New diagnosis of atypical ataxia-telangiectasia in a 17-year-old boy with T-cell acute lymphoblastic leukemia and a novel ATM mutation

Roohi, Jasmin; Crowe, Jennifer; Loredan, Denis G; Anyane‐Yeboa, Kwame; Mansukhani, Mahesh; Omesi, Lenore; Levine, Jennifer; Politi, Anya Revah; Zha, Shan

doi:10.1038/jhg.2017.6

Cited by 12 publications

(8 citation statements)

References 15 publications

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“…KAP1 was selected as a marker of ATM kinase activity, because of its strong ATM dependency for phosphorylation. Defective ATM kinase activity was confirmed in the LCLs from all patients in response to the topoisomerase1 inhibitor camptothecin, including in challenging atypical A‐T forms, confirming previous finding that phosphorylation of KAP1 is consistently decreased even in A‐T patients with missense mutations and atypical forms of A‐T (Roohi et al, ). However, KAP1 phosphorylation was variable among A‐T LCLs.…”

Section: Discussionsupporting

confidence: 86%

Functional classification of ATM variants in ataxia‐telangiectasia patients

et al. 2019

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Ataxia‐telangiectasia (A‐T) is a recessive disorder caused by biallelic pathogenic variants of ataxia‐telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western‐blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A‐T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell‐cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia‐TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification.

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Section: Discussionsupporting

confidence: 86%

Functional classification of ATM variants in ataxia‐telangiectasia patients

et al. 2019

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“…Approximately 75% of patients presented extrapyramidal features including dystonia, tremors, and chorea movements. Cerebellar atrophy was found in 35 (65%) individuals at age of 28 (22)(23)(24)(25)(26)(27)(28)(29)(30)(31) years, while 19 cases demonstrated normal imaging of the cerebellum. Expectedly, the frequency of cerebellar atrophy was higher in the severe group (83.8%) than the moderate (70.3%; p=0.6) and mild (38.4%; p=0.01) groups.…”

Section: Neurological Features Of Atypical At Patientsmentioning

confidence: 99%

Atypical Ataxia Presentation in Variant Ataxia Telangiectasia: Iranian Case-Series and Review of the Literature

et al. 2022

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Ataxia-telangiectasia (AT) is a rare autosomal recessive neurodegenerative multisystem disorder. A minority of AT patients can present late-onset atypical presentations due to unknown mechanisms. The demographic, clinical, immunological and genetic data were collected by direct interview and examining the Iranian AT patients with late-onset manifestations. We also conducted a systematic literature review for reported atypical AT patients. We identified three Iranian AT patients (3/249, 1.2% of total registry) with later age at ataxia onset and slower neurologic progression despite elevated alpha-fetoprotein levels, history of respiratory infections, and immunological features of the syndrome. Of note, all patients developed autoimmunity in which a decrease of naïve T cells and regulatory T cells were observed. The literature searches also summarized data from 73 variant AT patients with atypical presentation indicating biallelic mild mutations mainly lead to an atypical phenotype with an increased risk of cancer. Variant AT patients present with milder phenotype or atypical form of classical symptoms causing under- or mis- diagnosis. Although missense mutations are more frequent, an atypical presentation can be associated with deleterious mutations due to unknown modifying factors.

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“…In people with hypomorphic ATM mutations, onset of ataxia and neurological progression may emerge later and progress more slowly, and impairment of the immune system be less marked. 30 These individuals with hypomorphic ATM mutations, however, have similarly increased risk of malignancy as people with classic A-T. 31 Isolated patients with predicted protein null mutations have been identified who manifest similar mild progression of symptoms, indicating that the relationship between genotype and phenotype is complex. 32 , 33 …”

Section: Cardiovascular and Liver And Metabolic Conditionsmentioning

confidence: 99%

Multidisciplinary Management of Ataxia Telangiectasia: Current Perspectives

McGrath‐Morrow¹,

Rothblum-Oviatt²,

Wright³

et al. 2021

JMDH

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Ataxia telangiectasia (A-T) is a rare autosomal recessive disease caused by mutations in the ataxia telangiectasia mutated ( ATM ) gene. In the absence of a family history, the diagnosis of A-T is usually not made until the child is older and symptomatic. Classic A-T is characterized by a constellation of clinical symptoms including progressive ataxia, oculocutaneous telangiectasias and sinopulmonary disease and is usually associated with absence of ATM protein. Other laboratory features associated with A-T include elevated serum levels of alpha-fetoprotein (AFP) and increased chromosomal breakage with in vitro exposure to ionizing radiation. Sinopulmonary symptoms can occur to varying degrees across the lifespan. Some children will also have hypogammaglobulinemia and impaired antibody responses requiring supplemental gamma globulin. People with hypomorphic ATM mutations are often considered to have mild A-T with onset of ataxia and neurological progression occurring later in life with less impairment of the immune system. The risk of malignancy, however, is significantly increased in people with either classic or mild A-T. While hematological malignancies are most common in the first two decades of life, solid organ malignancies become increasingly common during young adulthood. Deterioration of neurologic function with age is associated with dysphagia with aspiration, growth faltering, loss of ambulation and decline in pulmonary function, morbidities that contribute to shortened life expectancy and decreased quality of life. Premature death is often due to malignancies or chronic respiratory insufficiency. A-T is currently managed with supportive care and symptomatic treatment. Current clinical trials, however, represent progress and hope towards disease-modifying therapies for A-T.

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New diagnosis of atypical ataxia-telangiectasia in a 17-year-old boy with T-cell acute lymphoblastic leukemia and a novel ATM mutation

Cited by 12 publications

References 15 publications

Functional classification of ATM variants in ataxia‐telangiectasia patients

Functional classification of ATM variants in ataxia‐telangiectasia patients

Atypical Ataxia Presentation in Variant Ataxia Telangiectasia: Iranian Case-Series and Review of the Literature

Multidisciplinary Management of Ataxia Telangiectasia: Current Perspectives

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