scholarly journals Genetic Associations with Age at Dementia Onset in the PSEN1 E280A Colombian Kindred

2020 ◽  
Author(s):  
J. Nicholas Cochran ◽  
Juliana Acosta-Uribe ◽  
Lucia Madrigal ◽  
David Aguillón ◽  
Gloria P. Garcia ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Late Onset ◽  
Small Sample Size ◽  
Age At Onset ◽  
Missense Variant ◽  
Small Sample ◽  
Population Heterogeneity ◽  
Genetic Associations ◽  
New Variant ◽  
Dementia Onset

Background: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) have revealed genetic variants with the potential for therapeutic application. Such studies in late onset AD are limited by population heterogeneity and co-morbidities associated with aging. Studies to date in ADAD (autosomal dominant AD) have been limited by their small sample size. The large Colombian kindred presented here provides a unique opportunity to discover AAO genetic associations. Methods: A genetic association study was conducted for AAO in 344 individuals with the PSEN1 E280A mutation via array imputation and whole genome sequencing in a subset of 80 individuals. Scrambled age conditions were used as a control, and replication was assessed using three studies on AD age of onset, age of onset survival, and meta-analysis. Results: The proportion of variance explained (+/- 95% CI) was 56% (+/-15%). 29 loci reached genome-wide significance, of which 23 had a GWAS hit from the NHGRI-EBI catalog within 500 kb relevant to neurodegeneration. Hits included a new variant in the CLU locus, rs35980966, (which replicated), a variant in a locus on a separate chromosome previously associated with plasma clusterin (rs138295139), and a missense variant in SORBS3 (rs34059820). Former GWAS index variants at the CLU locus also replicated in this cohort (rs4236673, rs9331896). APOE ϵ4 (rs429358) and APOE ϵ2 (rs7412)-associated variants exhibited modest (less than 3 years) associations with earlier and later age of dementia onset, respectively. Other nominal associations included coding variants in IL34 (rs4985556), TSPAN10 (rs6565617, rs7210026), STIM2 (rs1457401458), HTT (rs1473464204), and KCNT1 (rs557219607). Interpretation: A large proportion of the variability in AAO was explained by genetic variation at numerous loci. The unique demography of this population as a tri-continental admixture that passed through a bottleneck about 500 years ago might predict that drift would uncover rare variants with a large effect size on AAO. Indeed, candidates for large contributions from rare alleles were observed. Common variation, presumably ancestral to the bottleneck, was also associated with AAO. The detection of these effects in the presence of a strong mutation for ADAD reinforce the potentially impactful role of the identified variants.

CONTRIBUTION OF DNA COPY-NUMBER VARIATION (CNV) TO CANCER SUSCEPTIBILITY AND LARGE-SCALE GENOME ALTERATIONS IN OSTEOSARCOMA (OS)

2008 ◽  
Vol 31 (4) ◽  
pp. 19
Author(s):  
I Pasic ◽  
A Shlien ◽  
A Novokmet ◽  
C Zhang ◽  
U Tabori ◽  
...  
Keyword(s):  
Genomic Instability ◽  
Large Scale ◽  
Structural Variation ◽  
Age Of Onset ◽  
Cancer Susceptibility ◽  
Small Sample Size ◽  
Snp Array ◽  
Tumour Suppressor Gene ◽  
Small Sample ◽  
International Hapmap Project

Introduction: OS, a common Li-Fraumeni syndrome (LFS)-associated neoplasm, is a common bone malignancy of children and adolescents. Sporadic OS is also characterized by young age of onset and high genomic instability, suggesting a genetic contribution to disease. This study examined the contribution of novel DNA structural variation elements, CNVs, to OS susceptibility. Given our finding of excessive constitutional DNA CNV in LFS patients, which often coincide with cancer-related genes, we hypothesized that constitutional CNV may also provide clues about the aetiology of LFS-related sporadic neoplasms like OS. Methods: CNV in blood DNA of 26 patients with sporadic OS was compared to that of 263 normal control samples from the International HapMap project, as well as 62 local controls. Analysis was performed on DNA hybridized to Affymetrix genome-wide human SNP array 6.0 by Partek Genomic Suite. Results: There was no detectable difference in average number of CNVs, CNV length, and total structural variation (product of average CNV number and length) between individuals with OS and controls. While this data is preliminary (small sample size), it argues against the presence of constitutional genomic instability in individuals with sporadic OS. Conclusion: We found that the majority of tumours from patients with sporadic OS show CN loss at chr3q13.31, raising the possibility that chr3q13.31 may represent a “driver” region in OS aetiology. In at least one OS tumour, which displays CN loss at chr3q13.31, we demonstrate decreased expression of a known tumour suppressor gene located at chr3q13.31. We are investigating the role ofchr3q13.31 in development of OS.

Early and Late Onset Bipolar Disorders in Older Adults

2017 ◽  
Vol 41 (S1) ◽  
pp. S211-S211
Author(s):  
N. Smaoui ◽  
L. Zouari ◽  
N. Charfi ◽  
M. Maâlej-Bouali ◽  
N. Zouari ◽  
...  
Keyword(s):  
Older Adults ◽  
Bipolar Disorder ◽  
Early Onset ◽  
Age Of Onset ◽  
Late Onset ◽  
Age At Onset ◽  
Bipolar Disorders ◽  
Medical Diagnoses ◽  
The Mean ◽  
Bipolar Patients

IntroductionAge of onset of illness may be useful in explaining the heterogeneity among older bipolar patients.ObjectiveTo examine the relationship of age of onset with clinical, demographic and behavioral variables, in older patients with bipolar disorder.MethodsThis was a cross-sectional, descriptive and analytical study, including 24 patients suffering from bipolar disorders, aged 65 years or more and followed-up in outpatient psychiatry unit at Hedi Chaker university hospital in Sfax in Tunisia. We used a standardized questionnaire including socio-demographic, behavioral and clinical data. Age of onset was split at age 40 years into early-onset (< 40 years; n = 12) and late-onset (≥ 40 years; n = 12) groups.ResultsThe mean age for the entire sample was 68.95 years. The mean age of onset was 39.95 years. The majority (60%) of patients were diagnosed with bipolar I. Few meaningful differences emerged between early-onset and late-onset groups, except that tobacco use was significantly higher in the late-onset group (66.6% vs. 16.6%; P = 0.027). No significant differences between the early-onset and late-onset groups were seen on demographic variables, family history and number of medical diagnoses or presence of psychotic features.ConclusionOur study found few meaningful behavioral differences between early versus late age at onset in older adults with bipolar disorder.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Very Late-onset Schizophrenia-Like Psychosis: Case Report and Current Status of the Issue

2016 ◽  
Vol 33 (S1) ◽  
pp. S471-S471
Author(s):  
R. Martín Aragón ◽  
M. Gutiérrez Rodríguez ◽  
S. Bravo Herrero ◽  
C. Moreno Menguian ◽  
N. Rodríguez Criado ◽  
...  
Keyword(s):  
Case Report ◽  
Age Of Onset ◽  
Late Onset ◽  
Current Knowledge ◽  
Age At Onset ◽  
Review Literature ◽  
Current Status ◽  
Diagnostic Systems ◽  
Formal Thought Disorder ◽  
Pubmed Database

IntroductionSchizophrenia has traditionally been considered to strictly be an early-onset disorder. Current nosologies, including DSMV, are not restrictive with age of onset in schizophrenia and all patients that satisfy diagnostic criteria fall into the same category. Since 1998, International Late-Onset Schizophrenia Group consensus, patients after 60 are classified as very-late onset schizophrenia-like psychosis. Female overrepresentation, low prevalence of formal thought disorder, and a higher prevalence of visual hallucinations are associated with later age at onset. Atypical antipsychotics represent the election treatment because of the reduced likelihood of EPS and tardive dyskinesias, and should be started at very low doses, with slow increases.ObjectiveTo review the current knowledge about very late-onset schizophrenia through systematic review of the literature and the analysis of a case.MethodsCase Report. Review. Literature sources were obtained through electronic search in PubMed database of last fifteen years.ResultsWe present a case of a 86-year-old woman suffering from delusions and hallucinations, diagnosed with very late-onset schizophrenia-like psychosis, after differential diagnosis with other disorders. We analyze ethiology, epidemiology, clinical features and treatment in geriatric patients with schizophrenia.ConclusionsReluctance to diagnose schizophrenia in old people is still present today, probably in relation with the inconsistency in diagnostic systems and nomenclature, and consideration of medical conditions in the diagnosis. Identification of these patients is really important in order to start an appropriate treatment, which can lead to patient clinical stability.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Rare and Potentially Pathogenic Variants in Hydroxycarboxylic Acid Receptor Genes Identified in Breast Cancer Cases.

2020 ◽  
Author(s):  
Cierla McGuire Sams ◽  
Kasey Shepp ◽  
Jada Pugh ◽  
Madison R. Bishop ◽  
Nancy D. Merner
Keyword(s):  
Breast Cancer ◽  
Genetic Variants ◽  
Small Sample Size ◽  
Treatment Strategies ◽  
Missense Variant ◽  
Small Sample ◽  
Acid Oxidation ◽  
Cancer Proliferation ◽  
Hydroxycarboxylic Acid ◽  
Pathogenic Variants

Abstract BackgroundThree genes, clustered together on chromosome 12, comprise a group of Hydroxycarboxylic Acid Receptors (HCARs), HCAR1, HCAR2, and HCAR3. These paralogous genes encode different G-protein coupled receptors that are responsible for detecting glycolytic metabolites and controlling fatty acid oxidation. Though better known for regulating lipid metabolism in adipocytes, more recently HCARs have been functionally associated with breast cancer proliferation/survival; HCAR2 has been described as a tumor suppressor, and HCAR1 and HCAR3 as oncogenes. Thus, we sought to identify genetic variants in HCAR1, HCAR2, and HCAR3 that could potentially be associated with breast cancer. MethodsDue to the extreme homology between HCAR1, HCAR2, and HCAR3, primers were carefully designed to amplify each gene separately through nested PCRs followed by Sanger sequencing. Forty-six unrelated breast cancer cases were screened for rare, non-synonymous coding variants. ResultsUpon screening, a total of four variants were identified in four different cases, each with estrogen receptor-positive (ER+) breast cancer. The variants were identified exclusively in HCAR1 and HCAR3. In HCAR1, two highly conserved and potentially damaging missense variants were identified, c.58C>G;p.Pro20Ala and c.721C>T;p.Leu241Phe. Statistical analyses revealed that c.58C>G;p.Pro20Ala was in significantly more cases than controls. In HCAR3, in addition to the breast cancer-associated missense variant c.560G>A;p.Arg187Gln, a frameshift mutation, c.1117delC;p.Gln373Lysfs*82, was detected that greatly extends the C-terminus and changes the secondary and tertiary protein structure. ConclusionsDue to the important role of HCARs in breast cancer, it is vital to understand how these genetic variants play a role in breast cancer risk and proliferation, as well as their consequences on treatment strategies. Due to the small sample size, additional and larger studies will be needed to validate these findings. Nevertheless, the identification of these potentially pathogenic variants supports the need to investigate their functional consequences.

scholarly journals Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry

2019 ◽  
Vol 40 (35) ◽  
pp. 2964-2975 ◽  
Author(s):  
Lia Crotti ◽  
Carla Spazzolini ◽  
David J Tester ◽  
Alice Ghidoni ◽  
Alban-Elouen Baruteau ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Late Onset ◽  
Age At Onset ◽  
Poor Response ◽  
Response To Therapy ◽  
Polymorphic Ventricular Tachycardia ◽  
High Prevalence ◽  
Neurological Phenotype ◽  
Life Threatening ◽  
Neurological Features

Abstract Aims Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1–3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome. Methods and results A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1–5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0–8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively. Conclusion Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.

scholarly journals Frequency of the LRRK2 G2019S mutation in late-onset sporadic patients with Parkinson’s disease

2014 ◽  
Vol 72 (5) ◽  
pp. 356-359 ◽  
Author(s):  
Hsin Fen Chien ◽  
Tamires Rocha Figueiredo ◽  
Marianna Almeida Hollaender ◽  
Fabiano Tofoli ◽  
Leonel Takao Takada ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Late Onset ◽  
Small Sample Size ◽  
Clinical Manifestations ◽  
Small Sample ◽  
Genetical Analysis ◽  
G2019s Mutation ◽  
Lrrk2 Gene ◽  
And Gender

Mutations in the LRRK2 gene, predominantly G2019S, have been reported in individuals with autosomal dominant inheritance and sporadic Parkinson’s disease (PD). The G2019S mutation has an age-dependent penetrance and evidence shows common ancestry. The clinical manifestations are indistinguishable from idiopathic PD. Its prevalence varies according to the population studied ranging from less than 0.1% in Asians to 41% in North African Arabs. This study aimed to identify G2019S mutation in Brazilian idiopathic PD patients.Method:We sampled 100 PD patients and 100 age- and gender-matched controls. Genetical analysis was accomplished by polymerase chain reaction (PCR).Results:No G2019S mutations were found in both patients with sporadic PD and controls.Conclusions:Our results may be explained by the relatively small sample size.

scholarly journals Rare and Potentially Pathogenic Variants in Hydroxycarboxylic Acid Receptor Genes Identified in Breast Cancer Cases.

2020 ◽  
Author(s):  
Cierla McGuire Sams ◽  
Kasey Shepp ◽  
Jada Pugh ◽  
Madison R. Bishop ◽  
Nancy D. Merner
Keyword(s):  
Breast Cancer ◽  
Genetic Variants ◽  
Small Sample Size ◽  
Treatment Strategies ◽  
Missense Variant ◽  
Small Sample ◽  
Acid Oxidation ◽  
Cancer Proliferation ◽  
Hydroxycarboxylic Acid ◽  
Pathogenic Variants

Abstract Background: Three genes, clustered together on chromosome 12, comprise a group of Hydroxycarboxylic Acid Receptors (HCARs), HCAR1, HCAR2, and HCAR3. These paralogous genes encode different G-protein coupled receptors that are responsible for detecting glycolytic metabolites and controlling fatty acid oxidation. Though better known for regulating lipid metabolism in adipocytes, more recently HCARs have been functionally associated with breast cancer proliferation/survival; HCAR2 has been described as a tumor suppressor, and HCAR1 and HCAR3 as oncogenes. Thus, we sought to identify genetic variants in HCAR1, HCAR2, and HCAR3 that could potentially be associated with breast cancer. Methods: Due to the extreme homology between HCAR1, HCAR2, and HCAR3, primers were carefully designed to amplify each gene separately through nested PCRs followed by Sanger sequencing. Forty-six unrelated breast cancer cases were screened for rare, non-synonymous coding variants. Results: Upon screening, a total of four variants were identified in four different cases, each with estrogen receptor-positive (ER+) breast cancer. The variants were identified exclusively in HCAR1 and HCAR3. In HCAR1, two highly conserved and potentially damaging missense variants were identified, c.58C>G;p.Pro20Ala and c.721C>T;p.Leu241Phe. Statistical analyses revealed that c.58C>G;p.Pro20Ala was in significantly more cases than controls. In HCAR3, in addition to the breast cancer-associated missense variant c.560G>A;p.Arg187Gln, a frameshift mutation, c.1117delC;p.Gln373Lysfs*82, was detected that greatly extends the C-terminus and changes the secondary and tertiary protein structure. Conclusions: Due to the important role of HCARs in breast cancer, it is vital to understand how these genetic variants play a role in breast cancer risk and proliferation, as well as their consequences on treatment strategies. Due to the small sample size, additional and larger studies will be needed to validate these findings. Nevertheless, the identification of these potentially pathogenic variants supports the need to investigate their functional consequences.

scholarly journals Pregnancy Outcomes in Late Onset Pompe Disease and Enzyme Replacement Therapy

2020 ◽  
Author(s):  
Ozlem Goker-Alpan ◽  
Vellore G. Kasturi ◽  
Maninder K. Sohi ◽  
Renuka P. Limgala ◽  
Stephanie L. Austin ◽  
...  
Keyword(s):  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Pregnancy Outcomes ◽  
Pompe Disease ◽  
Late Onset ◽  
Small Sample Size ◽  
Respiratory Muscles ◽  
Small Sample ◽  
Enzyme Replacement ◽  
Initial Symptoms

There is limited data on pregnancy outcomes in Pompe Disease (PD) resulting from deficiency of the lysosomal enzyme acid alpha-glucosidase. Late-onset PD is characterized by progressive proximal muscle weakness and decline of respiratory function secondary to the involvement of the respiratory muscles. In a cohort of twenty-five females, the effects of both PD on the course of pregnancy and the effects of pregnancy on PD were investigated. Reproductive history, course of pregnancy, use of Enzyme replacement therapy (ERT), PD symptoms, and outcomes of each pregnancy were obtained through a questionnaire. Among 20 subjects that reported one or more pregnancies, one subject conceived while on ERT and continued therapy through two normal pregnancies with worsening of weakness during pregnancy and improvement postpartum. While fertility was not affected, pregnancy may worsen symptoms, or cause initial symptoms to arise. Complications with pregnancy or birth were not higher, except for an increase in the rate of stillbirths (3.8% compared to the national average of 0.2-0.7%). Given small sample size and possible bias of respondents being only women who have been pregnant, further data may be needed to better analyze the effects of pregnancy on PD, and the effects of ERT on pregnancy outcomes.

Social withdrawal and suicide risk: A descriptive study

2016 ◽  
Vol 33 (S1) ◽  
pp. S175-S175 ◽  
Author(s):  
A. Malagon ◽  
D. Córcoles ◽  
E. Pérez ◽  
L. Mollà ◽  
D. Bergé ◽  
...  
Keyword(s):  
Child Abuse ◽  
Social Isolation ◽  
Suicidal Behavior ◽  
Suicide Risk ◽  
Suicide Attempts ◽  
Social Withdrawal ◽  
Small Sample Size ◽  
Age At Onset ◽  
Small Sample ◽  
Major Health Problem

IntroductionSocial withdrawal is a major health problem that has been related with higher morbidity and mortality rates. There are few studies about the relationship between suicidal behavior and social isolation.AimTo describe the existence of suicidal risk in subjects with social isolation.MethodParticipants were 187 subjects referred to a Crisis Resolution Home Treatment because of social isolation. The inclusion criteria were: home isolation, avoiding of social situations and relationships, for at least 6 months. Suicide risk was assessed by the item of the Severity of Psychiatric Illness, dividing in four groups (from absence to high suicide risk). Socio-demographic and clinical data were also analysed.ResultsMost cases (n = 132, 70.5%) had absence of suicide risk. They were predominantly young males in all groups. There were no statistically significant differences in sociodemographic or clinical variables. The mean age at onset of social isolation was lower in the high suicide risk group, having lower socially withdrawn period. This group had also lower rates of child abuse and suicide attempt history. The more frequent diagnosis in all groups was psychotic, affective and anxiety disorders. Those cases with mild and high suicide risk needed more frequently hospitalization.ConclusionsSocial isolated people attended by CRHT do not have high frequency of suicide risk. Cases with higher suicide risk are younger and have a shorter period of isolation. The absence of child abuse history or previous suicide attempts contrasts with previous suicidal behavior research. These data can be influenced by the characteristics of functioning of CRHT and the small sample size.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Late-onset Huntington’s disease with 40–42 CAG expansion

2019 ◽  
Vol 41 (4) ◽  
pp. 869-876 ◽  
Author(s):  
Elisa Capiluppi ◽  
Luca Romano ◽  
Paola Rebora ◽  
Lorenzo Nanetti ◽  
Anna Castaldo ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Rating Scale ◽  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Late Onset ◽  
Age At Onset ◽  
Clinical Manifestations ◽  
Cag Repeats ◽  
Cag Expansion

Abstract Introduction Huntington’s disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by a CAG expansion greater than 35 in the IT-15 gene. There is an inverse correlation between the number of pathological CAG and the age of onset. However, CAG repeats between 40 and 42 showed a wider onset variation. We aimed to investigate potential clinical differences between patients with age at onset ≥ 60 years (late onset-HD) and patients with age at onset between 30 and 59 years (common-onset HD) in a cohort of patients with the same CAG expansions (40–42). Methods A retrospective analysis of 66 HD patients with 40–41–42 CAG expansion was performed. Patients were investigated with the Unified Huntington’s Disease Rating Scale (subitems I–II–III and Total Functional Capacity, Functional Assessment and Stage of Disease). Data were analysed using χ2, Fisher’s test, t test and Pearson’s correlation coefficient. GENMOD analysis and Kaplan-Meier analysis were used to study the disease progression. Results The age of onset ranged from 39 to 59 years in the CO subgroup, whereas the LO subgroup showed an age of onset from 60 to 73 years. No family history was reported in 31% of the late-onset in comparison with 20% in common-onset HD (p = 0.04). No difference emerged in symptoms of onset, in clinical manifestations and in progression of disease between the two groups. Conclusion There were no clinical differences between CO and LO subgroups with 40–42 CAG expansion. There is a need of further studies on environmental as well genetic variables modifying the age at onset.

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