Skin fibroblasts from ataxia telangiectasia (AT) patients, obligate AT heterozygotes (ATH) and normal individuals were studied for colony-forming ability and repair of DNA double-strand breaks (dsb) after gamma-irradiation. AT cells were three to four times more radiosensitive than normal cells at high and low dose-rate exposures; ATH cells, however, showed a marginally increased radiosensitivity after high dose-rate gamma-irradiation and an intermediate response after low dose-rate exposure. The repair of DNA dsb was studied by pulsed field gel electrophoresis. After high dose-rate gamma-irradiation the repair time constant (t1/2) was around 1 h for normal, ATH and AT cells. After low dose-rate gamma-irradiation the fraction of residual dsb was 1.4% for normal, 2.1% for ATH and 5.2% for AT cells, demonstrating a deficiency in the repair of a small fraction of dsb in AT. Thus the fraction of residual dsb after low dose-rate exposure was not only four times higher in AT than in normal cells, but was also significantly increased in ATH compared to normal cells.

Ataxia-oculomotor apraxia is a distinct entity first comprehensively described in 1988. The features include early childhood onset of ataxia and oculomotor apraxia, mimicking ataxia telangiectasia but without the extraneurologic findings of ataxia telangiectasia. We add to the clinical description of the ataxia-oculomotor apraxia syndrome by reporting eight patients, ages 2 to 15 years, from four families, suggesting autosomal recessive inheritance, with the longest follow-up over 6 years. After initial gait deterioration, all had a nonprogressive course. We have postulated that ataxia-oculomotor apraxia should be established as a separate disease from ataxia telangiectasia or its variants not only by clinical history, examination findings, and course, but primarily by the biologic markers of normal chromosome breakage and radiation sensitivity studies. We found no increased chromosome breakage in the four patients studied and intermediate sensitivity to chronic ionizing radiation of cultured skin fibroblasts on the three patients studied. Family studies revealed an intermediate radiosensitivity from two patients, their asymptomatic parents, and a sister. The lack of chromosome breakage strongly separates ataxia-oculomotor apraxia from ataxia telangiectasia. The radiation sensitivity studies are compatible with two possibilities: (1) symptomatic ataxia telangiectasia heterozygotes, but this would be highly unusual because the degree of clinical involvement in the ataxia-oculomotor apraxia patients is not mild, as would be expected if they were heterozygotes and (2) a separable disease entity, which is the interpretation we favor.

Cultured fibroblast cells from 19 patients with non-Hodgkin's lymphoma (NHL), 3 patients with ataxia telangiectasia (AT), 3 AT heterozygotes and 11 (presumed) normal subjects were studied for impaired colony-forming ability after chronic gamma irradiation. Five cell lines from the NHL patients were also examined for the sensitivity to acute gamma irradiation, as compared with those of normal subjects. To ascertain the degree of radiosensitivity of different cell lines, a comparison was made of the D10 values (radiation dose resulting in 10% survival) for each cell line, estimated "by eye" from the actual survival curves, and also from the calculated curves fitted to a log-linear model. It was observed that the acute gamma irradiation failed to show any appreciable difference in the radiation response of the cell lines from NHL patients as compared with those of normal subjects. However, chronic irradiation demonstrated significantly increased radiosensitivity in at least 10-12 NHL patients with a p value of less than 0.05, when the D10 values of each patient's cell line were compared with the calculated composite values for the normals. When the D10 values of the NHL patients and the normal subjects were compared as 2 groups, the former appeared to be significantly more sensitive to chronic gamma irradiation (p less than 0.0001). The same level of significant difference in radiosensitivity was found between the 2 groups when their D37 values (radiation dose resulting in 37% survival) were compared. In general, the radiation response of the NHL patients was similar to that of the AT homozygotes and heterozygotes used as a positive control group. Our data thus show that increased radiosensitivity is associated with the NHL patients studied, indicating an underlying abnormality of their DNA repair.

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