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Neuroepidemiology 2014Hereditary cerebellar ataxias (HCA) and hereditary spastic paraplegias (HSP) are two groups of neurodegenerative disorders that usually present with progressive gait... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Hereditary cerebellar ataxias (HCA) and hereditary spastic paraplegias (HSP) are two groups of neurodegenerative disorders that usually present with progressive gait impairment, often leading to permanent disability. Advances in genetic research in the last decades have improved their diagnosis and brought new possibilities for prevention and future treatments. Still, there is great uncertainty regarding their global epidemiology.
SUMMARY
Our objective was to assess the global distribution and prevalence of HCA and HSP by a systematic review and meta-analysis of prevalence studies. The MEDLINE, ISI Web of Science and Scopus databases were searched (1983-2013) for studies performed in well-defined populations and geographical regions. Two independent reviewers assessed the studies and extracted data and predefined methodological parameters. Overall, 22 studies were included, reporting on 14,539 patients from 16 countries. Multisource population-based studies yielded higher prevalence values than studies based primarily on hospitals or genetic centres. The prevalence range of dominant HCA was 0.0-5.6/10(5), with an average of 2.7/10(5) (1.5-4.0/10(5)). Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease was the most common dominant ataxia, followed by SCA2 and SCA6. The autosomal recessive (AR) HCA (AR-HCA) prevalence range was 0.0-7.2/10(5), the average being 3.3/10(5) (1.8-4.9/10(5)). Friedreich ataxia was the most frequent AR-HCA, followed by ataxia with oculomotor apraxia or ataxia-telangiectasia. The prevalence of autosomal dominant (AD) HSP (AD-HSP) ranged from 0.5 to 5.5/10(5) and that of AR-HSP from 0.0 to 5.3/10(5), with pooled averages of 1.8/10(5) (95% CI: 1.0-2.7/10(5)) and 1.8/10(5) (95% CI: 1.0-2.6/10(5)), respectively. The most common AD-HSP form in every population was spastic paraplegia, autosomal dominant, type 4 (SPG4), followed by SPG3A, while SPG11 was the most frequent AR-HSP, followed by SPG15. In population-based studies, the number of families without genetic diagnosis after systematic testing ranged from 33 to 92% in the AD-HCA group, and was 40-46% in the AR-HCA, 45-67% in the AD-HSP and 71-82% in the AR-HSP groups.
KEY MESSAGES
Highly variable prevalence values for HCA and HSP are reported across the world. This variation reflects the different genetic make-up of the populations, but also methodological heterogeneity. Large areas of the world remain without prevalence studies. From the available data, we estimated that around 1:10,000 people are affected by HCA or HSP. In spite of advances in genetic research, most families in population-based series remain without identified genetic mutation after extensive testing. © 2014 S. Karger AG, Basel.
Topics: Cerebellar Ataxia; Cross-Sectional Studies; Humans; Paraplegia; Prevalence; Spastic Paraplegia, Hereditary; Spinocerebellar Degenerations
PubMed: 24603320
DOI: 10.1159/000358801 -
Clinical Genetics Aug 2016Ataxia-telangiectasia (AT) is an autosomal recessive neurodegenerative disorder with immunodeficiency and an increased risk of developing cancer, caused by mutations in... (Meta-Analysis)
Meta-Analysis Review
Ataxia-telangiectasia (AT) is an autosomal recessive neurodegenerative disorder with immunodeficiency and an increased risk of developing cancer, caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. Logically, blood relatives may also carry a pathogenic ATM mutation. Female carriers of such a mutation have an increased risk of breast cancer. Other health risks for carriers are suspected but have never been studied systematically. Consequently, evidence-based guidelines for carriers are not available yet. We systematically analyzed all literature and found that ATM mutation carriers have a reduced life expectancy because of mortality from cancer and ischemic heart diseases (RR 1.7, 95% CI 1.2-2.4) and an increased risk of developing cancer (RR 1.5, 95% CI 0.9-2.4), in particular breast cancer (RRwomen 3.0, 95% CI 2.1-4.5), and cancers of the digestive tract. Associations between ATM heterozygosity and other health risks have been suggested, but clear evidence is lacking. Based on these results, we propose that all female carriers of 40-50 years of age and female ATM c.7271T>G mutation carriers from 25 years of age onwards be offered intensified surveillance programs for breast cancer. Furthermore, all carriers should be made aware of lifestyle factors that contribute to the development of cardiovascular diseases and diabetes.
Topics: Adult; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Breast Neoplasms; Evidence-Based Medicine; Female; Gastrointestinal Neoplasms; Gene Expression; Genetic Counseling; Genetic Predisposition to Disease; Heterozygote; Humans; Life Expectancy; Middle Aged; Mutation; Myocardial Ischemia; Practice Guidelines as Topic; Risk Factors
PubMed: 26662178
DOI: 10.1111/cge.12710 -
PloS One 2022Ataxia-telangiectasia is an autosomal recessive, multi-system, and life-shortening disease caused by mutations in the ataxia-telangiectasia mutated gene. Although widely...
BACKGROUND
Ataxia-telangiectasia is an autosomal recessive, multi-system, and life-shortening disease caused by mutations in the ataxia-telangiectasia mutated gene. Although widely reported, there are no studies that give a comprehensive picture of this intriguing condition.
OBJECTIVES
Understand the natural history of ataxia-telangiectasia (A-T), as reported in scientific literature.
SEARCH METHODS
107 search terms were identified and divided into 17 searches. Each search was performed in PubMed, Ovid SP (MEDLINE) 1946-present, OVID EMBASE 1980 -present, Web of Science core collection, Elsevier Scopus, and Cochrane Library.
SELECTION CRITERIA
All human studies that report any aspect of A-T.
DATA COLLECTION AND ANALYSIS
Search results were de-duplicated, data extracted (including author, publication year, country of origin, study design, population, participant characteristics, and clinical features). Quality of case-control and cohort studies was assessed by the Newcastle-Ottawa tool. Findings are reported descriptively and where possible data collated to report median (interquartile range, range) of outcomes of interest.
MAIN RESULTS
1314 cases reported 2134 presenting symptoms. The most common presenting symptom was abnormal gait (1160 cases; 188 studies) followed by recurrent infections in classical ataxia-telangiectasia and movement disorders in variant ataxia-telangiectasia. 687 cases reported 752 causes of death among which malignancy was the most frequently reported cause. Median (IQR, range) age of death (n = 294) was 14 years 0 months (10 years 0 months to 23 years 3 months, 1 year 3 months to 76 years 0 months).
CONCLUSIONS
This review demonstrates the multi-system involvement in A-T, confirms that neurological symptoms are the most frequent presenting features in classical A-T but variants have diverse manifestations. We found that most individuals with A-T have life limited to teenage or early adulthood. Predominance of case reports, and case series demonstrate the lack of robust evidence to determine the natural history of A-T. We recommend population-based studies to fill this evidence gap.
Topics: Adolescent; Adult; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Cohort Studies; Humans; Movement Disorders; Mutation
PubMed: 35290391
DOI: 10.1371/journal.pone.0264177 -
International Journal of Radiation... Apr 2015Studies of the association between ataxia telangiectasia-mutated (ATM) gene polymorphisms and acute radiation injuries are often small in sample size, and the results... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Studies of the association between ataxia telangiectasia-mutated (ATM) gene polymorphisms and acute radiation injuries are often small in sample size, and the results are inconsistent. We conducted the first meta-analysis to provide a systematic review of published findings.
METHODS AND MATERIALS
Publications were identified by searching PubMed up to April 25, 2014. Primary meta-analysis was performed for all acute radiation injuries, and subgroup meta-analyses were based on clinical endpoint. The influence of sample size and radiation injury incidence on genetic effects was estimated in sensitivity analyses. Power calculations were also conducted.
RESULTS
The meta-analysis was conducted on the ATM polymorphism rs1801516, including 5 studies with 1588 participants. For all studies, the cut-off for differentiating cases from controls was grade 2 acute radiation injuries. The primary meta-analysis showed a significant association with overall acute radiation injuries (allelic model: odds ratio = 1.33, 95% confidence interval: 1.04-1.71). Subgroup analyses detected an association between the rs1801516 polymorphism and a significant increase in urinary and lower gastrointestinal injuries and an increase in skin injury that was not statistically significant. There was no between-study heterogeneity in any meta-analyses. In the sensitivity analyses, small studies did not show larger effects than large studies. In addition, studies with high incidence of acute radiation injuries showed larger effects than studies with low incidence. Power calculations revealed that the statistical power of the primary meta-analysis was borderline, whereas there was adequate power for the subgroup analysis of studies with high incidence of acute radiation injuries.
CONCLUSIONS
Our meta-analysis showed a consistency of the results from the overall and subgroup analyses. We also showed that the genetic effect of the rs1801516 polymorphism on acute radiation injuries was dependent on the incidence of the injury. These support the evidence of an association between the rs1801516 polymorphism and acute radiation injuries, encouraging further research of this topic.
Topics: Ataxia Telangiectasia Mutated Proteins; Genetic Markers; Humans; Incidence; Neoplasms; Polymorphism, Genetic; Radiation Injuries; Sensitivity and Specificity
PubMed: 25832699
DOI: 10.1016/j.ijrobp.2014.12.041 -
Frontiers in Immunology 2021Ataxia-telangiectasia (AT) is a rare autosomal recessive neurodegenerative multisystem disorder. A minority of AT patients can present late-onset atypical presentations...
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.
Topics: Adolescent; Adult; Ataxia; Ataxia Telangiectasia; Child; Child, Preschool; Female; Humans; Iran; Male; Mutation, Missense; Phenotype; T-Lymphocytes, Regulatory; Young Adult; alpha-Fetoproteins
PubMed: 35095854
DOI: 10.3389/fimmu.2021.779502 -
Cancers Oct 2020Ataxia-Telangiectasia (A-T) is a rare autosomal recessive disorder, first reported in 1926, caused by a deficiency of ATM (Ataxia-Telangiectasia Mutated) protein. The... (Review)
Review
Ataxia-Telangiectasia (A-T) is a rare autosomal recessive disorder, first reported in 1926, caused by a deficiency of ATM (Ataxia-Telangiectasia Mutated) protein. The disease is characterized by progressive cerebellar neurodegeneration, immunodeficiency, leukemia, and lymphoma cancer predisposition. Immunoglobulin replacement, antioxidants, neuroprotective factors, growth, and anti-inflammatory hormones are commonly used for A-T treatment, but, to date, there is no known cure. Bone marrow transplantation (BMT) is a successful therapy for several forms of diseases and it is a valid approach for tumors, hemoglobinopathies, autoimmune diseases, inherited disorders of metabolism, and other pathologies. Some case reports of A-T patients have shown that BMT is becoming a good option, as a correct engraftment of healthy cells can restore some aspects of immunologic capacity. However, due to a high risk of mortality as a result of a clinical and cellular hypersensitivity to ionizing radiation and radiomimetic drugs, a specific non-myeloablative conditioning is required before BMT. Although BMT might be considered as one promising therapy for the treatment of immunological defects and cancer prevention in selected A-T patients, the therapy is currently not recommended or recognized and the eligibility of A-T patients for BMT is a point to deepen and deliberate.
PubMed: 33142696
DOI: 10.3390/cancers12113207 -
Cancer Cell International Sep 2021Breast cancer is the most common cancer in women, and its high mortality has become one of the biggest health problems globally. Several studies have reported an... (Review)
Review
Breast cancer is the most common cancer in women, and its high mortality has become one of the biggest health problems globally. Several studies have reported an association between breast cancer and ATM gene variants. This study aimed to demonstrate and analyze the relationship between ATM gene polymorphisms and breast cancer prevalence rate. A systematic literature review was undertaken using the following databases: Medline (PubMed), Web of sciences, Scopus, EMBASE, Cochrane, Ovid, and CINHAL to retrieve all cross-sectional studies between January 1990 and January 2020, which had reported the frequency of ATM variants in patients with breast cancer. A random-effects model was applied to calculate the pooled prevalence with a 95% confidence interval. The pooled prevalence of ATM variants in patients with breast cancer was 7% (95% CI: 5-8%). Also, the pooled estimate based on type of variants was 6% (95% CI: 4-8%; I square: 94%; P: 0.00) for total variants¸ 0% (95% CI: 0-1%; I square: 0%; P: 0.59) for deletion variants, 12% (95% CI: 7-18%; I square: 99%; P: 0.00) for substitution variants, and 2% (95% CI: 4-9%; I square: 67%; P: 0.08) for insertion variants. This meta-analysis showed that there is a significant relationship between ATM variants in breast cancer patients. Further studies are required to determine which of the variants of the ATM gene are associated with BRCA mutations.
PubMed: 34493284
DOI: 10.1186/s12935-021-02172-8 -
Medicine Apr 2016Studies on associations between ataxia telangiectasia-mutated (ATM) polymorphisms and late radiotherapy-induced adverse events vary in clinical settings, and the results... (Meta-Analysis)
Meta-Analysis Review
Single Nucleotide Polymorphism rs1801516 in Ataxia Telangiectasia-Mutated Gene Predicts Late Fibrosis in Cancer Patients After Radiotherapy: A PRISMA-Compliant Systematic Review and Meta-Analysis.
Studies on associations between ataxia telangiectasia-mutated (ATM) polymorphisms and late radiotherapy-induced adverse events vary in clinical settings, and the results are inconsistent.We conducted the first meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to investigate the role of the ATM polymorphism rs1801516 in the development of radiotherapy-induced late fibrosis.We searched PubMed, Embase, Web of Science, and Chinese National Knowledge Infrastructure databases to identify studies that investigated the effect of the ATM polymorphism rs1801516 on radiotherapy-induced late fibrosis before September 8, 2015. Summary odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were used to assess the association between late fibrosis and the rs1801516 polymorphism. Subgroup analyses were conducted to evaluate the influence of clinical features on the genetic association. Tests of interaction were used to compare differences in the effect estimates between subgroups.The overall meta-analysis of 2000 patients from 9 studies showed that the minor allele of the rs1801516 polymorphism was associated with a significantly increased risk of developing late fibrosis (OR = 1.78, 95% CI: 1.07, 2.94), with high between-study heterogeneity (I = 66.6%, P = 0.002). In subgroup analyses, we identified that the incidence of late fibrosis was a major source of heterogeneity across studies. The OR for patients with a high incidence of late fibrosis was 3.19 (95% CI: 1.86, 5.47), in contrast to 1.09 (95% CI: 1.01, 1.17) for those with a low incidence. There was a significant difference in the effect estimates between the 2 subgroups (ratio of OR = 2.94, 95% CI 1.70, 5.08, P = 0.031).This meta-analysis supported previously reported effect of the ATM polymorphism rs1801516 on radiotherapy-induced late fibrosis. This finding encouraged further researches to identify more genetic polymorphisms that were predictive for radiotherapy-induced adverse events. In addition, we showed that the inconsistency of the associations seen in these studies might be related to variations in the incidence of late fibrosis in the patients. This suggested that future studies should consider the incidence of radiotherapy-induced adverse events when investigating radiosensitivity signature genes.
Topics: Ataxia Telangiectasia Mutated Proteins; Fibrosis; Humans; Mutation; Neoplasms; Polymorphism, Single Nucleotide; Prognosis; Radiation Injuries
PubMed: 27057881
DOI: 10.1097/MD.0000000000003267 -
Biology of Reproduction Sep 2015Oocyte aging has a significant impact on reproductive outcomes both quantitatively and qualitatively. However, the molecular mechanisms underlying the age-related... (Meta-Analysis)
Meta-Analysis Review
Oocyte aging has a significant impact on reproductive outcomes both quantitatively and qualitatively. However, the molecular mechanisms underlying the age-related decline in reproductive success have not been fully addressed. BRCA is known to be involved in homologous DNA recombination and plays an essential role in double-strand DNA break repair. Given the growing body of laboratory and clinical evidence, we performed a systematic review on the current understanding of the role of DNA repair in human reproduction. We find that BRCA mutations negatively affect ovarian reserve based on convincing evidence from in vitro and in vivo results and prospective studies. Because decline in the function of the intact gene occurs at an earlier age, women with BRCA1 mutations exhibit accelerated ovarian aging, unlike those with BRCA2 mutations. However, because of the still robust function of the intact allele in younger women and because of the masking of most severe cases by prophylactic oophorectomy or cancer, it is less likely one would see an effect of BRCA mutations on fertility until later in reproductive age. The impact of BRCA2 mutations on reproductive function may be less visible because of the delayed decline in the function of normal BRCA2 allele. BRCA1 function and ataxia-telangiectasia-mutated (ATM)-mediated DNA repair may also be important in the pathogenesis of age-induced increase in aneuploidy. BRCA1 is required for meiotic spindle assembly, and cohesion function between sister chromatids is also regulated by ATM family member proteins. Taken together, these findings strongly suggest the implication of BRCA and DNA repair malfunction in ovarian aging.
Topics: Animals; BRCA1 Protein; BRCA2 Protein; DNA Repair; Female; Fertility; Genes, BRCA2; Humans; Infertility; Mice; Ovary
PubMed: 26224004
DOI: 10.1095/biolreprod.115.132290 -
BMC Cancer Jan 2021Ataxia telangiectasia-mutated (ATM) gene contributes to repair damaged DNA and to regulate cell cycle; therefore, ATM variants seem to increase breast cancer risk;... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Ataxia telangiectasia-mutated (ATM) gene contributes to repair damaged DNA and to regulate cell cycle; therefore, ATM variants seem to increase breast cancer risk; however, the results are controversial. So we conducted a systematic review and meta-analysis to clarify the pooled association between various ATM variants and the risk of breast cancer.
METHODS
The relevant studies were searched through Scopus, Web of Science, PubMed and Cochrane. Stratified and subgroup analyses were performed to explore heterogeneity between studies and assess effects of study quality. The pooled estimates logarithm with standard error logarithm of odds ratio and relative risk with confidence interval were calculated.
RESULTS
This study revealed that there is association between ATM variants and the risk of breast cancer; according to the seven adjusted case-control studies, OR of this association was estimated as 1.67 (95%CI: 0.73-3.82), according to nine unadjusted case-control studies, the crude OR was 2.27 (95% CI: 1.17-4.40) and according to two cohorts, the RR was estimated as 1.68 (95% CI: 1.17-2.40).
CONCLUSIONS
The ATM variants are associated with an increased risk of breast cancer that ATM V2424G mutation is detected as the most predisposing factor while ATM D1853V, L546V, and S707P variants have the least predictive ability.
Topics: Ataxia Telangiectasia Mutated Proteins; Breast Neoplasms; Case-Control Studies; Female; Genetic Predisposition to Disease; Humans; Polymorphism, Single Nucleotide; Prognosis
PubMed: 33402103
DOI: 10.1186/s12885-020-07749-6