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

Shad, Tannaz Moeini; Yazdani, Reza; Amirifar, Parisa; Delavari, Samaneh; Arani, Marzieh Heidarzadeh; Mahdaviani, Seyed Alireza; Sadeghi‐Shabestari, Mahnaz; Aghamohammadi, Asghar; Rezaei, Nima; Abolhassani, Hassan

doi:10.3389/fimmu.2021.779502

Cited by 10 publications

(10 citation statements)

References 87 publications

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“…However, it was until 3 years, after the onset of the disease that the symptoms of ataxia such as wobbliness and frequent falls appeared during walking. This differs from previously reported classical AT, as dystonia is thought to be the main feature of variant AT and is more prominent in late manifestations of classical AT ( 17 – 19 ). We found a typical case of AT reported by Nakayama with a compound heterozygous ATM genotype presenting with two truncating mutations, no detectable ATM protein activity in lymphoblast cell lysates, and the onset of dystonia-myoclonic jerks with ataxia, but ataxia symptoms progress slowly ( 16 ).…”

Section: Discussioncontrasting

confidence: 99%

Analysis of Clinical and Genetic Characterization of Three Ataxia–Telangiectasia Pedigrees With Novel ATM Gene Mutations

et al. 2022

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ObjectiveThe clinical manifestations of ataxia–telangiectasia (AT) are very complex and are easily misdiagnosed and missed. The purpose of this study was to explore the clinical characteristics and genetic features of five pediatric patients with AT from three pedigrees in china.MethodsRetrospectively collected and analyzed the clinical data and genetic testing results of five AT patients diagnosed by the Whole-exome sequencing followed by Sanger sequencing. The five patients with AT were from three pedigrees, including two female patients (case 1 and case 2) in pedigree I, one male patient (case 3) in pedigree II, and two male patients (case 4 and case 5) in pedigree III. According to the United Kingdom Association for Clinical Genomic Science Best Practice Guidelines for Variants Classification in Rare Disease 2020 to grade the genetic variants.ResultsFive patients had mainly clinical presentations including unsteady gait, dysarthria, bulbar conjunctive telangiectasia, cerebellar atrophy, intellectual disability, stunted growth, increase of alpha-fetoprotein in serum, lymphopenia. Notably, one patient with classical AT presented dystonia as the first symptom. One patient had recurrent infections, five patients had serum Immunoglobulin (Ig) A deficiency, and two patients had IgG deficiency. In three pedigrees, we observed five pathogenic variants of the ATM gene, which were c.1339C>T (p.Arg447Ter), c.7141_7151delAATGGAAAAAT (p.Asn2381GlufsTer18), c.437_440delTCAA (p.Leu146GlnfsTer6), c.2482A>T (p.Lys828Ter), and c.5495_5496+2delAAGT (p.Glu1832GlyfsTer4). Moreover, the c.437_440delTCAA, c.2482A>T, and c.5495_5496+2delAAGT were previously unreported variants.ConclusionsPediatric patients with classical AT may present dystonia as the main manifestation, or even a first symptom, besides typical cerebellar ataxia, bulbar conjunctive telangiectasia, etc. Crucially, we also found three novel pathogenic ATM gene variants (c.437_440delTCAA, c.2482A>T, and c.5495_5496+2delAAGT), expanding the ATM pathogenic gene mutation spectrum.

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Section: Discussioncontrasting

confidence: 99%

Analysis of Clinical and Genetic Characterization of Three Ataxia–Telangiectasia Pedigrees With Novel ATM Gene Mutations

et al. 2022

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“…It possibly stems from the shared immunologic features of hypogammaglobulinemia and normal B cell counts in the absence of remarkable facial abnormalities in our DNMT3B/ZBTB24 -mutated patients. Comparable to former reports ( 31 , 32 ), a few patients with ATM deficiency were initially classified as HIgM and IgAD. Lack of neurological manifestations and close immunologic results in these patients might have led to some variants of ATM being misdiagnosed as HIgM and IgAD.…”

Section: Discussionmentioning

confidence: 99%

Autoimmunity in monogenic combined immune deficiencies with associated or syndromic features

et al. 2022

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BackgroundCombined immune deficiencies (CIDs) with associated or syndromic features are a highly heterogeneous subgroup of inherited immune disorders. These patients represent specific clinical complications with an increased risk of autoimmune conditions.MethodsWe analyzed data of monogenic patients with syndromic CIDs adopted from the Iranian inborn errors of immunity registry up to January 2022. A comprehensive comparison in terms of demographic, clinical, and immunological features was performed between patients with and without autoimmunity and also among four mutation groups with the most registered cases including ATM, STAT3 (AD-LOF), DNMT3B/ZBTB24, and WAS mutations.ResultsA total of 137 patients with monogenic syndromic CIDs were included. Most commonly mutated genes were the ATM [80 (58.4%)] and STAT3 (AD-LOF) [19 (13.9%)], followed by DNMT3B [11 (8%)], and WAS [11 (8%)]. More than 18% of all patients with syndromic CIDs, including most DNMT3B/ZBTB24 mutations patients, were clinically diagnosed with antibody deficiencies before genetic evaluation. Patients with ATM and WAS mutations had the latest age of onset and the lowest age of diagnosis, respectively. Autoimmune disorders were diagnosed in 24 patients at a median age of 3.5 (2.6-6.0) years, 70.6% of which were diagnosed prior to the diagnosis of immunodeficiency. Lymphoproliferation, particularly hepatosplenomegaly, was significantly higher in patients with autoimmunity (p=0.004). Syndromic CID patients with autoimmunity had significantly lower IgG levels. Hematologic autoimmunity mainly immune thrombocytopenic purpura was the most frequent autoimmunity among major groups of ATM, STAT3 (AD-LOF), DNMT3B/ZBTB24, and WAS mutations, however ATM-mutated patients present more diversified involved organs including rheumatologic, gastrointestinal and dermatologic autoimmunity.ConclusionAbout 18% of patients with monogenic syndromic CIDs developed autoimmunity, mainly in the form of hematological immune diseases. Autoimmunity could be an early-onset involvement with a potential diagnostic impact on suspicious cases of syndromic CIDs.

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“…Ataxia-telangiectasia (AT) (OMIM #208900) is caused by mutation of the ATM gene, which encodes a protein belonging to a family of protein kinases with a phosphatidylinositol 3-kinase (Pi3K) domain 13 . The main function of the ATM protein is to regulate the DSB-induced DNA damage response, mediate the cellular antioxidant response, and activate the tumor suppressor p53 to regulate cell cycle arrest, apoptosis, senescence, and metabolism 14 .…”

Section: Introductionmentioning

confidence: 99%

Evaluation of T Cell Repertoire in Primary Immunodeficiencies With Dna Repair Defects

Karaaslan¹,

Demirkale²,

Turan³

et al. 2023

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Inborn errors of immunity include multiple genetic abnormalities affecting different components of the innate and adaptive immune systems. More than 450 genes have been described so far including DNA repair defects which may result in predisposition to infections, but also malignancies, neurologic abnormalities and growth retardation. The group of patients with DNA repair and methylation defects exhibit impaired adaptive immunity, which increases susceptibility to infections due to impaired repertoire diversity. In this context, we aimed to investigate the TCRvβ repertoire and its interaction with clinical entities in a group of IEI patients with DNA repair defects including ATM, DCLRE1C, DNA-PRKDC, DNA ligase-4, and BLM. Thirty-nine patients with evidence of DNA repair defects and radiosensitivity and 15 age-matched healthy controls were included in this study. Peripheral lymphocyte subset and TCR-vβ repertoire analyses were performed by flow cytometry. To contrast TCR-repertoire in patients with DNA repair defects to healthy controls, we extracted data on lymphocyte phenotype, thymic function, immunoglobulins, and analysis of the TCRvβ repertoire from a prior study. The entire TCR-vβ repertoire was detected in all patients. However, compared with the control group, 9 of 24 clones (37.5%) were statistically significantly lower, whereas only 3 clones had high levels (p < 0.05). In addition, 62.5% of all clones had lower values than the control group. Some unique vβ clones have been associated with some clinical entities. Clonotypes associated with infections, autoimmunity and lymphoid proliferation were detected in the patient group. Lower TCR-vβ-9 and TCR-vβ23, higher TCR-vβ7.2 were detected in the patients with pneumonia (n = 13) (respectively p = 0.018, p = 0.044 p = 0.032). In addition, AT patients with pneumonia (n = 10) had a lower TCR-vβ-9 clone than patients without pneumonia (n = 25) (p = 0.008). In summary, we observed skewed clonal proliferation of most TCR-vβ clones in DNA repair defects, especially AT. In addition, our study demonstrated that some TCR-vβ clones might be predictive of some clinical entities. To further investigate the impact of the diversity of the TCR repertoire on the clinical phenotype, future studies should focus on the analysis of naïve and memory T cells, the detection of the source of oligoclonality, and the relationship between clonality and clinical entities.

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

Cited by 10 publications

References 87 publications

Analysis of Clinical and Genetic Characterization of Three Ataxia–Telangiectasia Pedigrees With Novel ATM Gene Mutations

Analysis of Clinical and Genetic Characterization of Three Ataxia–Telangiectasia Pedigrees With Novel ATM Gene Mutations

Autoimmunity in monogenic combined immune deficiencies with associated or syndromic features

Evaluation of T Cell Repertoire in Primary Immunodeficiencies With Dna Repair Defects

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