Prof Sarah Bundey
The first report of Ataxia Telangiectasia (A-T) was in 1926 when Syllaba & Henner described 3 sibs with choreoathetosis and telangiectasia of conjuctivae and skin. Just a handful of cases was reported over the next 30 years, by Louis-Bar, Boder & Sedgwick, Biemond, and Wells & Shy. Why was there such a long delay before Boder & Sedgwick described a collection of 101 cases in 1963?? It usually takes some time before a new observation in the medical literature becomes accepted, but another factor was the gradual realisation that the telangiectasia, which were so prominent in the early cases, particularly in those children described by Wells & Shy, may not be obvious in some children with A-T. Indeed in a recent study from the UK by Woods & Taylor, skin telangiectasia were only present in about 20% of cases.
The natural history of A-T was documented in Boder & Sedgwick's series, and in later series, notably by Swift et al from the USA, Chessa et al from Italy, Ersoy et al from Turkey, and Woods et al from the UK. A progressive ataxia is the hallmark of the disease, and onset is usually within the first 4 years of life. All patients later develop chorea, and many also develop dystonia, which may initially lead to the erroneous diagnosis of cerebral palsy. In adult life, a peripheral neuropathy develops. Apraxia of eye movements and dysarthria are early signs. The telangiectasia, which may not be obvious, develop between birth and 15 years.
Boder & Sedgwick soon realised that A-T was associated with frequent infections of the respiratory tract; these occurred in about 80% of the 101 patients in their series. The infections were accompanied by a deficiency of immunoglobulins, particularly IgA, and also by impaired cellular immunity. In postmortems on patients, it was observed that lymphoid tissue was depleted in those tissues where it should have been plentiful, namely the thymus and lymphatic glands.
In 1963 Hecht reported that lymphoreticular malignancies (lymphomas, leukaemias, and Hodgkins disease) were common in patients with A-T. At any one time about 10% of patients are affected, but malignancy is either the main or contributory cause of death in about half the patients. In 1967, Gotoff et al described a boy who developed severe ulceration of buccal and pharyngeal mucosa following radiation for a tonsillar lymphosarcoma. Further examples of a severe reaction to radiation were then described and one such boy in Birmingham died within 3 weeks of his treatment. This case encouraged Malcolm Taylor to investigate the phenomenon in the laboratory and in 1975 he and colleagues reported that chromosomes and cell lines from patients with A-T were unduly sensitive to X- and g- irradiation. Other work during the period 1966-1976 (Hecht, Paterson, Taylor) demonstrated that the chromosomes of A-T patients showed spontaneous increase of structural abnormalities, which particularly involved chromosomes 7 and 14, and which were often present in lymphocytic clones. A further finding was the demonstration of impaired DNA repair and of a failure to reduce DNA synthesis following damage by irradiation (Lehmann & Stevens).
It was known from the earliest reports that A-T was a familial condition, but it was left to Tadjoedin & Fraser (1965) to produce evidence from reviewing the literature that A-T was inherited as an autosomal recessive. However, although the recurrence in sibs of index patients is compatible with a proportion of 0.25, as would be expected from autosomal recessive inheritance, it is lower than this figure in all studies except for that of Chessa et al (1994). Perhaps some cases are caused by a heterozygous new mutation, or alternatively perhaps there are some children who carry mutations on both number 11 chromosomes yet have no symptoms. Another unusual genetic finding is that fewer parents are consanguineous than would be expected for a rare disease like A-T. (Modern estimates of the incidence of A-T provide evidence that 1 in 100,000 to 1 in 300,000 is the correct range), J H Edwards has suggested that a homoygous mutation in a neighbouring gene causes lethality; this would mean that patients with a stretch of homozygosity (as would happen if the A-T mutation had been inherited from a common great grand parent) would never be ascertained. It will be very interesting to discover the answers to these conundrums as a result of analysts of mutations in the ATM gene.
Other curiosities about A-T include the suggestion by Swift et al (1976) that there is a probable increase of breast cancer in females who are heterozygous for A-T. This may be related to earlier exposure to therapeutic irradiation. However mutations in the A-T gene in patients with early onset breast cancer have not yet been observed, and the effect, if there is one, is probably small. Then there is the observation that in laboratory conditions, the increased sensitivity to ionising radiation may be reversed when cells from another patient are added to the experiment. Jaspers & Bootsma & others have postulated that there are 4-6 such complementation groups. With other conditions in which complementation has been demonstrated, the explanation lies in the fact the disease in question is caused by mutations in genes at different loci. However in the case of A-T, the mechanism must arise because of the nature of the different mutations in the single gene that is thought to be responsible for A-T, namely the ATM gene on the long arm of chromosome 11.
From 1987 onwards, it has been noted that there are some patients whose features do not fit the recognised pattern of A-T. For example, in 1987, Malcolm Taylor et al described some patients with a mild course of the disease, and with intermediate levels of radiation sensitivity. In considering these and other 'variants' of A-T, we must define the diagnostic criteria for A-T. These are: a progressive ataxia, the spontaneous occurrence of structural chromosomal anomalies, and, if radiation studies are carried out, then these should show increased sensitivity. I do not think that telangiectasia or oculomotor apraxia are absolutely necessary for the diagnosis. However I do consider that the Nijmegen breakage syndrome, which has many of the features of A-T, must be excluded since it is not accompanied by a progressive ataxia.
The final chapters in the story of A-T come with the mapping of the locus to 11q22-23 in 1988, by Gatti et al followed 7 years later by the cloning of the gene by Savitsky et al in 1995, from the Department headed by Dr Yosef Shiloh. During the following presentations we shall hear to what extent analysis of mutations in the ATM gene help us to understand the great variability in clinical manifestation, the occurrence of complementation groups, and the genetic oddities that I mentioned earlier.
Prof Sarah Bundey
Dept of Clinical Genetics
Birmingham Women's Hospital
Edgbaston
BIRMINGHAM
OTHER PRESENTATIONS:
Increased Radiation Sensitivity and Cancer Associated with Ataxia-Telangiectasia
The Neurological Aspects of Ataxia-Telangiectasia
Immunodeficiency and Infections Associated with Ataxia-Telangiectasia
Ataxia-Telangiectasia and ATM: The Next Stage
Why it is Important to Identify Cases of Ataxia-Telangiectasia