Ataxia-telangiectasia

A T1-weighted magnetic resonance (MR) image of the brain through the upper portion of the cerebellum shows a small cerebellum with prominent folia due to the cerebellar atrophy (Figure 1). An axial T2-weighted MR image of the brain obtained at the same level as the T1weighted image in Figure 1 shows prominent cerebrospinal fluid spaces surrounding the cerebellum along with marked cerebellar atrophy (Figure 2). A sagittal noncontrast T1-weighted MR image shows cerebellar atrophy that is most prominent in the region of the cerebellar vermis (Figure 3). The vermian atrophy is more prominent than the atrophy of the cerebellar hemispheres and is characteristic of the type of anatomic appearance seen in ataxia-telangiectasia.

Discussion

Ataxia-telangiectasia (AT), also known as Louis-Bar syndrome, is a hereditary autosomal recessive progressive multisystem disease. Madame Louis-Bar first described its clinical characteristics in 1941, followed by Boder and Sedgwick in 1957, who first described its clinical and pathologic findings.¹ The disorder is rare, with an average worldwide incidence of approximately 1:40,000 to 1:300,000 live births.^2,3

Ataxia-telangiectasia is chiefly characterized by progressive cerebellar ataxia, conjunctival and cutaneous telangiectasias, severe immune deficiencies, recurrent sinopulmonary infections, and a markedly increased risk of malignancy. The disease begins in early childhood and is usually first recognized when the child begins to walk with an ataxic gait, swaying the head and trunk. The progressive ataxia is a result of degeneration of the Purkinje cells as well as the granular cells of the cerebellum.⁴ This ataxia usually becomes severe enough to warrant the use of a wheelchair by 10 to 15 years of age.

Ocular telangiectasias usually appear after the onset of ataxia, which is typically observed between 3 and 6 years old. These telangiectasias are bright red horizontal streaks that cause the eyes to look "bloodshot" and eventually involve the rest of the conjunctivae, eyelids, adjoining facial regions, external ears, neck, and antecubital and popliteal spaces. The development of cutaneous telangiectasias soon follows. The patients also have complex immune deficiencies of both the cellular and humoral components that predispose them to recurrent sinopulmonary infections. Other findings associated with AT include choreoathetosis, oculomotor apraxia, dysarthria, hypoplastic or absent thymus, increased or decreased skin pigmentation, hypoplastic genitalia, and marked sensitivity to ionizing radiation.

Patients with primary immunodeficiencies have a significantly higher incidence of developing a malignancy compared with the general population. Patients with AT have a higher risk of malignancy than individuals with any other type of primary immunodeficiency, accounting for >30% of all tumors listed in the international Immunodeficiency Cancer Registry of the early 1970s.⁵ The incidence of malignancy in AT is approximately 10% to 11%, with a cancer mortality rate >100 times that of the general pediatric population.⁶ The most common malignancy is NHL, but others include: Hodgkin's lymphoma, leukemia, astrocytoma, medulloblastoma, gastric carcinoma, and various cutaneous neoplasms.

The disease process is due to abnormal chromosomal instability and a mutation of the ataxia-telangiectasia, mutated (ATM) gene, which is responsible for production of a protein kinase, which, in turn, is responsible for cell cycle checkpoints. The ATM gene is therefore unable to respond to DNA strand-break damage by arresting the cell cycle at various phases. This prevents cell death but causes the cell to cease its normal function.⁷ In addition, AT patients also have excessive susceptibility to this DNA strand-breakage, further compounding the problem.

The most characteristic radiographic finding of AT seen on computed tomography (CT) or MRI examination of the head is diffuse, progressive cerebellar atrophy, with atrophy of the vermis usually more prominent than that of the hemispheres⁸ (Figure 1). Other findings on CT or MRI of the head include dilatation of the fourth ventricle, enlargement of the cisterna magna, and sinusitis. Occasionally, lesions that are consistent with small vessel ischemic or degenerative changes have been noted in the deep white matter of the cerebral hemispheres.

The telangiectasias in AT do not involve the brain or lung and are not predisposed to hemorrhage.⁹ In addition, chest X-ray and chest CT often reveal evidence of acute and/or chronic pulmonary infection. These recurrent or chronic infections often lead to progressive bronchiectasis and emphysematous changes in the lungs.¹⁰ Patients with AT have very little lymphoid tissue; hence, the presence of adenopathy is highly worrisome for malignancy. It should be noted that AT patients are at least 4 times more sensitive to ionizing radiation than the average age-matched patient.¹¹ The prognosis for patients with AT is poor. Death before the age of 20 is common and is usually caused by pulmonary diseases or malignancy.

CONCLUSION

Ataxia-telangiectasia is a hereditary progressive multisystem disease. Initial presentation is most commonly progressive cerebellar ataxia early in life followed by conjunctival and cutaneous telangiectasias, immune deficiencies, and recurrent sinopulmonary infections. There is also an associated 100-fold increased cancer mortality risk. MRI yields cerebellar atrophy most prominent in the region of the vermis, with prominent folia and increased surrounding cerebrospinal spaces.

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