Recent developments in sequencing technologies led to the discovery of a novel form of genomic instability, termed chromothripsis. This catastrophic genomic event, involved in tumorigenesis, is characterized by tens to hundreds of simultaneously acquired locally clustered rearrangements on one chromosome. We hypothesized that leukemias developing in individuals with Ataxia Telangiectasia, who are born with two mutated copies of the ATM gene, an essential guardian of genome stability, would show a higher prevalence of chromothripsis due to the associated defect in DNA double-strand break repair. Using whole-genome sequencing, fluorescence in situ hybridization and RNA sequencing, we characterized the genomic landscape of Acute Lymphoblastic Leukemia (ALL) arising in patients with Ataxia Telangiectasia. We detected a high frequency of chromothriptic events in these tumors, specifically on acrocentric chromosomes, as compared with tumors from individuals with other types of DNA repair syndromes (27 cases total, 10 with Ataxia Telangiectasia). Our data suggest that the genomic landscape of Ataxia Telangiectasia ALL is clearly distinct from that of sporadic ALL. Mechanistically, short telomeres and compromised DNA damage response in cells of Ataxia Telangiectasia patients may be linked with frequent chromothripsis. Furthermore, we show that ATM loss is associated with increased chromothripsis prevalence in additional tumor entities.

BACKGROUND:

Ataxia telangiectasia (AT) is a primary immunodeficiency associated with recurrent infections. We aimed to investigate clinical and immunological classification in AT patients who suffer from a different spectrum of humoral immune defects.

METHODS:

AT patients were categorized according to the ability of class switching and patients with hyper IgM (HIgM) profile were defined as class switching defect (CSD).

RESULTS:

Serum immunoglobulin profile in 66 AT patients showed normal immunoglobulin level (22.8%), IgA deficiency (37.9%) and hypogammaglobulinemia (18.1%) in the majority of patients, while 21.2% had HIgM profile revealing CSD. CSD does not affect the frequency of infections, however, the frequency of lymphoproliferation (p < 0.001), and autoimmunity (p = 0.004) were significantly higher in this group. Neurologic symptoms in CSD patients are mild or appear after recurrent infections, therefore these patients were usually misdiagnosed as HIgM syndrome.

CONCLUSIONS:

Although most of AT patients have reduced IgA levels or normal immunoglobulin levels, but a fraction of these patients may show CSD ensuing HIgM-profile. CSD poses affected individuals at higher risk of non-infectious complications.

Ataxia-telangiectasia (AT) is a neurodegenerative disorder characterized by ataxia, telangiectasia, and immunodeficiency. An increased risk of malignancies and respiratory diseases dramatically reduce life expectancy. To better counsel families, develop individual follow-up programs, and select patients for therapeutic trials, more knowledge is needed on factors influencing survival. This retrospective cohort study of 61 AT patients shows that classical AT patients had a shorter survival than variant patients (HR 5.9, 95%CI 2.0-17.7), especially once a malignancy was diagnosed (HR 2.5, 95%CI 1.1-5.5, compared to classical AT patients without malignancy). Patients with the hyper IgM phenotype with hypogammaglobulinemia (AT-HIGM) and patients with an IgG₂ deficiency showed decreased survival compared to patients with normal IgG (HR 9.2, 95%CI 3.2-26.5) and patients with normal IgG₂ levels (HR 7.8, 95%CI 1.7-36.2), respectively. If high risk treatment trials will become available for AT, those patients with factors indicating the poorest prognosis might be considered for inclusion first.

Ataxia-telangiectasia (A-T) is an autosomal recessive chromosome breakage disorder caused by mutations in the ATM gene. Typically, it presents in early childhood with progressive cerebellar dysfunction along with immunodeficiency and oculocutaneous telangiectasia. An increased risk of malignancy is also associated with the syndrome and, rarely, may be the presenting feature in small children. We describe a 17-year-old boy with slurred speech, mild motor delays and learning disability diagnosed with atypical A-T in the setting of T-cell acute lymphoblastic leukemia. Suspicion for A-T was raised after review of a peripheral blood karyotype demonstrating rearrangements involving chromosomes 7 and/or 14. The diagnosis was confirmed after molecular testing identified a novel homozygous missense variant in ATM (c.5585T>A; p.Leu1862His) that resulted in protein instability and abolished serine/threonine protein kinase activity. To our knowledge, this is the first report of concurrent A-T and lymphoid malignancy diagnoses in an older child or adult with only mild neurological disease. Our experience suggests that screening for the disorder should be considered in any individual with lymphoid malignancy and neurological findings, especially as radiation and certain chemotherapy protocols are contraindicated in A-T.

BACKGROUND:

Ataxia telangiectasia (AT) is a genetically based multisystemic disorder. We aimed to make a comprehensive evaluation of multisystem involvement in AT by describing clinical features and outcome of 91 patients.

METHODS:

Medical records of the patients who were diagnosed and followed by a multidisciplinary approach during a 27-year period (1988-2015) were reviewed retrospectively.

RESULTS:

Forty six female and 45 male patients with a mean follow-up period of 39.13±4.28 months were evaluated. The mean age at the time of symptom onset and diagnosis were 15.4±1.09 months and 73.61±4.11 months, respectively. Neurological abnormalities were progressive truncal ataxia, nystagmus, dysarthria, oculomotor apraxia and choreoathetosis. Thirty one patients (34.1%) became dependent on wheelchair at a mean age of 12.1±2.8 years. Eleven patients (12.1%) became bedridden by a mean age of 14.7±1.8 years. Cranial magnetic resonance imaging revealed pathological findings in 47/66 patients. Abnormal immunological parameters were determined in 51/91 patients: immunoglobulin (Ig)A deficiency (n=38), lymphopenia (n=30), IgG (n=15) and IgG₂ (n=11) deficiency. Occurrence of recurrent sinopulmonary infections (n=45) and bronchiectasis (n=22) were found to be more common in patients with impaired immunological parameters (P=0.029 and P=0.023, respectively). Malignancy developed in 5 patients, being mostly lymphoreticular in origin and resulted in death of 4 patients.

CONCLUSIONS:

AT is a long lasting disease with multisystem involvement necessitating multidisciplinary follow up, as described in our cohort. Early diagnosis of malignancy and supportive treatments regarding pulmonary and neurological health may prolong survival and increase the quality of life.

We report, to the best of our knowledge, the first case of a child with typical ataxia telangiectasia (A-T) who developed juvenile idiopathic arthritis (JIA). The patient was a 15-year-old boy with A-T who presented with noninfectious polyarthritis. A-T is a rare, autosomal recessive disorder characterized by cerebellar atrophy, oculocutaneous telangiectasia, immunodeficiency, radiosensitivity, and predisposition to cancer. The gene responsible for A-T is the A-T mutated (ATM) gene. Clinical manifestations of the disorder are the result of lacking ATM protein, which is involved in DNA repair, apoptosis, various checkpoints in the cell cycle, gene regulation, translation, initiation, and telomere maintenance. There are a few articles that describe deficiency of the DNA repair enzyme, ATM, in rheumatoid arthritis, but the connection between the absence of ATM protein and JIA has not been presented or studied yet. JIA is a heterogeneous group of diseases characterized by arthritis of unknown origin with onset before the age of 16 years. It is the most common childhood chronic rheumatic disease and causes significant disability. Because immunodeficiency can be part of A-T, infectious arthritis can occur, but chronic autoimmune arthritis in these patients is rare. We report a rare case of a 15-year-old boy with A-T and JIA. This case shows a possible relationship between altered function of ATM protein and the pathogenesis of JIA.

BACKGROUND:

Our previous studies of Alzheimer's disease (AD) suggested that glutamine broadly improves cellular readiness to respond to stress and acts as a neuroprotectant both in vitro and in AD mouse models. We now expand our studies to a second neurodegenerative disease, ataxia-telangiectasia (A-T). Unlike AD, where clinically significant cognitive decline does not typically occur before age 65, A-T symptoms appear in early childhood and are caused exclusively by mutations in the ATM (A-T mutated) gene.

RESULTS:

Genetically ATM-deficient mice and wild type littermates were maintained with or without 4 % glutamine in their drinking water for several weeks. In ATM mutants, glutamine supplementation restored serum glutamine and glucose levels and reduced body weight loss. Lost neurophysiological function assessed through the magnitude of hippocampal long term potentiation was significantly restored. Glutamine supplemented mice also showed reduced thymus pathology and, remarkably, a full one-third extension of lifespan. In vitro assays revealed that ATM-deficient cells are more sensitive to glutamine deprivation, while supra-molar glutamine (8 mM) partially rescued the reduction of BDNF expression and HDAC4 nuclear translocation of genetically mutant Atm(-/-) neurons. Analysis of microarray data suggested that glutamine metabolism is significantly altered in human A-T brains as well.

CONCLUSION:

Glutamine is a powerful part of an organism's internal environment. Changes in its concentrations can have a huge impact on the function of all organ systems, especially the brain. Glutamine supplementation thus bears consideration as a therapeutic strategy for the treatment of human A-T and perhaps other neurodegenerative diseases.

Rare pleiotropic genetic disorders, Ataxia-telangiectasia (A-T), Bloom syndrome (BS) and Nijmegen breakage syndrome (NBS) are characterised by immunodeficiency, extreme radiosensitivity, higher cancer susceptibility, premature aging, neurodegeneration and insulin resistance. Some of these functional abnormalities can be explained by aberrant DNA damage response and chromosomal instability. It has been suggested that one possible common denominator of these conditions could be chronic oxidative stress caused by endogenous ROS overproduction and impairment of mitochondrial homeostasis. Recent studies indicate new, alternative sources of oxidative stress in A-T, BS and NBS cells, including NADPH oxidase 4 (NOX4), oxidised low-density lipoprotein (ox-LDL) or Poly (ADP-ribose) polymerases (PARP). Mitochondrial abnormalities such as changes in the ultrastructure and function of mitochondria, excess mROS production as well as mitochondrial damage have also been reported in A-T, BS and NBS cells. A-T, BS and NBS cells are inextricably linked to high levels of reactive oxygen species (ROS), and thereby, chronic oxidative stress may be a major phenotypic hallmark in these diseases. Due to the presence of mitochondrial disturbances, A-T, BS and NBS may be considered mitochondrial diseases. Excess activity of antioxidant enzymes and an insufficient amount of low molecular weight antioxidants indicate new pharmacological strategies for patients suffering from the aforementioned diseases. However, at the current stage of research we are unable to ascertain if antioxidants and free radical scavengers can improve the condition or prolong the survival time of A-T, BS and NBS patients. Therefore, it is necessary to conduct experimental studies in a human model.

AIM:

To assess peripheral and central hearing in children with A-T.

METHOD:

3 children diagnosed with A-T according to the diagnostic criteria for A-T of the European Society for Immunodeficiencies. Involuntary movements were seen in the form of chorea-athetosis together with tremors. They were examined to assess both peripheral and central hearing was assessed (hearing thresholds). Sound-field testing, tympanometry, acoustic reflexes, Otoacoustic Emissions (OAEs) and Auditory Brainstem Responses (ABR) were done for all of them.

RESULTS:

Basic Audiological evaluation is of a limited value as the children are not co-operative. Sound field testing could not be done. Bilateral normal middle ear functions as reflected by Tympanometry and Acoustic Reflexes. Advanced Audiological evaluation including OAEs and ABR are more valuable in assessing hearing in children with A-T. Bilateral pass response at all test frequencies in DPOAEs. Abnormal ABR findings were obtained in the form of a delay in wave V latency more than 2 SD with subsequent increased in I-V interpeak latency with no significant interaural latency difference.

CONCLUSION:

Consistent with bilateral normal peripheral hearing sensitivity with central hearing affection.

LIMITATIONS:

The rarity of the disease, make it difficult to be applied on many cases.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Ataxia-telangiectasia (A-T), an autosomal recessive disease caused by mutations in the ATM gene is characterised by cerebellar atrophy and progressive neurodegeneration which has been poorly recapitulated in Atm mutant mice. Consequently, pathways leading to neurodegeneration in A-T are poorly understood. We describe here the generation of an Atm knockout rat model that does not display cerebellar atrophy but instead paralysis and spinal cord atrophy, reminiscent of that seen in older patients and milder forms of the disorder. Loss of Atm in neurons and glia leads to accumulation of cytosolic DNA, increased cytokine production and constitutive activation of microglia consistent with a neuroinflammatory phenotype. Rats lacking ATM had significant loss of motor neurons and microgliosis in the spinal cord, consistent with onset of paralysis. Since short term treatment with steroids has been shown to improve the neurological signs in A-T patients we determined if that was also the case for Atm-deficient rats. Betamethasone treatment extended the lifespan of Atm knockout rats, prevented microglial activation and significantly decreased neuroinflammatory changes and motor neuron loss. These results point to unrepaired damage to DNA leading to significant levels of cytosolic DNA in Atm-deficient neurons and microglia and as a consequence activation of the cGAS-STING pathway and cytokine production. This in turn would increase the inflammatory microenvironment leading to dysfunction and death of neurons. Thus the rat model represents a suitable one for studying neurodegeneration in A-T and adds support for the use of anti-inflammatory drugs for the treatment of neurodegeneration in A-T patients.

Ataxia telangiectasia is a rare genetic disease and no therapy is currently available. Glucocorticoid analogues have been shown to improve the neurological symptoms of treated patients. In the present study ataxia telangiectasia and wild type cells were used as a cellular model and treated with dexamethasone. The cells were subsequently investigated for membrane and whole cell mechanical properties by atomic force microscopy. In addition, cytoskeleton protein dynamics and nuclear shapes were assayed by fluorescence microscopy, while western blots were used to assess actin and tubulin content. At the macro level, dexamethasone directly modified the cell shape, Young's modulus and cytoskeleton protein dynamics. At the nano level, the roughness of the cell surface and the local nano-mechanical proprieties were found to be affected by Dexa. Our results show that ataxia telangiectasia and wild type cells are affected by Dexa, although there are dissimilarities in some macro-level and nano-level features between the tested cell lines. The Young's modulus of the cells appears to depend mainly on nuclear shape, with a slight contribution from the tested cytoskeleton proteins. The current study proposes that dexamethasone influences ataxia telangiectasia cell membranes contents, cell components and cell shape.

Ataxia telangiectasia (A-T) is an incurable and rare hereditary syndrome. In recent times, treatment with glucocorticoid analogues has been shown to improve the neurological symptoms that characterize this condition, but the molecular mechanism of action of these analogues remains unknown. Hence, the aim of this study was to gain insight into the molecular mechanism of action of glucocorticoid analogues in the treatment of A-T by investigating the role of Dexamethasone (Dexa) in A-T lymphoblastoid cell lines. We used 2DE and tandem MS to identify proteins that were influenced by the drug in A-T cells but not in healthy cells. Thirty-four proteins were defined out of a total of 746±63. Transcriptome analysis was performed by microarray and showed the differential expression of 599 A-T and 362 wild type (WT) genes and a healthy un-matching between protein abundance and the corresponding gene expression variation. The proteomic and transcriptomic profiles allowed the network pathway analysis to pinpoint the biological and molecular functions affected by Dexamethasone in Dexa-treated cells. The present integrated study provides evidence of the molecular mechanism of action of Dexamethasone in an A-T cellular model but also the broader effects of the drug in other tested cell lines.

Ataxia telangiectasia (A-T) is a rare incurable neurodegenerative disease caused by biallelic mutations in the gene for ataxia-telangiectasia mutated (ATM). The lack of a functional ATM kinase leads to a pleiotropic phenotype, and oxidative stress is considered to have a crucial role in the complex physiopathology. Recently, steroids have been shown to reduce the neurological symptoms of the disease, although the molecular mechanism of this effect is largely unknown. In the present study, we have demonstrated that dexamethasone treatment of A-T lymphoblastoid cells increases the content of two of the most abundant antioxidants [glutathione (GSH) and NADPH] by up to 30%. Dexamethasone promoted the nuclear accumulation of the transcription factor nuclear factor (erythroid-derived 2)-like 2 to drive expression of antioxidant pathways involved in GSH synthesis and NADPH production. The latter effect was via glucose 6-phosphate dehydrogenase activation, as confirmed by increased enzyme activity and enhancement of the pentose phosphate pathway rate. This evidence indicates that glucocorticoids are able to potentiate antioxidant defenses to counteract oxidative stress in ataxia telangiectasia, and also reveals an unexpected role for dexamethasone in redox homeostasis and cellular antioxidant activity.

We report the case of a 6-year-old female patient with Ataxia Telangiectasia, an extremely rare condition, who developed in addition a left cerebellar astrocytoma and a right cerebellar infarction, considered as two independent events. Children with AT have an increased risk of developing cancer, but only few cases of glioma are reported and, at our knowledge, no other case of unrelated cerebellar glioma and cerebellar infarction in with the same AT patient have been described. The molecular analysis of ATM (Ataxia Telangiectasia Mutated) gene showed that the patient is compound heterozygote for two previously unreported mutations: c.3291delC (p.Phe1097fs) at exon 25 and c.8198A>C (p.Gln2733Pro) at exon 58. The role of the identified ATM gene mutations in the pathogenesis of Ataxia Telangiectasia and the coexisting cerebellar disorders is discussed.

Peripheral blood was obtained from a 12-year old male carrying bialleleic inactivating mutations at the ATM locus, causing Ataxia-Telangiectasia (A-T). Blood erythroid cells were briefly expanded in vitro and induced pluripotent stem cells (iPSCs) were generated via transfection with episomal vectors carrying hOCT4, hSOX2, hKLF4, hMYC and hBCL2L1. SF-003 iPSCs were free of genomically integrated reprogramming genes, had the specific compound heterozygous mutations, stable karyotype, expressed pluripotency markers and formed teratomas in immunodeficient (NOD scid gamma; NGS) mice. The SF-003 iPSC line may be a useful resource for in vitro modeling of A-T.

BACKGROUND AND AIMS:

Ataxia telangiectasia (A-T) is a rare progressive, multisystem genetic disease. Families of children with ultra-rare diseases often experience significant diagnostic delays. We reviewed the diagnostic process for A-T in order to identify causes of delay in an attempt to facilitate earlier identification of A-T in the future.

METHODS:

A retrospective case note review of 79 children at the National Paediatric A-T clinic seen since May 2009. Data were collected on the nature and age of initial symptoms, the age at first presentation, measurement of alpha feto-protein (AFP) and age of genetic diagnostic confirmation.

RESULTS:

At presentation, 71 children (90%) had ataxia. The median presentation delay (from first parental concern to presentation) was 8 months (range 0-118 months), and the median diagnostic delay (genetic confirmation of diagnosis) was 12 months (range 1-109 months).

CONCLUSIONS:

There are significant delays in presentation and diagnostic confirmation of A-T. A greater awareness of A-T and early measurement of AFP may help to improve this.

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Biallelic mutations in ATM result in the neurodegenerative syndrome Ataxia-Telangiectasia, while ATM haploinsufficiency increases the risk of cancer and other diseases. Previous studies revealed low reprogramming efficiency from A-T and carrier fibroblasts, a barrier to iPS cell-based modeling and regeneration. Here, we tested the feasibility of employing circulating erythroid cells, a compartment no or minimally affected in A-T, for the generation of A-T and carrier iPS cells. Our results indicate that episomal expression of Yamanaka factors plus BCL-xL in erythroid cells results in highly efficient iPS cell production in feeder-free, xeno-free conditions. Moreover, A-T iPS cells generated with this protocol maintain long-term replicative potential, stable karyotypes, re-elongated telomeres and capability to differentiate along the neural lineage in vitro and to form teratomas in vivo. Finally, we find that haploinsufficiency for ATM does not limit reprogramming from human erythroid cells or in vivo teratoma formation in the mouse.