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.

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.

scholarly journals Clinical and therapeutic features of myasthenia gravis in adults based on age at onset

Neurology ◽  
2020 ◽  
Vol 94 (11) ◽  
pp. e1171-e1180 ◽  
Author(s):  
Elena Cortés-Vicente ◽  
Rodrigo Álvarez-Velasco ◽  
Sonia Segovia ◽  
Carmen Paradas ◽  
Carlos Casasnovas ◽  
...  
Keyword(s):  
Myasthenia Gravis ◽  
Early Onset ◽  
Late Onset ◽  
Age At Onset ◽  
Neuromuscular Diseases ◽  
Cross Sectional ◽  
Life Threatening ◽  
Onset Group ◽  
Anti Acetylcholine

ObjectiveTo describe the characteristics of patients with very-late-onset myasthenia gravis (MG).MethodsThis observational cross-sectional multicenter study was based on information in the neurologist-driven Spanish Registry of Neuromuscular Diseases (NMD-ES). All patients were >18 years of age at onset of MG and onset occurred between 2000 and 2016 in all cases. Patients were classified into 3 age subgroups: early-onset MG (age at onset <50 years), late-onset MG (onset ≥50 and <65 years), and very-late-onset MG (onset ≥65 years). Demographic, immunologic, clinical, and therapeutic data were reviewed.ResultsA total of 939 patients from 15 hospitals were included: 288 (30.7%) had early-onset MG, 227 (24.2%) late-onset MG, and 424 (45.2%) very-late-onset MG. The mean follow-up was 9.1 years (SD 4.3). Patients with late onset and very late onset were more frequently men (p < 0.0001). Compared to the early-onset and late-onset groups, in the very-late-onset group, the presence of anti–acetylcholine receptor (anti-AChR) antibodies (p < 0.0001) was higher and fewer patients had thymoma (p < 0.0001). Late-onset MG and very-late-onset MG groups more frequently had ocular MG, both at onset (<0.0001) and at maximal worsening (p = 0.001). Although the very-late-onset group presented more life-threatening events (Myasthenia Gravis Foundation of America IVB and V) at onset (p = 0.002), they required fewer drugs (p < 0.0001) and were less frequently drug-refractory (p < 0.0001).ConclusionsPatients with MG are primarily ≥65 years of age with anti-AChR antibodies and no thymoma. Although patients with very-late-onset MG may present life-threatening events at onset, they achieve a good outcome with fewer immunosuppressants when diagnosed and treated properly.

scholarly journals Validation of distinct pathogenic patterns in a cohort of membranoproliferative glomerulonephritis patients by cluster analysis

2019 ◽  
Vol 13 (2) ◽  
pp. 225-234
Author(s):  
Nóra Garam ◽  
Zoltán Prohászka ◽  
Ágnes Szilágyi ◽  
Christof Aigner ◽  
Alice Schmidt ◽  
...  
Keyword(s):  
Cluster Analysis ◽  
Membranoproliferative Glomerulonephritis ◽  
Late Onset ◽  
Age At Onset ◽  
Disease Onset ◽  
Membrane Attack Complex ◽  
Hierarchical Cluster ◽  
Nephritic Syndrome ◽  
Significant Difference ◽  
High Prevalence

Abstract Background A novel data-driven cluster analysis identified distinct pathogenic patterns in C3-glomerulopathies and immune complex-mediated membranoproliferative glomerulonephritis. Our aim was to replicate these observations in an independent cohort and elucidate disease pathophysiology with detailed analysis of functional complement markers. Methods A total of 92 patients with clinical, histological, complement and genetic data were involved in the study, and hierarchical cluster analysis was done by Ward method, where four clusters were generated. Results High levels of sC5b-9 (soluble membrane attack complex), low serum C3 levels and young age at onset (13 years) were characteristic for Cluster 1 with a high prevalence of likely pathogenic variations (LPVs) and C3 nephritic factor, whereas for Cluster 2—which is not reliable because of the small number of cases—strong immunoglobulin G staining, low C3 levels and high prevalence of nephritic syndrome at disease onset were observed. Low plasma sC5b-9 levels, decreased C3 levels and high prevalence of LPV and sclerotic glomeruli were present in Cluster 3, and patients with late onset of the disease (median: 39.5 years) and near-normal C3 levels in Cluster 4. A significant difference was observed in the incidence of end-stage renal disease during follow-up between the different clusters. Patients in Clusters 3–4 had worse renal survival than patients in Clusters 1–2. Conclusions Our results confirm the main findings of the original cluster analysis and indicate that the observed, distinct pathogenic patterns are replicated in our cohort. Further investigations are necessary to analyse the distinct biological and pathogenic processes in these patient groups.

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 Onset features and time to diagnosis in Friedreich's Ataxia

2020 ◽  
Author(s):  
Elisabetta Indelicato ◽  
Wolfgang Nachbauer ◽  
Andreas Eigentler ◽  
Matthias Amprosi ◽  
Raffaella Matteucci Gothe ◽  
...  
Keyword(s):  
Late Onset ◽  
Genetic Disorder ◽  
Age At Onset ◽  
Positive Family History ◽  
Diagnostic Delay ◽  
Repeat Length ◽  
Presenting Symptoms ◽  
Time To Diagnosis ◽  
Neurological Presentation ◽  
Neurological Features

Abstract Background: In rare disorders diagnosis may be delayed due to limited awareness and unspecific presenting symptoms. Herein, we address the issue of diagnostic delay in Friedreich´s Ataxia (FRDA), a genetic disorder caused by homozygous GAA-repeat expansions.Methods: 611 genetically confirmed FRDA patients were recruited within a multicentric natural history study conducted by the EFACTS (European FRDA Consortium for Translational Studies, ClinicalTrials.gov-Identifier NCT02069509). Age and symptoms at onset as well as age at suspicion of FRDA were collected retrospectively at the baseline visit.Results: In 554 of cases (90.7%), disease presented with gait or coordination disturbances. In the others (n=57, 9.3%), non-neurological features such as scoliosis or cardiomyopathy predated ataxia. Before the discovery of the causal mutation in 1996, median time to diagnosis was 4(IQR=2-9) years and it improved significantly after the introduction of genetic testing (2(IQR=1-5) years, p <0.001). Still after 1996, time to diagnosis was longer in patients with a) non-neurological presentation (mean 6.7, 95%CI[5.5,7.9] vs 4.5, [4.2,5] years, p =0.001) as well as in b) patients with late-onset (3(IQR=1-7) vs 2(IQR=1-5) years compared to early onset <25 years of age, p =0.03). Age at onset significantly correlated with GAA-repeat length in case of neurological onset (r=-0,6; p <0,0001), but not in patients with non-neurological presentation (r=-0,1; p =0,4). Across 54 siblings’ pairs, differences in age at onset did not correlate with differences in GAA-repeat length (r=-0,14, p =0,3).Conclusions: In the genetic era, presentation with non-neurological features or in the adulthood still leads to a significant diagnostic delay in FRDA. Well-known correlations between GAA and disease milestones are not valid in case of atypical presentations or positive family history.

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.

Clinical characteristics of late-onset neuromyelitis optica spectrum disorder: A multicenter retrospective study in Korea

2017 ◽  
Vol 23 (13) ◽  
pp. 1748-1756 ◽  
Author(s):  
Jin Myoung Seok ◽  
Hye-Jin Cho ◽  
Suk-Won Ahn ◽  
Eun Bin Cho ◽  
Min Su Park ◽  
...  
Keyword(s):  
Neuromyelitis Optica ◽  
Clinical Laboratory ◽  
Age Of Onset ◽  
Late Onset ◽  
Brain Mri ◽  
Age At Onset ◽  
Spectrum Disorder ◽  
Neuromyelitis Optica Spectrum Disorder ◽  
Tertiary Hospitals ◽  
Characteristic Features

Background: There are currently few studies regarding late-onset neuromyelitis optica spectrum disorder (LO-NMOSD). Objective: We aimed to describe the characteristic features of patients with LO-NMOSD in Korea. Methods: Anti-aquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorder (NMOSD) from nine tertiary hospitals were reviewed retrospectively. The patients were divided into two groups based on age of onset: LO-NMOSD (⩾50 years of age at onset) versus early-onset neuromyelitis optica spectrum disorder (EO-NMOSD) (<50 years of age at onset). Clinical, laboratory, and magnetic resonance imaging (MRI) parameters were investigated. Results: Among a total of 147 patients (125 female; age of onset, 39.4 ± 15.2 years), 45 patients (30.6%) had an age of onset of more than 50 years. Compared to patients with EO-NMOSD, patients with LO-NMOSD had more frequent isolated spinal cord involvement at onset (64.4% vs 37.2%, p = 0.002), less frequent involvement of the optic nerve (40.0% vs 67.7%, p = 0.002), and less frequent brain MRI lesions (31.1% vs 50.0%, p = 0.034). Furthermore, there was a significant positive correlation between age of onset and Expanded Disability Status Scale (EDSS) score at last follow-up ( r = 0.246, p = 0.003). Conclusion: Age of onset could be an important predictor of lesion location and clinical course of patients with NMOSD.

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.

scholarly journals Onset features and time to diagnosis in Friedreich´s Ataxia

2020 ◽  
Author(s):  
Elisabetta Indelicato ◽  
Wolfgang Nachbauer ◽  
Andreas Eigentler ◽  
Matthias Amprosi ◽  
Raffaella Matteucci Gothe ◽  
...  
Keyword(s):  
Late Onset ◽  
Genetic Disorder ◽  
Age At Onset ◽  
Positive Family History ◽  
Diagnostic Delay ◽  
Repeat Length ◽  
Presenting Symptoms ◽  
Time To Diagnosis ◽  
Neurological Presentation ◽  
Neurological Features

Abstract Background: In rare disorders diagnosis may be delayed due to limited awareness and unspecific presenting symptoms. Herein, we address the issue of diagnostic delay in Friedreich´s Ataxia (FRDA), a genetic disorder usually caused by homozygous GAA-repeat expansions. Methods: 611 genetically confirmed FRDA patients were recruited within a multicentric natural history study conducted by the EFACTS (European FRDA Consortium for Translational Studies, ClinicalTrials.gov-Identifier NCT02069509). Age at first symptoms as well as age at first suspicion of FRDA by a physician were collected retrospectively at the baseline visit. Results: In 554 of cases (90.7%), disease presented with gait or coordination disturbances. In the others (n=57, 9.3%), non-neurological features such as scoliosis or cardiomyopathy predated ataxia. Before the discovery of the causal mutation in 1996, median time to diagnosis was 4(IQR=2-9) years and it improved significantly after the introduction of genetic testing (2(IQR=1-5) years, p<0.001). Still, after 1996, time to diagnosis was longer in patients with a) non-neurological presentation (mean 6.7, 95%CI[5.5,7.9] vs 4.5, [4.2,5] years in those with neurological presentation, p=0.001) as well as in b) patients with late-onset (3(IQR=1-7) vs 2(IQR=1-5) years compared to typical onset <25 years of age, p=0.03). Age at onset significantly correlated with the length of the shorter GAA repeat (GAA1) in case of neurological onset (r=-0,6; p<0,0001), but not in patients with non-neurological presentation (r=-0,1; p=0,4). Across 54 siblings’ pairs, differences in age at onset did not correlate with differences in GAA-repeat length (r=-0,14, p=0,3).Conclusions: In the genetic era, presentation with non-neurological features or in the adulthood still leads to a significant diagnostic delay in FRDA. Well-known correlations between GAA1 repeat length and disease milestones are not valid in case of atypical presentations or positive family history.

scholarly journals Personality traits among ADHD adults: implications of late-onset and subthreshold diagnoses

2008 ◽  
Vol 39 (4) ◽  
pp. 685-693 ◽  
Author(s):  
S. V. Faraone ◽  
A. Kunwar ◽  
J. Adamson ◽  
J. Biederman
Keyword(s):  
Personality Traits ◽  
Age Of Onset ◽  
Late Onset ◽  
Age At Onset ◽  
Novelty Seeking ◽  
Personality Profiles ◽  
Co Morbidity ◽  
Dsm Iv ◽  
Self Transcendence ◽  
Symptom Criteria

BackgroundDiagnosing attention deficit hyperactivity disorder (ADHD) in adults is difficult when diagnosticians cannot establish onset prior to the DSM-IV criterion of age 7 or if the number of symptoms does not achieve the DSM threshold for diagnosis. Previous work has assessed the validity of such diagnoses based on psychiatric co-morbidity, family history and neuropsychological functions but none of these studies have used personality as a validation criterion.MethodWe compared four groups of adults: (1) full ADHD subjects who met all DSM-IV criteria for childhood-onset ADHD; (2) late-onset subjects who met all criteria except the age at onset criterion, (3) subthreshold subjects who did not meet full symptom criteria and (4) non-ADHD subjects who did not meet any of the above criteria. Diagnoses were made by using the Structured Clinical Interview for DSM-IV (SCID) and the Temperament and Character Inventory (TCI) was used to assess personality traits.ResultsWe found that full ADHD and late-onset ADHD showed similar personality profiles with significant deviations on all TCI scales except reward dependence and self-transcendence. By contrast, subthreshold cases only showed deviations on novelty seeking and self-directiveness.ConclusionsThese data call into question the stringent age of onset of ADHD symptom criteria for adults when making retrospective diagnoses of ADHD. Subthreshold ADHD seems to be a milder form of the disorder that is consistent with dimensional views of the disorder.

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