Antibody deficiency in patients with ataxia telangiectasia is caused by disturbed B- and T-cell homeostasis and reduced immune repertoire diversity.

BACKGROUND: Ataxia telangiectasia (AT) is a multisystem DNA-repair disorder caused by mutations in the ataxia telangiectasia mutated (ATM) gene. Patients with AT have reduced B- and T-cell numbers and a highly variable immunodeficiency. ATM is important for V(D)J recombination and immunoglobulin class-switch recombination (CSR); however, little is known about the mechanisms resulting in antibody deficiency severity. OBJECTIVE: We sought to examine the immunologic mechanisms responsible for antibody deficiency heterogeneity in patients with AT. METHODS: In this study we included patients with classical AT plus early-onset hypogammaglobulinemia (n = 3), classical AT (n = 8), and variant AT (late onset, n = 4). We studied peripheral B- and T-cell subsets, B-cell subset replication history, somatic hypermutation frequencies, CSR patterns, B-cell repertoire, and ATM kinase activity. RESULTS: Patients with classical AT lacked ATM kinase activity, whereas patients with variant AT showed residual function. Most patients had disturbed naive B-cell and T-cell homeostasis, as evidenced by low cell numbers, increased proliferation, a large proportion CD21(low)CD38(low) anergic B cells, and decreased antigen receptor repertoire diversity. Impaired formation of T cell-dependent memory B cells was predominantly found in patients with AT plus hypogammaglobulinemia. These patients had extremely low naive CD4(+) T-cell counts, which were more severely reduced compared with those seen in patients with classical AT without hypogammaglobulinemia. Finally, AT deficiency resulted in defective CSR to distal constant regions that might reflect an impaired ability of B cells to undergo multiple germinal center reactions. CONCLUSION: The severity of the antibody deficiency in patients with AT correlates with disturbances in B- and T-cell homeostasis resulting in reduced immune repertoire diversity, which consequently affects the chance of successful antigen-dependent cognate B-T interaction.

Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study.

Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder with multisystem involvement and cancer predisposition, caused by mutations in the A-T mutated (ATM) gene. To study genotype-phenotype correlations, we evaluated the clinical and laboratory data of 51 genetically proven A-T patients, and additionally measured ATM protein expression and kinase activity. Patients without ATM kinase activity showed the classical phenotype. The presence of ATM protein, correlated with slightly better immunological function. Residual kinase activity correlated with a milder and essentially different neurological phenotype, absence of telangiectasia, normal endocrine and pulmonary function, normal immunoglobulins, significantly lower X-ray hypersensitivity in lymphocytes, and extended lifespan. In these patients, cancer occurred later in life and generally consisted of solid instead of lymphoid malignancies. The genotypes of severely affected patients generally included truncating mutations resulting in total absence of ATM kinase activity, while patients with milder phenotypes harbored at least one missense or splice site mutation resulting in expression of ATM with some kinase activity. Overall, the phenotypic manifestations in A-T show a continuous spectrum from severe classical childhood-onset A-T to a relatively mild adult-onset disorder, depending on the presence of ATM protein and kinase activity. Each patient is left with a tremendously increased cancer risk.

Neuropathology in classical and variant ataxia-telangiectasia.

Ataxia-telangiectasia (A-T) is classically characterized by progressive neurodegeneration, oculocutaneous telangiectasia, immunodeficiency and elevated α-fetoprotein levels. Some patients, classified as variant A-T, exhibit a milder clinical course. In the latter patients extrapyramidal symptoms, instead of cerebellar ataxia, tend to be the dominating feature and other classical disease hallmarks, like telangiectasia, appear later or even may be absent. Some patients with variant disease have clinically pronounced anterior horn cell degeneration. Neuropathological studies of genetically proven A-T patients are lacking. The aims of our study were to describe the neuropathology of three A-T patients; in two of them the diagnosis was genetically confirmed. The neuropathological findings were compared with those of all known published autopsy findings in A-T patients up to now. Two classical A-T patients aged 19 and 22 and a 33-year-old patient with variant disease were autopsied. In line with previous reports, our patients had severe cerebellar atrophy, less pronounced degeneration of the dentate nucleus and inferior olive, degeneration of the posterior columns and neurogenic muscular atrophy. In addition, all three had anterior horn cell degeneration, which was most prominent at the lumbar level. Compared to the literature, the degenerative changes in the brain stem of the variant A-T patient were somewhat less than anticipated for his age. Degenerative changes in the cerebellum and spinal cord were comparable with those in the literature. Progeric changes were lacking. In conclusion, compared to classical A-T, the variant A-T patient showed essentially the same, only slightly milder neuropathological abnormalities, except for anterior horn degeneration.

Cognitive and speech-language performance in children with ataxia telangiectasia.

OBJECTIVE: To describe cognitive and speech-language functioning of patients with ataxia-telangiectasia (A-T) in relation to their deteriorating (oculo)motor function. DESIGN: Observational case series. METHODS: Cognitive functioning, language, speech and oral-motor functioning were examined in eight individuals with A-T (six boys, two girls), taking into account the confounding effects of motor functioning on test performance. RESULTS: All patients, except the youngest one, suffered from mild-to-moderate/severe intellectual impairment. Compared to developmental age, patients showed cognitive deficits in attention, (non)verbal memory and verbal fluency. Furthermore, dysarthria and weak oral-motor performance was found. Language was one of the patients' assets. CONCLUSION: In contrast to the severe deterioration of motor functioning in A-T, cognitive and language functioning appeared to level off with a typical profile of neuropsychological strengths and weaknesses. Based on our experiences with A-T, suggestions are made to determine a valid assessment of the cognitive and speech-language manifestations.