Identifying ataxia-telangiectasia in cancer patients: Novel insights from an interesting case and review of literature.
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ABSTRACT:
SUBMITTER: Cao J
PROVIDER: S-EPMC7869391 | biostudies-literature | 2021 Feb
REPOSITORIES: biostudies-literature
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Identifying ataxia-telangiectasia in cancer patients: Novel insights from an interesting case and review of literature.
Cao Jinyi J Tan Ryan Ying Cong RYC Li Shao-Tzu ST Courtney Eliza E Goh Ronald Chin Hong RCH Fan Bingwen Eugene BE Sommat Kiattisa K Nadarajah Ravichandran R Ngeow Joanne J
Clinical case reports 20201230 2
Timely genetic testing leading to early diagnosis of A-T is crucial due to its plethora of implications on clinical management, particularly in those who develop malignancies. Thus, clinicians have to be astute in identifying diagnostic clues of A-T. ...[more]
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Project description: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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Project description:Ataxia telangiectasia (A-T) is an autosomal recessive disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility and radiation sensitivity. A-T is often referred to as a genome instability or DNA damage response syndrome.The world-wide prevalence of A-T is estimated to be between 1 in 40,000 and 1 in 100,000 live births.A-T is a complex disorder with substantial variability in the severity of features between affected individuals, and at different ages. Neurological symptoms most often first appear in early childhood when children begin to sit or walk. They have immunological abnormalities including immunoglobulin and antibody deficiencies and lymphopenia. People with A-T have an increased predisposition for cancers, particularly of lymphoid origin. Pulmonary disease and problems with feeding, swallowing and nutrition are common, and there also may be dermatological and endocrine manifestations.A-T is caused by mutations in the ATM (Ataxia Telangiectasia, Mutated) gene which encodes a protein of the same name. The primary role of the ATM protein is coordination of cellular signaling pathways in response to DNA double strand breaks, oxidative stress and other genotoxic stress.The diagnosis of A-T is usually suspected by the combination of neurologic clinical features (ataxia, abnormal control of eye movement, and postural instability) with one or more of the following which may vary in their appearance: telangiectasia, frequent sinopulmonary infections and specific laboratory abnormalities (e.g. IgA deficiency, lymphopenia especially affecting T lymphocytes and increased alpha-fetoprotein levels). Because certain neurological features may arise later, a diagnosis of A-T should be carefully considered for any ataxic child with an otherwise elusive diagnosis. A diagnosis of A-T can be confirmed by the finding of an absence or deficiency of the ATM protein or its kinase activity in cultured cell lines, and/or identification of the pathological mutations in the ATM gene.There are several other neurologic and rare disorders that physicians must consider when diagnosing A-T and that can be confused with A-T. Differentiation of these various disorders is often possible with clinical features and selected laboratory tests, including gene sequencing.Antenatal diagnosis can be performed if the pathological ATM mutations in that family have been identified in an affected child. In the absence of identifying mutations, antenatal diagnosis can be made by haplotype analysis if an unambiguous diagnosis of the affected child has been made through clinical and laboratory findings and/or ATM protein analysis.Genetic counseling can help family members of a patient with A-T understand when genetic testing for A-T is feasible, and how the test results should be interpreted.Treatment of the neurologic problems associated with A-T is symptomatic and supportive, as there are no treatments known to slow or stop the neurodegeneration. However, other manifestations of A-T, e.g. immunodeficiency, pulmonary disease, failure to thrive and diabetes can be treated effectively.
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Project description:Ataxia telangiectasia (A-T) is a common, genetically inherited cause of early childhood-onset ataxia that is classically characterized by progressive cerebellar malfunction, oculocutaneous telangiectasia, genome instability, and immunodeficiency. There is vast phenotype variation in patients with A-T and recently, dystonia, an extrapyramidal movement disorder. Here, we report the case of a 10-year-old girl who had experienced repeated diarrhea and mild gait ataxia since the age of two years. At age seven, ataxia and ocular telangiectasia were evident and immunoglobulin level assessment showed hyper IgM immune phenotype, thus a diagnosis of A-T was made based on clinical and laboratory findings, and she was started on intravenous immunoglobulin therapy. Generalized dystonia appeared when she was 10-years-old. Molecular analysis revealed two heterozygous mutations, c.6259delG and c.6658C>T, in the ATM gene of which one (c.6259delG) is novel. Dystonia can be part of the clinical picture in the A-T disorder and may even mask ataxia. This should be considered as a major feature mainly in variant A-T, which may occur without general ataxia and may be misdiagnosed in adults with primary dystonia.
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Project description:BackgroundAtaxia-telangiectasia (A-T) is an autosomal recessive disorder with high clinical heterogeneity. A-T may present in complicated variable forms, including classic A-T and milder form of AT. Contrary to the classic A-T, the milder form does not present the cardinal features of A-T such as ataxia and telangiectasia. A few ATM mutations have been reported in variant A-T cases manifesting isolated generalized or segmental dystonia without any signs of classical A-T.MethodsAn A-T pedigree with predominant dystonia was collected. Genetic testing was performed by targeted panel of genes involved in movement disorders. The candidate variants were further confirmed by Sanger sequencing. We then reviewed previously published literatures of genetically confirmed A-T cases with predominant dystonia and summarized the clinical characteristics of dystonia-dominant A-T.ResultsTwo novel ATM mutations, p.I2683T and p.S2860P, were identified in the family. The proband presented isolated segmental dystonia without any signs of ataxia and telangiectasias. We reviewed the literatures and found that the patients with dystonia-dominant A-T tend to have a later-onset and slower progression of the disease.ConclusionTo our knowledge, this is the first report of A-T patient with predominant dystonia in China. Dystonia may appear as one of the predominant manifestations or initial symptom of A-T. Early ATM genetic testing should be considered for those patients with predominant dystonia, despite without accompanying ataxia or telangiectasia.
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Project description:Ataxia-telangiectasia-like disorder 1 (ATLD1) is a rare neurodegenerative disorder associated with early onset ataxia and oculomotor apraxia. The genetic determination of ATLD1 is a mutation in the MRE11 gene (meiotic recombination 11 gene), which causes DNA-double strand break repair deficits. Clinical features of patients with ATLD1 resemble those of ataxia telangiectasia (AT), with slower progression and milder presentation. Main symptoms include progressive cerebellar ataxia, oculomotor apraxia, cellular hypersensitivity to ionizing radiations. Facial dyskinesia, dystonia, dysarthria have also been reported. Here we present a 45-year old woman with cervical and facial dystonia, dysarthria and ataxia, who turned out to be the first case of ATLD without oculomotor apraxia, and with dystonia as a main manifestation of the disease. She had presented those non-specific symptoms for years, before whole exome sequencing confirmed the diagnosis.
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Project description:Bullous pemphigoid (BP) is a rare, life-threatening autoimmune blistering disease with pruritus and tension blisters/bullous as the main clinical manifestations. Glucocorticosteroids are the main therapeutic agents for it, but their efficacy is poor in some patients. Tofacitinib, a small molecule agent that inhibits JAK1/3, has shown incredible efficacy in a wide range of autoimmune diseases and maybe a new valuable treatment option for refractory BP. To report a case of refractory BP successfully treated with tofacitinib, then explore the underlying mechanism behind the treatment, and finally review similarities to other cases reported in the literature. Case report and literature review of published cases of successful BP treatment with JAK inhibitors. The case report describes a 73-year-old male with refractory BP that was successfully managed with the combination therapy of tofacitinib and low-dose glucocorticoids for 28 weeks. Immunohistochemistry and RNA sequencing were performed to analyze the underlying mechanism of tofacitinib therapy. A systematic literature search was conducted to identify other cases of treatment with JAK inhibitors. Throughout the 28-week treatment period, the patient experienced clinical, autoantibody and histologic resolution. Immunohistochemical analysis showed tofacitinib significantly decreased the pSTAT3 and pSTAT6 levels in the skin lesions of this patient. RNA sequencing and immunohistochemical testing of lesion samples from other BP patients identified activation of the JAK-STAT signaling pathway. Literature review revealed 17 previously reported cases of BP treated with four kinds of JAK inhibitors successfully, including tofacitinib (10), baricitinib (1), upadacitinib (3) and abrocitinib (3). Our findings support the potential of tofacitinib as a safe and effective treatment option for BP. Larger studies are underway to better understand this efficacy and safety.
2024-11-13 | GSE278926 | GEO
Project description:Ataxia-telangiectasia (A-T) is an infrequent autosomal recessive disorder that involves multiple systems and is characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, radiosensitivity, immune deficiency with recurrent respiratory infections, and a tendency to develop lymphoid malignancies. A-T is caused by mutations in the ATM gene, with >1,000 mutations reported to date and gradually increasing in number. Patients with A-T have an increased incidence of cancers. The aim of the present study was to retrospectively review the case of a patient who presented at the age of 5 years with cerebellar ataxia without telangiectasia, and was diagnosed with Burkitt leukemia by bone marrow biopsy and molecular testing at the age of 7 years at the Xiangya Hospital of Central South University (Changsha, China). The patient received chemotherapy with the pediatric CCCG-BNHL-2015 regimen (R4 group) and achieved a complete remission after 2 courses. However, recurrent respiratory infections and thrombosis occurred during chemotherapy. The diagnosis of A-T was confirmed by uncovering two variants of the ATM gene, including c.742C>T (p.R248X; rs730881336) in exon 7 and c.6067-c.6068 ins GAGGGAAGAT in exon 41 by whole-exome sequencing. Unfortunately, the patient's parents refused follow-up treatment and he succumbed to recurrent severe infections 4 months after the diagnosis of Burkitt leukemia. The diagnosis of A-T may be challenging, as its phenotype can be incomplete early in the course of the disease. Detailed medical history, characteristic clinical manifestations and increasingly developed exome sequencing techniques may be helpful in diagnosing this rare disease. Management should be based on multidisciplinary guidance and other treatment options must be investigated in the future.
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Project description:Large-scale transcriptome and methylome data analyses obtained by high-throughput technologies have been enabling the identification of novel imprinted genes. We investigated genome-wide DNA methylation patterns in multiple human tissues, using a high-resolution microarray to uncover hemimethylated CpGs located in promoters overlapping CpG islands, aiming to identify novel candidate imprinted genes. Using our approach, we recovered ~30% of the known human imprinted genes, further 168 candidates were identified, 61 of which with at least three hemimethylated CpGs shared by more than two tissue types. Thirty-four of these candidate genes are members of the protocadherins cluster on 5q31.3; in mice, protocadherin genes have non-imprinted monoallelic randomic expression, which might be the case in humans. Among the remaining 27 genes, ZNF331 was recently validated as an imprinted gene, and six of them have been reported as candidates, supporting our prediction. Five candidates (CCDC166, ARC, PLEC, TONSL and VPS28) map to 8q24.3, and might constitute a novel imprinted cluster. Additionally, we performed a comprehensive compilation of known human and mice imprinted genes from literature and databases, and a comparison among high-throughput imprinting studies in humans. The screening for hemimethylated CpGs shared by multiple human tissues, together with the extensive review, appears as a useful approach to reveal candidate imprinted genes.
2017-09-26 | GSE103413 | GEO
Project description:IntroductionAtaxia telangiectasia is a rare genetic condition with an estimated prevalence of 1 in 40,000-100,000 live births. This condition predominantly affects the nervous and immune systems. It is characterized by progressive ataxia beginning from early childhood. The neurological deficit associated with this condition affects one's balance, coordination, walking, and speech and can be accompanied by chorea, myoclonus, and neuropathy. They may also have ocular telangiectasias and high levels of blood alpha-fetoprotein (AFP). The ataxia telangiectasia mutated gene (ATM) is associated with this condition and codes for the ATM protein which is a phosphatidylinositol 3-kinase. This gene occupies 150 kb on chromosome 11q22-23 and contains 66 exons encoding a 13 kb transcript. ATM is a relatively large protein with a molecular weight of 350 kDa and 3,056 amino acids.MethodsFour patients of Sri Lankan origin presenting with features suggestive of ataxia telangiectasia were referred to our genetics center for specialized genetic counseling and testing. Whole-exome sequencing followed by Sanger sequencing was used to confirm the candidate variants. Protein modeling and genotype to phenotype correlation was performed in the identified variants.ResultsWe observed 6 novel ATM gene variants in four patients with ataxia telangiectasia. The identified variants are as follows: homozygous c.7397C > A (p.Ala2466Glu) and c.510_511delGT (p.Tyr171fs) and compound heterozygous c.5347_5350delGAAA (p.Glu1783fs), c.8137A > T (p.Arg2713 ∗ ) and c.1163A > C (p.Lys388Thr), and c.5227A > C (p.Thr1743Pro). Variant analysis was followed by modeling of the native and altered protein structures.ConclusionWe report novel ATM gene variants that have implications on the molecular diagnosis of ataxia telangiectasia.
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2017-03-24 | GSE96980 | GEO