ATAXIA TELANGIECTASIA
Ataxia Telangiectasia (AT) is an autosomal recessive hereditary progressive neurodegenerative and multisystem disease characterized by cerebellar ataxia, telangiectasias, recurrent sinopulmonary infections, and variable immunologic defects. Its diagnosis is obvious when ataxia and telangiectasia are both present. However, the diagnosis can be made upon the onset of ataxia and before the appearance of telangiectasia if confirmed by laboratory tests. Early diagnosis is important for genetic counseling, appropriate care, and avoidance of unnecessary tests (1998).
Serum IgA is low to absent in 60 to 80% of cases; less common B cell defects include low to absent secretory IgA, increased catabolism of serum IgA, development of anti-IgA, and deficiency of serum IgE. Evidence of impaired T cell function includes periodic lymphopenia, a decreased response to delayed hypersensitivity tests and to in vitro tests of lymphocyte function, and thymus abnormalities (small gland; decreased lymphocytes; absence of Hassall’s corpuscles).
Both neurologic symptoms and evidence of immunodeficiency are variable in onset. Ataxia usually develops at about the time when patients begin to walk but may be delayed until the age of four years. Its progression leads to severe disability. Speech becomes slurred, choreoathetoid movements and opthalmoplegia occur, and muscle weakness usually progresses to muscle atrophy.
Telangiectasias develop between 1 and 6 years of age, most prominently on the bulbar conjunctiva, ears, antecubital and popliteal fossas, and sides of the nose. The recurrent sinopulmonary infections, which result from the immunologic deficits, lead to recurrent pneumonia, bronchiectasis, and chronic obstructive and restrictive lung disease.
Endocrine abnormalities may occur, including gonadal dysgenesis, testicular atrophy, and an unusual form of diabetes mellitus characterized by marked hyperglycemia, resistance to ketosis, absence of glycosuria, and a marked plasma insulin response to glucose or tulbutamide.
The incidence of cancer is increased, most often as lymphosarcoma but also including Hodgkin’s disease, leukemia, gastric adenocarcinoma, cerebellar medulloblastoma, reticulum cell carcinoma, and frontal lobe glioma.
Prognosis is usually poor, with death occurring from chronic sinopulmonary infections or malignancy. However, the progressively and severely handicapped patients may survive into their 30s.
Proper diagnosis of the hereditary disorder AT can be done when only the ataxia or staggering balance problems have appeared but not the telangiecatasia with its characteristic dilation of capillaries on the ears, faces, and eyes. The name of the disorder itself is an impediment to early diagnosis, as it includes both symptoms. A serum alpha-fetoprotein test done on all children who have a lasting ataxia would identify the AT earlier and allow treatment and counseling (1998).
Although it is difficult to reconstruct all the factors that lead physicians to a correct diagnosis of AT, we hypothesize that physicians rely on telangiectasia to make this diagnosis and do not consider AT until telngiectasia appear. This may be attributable to the fact that AT is a rare cause of ataxia and/or the physician’s unfamiliarity with laboratory methods that may support a diagnosis at an earlier stage of the disease. Furthermore, affected children may not seem to deteriorate in function until the early school years so that the diagnosis of a static condition seems reasonable for a time. Our experience with AT suggests that the name, although a concise and memorable label for the disorder, is also a barrier to early diagnosis ( 1998).
Laboratory tests that may help support a diagnosis of AT include measurement of serum AFP levels and examination of the karyotype. AFP is a human fetal serum protein found at levels less than 10 ng/mL in children more than the age of 1 year. Rising levels of AFP in young children are distinctly unusual, and characteristic of patients with AT or certain rare tumors. Increased frequency of spontaneous- and x-irradiation-induced chromosomal breaks are also associated with the diagnosis of AT. Recent identification of the gene responsible for AT (ATM) may improve diagnosis and reveal a wider spectrum of the disease. However, the large size of the ATM gene and the finding that most pathogenic mutations are unique make genetic evaluation of the individual patient highly labor intensive and genetic diagnosis more specific than sensitive (1998).
Although the AT is diagnosed based on clinical presentation as is presented in the first few paragraphs, it is sometimes necessary to perform a cytological test to confirm diagnosis. This is done by demonstrating that cells from patients are sensitive to irradiation (IR). This procedure is done by irradiating blood lymphocytes, or skin fibroblast cells from AT patients followed by monitoring frequencies of CAs in metaphase cells relative to frequencies of CAs found in cells from normal, control individuals. In a typical analysis four cells sampled are generated: untreated AT sample, irradiated AT sample, untreated normal sample, and irradiated normal sample.
As the analysis is performed in a way that the person analyzing the samples is not aware of which sample is which, there is no chance for the experiment to be manually manipulated by the researchers in order to come up with the desired results.
The irradiated normal sample showed a total of 12 chromosomal aberrations. The irradiated AT sample on the other hand had a total of 35 chromosomal aberrations. The untreated AT sample had a total of 6 chromosomal aberrations.
The frequency of chromosomal aberrations induced by radiation in each of the samples was found to be similar in the cells irradiated. A similar frequency was recorded also in the cells of genetically or AT defective individuals. However, the incidence of aberrations in specific chromosomes of normal and genetically defective or AT individuals differed and the frequency was found to be higher in the latter group. From the data it is evident that the response of chromosomes of AT patients was significantly different compared to those of healthy individuals.
The radiosensitivity of individual chromosomes and the location of the radiation-induced chromosomal break points are found to be genetically controlled. There exists an intra and interchromosomal variation in the production of radiation-induced chromosomal aberrations.
A delay in the diagnosis of AT may compromise care of the patient and other family members. Early diagnosis of AT alerts the physician to possible immunodeficiency and the need to limit exposure to ultraviolet light and diagnostic radiographs. Early diagnosis also allows the opportunity for genetic counseling because parents are at risk for having other children with AT. Timely diagnosis identifies heterozygous parents who may have an increased risk for cancer or complications from cancer therapy.
Finally early diagnosis can avoid further costly and unnecessary tests. Many of our patients have had one, if not multiple, neuroimaging studies. In contrast, the cost of determining serum AFP levels is low. On a macroeconomic level, routine determination of AFP for all pediatric patients with chronic ataxia may be cost-effective. AFP measurements are certainly cost-effective in the evaluation of young children with progressive ataxia. In summary, the diagnosis of AT is often delayed, but can be made earlier with readily available and inexpensive laboratory studies. The delay is costly for the patient, family, and society ( 1998).
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