scholarly journals Ataxia teleangiectasia. Az idegrendszeri érintettség prototípusa primer immundefektusokban

2018 ◽  
Vol 159 (49) ◽  
pp. 2057-2064
Author(s):  
Zoltán Liptai
Keyword(s):  
Immune Deficiency ◽  
Ataxia Telangiectasia ◽  
Late Onset ◽  
Brain Mri ◽  
Cerebellar Atrophy ◽  
Biallelic Mutation ◽  
Pathogenic Variants ◽  
Diagnostic Difficulties ◽  
Immune Deficiencies ◽  
Atm Gene

Abstract: The number of primary immune deficiencies exceeds 350, approximately a quarter of them having neurological implications. Severe central nervous system infections may occur in an even higher proportion. Beyond listing in a table of all diseases with a neurological impact, the author gives detailed analysis of one typical disorder. Ataxia telangiectasia is caused by biallelic mutation of the ATM gene resulting in genomic instability, increased cancer risk, immune deficiency and a predominantly cerebellar neurodegeneration. The most common classic form is characterized by gait and limb ataxia, oculomotor apraxia, choreoathetosis, disturbance of speech and swallowing, less often by other movement disorders. There is no remarkable cognitive deficit. Telangiectasia of the conjunctivae and skin usually appears after 6 years of age. Frequent, especially severe sino-pulmonary infections may indicate the immune deficiency present in 60 to 80% of patients, who are also prone to malignancies. The clinical course is sometimes atypical or has a late onset which results in diagnostic difficulties. Serum alpha-fetoprotein level is elevated in nearly all patients. Brain MRI shows progressive cerebellar atrophy starting at the age of 7–8 years. DNA testing of the ATM gene is necessary for the diagnosis. The detected biallelic pathogenic variants provide help for family planning and for possible gene therapies in the future. Ataxia telangiectasia has to be differentiated from a number of other disorders, some of which also belong to primary immune deficiencies. The disorder has no causal treatment at present, the patients live until their young adult ages. Orv Hetil. 2018; 159(49): 2057–2064.

scholarly journals Germline pathogenic variants in the Ataxia Telangiectasia Mutated (ATM) gene are associated with high and moderate risks for multiple cancers

2021 ◽  
pp. canprevres.0448.2020
Author(s):  
Michael J Hall ◽  
Ryan Bernhisel ◽  
Elisha Hughes ◽  
Katie Larson ◽  
Eric T. Rosenthal ◽  
...  
Keyword(s):  
Ataxia Telangiectasia ◽  
Ataxia Telangiectasia Mutated ◽  
Multiple Cancers ◽  
Pathogenic Variants ◽  
Atm Gene

An atypical presentation of ataxia telangiectasia in a school-aged boy secondary to an intronic mutation

2020 ◽  
Vol 7 (2) ◽  
pp. 57-60
Author(s):  
Ori Scott ◽  
Yael Dinur-Schejter ◽  
Julia Upton ◽  
Stephen Feanny
Keyword(s):  
Splice Site ◽  
Ataxia Telangiectasia ◽  
Late Onset ◽  
Gene Sequencing ◽  
Splice Site Mutation ◽  
Site Mutation ◽  
Intronic Mutation ◽  
Progressive Cerebellar Ataxia ◽  
Atm Gene ◽  
High Index Of Suspicion

Background: Ataxia telangiectasia typically presents in early pre-school years with progressive cerebellar ataxia and oculocutaneous telangiectasias. Referral to Immunology is often made after diagnosis has been established, as patients are prone to both humoral and cellular immune abnormalities. Case presentation: We herein report a 10-year old boy, previously undiagnosed, who presented with recurrent pneumonias. On history, frequent falls and speech difficulty were reported, with no telangiectasias on exam. Screening with alpha-fetoprotein was abnormal, followed by ATM gene sequencing, showing a homozygous intronic mutation. Over the next 3 years the patient deteriorated neurologically, and developed appreciable telangiectasias. Conclusion: A review of the literature demonstrates that intronic/splicing mutations may result in atypical ataxia telangiectasia phenotypes and delayed presentations. We advise immunologists to have a high index of suspicion for ataxia telangiectasia when assessing a patient with immunodeficiency and neurologic regression, regardless of age, and even in the absence of telangiectasias. Statement of novelty: We present a case of phenotypically atypical (“leaky”) ataxia telangiectasia resulting from a novel homozygous splice-site mutation in the ATM gene. Given high reported prevalence of intronic and splice-site mutations in ATM, we recommend full gene sequencing in patients suspected to have ataxia telangiectasia, especially in those with late onset or unusual manifestations.

scholarly journals Progressive Ataxia and Neurologic Regression in RFXANK-Associated Bare Lymphocyte Syndrome

2021 ◽  
Vol 7 (3) ◽  
pp. e586
Author(s):  
Essa Alharby ◽  
Mona Obaid ◽  
Mohammed A.O. Elamin ◽  
Makki Almuntashri ◽  
Ismail Bakhsh ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Late Onset ◽  
Brain Mri ◽  
Cerebellar Atrophy ◽  
Index Patient ◽  
Complementation Group ◽  
Type Ii ◽  
Loss Of Function ◽  
Bare Lymphocyte Syndrome ◽  
The Impact

ObjectiveTo identify the genetic cause of a late-onset immunodeficiency and subacute progressive neurodegenerative disease affecting cognition, motor, visual, and cerebellar systems in a patient with a family history of 2 younger siblings with an early-onset immunodeficiency disease.MethodsPhysical examinations, immunologic, brain MRI, whole-exome sequencing, and segregation studies were used to identify the genetic and neuroimmunologic etiology of disease in this family.ResultsWe identified a homozygous loss-of-function (LOF) mutation (c.271+1G>C) in the RFXANK gene in the index patient and one of his younger affected siblings. Biallelic mutations in the RFXANK gene are known to cause bare lymphocyte syndrome (BLS) type II, complementation group B. The clinical and immunologic investigations were consistent with a clinical diagnosis of BLS type II. MRI demonstrated global cerebral and cerebellar atrophy with white matter signal changes in the index case.ConclusionsIn addition to BLS type II, our study has expanded and further characterized the phenotype associated with the LOF of RFXANK to include progressive neurodegenerative disease. Our study also provides evidence for the impact of LOF on brain development and function. Thus, early bone marrow transplantation, as a standard of care for BLS, could prove to be protective against the neurologic phenotypes in this group of patients.

Homozygosity for c 6325T>G transition in the ATM gene causes an atypical, late-onset variant form of ataxia-telangiectasia

2010 ◽  
Vol 257 (10) ◽  
pp. 1738-1740 ◽  
Author(s):  
Gabriella Silvestri ◽  
Marcella Masciullo ◽  
Maria Piane ◽  
Camilla Savio ◽  
Anna Modoni ◽  
...  
Keyword(s):  
Ataxia Telangiectasia ◽  
Late Onset ◽  
Variant Form ◽  
Atm Gene

scholarly journals Ataxia-telangiectasia-like disorder in a family deficient for MRE11A, caused by a MRE11 variant

2018 ◽  
Vol 4 (6) ◽  
pp. e295 ◽  
Author(s):  
Maryam Sedghi ◽  
Mehri Salari ◽  
Ali-Reza Moslemi ◽  
Ariana Kariminejad ◽  
Mark Davis ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Ataxia Telangiectasia ◽  
Index Case ◽  
Brain Mri ◽  
Critical Role ◽  
Deep Tendon Reflex ◽  
Cerebellar Atrophy ◽  
Next Generation ◽  
Synonymous Variant ◽  
Generation Sequencing

ObjectiveWe report 3 siblings with the characteristic features of ataxia-telangiectasia-like disorder associated with a homozygous MRE11 synonymous variant causing nonsense-mediated mRNA decay (NMD) and MRE11A deficiency.MethodsClinical assessments, next-generation sequencing, transcript and immunohistochemistry analyses were performed.ResultsThe patients presented with poor balance, developmental delay during the first year of age, and suffered from intellectual disability from early childhood. They showed oculomotor apraxia, slurred and explosive speech, limb and gait ataxia, exaggerated deep tendon reflex, dystonic posture, and mirror movement in their hands. They developed mild cognitive abilities. Brain MRI in the index case revealed cerebellar atrophy. Next-generation sequencing revealed a homozygous synonymous variant in MRE11 (c.657C>T, p.Asn219=) that we show affects splicing. A complete absence of MRE11 transcripts in the index case suggested NMD and immunohistochemistry confirmed the absence of a stable protein.ConclusionsDespite the critical role of MRE11A in double-strand break repair and its contribution to the Mre11/Rad50/Nbs1 complex, the absence of MRE11A is compatible with life.

scholarly journals Ataxia-telangiectasia

2018 ◽  
Vol 4 (2) ◽  
pp. e228 ◽  
Author(s):  
Vincenzo Leuzzi ◽  
Daniela D'Agnano ◽  
Michele Menotta ◽  
Caterina Caputi ◽  
Luciana Chessa ◽  
...  
Keyword(s):  
Ataxia Telangiectasia ◽  
Late Onset ◽  
Brain Mri ◽  
Healthy Controls ◽  
Transcriptome Profile ◽  
Factors Affecting ◽  
Therapeutic Implications ◽  
Atm Protein ◽  
Disease Variant ◽  
Blood Transcriptome

ObjectiveAtaxia-telangiectasia (AT) is a rare, severe, and ineluctably progressive multisystemic neurodegenerative disease. Variant AT phenotypes have been described in patients with mild- and late-onset neurologic deterioration and atypical features (dystonia and myoclonus). We report on the clinical characteristics and transcriptome profile of patients with a typical AT presentation and genotype who experienced an unexpected favorable course.MethodsA 24-year-old woman developed, by the age of 3 years, all the classic symptoms of AT associated with increased alpha-fetoprotein levels, a compound AT-mutated (ATM) genotype with an inframe deletion c.2250G>A (p.Glu709_Lys750del42) and a missense mutation c.8122G>A (p.Asp2708Gln), and no residual ATM protein expression. By the age of 12 years, ataxia slowly disappeared, and a very mild choreic disorder was the only neurologic feature in adulthood. Brain MRI was normal. The blood transcriptome profile was assessed and compared with that of healthy controls and patients with the classic AT phenotype.ResultsThe atypical clinical course of the patient was associated with a transitional transcriptome profile: while 90% of transcripts were expressed as in patients with the classic AT presentation, 10% of transcripts were expressed as in healthy controls.ConclusionsThe unexpected mild clinical outcome and transcriptome profile of this patient with AT suggest the existence of individual resilience to the altered ATM synthesis. Because of their possible prognostic and therapeutic implications, the identification of modifier factors affecting the phenotype would deserve further studies.

scholarly journals Idiopathic very late-onset cerebellar ataxia: a Brazilian case series

2015 ◽  
Vol 73 (11) ◽  
pp. 903-905 ◽  
Author(s):  
Hélio A. G. Teive ◽  
Mariana Moscovich ◽  
Adriana Moro ◽  
Marina Farah ◽  
Walter O. Arruda ◽  
...  
Keyword(s):  
Cerebellar Ataxia ◽  
Visual Loss ◽  
Age Of Onset ◽  
Late Onset ◽  
Brain Mri ◽  
Cerebellar Atrophy ◽  
Case Series ◽  
Gait Ataxia ◽  
The One ◽  
Brazilian Case

ABSTRACTThe authors present a Brazilian case series of eight patients with idiopathic very-late onset (mean 75.5 years old) cerebellar ataxia, featuring predominantly gait ataxia, associated with cerebellar atrophy.Method: 26 adult patients with a diagnosis of idiopathic late onset cerebellar ataxia were analyzed in a Brazilian ataxia outpatient clinic and followed regularly over 20 years. Among them, 8 elderly patients were diagnosed as probable very late onset cerebellar ataxia. These patients were evaluated with neurological, ophthalmologic and Mini-Mental Status examinations, brain MRI, and EMG.Results: 62.5% of patients were males, mean age was 81.9 years-old, and mean age of onset was 75.5 years. Gait cerebellar ataxia was observed in all patients, as well as, cerebellar atrophy on brain MRI. Mild cognitive impairment and visual loss, due to macular degeneration, were observed in 50% of cases. Chorea was concomitantly found in 3 patients.Conclusion: We believe that this condition is similar the one described by Marie-Foix-Alajouanine presenting with mild dysarthria, associated with gait ataxia, and some patients had cognitive dysfunction and chorea.

Abstract P5-03-02: Cancer risks associated with pathogenic variants in the ataxia telangiectasia mutated (ATM) gene

2020 ◽  
Author(s):  
Michael J Hall ◽  
Katie Larson ◽  
Ryan Bernhisel ◽  
Elisha Hughes ◽  
Eric Rosenthal ◽  
...  
Keyword(s):  
Ataxia Telangiectasia ◽  
Ataxia Telangiectasia Mutated ◽  
Cancer Risks ◽  
Pathogenic Variants ◽  
Atm Gene

scholarly journals Diagnostic difficulties and possibilities of NF1-like syndromes in childhood

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Eva Pinti ◽  
Krisztina Nemeth ◽  
Krisztina Staub ◽  
Anna Lengyel ◽  
Gyorgy Fekete ◽  
...  
Keyword(s):  
Diagnostic Criteria ◽  
Neurofibromatosis Type ◽  
Early Years ◽  
Diagnostic Efficiency ◽  
Clinical Criteria ◽  
Pathogenic Variants ◽  
Clinical Diagnostic ◽  
Long Time ◽  
Diagnostic Difficulties ◽  
Clinical Diagnostic Criteria

Abstract Background Neurofibromatosis type 1 (NF1), which is caused by heterozygous inactivating pathogenic variants in the NF1, has poor phenotypic expressivity in the early years of life and there are numerous conditions, including many other tumor predisposition syndromes, that can mimic its appearance. These are collectively termed NF1-like syndromes and are also connected by their genetic background. Therefore, the NF1’s clinical diagnostic efficiency in childhood could be difficult and commonly should be completed with genetic testing. Methods To estimate the number of syndromes/conditions that could mimic NF1, we compiled them through an extensive search of the scientific literature. To test the utility of NF1’s National Institutes of Health (NIH) clinical diagnostic criteria, which have been in use for a long time, we analyzed the data of a 40-member pediatric cohort with symptoms of the NF1-like syndromes’ overlapping phenotype and performed NF1 genetic test, and established the average age when diagnostic suspicion arises. To facilitate timely identification, we compiled strongly suggestive phenotypic features and anamnestic data. Results In our cohort the utility of NF1’s clinical diagnostic criteria were very limited (sensitivity: 80%, specificity: 30%). Only 53% of children with clinically diagnosed NF1 had a detectable NF1 pathogenic variation, whereas 40% of patients without fulfilled clinical criteria tested positive. The average age at first genetic counseling was 9 years, and 40% of children were referred after at least one tumor had already been diagnosed. These results highlight the need to improve NF1-like syndromes’ diagnostic efficiency in childhood. We collected the most extensive spectrum of NF1-like syndromes to help the physicians in differential diagnosis. We recommend the detailed, non-invasive clinical evaluation of patients before referring them to a clinical geneticist. Conclusions Early diagnosis of NF1-like syndromes can help to prevent severe complications by appropriate monitoring and management. We propose a potential screening, diagnostic and management strategy based on our findings and recent scientific knowledge.

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