Ataxia (loss of equilibrium) is usually seen before three years of age. This progresses so that the A-T child needs a wheelchair by age ten. Some children have a slower progression. The loss of coordinated movement is also seen in eye tracking, hand coordination, and speaking (tongue movements).

Dilated blood vessels (telangiectasia) in the eyes are seen in most patients, but this sign does not usually appear until several years after the ataxia becomes obvious.

A-T patients are prone to infections in the lungs and sinuses, and to developing cancer, usually of the lymphoid system.

They are sensitive to ionizing radiation, such as X-rays. Therefore, when administering radiation therapy to tumors in such children, extreme care must be taken to reduce the radiation dosages.

The initial suspected diagnosis depends primarily on the symptoms observed by the physician and parents. MRI shows a dystrophic cerebellum. Our laboratory plays a major role in assisting physicians from many countries to confirm a diagnosis of A-T. We study blood samples on several new patients each week. We offer a unique blood test for radiosensitivity (colony survival assay) for A-T, NBS, Mre11 deficiency, as well as for patients with unusual reactions to radiation therapy. We perform prenatal diagnosis for A-T, identification of ATM protein, a functional kinase assay for ATM, and mutation analyses for ATM and NBS.

Treatment is presently aimed at:

1. remaining physically active through exercise

2. speech therapy to improve the clarity of speech

3. antioxidants to minimize free radical damage to DNA, such as Vitamin E (tocopherols) and alpha-lipoic acid

4. folic acid to reduce chromosome breaks, which A-T patients have trouble repairing.

The childhood syndrome of progressive ataxia with telangiectasia was first noticed by two Czech physicians in 1926. In the late fifties two pediatric neurologists, Boder and Sedgwick rediscovered the syndrome in the Los Angeles public schools and named the disease. They reviewed records of 101 patients and noted a very high incidence of cancer, an absent or dystrophic thymus, and some signs of premature aging. Other historical discoveries include:

1961 IgA deficiency noted in many patients

1964 Abnormal thymus and cellular immunodeficiency

1967 Untoward response to radiation therapy

1972 Elevated serum alphafetoprotein

1978 Carriers have intermediate radiosensitivity in vitro

1988 Gene located on chromosome 11q22-23

1995 ATM gene isolated -- with PI-3 kinase homology

1996 Over 150 ATM mutations described

1998 ATM phosphorylates p53, c-abl, and other proteins

1999 ATM mutations found in association with various cancers

In 1988, the ataxia-telangiectasia gene was located on chromosome 11q22-23 by studying a very large Amish pedigree with many genetic markers. The inheritance of these markers was then compared to the inheritance of A-T. This took seven years. Later, an international consortium was formed that included over 200 families. These analyses allowed the gene to be pinpointed to a region of the genome that was small enough to be cloned and analyzed. In 1995, the Israeli members of the consortium, lead by Yosef Shiloh, PhD, isolated the gene (named ATM for Ataxia Telangiectasia Mutated). ATM is very large gene and appears to be evolutionarily related to a group of proteins called kinases, which function to activate other proteins. All previously described complementation groups could be explained by mutations in this single gene.

The ATM protein plays important roles both in the cytoplasm and in the nucleus. It maintains the integrity of DNA, especially when breaks occur in both strands -- double strand breaks. ATM sets in motion many biochemical pathways for controlling the stages through which a cell passes during its growth and development – the cell cycle. These facts are helping to understand cancer, aging, neurological and immunological development, as well as endocrine problems such as diabetes, sexual development, and fertility. Carriers have only one defective ATM copy but they may also age prematurely and develop cancer and heart disease. Because the ATM protein is found primarily in the cytoplasm of Purkinje cells in the cerebellum, one can speculate that the ataxia results from one of ATM protein’s cytoplasmic, rather than nuclear, functions.

Three other syndromes overlap with A-T: Nijmegen Breakage Syndrome (NBS), Mre11-deficiency, and A-TFresno. While NBS patients do not have ataxia or telangiectasia, they are radiosensitive, immunodeficient, and cancer prone, and they have the same characteristic chromosomal translocations as those seen in A-T. In 1998, the NBS gene was cloned. Recent evidence indicates that the NBS protein, nibrin, is phosphorylated by ATM. This would explain the overlapping symptoms. Mre11 protein forms a complex with nibrin that functions to process double strand breaks in DNA. Human Mre11may also be phosphorylated by ATM. Patients lacking Mre11 have a milder ataxia, with a slower progression. Tests are now available to distinguish A-T, NBS, and Mre11 deficiency from one another. Yeast geneticists have played a crucial role in unravelling the above relationships. A third related syndrome, AT_Fresno, shares features of both A-T and NBS and results from mutations in the ATM gene.

Mahnoush Babaei, Iran

Olivier Bay, France (supported by APRAT)

Ewa Bernatowska, Poland

Anne-Lise Borresen-Dale, Norway

Luciana Chessa, Italy

Thilo Doerk, Germany

Hulye Kayseri, Turkey ( Istanbul)

Martin Lavin, Australia

Eugenia Monros, Spain

Oscar Porras, Costa Rica

Igor Resnick, Russia

Chaim Roifman, Canada

Ozden Sanal, Turkey (Ankara)

Yosef Shiloh, Israel

Malcolm Taylor, United Kingdom

Corry Weemaes, Netherlands

Marta Zelasko, Argentina

At UCLA, we have ongoing collaborations with David Rawlings, MD, PhD (Pediatrics), Ken Lange (Biomathematics), Jean DeVellis (Neurobiology), Renato Aguilera, PhD (Molecular, Cellular, Developmental Biology), Ram Iyer, PhD (Pathology), Paul Mischel, MD, PhD (Pathology), and Faramarz Naeim, MD (Pathology). The A-T Research Center at UCLA is supported by the A-T Medical Research Foundation, as well as by grants from the National Institutes of Health.