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Developmental Medicine and Child... Jul 2017Ataxia-telangiectasia is a rare, neurodegenerative, and multisystem disease, characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency,... (Review)
Review
Ataxia-telangiectasia is a rare, neurodegenerative, and multisystem disease, characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, progressive respiratory failure, and an increased risk of malignancies. It demands specialized care tailored to the individual patient's needs. Besides the classic ataxia-telangiectasia phenotype, a variant phenotype exists with partly overlapping but some distinctive disease characteristics. This guideline summarizes frequently encountered medical problems in the disease course of patients with classic and variant ataxia-telangiectasia, in the domains of neurology, immunology and infectious diseases, pulmonology, anaesthetic and perioperative risk, oncology, endocrinology, and nutrition. Furthermore, it provides a practical guide with evidence- and expert-based recommendations for the follow-up and treatment of all these different clinical topics.
Topics: Ataxia Telangiectasia; Humans
PubMed: 28318010
DOI: 10.1111/dmcn.13424 -
Orphanet Journal of Rare Diseases Nov 2016Ataxia telangiectasia (A-T) is an autosomal recessive disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer... (Review)
Review
DEFINITION OF THE DISEASE
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.
EPIDEMIOLOGY
The world-wide prevalence of A-T is estimated to be between 1 in 40,000 and 1 in 100,000 live births.
CLINICAL DESCRIPTION
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.
ETIOLOGY
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.
DIAGNOSIS
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.
DIFFERENTIAL DIAGNOSIS
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
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
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.
MANAGEMENT AND PROGNOSIS
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.
Topics: Animals; Ataxia Telangiectasia; Cerebellum; Humans; Lung Diseases; Mutation; Purkinje Cells
PubMed: 27884168
DOI: 10.1186/s13023-016-0543-7 -
Annals of Neurology Feb 2019Variant ataxia-telangiectasia is caused by mutations that allow some retained ataxia telangiectasia-mutated (ATM) kinase activity. Here, we describe the clinical...
OBJECTIVE
Variant ataxia-telangiectasia is caused by mutations that allow some retained ataxia telangiectasia-mutated (ATM) kinase activity. Here, we describe the clinical features of the largest established cohort of individuals with variant ataxia-telangiectasia and explore genotype-phenotype correlations.
METHODS
Cross-sectional data were collected retrospectively. Patients were classified as variant ataxia-telangiectasia based on retained ATM kinase activity.
RESULTS
The study includes 57 individuals. Mean age at assessment was 37.5 years. Most had their first symptoms by age 10 (81%). There was a diagnostic delay of more than 10 years in 68% and more than 20 years in one third of probands. Disease severity was mild in one third of patients, and 43% were still ambulant 20 years after disease onset. Only one third had predominant ataxia, and 18% had a pure extrapyramidal presentation. Individuals with extrapyramidal presentations had milder neurological disease severity. There were no significant respiratory or immunological complications, but 25% of individuals had a history of malignancy. Missense mutations were associated with milder neurological disease severity, but with a higher risk of malignancy, compared to leaky splice site mutations.
INTERPRETATION
Individuals with variant ataxia-telangiectasia require malignancy surveillance and tailored management. However, our data suggest the condition may sometimes be mis- or underdiagnosed because of atypical features, including exclusive extrapyramidal symptoms, normal eye movements, and normal alpha-fetoprotein levels in some individuals. Missense mutations are associated with milder neurological presentations, but a particularly high malignancy risk, and it is important for clinicians to be aware of these phenotypes. ANN NEUROL 2019;85:170-180.
Topics: Adolescent; Adult; Ataxia Telangiectasia; Basal Ganglia Diseases; Child; Cohort Studies; Cross-Sectional Studies; Female; Genotype; Humans; Male; Middle Aged; Mutation, Missense; Retrospective Studies; Severity of Illness Index; Young Adult
PubMed: 30549301
DOI: 10.1002/ana.25394 -
Pediatrics and Neonatology Sep 2022
Topics: Ataxia Telangiectasia; Humans
PubMed: 35431147
DOI: 10.1016/j.pedneo.2022.01.004 -
Neuromolecular Medicine Sep 2013Ataxia telangiectasia (A-T) is an autosomal recessive disease characterized mainly by progressive cerebellar ataxia, oculocutaneous telangiectasia, and immunodeficiency....
Ataxia telangiectasia (A-T) is an autosomal recessive disease characterized mainly by progressive cerebellar ataxia, oculocutaneous telangiectasia, and immunodeficiency. This disease is caused by mutations of the ataxia telangiectasia mutated (Atm) gene. More than 500 Atm mutations that are responsible for A-T have been identified so far. However, there have been very few A-T cases reported in China, and only two Chinese A-T patients have undergone Atm gene analysis. In order to systemically investigate A-T in China and map their Atm mutation spectrum, we recruited eight Chinese A-T patients from six unrelated families nationwide. Using direct sequencing of genomic DNA and the multiplex ligation-dependent probe amplification, we identified twelve pathogenic Atm mutations, including one missense, four nonsense, five frameshift, one splicing, and one large genomic deletion. All the Atm mutations we identified were novel, and no homozygous mutation and founder-effect mutation were found. These results suggest that Atm mutations in Chinese populations are diverse and distinct largely from those in other ethnic areas.
Topics: Adolescent; Asian People; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Atrophy; Cerebellum; Child; Child, Preschool; China; Codon, Nonsense; DNA Mutational Analysis; Exons; Female; Frameshift Mutation; Humans; Male; Multiplex Polymerase Chain Reaction; Mutation; RNA Splice Sites; Sequence Deletion; alpha-Fetoproteins
PubMed: 23807571
DOI: 10.1007/s12017-013-8240-3 -
Ageing Research Reviews Aug 2022Ataxia-telangiectasia (A-T) is caused by absence of the catalytic activity of ATM, a protein kinase that plays a central role in the DNA damage response, many branches... (Review)
Review
Ataxia-telangiectasia (A-T) is caused by absence of the catalytic activity of ATM, a protein kinase that plays a central role in the DNA damage response, many branches of cellular metabolism, redox and mitochondrial homeostasis, and cell cycle regulation. A-T is a complex disorder characterized mainly by progressive cerebellar degeneration, immunodeficiency, radiation sensitivity, genome instability, and predisposition to cancer. It is increasingly recognized that the premature aging component of A-T is an important driver of this disease, and A-T is therefore an attractive model to study the aging process. This review outlines the current state of knowledge pertaining to the molecular and cellular signatures of aging in A-T and proposes how these new insights can guide novel therapeutic approaches for A-T.
Topics: Aging; Aging, Premature; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; DNA Damage; Genomic Instability; Humans
PubMed: 35644374
DOI: 10.1016/j.arr.2022.101653 -
American Journal of Human Genetics Jun 1999Mutations resulting in defective splicing constitute a significant proportion (30/62 [48%]) of a new series of mutations in the ATM gene in patients with...
Mutations resulting in defective splicing constitute a significant proportion (30/62 [48%]) of a new series of mutations in the ATM gene in patients with ataxia-telangiectasia (AT) that were detected by the protein-truncation assay followed by sequence analysis of genomic DNA. Fewer than half of the splicing mutations involved the canonical AG splice-acceptor site or GT splice-donor site. A higher percentage of mutations occurred at less stringently conserved sites, including silent mutations of the last nucleotide of exons, mutations in nucleotides other than the conserved AG and GT in the consensus splice sites, and creation of splice-acceptor or splice-donor sites in either introns or exons. These splicing mutations led to a variety of consequences, including exon skipping and, to a lesser degree, intron retention, activation of cryptic splice sites, or creation of new splice sites. In addition, 5 of 12 nonsense mutations and 1 missense mutation were associated with deletion in the cDNA of the exons in which the mutations occurred. No ATM protein was detected by western blotting in any AT cell line in which splicing mutations were identified. Several cases of exon skipping in both normal controls and patients for whom no underlying defect could be found in genomic DNA were also observed, suggesting caution in the interpretation of exon deletions observed in ATM cDNA when there is no accompanying identification of genomic mutations.
Topics: Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Base Sequence; Cell Cycle Proteins; DNA Primers; DNA, Complementary; DNA-Binding Proteins; Humans; Mutation; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Protein Serine-Threonine Kinases; Proteins; RNA Splicing; Tumor Suppressor Proteins
PubMed: 10330348
DOI: 10.1086/302418 -
Nature Jul 2023Splice-switching antisense oligonucleotides (ASOs) could be used to treat a subset of individuals with genetic diseases, but the systematic identification of such...
Splice-switching antisense oligonucleotides (ASOs) could be used to treat a subset of individuals with genetic diseases, but the systematic identification of such individuals remains a challenge. Here we performed whole-genome sequencing analyses to characterize genetic variation in 235 individuals (from 209 families) with ataxia-telangiectasia, a severely debilitating and life-threatening recessive genetic disorder, yielding a complete molecular diagnosis in almost all individuals. We developed a predictive taxonomy to assess the amenability of each individual to splice-switching ASO intervention; 9% and 6% of the individuals had variants that were 'probably' or 'possibly' amenable to ASO splice modulation, respectively. Most amenable variants were in deep intronic regions that are inaccessible to exon-targeted sequencing. We developed ASOs that successfully rescued mis-splicing and ATM cellular signalling in patient fibroblasts for two recurrent variants. In a pilot clinical study, one of these ASOs was used to treat a child who had been diagnosed with ataxia-telangiectasia soon after birth, and showed good tolerability without serious adverse events for three years. Our study provides a framework for the prospective identification of individuals with genetic diseases who might benefit from a therapeutic approach involving splice-switching ASOs.
Topics: Child; Humans; Ataxia Telangiectasia; Oligonucleotides, Antisense; Prospective Studies; RNA Splicing; Whole Genome Sequencing; Introns; Exons; Precision Medicine; Pilot Projects
PubMed: 37438524
DOI: 10.1038/s41586-023-06277-0 -
Cerebellum (London, England) Jun 2022With disease-modifying approaches under evaluation in ataxia-telangiectasia and other ataxias, there is a need for objective and reliable biomarkers of free-living motor...
With disease-modifying approaches under evaluation in ataxia-telangiectasia and other ataxias, there is a need for objective and reliable biomarkers of free-living motor function. In this study, we test the hypothesis that metrics derived from a single wrist sensor worn at home provide accurate, reliable, and interpretable information about neurological disease severity in children with A-T.A total of 15 children with A-T and 15 age- and sex-matched controls wore a sensor with a triaxial accelerometer on their dominant wrist for 1 week at home. Activity intensity measures, derived from the sensor data, were compared with in-person neurological evaluation on the Brief Ataxia Rating Scale (BARS) and performance on a validated computer mouse task.Children with A-T were inactive the same proportion of each day as controls but produced more low intensity movements (p < 0.01; Cohen's d = 1.48) and fewer high intensity movements (p < 0.001; Cohen's d = 1.71). The range of activity intensities was markedly reduced in A-T compared to controls (p < 0.0001; Cohen's d = 2.72). The activity metrics correlated strongly with arm, gait, and total clinical severity (r: 0.71-0.87; p < 0.0001), correlated with specific computer task motor features (r: 0.67-0.92; p < 0.01), demonstrated high reliability (r: 0.86-0.93; p < 0.00001), and were not significantly influenced by age in the healthy control group.Motor activity metrics from a single, inexpensive wrist sensor during free-living behavior provide accurate and reliable information about diagnosis, neurological disease severity, and motor performance. These low-burden measurements are applicable independent of ambulatory status and are potential digital behavioral biomarkers in A-T.
Topics: Ataxia; Ataxia Telangiectasia; Gait; Humans; Motor Activity; Reproducibility of Results
PubMed: 34302287
DOI: 10.1007/s12311-021-01306-y -
Orphanet Journal of Rare Diseases Mar 2021Ataxia telangiectasia (A-T) is a DNA repair disorder that affects multiple body systems. Neurological problems and immunodeficiency are two important features of this...
BACKGROUND
Ataxia telangiectasia (A-T) is a DNA repair disorder that affects multiple body systems. Neurological problems and immunodeficiency are two important features of this disease. At this time, two main severity groups are defined in A-T: classic (the more severe form) and mild. Poor growth is a common problem in classic A-T. An objective of this study was to develop growth references for classic A-T. Another objective was to compare growth patterns in classic A-T and mild A-T with each other and with the general population, using the CDC growth references. A final objective was to examine the effects of chronic infection on height.
RESULTS
We found that classic A-T patients were smaller overall, and suffered from height and weight faltering that continued throughout childhood and adolescence. When compared to the CDC growth references, the median heights and weights for both male and female patients eventually fell to or below the 3rd centile on the CDC charts. Height faltering was more pronounced in females. Birthweight was lower in the classic A-T group compared to mild A-T and the general population, whereas birth length was not. Finally, we investigated height and BMI faltering in relation to number of infections and found no association.
CONCLUSIONS
Classic A-T appears to affect growth in utero. Although children appear to grow well in very early life, faltering begins early, and is unrelenting.
Topics: Adolescent; Ataxia Telangiectasia; Body Height; Body Weight; Child; Female; Growth Disorders; Humans; Male
PubMed: 33691726
DOI: 10.1186/s13023-021-01716-5