92 Ataxia telangiectasia is a rare hereditary disorder character- ized by progressive cerebellar ataxia, conjunctival telangiec- tasias, recurrent sinopulmonary infections, radiosensitivity, and a predisposition to malignancy. It is the most common cause of progressive cerebellar ataxia in childhood. The prevalence is estimated to be 1 in 40,000 to 1 in 100,000 live births.
GENETICS/BASIC DEFECTS
1. Inheritance
a. Autosomal recessive
b. Genetic heterogeneity in at least 5 complementation groups (A–E)
2. Cause
a. Mutations in the ataxia telangiectasia mutated gene (ATM) which is mapped to 11q22.3
b. Affected individuals completely lack functional ATM protein
c. A high prevalence of specific ATM mutations in cer- tain ethnic groups (Amish, Mennonite, Costa Rican, Polish, British, Italian, Turkish, Iranian, and Israeli) with a founder effect, resulting in a small number of mutations that accounts for the majority of disease- causing mutant alleles
3. Pathophysiology
a. Basic defect: abnormal sensitivity of A-T cells to X-rays and certain radiomimetic chemicals, leading to chro- mosome and chromatid breaks. However, sensitivity of A-T cells to ultraviolet irradiation is normal b. Random distribution of breakpoints
c. Nonrandom chromosome rearrangements selectively affect chromosomes 7 and 14 at sites that are con- cerned with T-cell receptors and heavy-chain immunoglobulin coding and with the development of hematologic malignancies
d. Mechanisms responsible for neurologic disease, thy- mus aplasia, telangiectasias, growth retardation, and impaired organ mutation
i. Have not been elucidated
ii. Most likely linked to accelerated telomere loss 4. Genotype-phenotype correlations
a. 576ins137nt mutation
i. Somewhat slower rate of neurological deterio- ration
ii. Later onset of symptoms iii. Intermediate radiosensitivity
iv. Little or no cancer risk b. 8494C>T mutation
i. Milder phenotype ii. Longer lifespan
CLINICAL FEATURES
1. CNS manifestations
a. Functional neurologic abnormalities rare in infancy b. Cerebellar ataxia
i. A presenting symptom ii. Slowly progressive
iii. Truncal ataxia preceding appendicular ataxia and peripheral incoordination
iv. Swaying of the head and trunk while standing and sitting: early sign of ataxia
c. Diminished or absent deep reflexes by school age d. Hypotonia
e. Dystonia and progressive spinal muscular atrophy affecting hands and feet in affected young adults, resulting in extension contractures
f. Dysarthric speech g. Flexor plantar response
h. Choreoathetosis in almost all patients
i. Myoclonic jerking and intention tremors in about 25% of patients
j. Drooling
k. Oculomotor apraxia (total or partial loss of the ability to perform coordinated movement or manipulate objects in the absence of motor or sensory impair- ment) affecting reading (eye tracking) and writing (affected by 7–8 years of age)
l. Intellectual function generally preserved 2. Telangiectasias (dilated small blood vessels)
a. Ocular conjunctiva: most frequently observed b. Other sites: nose, ears, behind the knees, antecubital
fossae, suprasternal notch, dorsum of the hands and feet, and hard and soft palate
c. Usually noticed during 3–6 years of age, i.e., a few years after ataxia
3. Immunodeficiency
a. Frequent sinopulmonary infections
i. Mucopurulent rhinitis, retropharyngeal dis- charge, otitis media, and sinusitis
ii. Bronchitis and pneumonia
iii. Progress to chronic lung disease: bronchiectasis, pulmonary fibrosis, and respiratory insufficiency b. A small embryoniclike thymus
c. Problems associated with defects in humoral and cel- lular immunity
i. T-cell deficiency in about 30% of patients ii. Severe immunodeficiency in about 10% of patients iii. IgA deficiency
d. Most frequent cause of death in adolescence: bronchiec- tasis complicated by pneumonitis
Ataxia Telangiectasia
ATAXIA TELANGIECTASIA 93
4. Malignancy
a. The second most frequent cause of death
b. Eventual malignancy during lifetime in 38% of patients c. Malignancy of hematologic origin most common
(85% of patients)
i. Predominance of malignant lymphomas, usually of B-cell type
ii. Acute lymphocytic leukemia of T-cell origin in younger patients
iii. T-cell prolymphocytic leukemia in older patients d. Other neoplasms
i. Breast cancer, even in female relatives who do not have ataxia telangiectasia
ii. Gastric cancer iii. Melanoma
iv. Leiomyoma v. Sarcoma 5. Ectodermal changes
a. Appearance of premature aging i. Diffuse graying of the hair
ii. Atrophic and hidebound facial skin iii. Inelastic ears
iv. Facial wasting
b. Frequent pigmentary changes: hyperpigmentation/
hypopigmentation with cutaneous atrophy and telang- iectasia
c. Partial albinism d. Vitiligo
e. Café-au-lait spots f. Seborrheic dermatitis 6. Endocrine manifestations
a. Occasional female hypogonadism associated with ovarian hypoplasia or dysplasia
b. Male hypogonadism with delayed puberty and char- acteristic high-pitched voice
7. Clubbing: observed in 40% of Costa Rican patients not correlated with chronic lung disease, humoral immunod- eficiency, or with a particular mutation
8. Other features
a. Mild postnatal growth retardation b. Hypersensitivity to ionizing radiation c. Wheelchair-bound by 10 years of age
DIAGNOSTIC INVESTIGATIONS
1. Significant humoral and cellular immune defects in most patients
a. Thymic hypoplasia
b. Low numbers of circulating T-cells
c. Functional impairment of T-cell-mediated immunity d. Selective deficiencies of IgA, IgE, IgG
2, and IgG
4e. Low or absent serum levels of IgA in 60% of patients
f. Low or absent serum levels of IgG
2in 80% of patients
g. Hyper-IgM in approximately 1% of patients, some- times associated with myeloma-like gammopathy, lymphadenopathy, hepatosplenomegaly, and lympho- cytic interstitial pneumonitis
2. Increased serum levels of alpha-fetoprotein (AFP) levels in over 90% of older children with A-T
3. Increased plasma levels of carcinoembryonic antigen
4. Colony survival assay by in vitro testing for radiosensitiv- ity on lymphoblastoid cell line to measure the colony sur- vival fraction after 1 Gy of in vitro radiation: sensitivity and specificity exceeding 95% but takes 2–3 months to complete
5. Western blot analysis to detect ATM protein in lysates of a lymphoblastoid cell line
6. DNA-based mutation analysis of the ATM gene available clinically
a. Sequence analysis of the ATM coding region
b. Linkage analysis to identify carriers among family members at risk if direct DNA testing fails to identify two disease-causing mutations in the index case 7. Chromosome analysis to identify genetic instability, a
hallmark of the A-T phenotype
a. Types of spontaneous in vitro chromosome aberrations, frequent in both lymphoid and nonlymphoid cells
i. Chromosome breaks ii. Acentric fragments iii. Dicentric chromosomes
iv. Structural arrangements v. Aneuploidy
b. A-T lymphocytes
i. Increased chromosome breaks. Common break- age points include 7p14, 7q35, 14q12, 14qter, 2p11, 2p12, and 22q11-q12
ii. Clonal rearrangements involving abnormalities of chromosome 14, especially tandem duplica- tion of 14q at 14q11-q12 and t(7;14)
c. Nonlymphoid cells: break points randomly distrib- uted
8. Radiography
a. Decreased or absent adenoidal tissue in the nasopharynx b. Small or absent thymic shadow
c. Decreased mediastinal lymphoid tissue
d. Pulmonary changes similar to those seen in cystic fibrosis
9. EMG and nerve conduction velocities a. Frequently normal in children
b. Showing denervation on EEG and reduced nerve con- duction in the late stage of the disease, especially in sensory fibers
10. Electrooculography
a. Shows characteristic oculomotor abnormality of A-T
b. Differentiates A-T from Friedreich ataxia 11. MRI of the brain
a. A small cerebellum b. Widened sulci
c. Enlargement of the fourth ventricle 12. Histology
a. Degeneration of Purkinje and granule cells in the cerebellum: the major pathological marker of A-T in the CNS
b. Late degenerative gliovascular nodules in the white matter
c. Lesions of the basal ganglia observed only occasionally d. Degeneration of spinal tracts and anterior horn cells
often present in late stages
e. Nucleocytomegaly, a feature of several cell types
throughout the body
94 ATAXIA TELANGIECTASIA
GENETIC COUNSELING
1. Recurrence risk: counseling according to autosomal recessive inheritance
a. Patient’s sib
i. A 25% recurrence risk
ii. Two-thirds of unaffected sibs are carriers b. Patient’s offspring: most patients with A-T do not
reproduce 2. Prenatal diagnosis
a. Elevated maternal serum AFP levels
b. Demonstration of chromosome breaks in amniocytes c. Molecular genetic analysis
i. Direct DNA mutation analysis on fetal DNA obtained from amniocentesis or CVS for preg- nancies at-risk with previously identified spe- cific disease-causing mutation
ii. DNA-based testing with linkage analysis for at- risk family members if no specific disease-causing mutation identified
3. Management
a. No specific treatment available
b. Early physical therapy, occupational therapy, and speech therapy
c. Antibiotics for infections
d. Prevention of infection by regular injection of immunoglobulins in patients with antibody deficiency e. Beta-Adrenergic blockers may improve fine motor
coordination in some cases
f. Controversial use and doses of radiation therapy and chemotherapy
g. Avoid bleomycin, actinomycin D, and cyclophos- phamide
h. Regular cancer surveillance of heterozygotes essen- tial. ATM heterozygosity is a risk factor for breast and lung cancers
i. Desferroxamine: recently shown to increase genomic stability of A-T cells and may present a promising tool in A-T treatment
j. Usually requires wheelchair by ten years of age
REFERENCES
Anmann AJ, Cain WA, Ishizaka K, et al.: Immunoglobulin deficiency in ataxia- telangiectasia. N Engl J Med 281:469–472, 1969.
Calonje D, El-Harazi SM: Ataxia-telangiectasia. Emedicine, 2001. http://www.
emedicine.com
Chessa L, Piane M, Prudente S, et al.: Molecular prenatal diagnosis of ataxia telangiectasia heterozygosity by direct mutational assays. Prenat Diagn 19:542–545, 1999.
Concannon P, Gatti RA: Diversity of ATM gene mutations detected in patients with ataxia-telangiectasia. Hum Mutat 10:100–107, 1997.
Gatti RA: Diversity of ATM gene mutations detected in patients with ataxia- telangiectasia. Hum Mutat 10:100–107, 1997.
Gatti RA: Ataxia-telangiectasia. Gene Reviews, 2003. http://genetests.org Gatti RA, Boder E, Vinters H, et al.: Ataxia-telangiectasia: an interdisciplinary
approach to pathogenesis. Medicine 70:99–117, 1991.
Huo YK, Wang Z, Hong JH, et al.: Radiosensitivity of ataxia-telangiectasia, X- linked agammaglobulinemia, and related syndromes using a modified colony survival assay. Cancer Res 54:2544–2547, 1994.
Jozwiak S, Janniger CK: Ataxia-telangiectasia. Emedicine, 2004. http://www.
emedicine.com
Meyn MS: Ataxia-telangiectasia, cancer and the pathobiology of the ATM gene. Clin Genet 55:289–304, 1999.
Petersen RD, Kelly WD, Good RA: Ataxia-telangiectasia: its association with a defective thymus, immunological-deficiency disease and malignancy.
Lancet 1:1189–1193, 1964.
Regueiro JR, Porras O, Lavin M, et al.: Ataxia-telangiectasia. A primary immun- odeficiency revisited. Immunol Allergy Clin N Am 20(1):177–206, 2000.
Spacey SD, Gatti RA, Bebb G: The molecular basis and clinical management of ataxia telangiectasia. Can J Neurol Sci 27:184–191, 2000.
Sparkes RS, Como R, Golde DW: Cytogenetic abnormalities in ataxia telangiectasia with T-cell chronic lymphocytic leukemia. Cancer Genet Cytogenet 1:329–336, 1980.
Sun X, Becker-Catania SG, Chun HH, et al.: Early diagnosis of ataxia-telang- iectasia using radiosensitivity testing. J Pediatr 140:724–731, 2002.
Swift M, Morrell D, Cromartie E, et al.: The incidence and gene frequency of ataxia-telangiectasia in the United States. Am J Hum Genet 39:573–583, 1986.
Swift M, Reitnauer PJ, Morrell D, et al.: Breast and other cancers in families with ataxia-telangiectasia. N Engl J Med 316:1289–1294, 1987.
Swift M, Morrell D, Massey RB, et al.: Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med 325:1831–1836, 1991.
Taylor AM, Metcalfe AJA, Thick J, et al.: Leukemia and lymphoma in ataxia telangiectasia. Blood 87:423–438, 1996.
Taylor M, Teraoka S, Wang Z, et al.: Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic popula- tions. Am J Hum Genet 62:86–97, 1998.
Woods CG, Taylor AMR: Ataxia-telangiectasia in the British Isles: the clinical and laboratory features of 70 affected individuals. Quart J Med 82:169–179, 1992.
Fig. 1. A boy with ataxia-telangiectasia showing conjunctival telang- iectasis and chronic lung disease requiring oxygen support.
Fig. 2. A girl with ataxia-telangiectasia showing conjunctival telang- iectasis and anemia.
ATAXIA TELANGIECTASIA 95
