectasia [review]. Adv Neurol 1993;61:115-25. PMID 8421962
66: Swift M, Morrell D, Cromartie E, Chamberlin AR, Skolnick MH, Bishop DT. The incidence and gene frequency of ataxia telangiectasia in United States. Am J Hum Genet 1986;39:573-83. PMID 3788973
67: Tavani F, Zimmerman RA, Berry GT, Sullivan K, Gatti, Bingham P. Ataxia-telangiectasia: the pattern of cerebellar atrophy on MRI. Neuroradiology 2003;45(5):315-9. PMID 12740724
68: Taylor AM, Metcalfe JA, Thick J, Mak YF. Leukemia and lymphoma in ataxia telangiectasia. Blood 1996;87:423-38. PMID 8555463
69: Termsarasab P, Yang AC, Frucht SJ. Myoclonus in ataxia-telangiectasia. Tremor Other Hyperkinet Mov (N Y) 2015;5;298. PMID 25793145
70: Uhrhammer N, Bay JO, Bignon YJ. Seventh International Workshop on Ataxia-Telangiectasia. [Review]. Cancer Res 1998;58:3480-5. PMID 9699683
71: Van Os NJ, Haaxma CA, Van Der Flier M, et al. Ataxia-telangiectasia: recommendations for multidisciplinary treatment. Dev Med Chlid Neurol 2017;59:680-9. PMID 28318010
72: Van Os NJ, Hensiek A, van Gaalen J, et al. Trajectories of motor abnormalities in milder phenotypes of ataxia telangiectasia. Neurology 2019;92(1):e19-e29. PMID 30549301
73: van Os NJ, van Deuren M, Weemaes CM, et al. Classic ataxia-telangiectasia: the phenotype of long-term survivors. J Neurol 2020;267(3):830-7. PMID 31776720
74: Veenhuis SJG, van Os NJH, van Gerven MHJC, et al. Dysarthria in children and adults with ataxia telangiectasia. Dev Med Child Neurol 2021;63(4):450-6. PMID 33521952
75: Verhagen MM, Abdo WF, Willemsen MA, et al. Clinical spectrum of ataxia-telangiectasia in adulthood. Neurology 2009;73(6):430-7. PMID 19535770
76: Verhagen MM, Last JI, Hogervorst FB, et al. Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study. Hum Mutat 2012;33(3):561-71. PMID 22213089
77: Watanabe M, Sugai Y, Concannon P, et al. Familial spinocerebellar ataxia with cerebellar atrophy, peripheral neuropathy, and elevated level of serum creatine kinase, gamma-globulin, and alpha-fetoprotein. Ann Neurol 1998;44:265-9. PMID 9708552
78: Watters DJ. Oxidative stress in ataxia telangiectasia. Redox Report 2003;8(1):23-9. PMID 12631440
79: Willems PJ, Van Roy BC, Kleijer WJ, Van der Kraan M, Martin JJ. Atypical clinical presentation of ataxia telangiectasia [review]. Am J Med Genet 1993;45:777-82. PMID 8456862
80: Woods CG, Taylor AM. Ataxia telangiectasia in the British Isles: the clinical and laboratory features of 70 affected individuals. Q J Med 1992;82:169-79. PMID 1377828
81: Zannolli R, Buoni S, Betti G, et al. A randomized trial of oral betamethasone to reduce ataxia symptoms in ataxia telangiectasia. Mov Disord 2012;27(10):1312-6. PMID 22927201
82: Zhang L, Jia Y, Qi X, et al. Trihexphenidyl for treatment of dystonia in ataxia telangiectasia: a case report. Childs Nerv Syst 2020;36(4):873-5. PMID 31691010
83: Zielen S, Duecker RP, Woelke S, et al. Simple measurement of IgA predicts immunity and mortality in ataxia-telangiectasia. J Clin Immunol 2021;41(8):1878-92. PMID 34477998

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

David T Hsieh MD

Dr. Hsieh of the Uniformed Services University of the Health Sciences has no relevant financial relationships to disclose.
See Profile

Editor

Ann Tilton MD

Dr. Tilton has received honorariums from Allergan and Ipsen as an educator, advisor, and consultant.
See Profile

Former Authors

Michael V Johnston MD†
Raymond Kandt MD (original author), William M McClintock MD, Kenneth J Mack MD PhD, E Brannon Morris MD, and Peter S Easter DO

Patient Profile

Age range of presentation: 1 months to 18 years
Sex preponderance: male=female
Heredity: heredity typical

heredity may be a factor
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Ataxia-telangiectasia: 334.8
ICD-10: Ataxia-telangiectasia: G11.3
OMIM: Ataxia-telangiectasia: #208900

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Ataxia-telangiectasia

Associated Disorders

Cancer

Differential Diagnosis

cerebral palsy
Friedreich ataxia
Abetalipoproteinemia (Bassen-Kornzweig disease)
Marinesco-Sjögren syndrome
syndrome of ataxia-ocular motor apraxia
- metachromatic leukodystrophy
- Niemann-Pick disease
- GM2 gangliosidoses
- Krabbe disease
- autosomal dominant cerebellar ataxias
- mitochondrial disorders

Also Relevant

Ataxia
Autosomal dominant hereditary ataxias
Childhood movement disorders
Neurocutaneous syndromes
Nondominant hereditary ataxias

Ataxia-telangiectasia …

Ataxia-telangiectasia

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

NF2-related schwannomatosis

Common maculopathies

Breath-holding spells

Toxic and nutritional deficiency optic neuropathies

Nystagmus

Third nerve palsy

Acute cerebellar ataxia in children

Chronic progressive external ophthalmoplegia

Ataxia-telangiectasia

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

NF2-related schwannomatosis

Common maculopathies

Breath-holding spells

Toxic and nutritional deficiency optic neuropathies

Nystagmus

Third nerve palsy

Acute cerebellar ataxia in children

Chronic progressive external ophthalmoplegia

This is an article preview.
Start a Free Account
to access the full version.