Classical Ataxia Telangiectasia Research Articles

The natural history of ataxia-telangiectasia (A-T): A systematic review.

Ataxia-telangiectasia is an autosomal recessive, multi-system, and life-shortening disease caused by mutations in the ataxia-telangiectasia mutated gene. Although widely reported, there are no studies that give a comprehensive picture of this intriguing condition. Understand the natural history of ataxia-telangiectasia (A-T), as reported in scientific literature. 107 search terms were identified and divided into 17 searches. Each search was performed in PubMed, Ovid SP (MEDLINE) 1946-present, OVID EMBASE 1980 -present, Web of Science core collection, Elsevier Scopus, and Cochrane Library. All human studies that report any aspect of A-T. Search results were de-duplicated, data extracted (including author, publication year, country of origin, study design, population, participant characteristics, and clinical features). Quality of case-control and cohort studies was assessed by the Newcastle-Ottawa tool. Findings are reported descriptively and where possible data collated to report median (interquartile range, range) of outcomes of interest. 1314 cases reported 2134 presenting symptoms. The most common presenting symptom was abnormal gait (1160 cases; 188 studies) followed by recurrent infections in classical ataxia-telangiectasia and movement disorders in variant ataxia-telangiectasia. 687 cases reported 752 causes of death among which malignancy was the most frequently reported cause. Median (IQR, range) age of death (n = 294) was 14 years 0 months (10 years 0 months to 23 years 3 months, 1 year 3 months to 76 years 0 months). This review demonstrates the multi-system involvement in A-T, confirms that neurological symptoms are the most frequent presenting features in classical A-T but variants have diverse manifestations. We found that most individuals with A-T have life limited to teenage or early adulthood. Predominance of case reports, and case series demonstrate the lack of robust evidence to determine the natural history of A-T. We recommend population-based studies to fill this evidence gap.

Accumulation of Brain Hypointense Foci on Susceptibility-Weighted Imaging in Childhood Ataxia Telangiectasia.

SWI hypointense cerebral lesions have been reported in adults with the inherited cerebellar neurodegenerative disorder ataxia telangiectasia. This study aims to establish the prevalence, age-dependency, and spatial distribution of these lesions in children and young people with ataxia telangiectasia. Participants with classic ataxia telangiectasia and matched controls underwent SWI acquisition at 3T at 1 or 2 time points. SWI hypointense lesions were manually labeled according to the Microbleed Anatomical Rating Scale. Differences in prevalence of lesion number between groups with ataxia telangiectasia and without ataxia telangiectasia were tested with the Fisher exact test, and differences in age between participants with ataxia telangiectasia with and without lesions were tested using independent samples Mann-Whitney U test. The relationship between age and lesion number was modeled as an exponential function. Analyzable SWI datasets from 17 participants with ataxia telangiectasia (with median age at first scan of 12.4 years; range, 4.6-20.2 years; 8 [47%] were female) and 22 matched healthy controls showed prevalence of SWI hypointense lesions in 41% of participants with ataxia telangiectasia and 0% in controls (P = .001, Fisher exact test). Lesions were exclusively supratentorial and predominantly lobar. Participants with ataxia telangiectasia with SWI hypointense lesions were older than those without (median age 5.2 years versus 9.3 years, U = 10.5, P = .014). An exponential curve described the relationship between age and lesion number (R 2 = 0.67). SWI hypointense lesions are common in children and young people with ataxia telangiectasia, accumulating from 12 years of age onward. In contrast to cerebellar-dominant neurodegeneration in ataxia telangiectasia, SWI hypointense lesions were exclusively supratentorial. Further investigation is needed to establish the clinical relevance of these imaging-detected lesions.

Functional parameter measurements in children with ataxia telangiectasia.

To collect preliminary functional data on ataxia telangiectasia and create a disease specific scale: the Ataxia Telangiectasia Functional Scale (ATFS). Retrospective information on patients with ataxia telangiectasia referred to the Assistive Technology Unit was included. Functional mobility scales (the Gross Motor Function Classification System [GMFCS] and the Functional Mobility Scale [FMS]-5, FMS-50, FMS-500) and activities of daily living [ADL] parameters were recorded. We created a 51-point ATFS, that consisted of three ambulation items adapted for ataxia telangiectasia in the frame of FMS (home, school, outdoors), five ADL items, and one schooling item. Twenty-seven participants (17 males, 10 females; mean age 10y 8mo [SD 5y 1mo], range 1y 9mo-25y 6mo), were enrolled; 168 measurements were recorded. Patients walked at a mean age of 1year 4months (SD 5y 4mo) and lost ambulatory capacity at 8years 8months (SD 2y 1mo). GMFCS level and FMS-5, FMS-50, FMS-500 assessments correlated with age (Spearman's correlations r=0.555, -0.617, -0.639, -0.662 respectively, p<0.01 for all), but plateaued after 12years of age. ATFS mean score was 37.46 (SD 7.88) and increased with age (Spearman's correlation r=0.585, p<0.01). The scale showed threestages of disease progression. In this pilot study we show longitudinal functional data of ambulation and ADL skills in ataxia telangiectasia, and created a framework for a functional scale. This functional scale closely approximated disease course, but further validation is required. The Gross Motor Function Classification System and the Functional Mobility Scale are ill-suited for ataxia telangiectasia assessments. Three functional mobility scales (home, school, outdoors) suited to ataxia telangiectasiawere created. The Ataxia Telangiectasia Functional Scale (ATFS) combines mobility and items of activities of daily living. The ATFS closely approximates the three-stage progression of the disorder.

Inflammation and transcriptional responses of peripheral blood mononuclear cells in classic ataxia telangiectasia.

IntroductionClassic ataxia telangiectasia (A-T) is an autosomal recessive disease characterized by early onset ataxia, immune deficiency, sino-pulmonary disease, lymphoid/solid malignancies and telangiectasias. Prior studies have suggested that chronic inflammation and premature aging may contribute to the development of malignancy and pulmonary disease in people with A-T. To further examine the link between A-T and inflammation, we hypothesized that subjects with classic A-T would have greater enrichment of inflammatory pathways in peripheral blood mononuclear cells (PBMCs) compared to non A-T age-matched controls. To test this hypothesis we used RNAseq as an unsupervised approach to identify biological processes altered in people with classic A-T.MethodsPBMCs were isolated from subjects with classic A-T and compared to non-A-T age-matched healthy controls. RNAseq with differential gene expression analyses was then performed. Selected genes were validated by RT-qPCR using cohorts of subjects consisting of classic A-T, mild A-T or non-A-T controls. Subjects with mild A-T were characterized by later onset/mild neurologic features and normal/near normal immune status.ResultsRNAseq revealed 310 differentially expressed genes (DEGs) including genes involved in inflammation, immune regulation, and cancer. Using gene set enrichment analysis, A-T subjects were found to have biological processes enriched for inflammatory and malignancy pathways. In examining a cohort of A-T subjects in which baseline serum IL8 and IL6 levels were measured previously, an association was found between higher serum IL8 levels and higher likelihood of developing malignancy and/or death in a subsequent 4–6 year period.ConclusionRNAseq using PBMCs from subjects with classic A-T uncovered differential expression of immune response genes and biological processes associated with inflammation, immune regulation, and cancer. Follow-up of A-T subjects over a 4–6 year period revealed an association between higher baseline serum IL8 levels and malignancy/death. These findings support a role for inflammation as a contributing factor in A-T phenotypes.

Ataxia-telangiectasia: recommendations for multidisciplinary treatment.

Ataxia-telangiectasia is a rare, neurodegenerative, and multisystem disease, characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, progressive respiratory failure, and an increased risk of malignancies. It demands specialized care tailored to the individual patient's needs. Besides the classic ataxia-telangiectasia phenotype, a variant phenotype exists with partly overlapping but some distinctive disease characteristics. This guideline summarizes frequently encountered medical problems in the disease course of patients with classic and variant ataxia-telangiectasia, in the domains of neurology, immunology and infectious diseases, pulmonology, anaesthetic and perioperative risk, oncology, endocrinology, and nutrition. Furthermore, it provides a practical guide with evidence- and expert-based recommendations for the follow-up and treatment of all these different clinical topics.

Atypical Presentation of Previously Described Classical Ataxia Telangiectasia Pathogenic Mutation

Ataxia Telangiectasia (A-T) is a rare genetic disorder characterized by Cerebellar ataxia, telangiectasia, immunodeficiency and susceptibility for malignancies. The clinical presentation and severity varies in affected patients, which could point out an aspect of gene heterogeneity of this disease that is yet to be identified. This case highlights a rare presentation of a patient diagnosed with A-T, with absence of recurrent and/or severe sinopulmonary disease. A multidisciplinary approach, genetic counselling and preventive care for early cancer detection should be ensured.

Classical Ataxia Telangiectasia Patients Have a Congenitally Aged Immune System with High Expression of CD95

Ataxia-telangiectasia (A-T) is a rare neurodegenerative immunodeficiency disorder caused by mutations in the ataxia telangiectasia mutated gene. Patients commonly have lymphopenia and Ig-production abnormalities. We used multicolor flow cytometry and IL-7 ELISA to investigate the effect of A-T and age on the proportions of major lymphocyte subsets and their pattern of CD95 expression in relation to IL-7 levels in 15 classical A-T patients. We also analyzed the sensitivity of T cells from four classical A-T patients to CD95-mediated apoptosis using TUNEL and caspase-activation assays. Our results confirmed lymphopenia and a deficiency in naive T and B cells in A-T patients. In contrast to controls, the proportions of naive and memory T and B cell subsets in A-T patients did not vary in relation to age. There was no evidence of a deficiency in plasma IL-7 or IL-7R expression, and IL-7 concentration correlated positively with CD95 expression on CD4(+) T cells. CD95 expression on unstimulated A-T lymphocytes was high, and the apoptotic sensitivity of activated naive and central memory T cells was increased. These findings show that the immunodeficiency in A-T patients may be described as congenitally aged and is not progressive. The naive cell deficiency is not related to a deficiency in IL-7 or its receptor. However, IL-7 may upregulate CD95 on A-T lymphocytes. High CD95 expression and increased apoptotic sensitivity of activated naive and central memory T cells may result in an increased level of CD95-mediated apoptosis, which could contribute to the congenital lymphopenia in A-T.

Severe reaction to radiotherapy for breast cancer as the presenting feature of ataxia telangiectasia

Background:Severe early and late radiation reaction to radiotherapy is extremely rare in breast cancer patients. Such a reaction prompted an investigation into a 44-year-old mother (patient A-T213).Methods:A neurological examination was performed and blood lymphocytes and skin fibroblasts were assessed for radiosensitivity chromosomally and by colony-forming assay. The ATM gene was sequenced and ATM mutations modelled by site-directed mutagenesis. The ATM kinase activity was also assessed.Results:Patient A-T213 was normally ambulant with no ataxia and minimal other neurological features. T lymphocytes and skin fibroblasts were unusually radiosensitive, although less sensitive than in classical ataxia telangiectasia (A-T). A lymphoblastoid cell line and skin fibroblasts expressed ATM protein with some retained kinase activity. One missense ATM mutation c.8672G>A (p.Gly2891Asp) and a c.1A>G substitution were identified. In the modelling system, the p.Gly2891Asp mutant protein was expressed and shown to have residual ATM kinase activity.Conclusion:Patient A-T213 has a milder form of A-T with biallelic ATM mutations, which may have contributed to breast cancer development, and certainly caused the severe radiation reaction. Ataxia telangiectasia should be investigated as a potential cause of untoward severe early and late radiation reactions in breast cancer patients.

Ataxia-telangiectasia

Classic ataxia-telangiectasia (AT) is a rare autosomal recessive disorder characterized by progressive cerebellar dysfunction leading to unsteady gait in early childhood, oculomotor apraxia, and ocular and cutaneous telangiectasias.1,2 Other neurologic features such as movement disorders, dysarthria, and peripheral neuropathy are usually present, and non-neurologic features include sinopulmonary infections, immune dysfunction, endocrine disorders, malignancies, and an increased sensitivity to ionizing radiation. AT is caused by mutations in the ataxia telangiectasia mutated (ATM) protein, which is integral to cell cycle checkpoint control and repair of double-stranded DNA breaks.3 No known treatment for AT exists. AT may infrequently present in milder “variant” forms in which the neurologic features are not as rapidly progressive1,4,5; however, the risk of malignancy is likely elevated and such patients may also be radiosensitive. In this issue of Neurology ®, Verhagen et al.6 compare the clinical and diagnostic features of 13 adults with variant AT to those of 6 patients with classic AT. While patients …

Clinical spectrum of ataxia-telangiectasia in adulthood

To describe the phenotype of adult patients with variant and classic ataxia-telangiectasia (A-T), to raise the degree of clinical suspicion for the diagnosis variant A-T, and to assess a genotype-phenotype relationship for mutations in the ATM gene. Retrospective analysis of the clinical characteristics and course of disease in 13 adult patients with variant A-T of 9 families and 6 unrelated adults with classic A-T and mutation analysis of the ATM gene and measurements of ATM protein expression and kinase activity. Patients with variant A-T were only correctly diagnosed in adulthood. They often presented with extrapyramidal symptoms in childhood, whereas cerebellar ataxia appeared later. Four patients with variant A-T developed a malignancy. Patients with classic and variant A-T had elevated serum alpha-fetoprotein levels and chromosome 7/14 rearrangements. The mildest variant A-T phenotype was associated with missense mutations in the ATM gene that resulted in expression of some residual ATM protein with kinase activity. Two splicing mutations, c.331 + 5G>A and c.496 + 5G>A, caused a more severe variant A-T phenotype. The splicing mutation c.331 + 5G>A resulted in less ATM protein and kinase activity than the missense mutations. Ataxia-telangiectasia (A-T) should be considered in patients with unexplained extrapyramidal symptoms. Early diagnosis is important given the increased risk of malignancies and the higher risk for side effects of subsequent cancer treatment. Measurement of serum alpha-fetoprotein and chromosomal instability precipitates the correct diagnosis. There is a clear genotype-phenotype relation for A-T, since the severity of the phenotype depends on the amount of residual kinase activity as determined by the genotype.

Neuromuscular Abnormalities in Ataxia Telangiectasia: A Clinical, Electrophysiological and Muscle Ultrasound Study

Thirteen classical ataxia telangiectasia (A-T) patients, varying in age from 1 to 25 years, were studied clinically, electrophysiologically as well as by muscle ultrasound to chart the development and spectrum of neuromuscular abnormalities in A-T. The most prominent finding was a progressive axonal sensorimotor polyneuropathy, apparent by electromyography and muscle ultrasound from the age of 8 years and becoming clinically discernible around 12 years of age. Before the age of 8 years decreased tendon reflexes and slightly slowed sensory nerve conduction velocities could already be observed. With routine electrophysiological techniques the severe polyneuropathy precludes conclusions about the presence of anterior horn cell loss in older patients.

Six novel ATM mutations in Italian patients with classical ataxia-telangiectasia.

Mutations in the ATM gene are responsible for the autosomal recessive syndrome Ataxia Telangiectasia (AT). In a group of 26 classical AT Italian patients studied by protein truncation test (PTT), we identified six new mutations, never reported so far. Mutations -spread over the entire ATM coding sequence with not clear "hot-spot"- are four frameshifts (2192_2193insA, 3110delC, 7150delA, 8368delA), one splice site alteration (8850G>T, causing exon 63 skipping) and one nonsense change (6913C>T, Q2305X). The identification of ATM gene mutations is important for understanding the molecular basis of the disease, and is essential for diagnosis and genetic counseling.

Residual Ataxia Telangiectasia Mutated Protein Function in Cells from Ataxia Telangiectasia Patients, with 5762ins137 and 7271T→G Mutations, Showing a Less Severe Phenotype

We have assessed several ataxia Telangiectasia mutated (ATM)-dependent functions in cells derived from ataxia telangiectasia patients, carrying either an ATM 5762ins137 splice site or a 7271T-->G missense mutation, with a less severe phenotype compared with the classical disorder. ATM kinase in vitro, from 5762ins137 cells, showed the same specific activity as ATM in normal cells, but the protein was present at low levels. In contrast, mutant ATM kinase activity in the 7271T-->G cells was only about 6% that of the activity in normal cells, although the level of mutant protein expressed was similar to normal cells. Phosphorylation of the DNA double strand break repair proteins Nbs1 and hMre11, following DNA damage, was observed in normal and 7271T-->G cells but was almost absent in both 5762ins137 and classical ataxia telangiectasia cells. The kinetics of p53 response was intermediate between normal and classical ataxia telangiectasia cells in both the 7271T-->G and 5762ins137 cells, but interestingly, c-Jun kinase activation following DNA damage was equally deficient in cell lines derived from all the ataxia telangiectasia patients. Our results indicate that levels of ATM kinase activity, but not induction of p53 or c-Jun kinase activity, in these cells correlate with the degree of neurological disorder in the patients.

ATM germline mutations in classical ataxia-telangiectasia patients in the Dutch population.

Germline mutations in the ATM gene are responsible for the autosomal recessive disorder ataxia-telangiectasia (A-T). In our study, we have determined the ATM mutation spectrum in 19 classical A-T patients, including some immigrant populations, as well as 12 of Dutch ethnic origin. Both the protein truncation test (PTT) and the restriction endonuclease fingerprinting (REF) method were used and compared for their detection efficiency, identifying 76% and 60% of the mutations, respectively. Most patients were found to be compound heterozygote. Seventeen mutations were distinct, of which 10 were not reported previously. Mutations are small deletions or point mutations frequently affecting splice sites. Moreover, a 16.7-kb genomic deletion of the 3' end of the gene, most likely a result of recombination between two LINE elements, was identified. The most frequently found mutation, identified in three unrelated Turkish A-T individuals, was previously described to be a Turkish A-T founder mutation. The presence of a founder mutation among relatively small ethnic population groups in Western Europe could indicate a high carrier frequency in such communities. In patients of Dutch ethnic origin, however, no significant founder effect could be identified. The observed genetic heterogeneity including the relative high percentage of splice-site mutations had no reflection on the phenotype. All patients manifested classical A-T and increased cellular radioresistant DNA synthesis.

Transformation of chromosome breakage syndrome fibroblasts by SV 40 DNA transfection

SV 40 DNA was transfected into three Fanconi's anemia, two classical ataxia-telangiectasia, two variant ataxia-telangiectasia, three Bloom's syndrome, and three normal fibroblast cultures in order to study T-antigen expression, growth transformation, and survival of the crisis phase. Although Fanconi's anemia cells exhibited an initially higher frequency of uptake of transfected DNA compared with all the other cell strains studied, they did not acquire the transformed phenotype any faster than the others. Classical ataxia-telangiectasia fibroblasts, on the other hand, showed approximately the same rate of initial uptake of SV 40, but were significantly slower than all other cell strains in expressing the transformed phenotype. The uptake and growth transformation properties of Bloom's syndrome and variant ataxia-telangiectasia cells were similar to those of normals. Serial subculturing of transfected cells was found to accelerate the appearance of growth-transformed cells. Although a number of transformed sublines of Fanconi's anemia, classical and variant ataxia-telangiectasia, and Bloom's syndrome strains apparently survived the crisis phase, no immortalized strains emerged from them.