scholarly journals Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH

Blood ◽  
2011 ◽  
Vol 118 (22) ◽  
pp. 5794-5798 ◽  
Author(s):  
Kejian Zhang ◽  
Michael B. Jordan ◽  
Rebecca A. Marsh ◽  
Judith A. Johnson ◽  
Diane Kissell ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Late Onset ◽  
Adult Patients ◽  
Adult Onset ◽  
Test Results ◽  
Primary Immunodeficiency Disorder ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Immunodeficiency Disorder ◽  
Splice Site Sequence ◽  
Immunologic Test

Abstract Familial hemophagocytic lymphohistiocytosis (HLH) is a rare primary immunodeficiency disorder characterized by defects in cell-mediated cytotoxicity that results in fever, hepatosplenomegaly, and cytopenias. Familial HLH is well recognized in children but rarely diagnosed in adults. We conducted a retrospective review of genetic and immunologic test results in patients who developed HLH in adulthood. Included in our study were 1531 patients with a clinical diagnosis of HLH; 175 patients were 18 years or older. Missense and splice-site sequence variants in PRF1, MUNC13-4, and STXBP2 were found in 25 (14%) of the adult patients. The A91V-PRF1 genotype was found in 12 of these patients (48%). The preponderance of hypomorphic mutations in familial HLH–causing genes correlates with the later-onset clinical symptoms and the more indolent course in adult patients. We conclude that late-onset familial HLH occurs more commonly than was suspected previously.

scholarly journals Distinct epigenetic signatures between adult-onset and late-onset depression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hirotaka Yamagata ◽  
Hiroyuki Ogihara ◽  
Koji Matsuo ◽  
Shusaku Uchida ◽  
Ayumi Kobayashi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bisulfite Sequencing ◽  
Clinical Symptoms ◽  
Late Onset ◽  
Adult Onset ◽  
Blood Biomarkers ◽  
Major Depressive ◽  
Genome Wide ◽  
Healthy Control ◽  
Epigenetic Signatures

AbstractThe heterogeneity of major depressive disorder (MDD) is attributed to the fact that diagnostic criteria (e.g., DSM-5) are only based on clinical symptoms. The discovery of blood biomarkers has the potential to change the diagnosis of MDD. The purpose of this study was to identify blood biomarkers of DNA methylation by strategically subtyping patients with MDD by onset age. We analyzed genome-wide DNA methylation of patients with adult-onset depression (AOD; age ≥ 50 years, age at depression onset < 50 years; N = 10) and late-onset depression (LOD; age ≥ 50 years, age at depression onset ≥ 50 years; N = 25) in comparison to that of 30 healthy subjects. The methylation profile of the AOD group was not only different from that of the LOD group but also more homogenous. Six identified methylation CpG sites were validated by pyrosequencing and amplicon bisulfite sequencing as potential markers for AOD in a second set of independent patients with AOD and healthy control subjects (N = 11). The combination of three specific methylation markers achieved the highest accuracy (sensitivity, 64%; specificity, 91%; accuracy, 77%). Taken together, our findings suggest that DNA methylation markers are more suitable for AOD than for LOD patients.

scholarly journals Progressive Immunodeficiency with Gradual Depletion of B and CD4+ T Cells in Immunodeficiency, Centromeric Instability and Facial Anomalies Syndrome 2 (ICF2)

Diseases ◽  
2019 ◽  
Vol 7 (2) ◽  
pp. 34 ◽  
Author(s):  
Georgios Sogkas ◽  
Natalia Dubrowinskaja ◽  
Anke K. Bergmann ◽  
Jana Lentes ◽  
Tim Ripperger ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Late Onset ◽  
Epigenetic Modification ◽  
Primary Immunodeficiency Disorder ◽  
Hematopoietic Stem ◽  
Facial Anomalies ◽  
Immunodeficiency Disorder ◽  
Centromeric Instability ◽  
Tract Infections

Immunodeficiency, centromeric instability and facial anomalies syndrome 2 (ICF2) is a rare autosomal recessive primary immunodeficiency disorder. So far, 27 patients have been reported. Here, we present three siblings with ICF2 due to a homozygous ZBTB24 gene mutation (c.1222 T>G, p. (Cys408Gly)). Immune deficiency in these patients ranged from late-onset combined immunodeficiency (CID) with severe respiratory tract infections and recurrent shingles to asymptomatic selective antibody deficiency. Evident clinical heterogeneity manifested despite a common genetic background, suggesting the pathogenic relevance of epigenetic modification. Immunological follow-up reveals a previously unidentified gradual depletion of B and CD4+ T cells in all three presented patients with transition of a common variable immunodeficiency (CVID)-like disease to late-onset-CID in one of them. Considering all previously published cases with ICF2, we identify inadequate antibody responses to vaccines and reduction in CD27+ memory B cells as prevalent immunological traits. High mortality among ICF2 patients (20%) together with the progressive course of immunodeficiency suggest that hematopoietic stem cell transplantation (HSCT) should be considered as a treatment option in due time.

scholarly journals Adult-onset systemic autoinflammatory disorders: a clinical approach

Reumatismo ◽  
2020 ◽  
Vol 71 (4) ◽  
pp. 177-188
Author(s):  
T. Borges ◽  
A. Barbosa ◽  
S. Silva
Keyword(s):  
Late Onset ◽  
Interleukin 1 ◽  
Immunosuppressive Agents ◽  
Unknown Origin ◽  
Adult Patients ◽  
Clinical Approach ◽  
Adult Onset ◽  
Autoinflammatory Disorders ◽  
Acute Phase Reactants ◽  
Mixed Pattern

Autoinflammatory disorders (AIDs) are a subgroup of immune-mediated syndromes that result from a primary dysfunction of the innate immune system. AIDs can be either monogenic or polygenic diseases. Unlike organspecific AIDs, systemic AIDs are characterized by fever and/or elevation of acute-phase reactants. This review aims to describe the most common adult-onset systemic AIDs, focusing mostly on polygenic and mixed-pattern diseases which are expected to be more prevalent in adult patients than monogenic AIDs overall. The literature was searched in Medline database. Organ-specific or childhood-onset systemic AIDs were excluded. AIDs were divided in three distinct groups: mixed-pattern, polygenic and adult-onset monogenic AIDs. Most adult-onset AIDs are polygenic but late-onset disease is not rare among monogenic AIDs such as familial Mediterranean fever (FMF). The diagnosis of systemic AIDs in adults is often delayed due to several factors and sometimes it is only established when amyloidosis or other complications are present. Therefore, it probably makes sense to primarily exclude common AIDs in adult patients with fever of unknown origin (and probably different presentations such as polyserositis) since a high prevalence of adult-onset Still’s disease or FMF is usually expected. Colchicine, nonsteroidal anti-inflammatory drugs, steroids, immunosuppressive agents, interleukin-1 inhibitors and tumor necrosis factor antagonists constitute common therapeutic options for systemic AIDs.

scholarly journals Rare Variants in Autophagy and Non-Autophagy Genes in Late-Onset Pompe Disease: Suggestions of Their Disease-Modifying Role in Two Italian Families

2021 ◽  
Vol 22 (7) ◽  
pp. 3625
Author(s):  
Filomena Napolitano ◽  
Giorgia Bruno ◽  
Chiara Terracciano ◽  
Giuseppina Franzese ◽  
Nicole Piera Palomba ◽  
...  
Keyword(s):  
Pompe Disease ◽  
Rare Variants ◽  
Clinical Symptoms ◽  
Late Onset ◽  
Respiratory Muscles ◽  
Autosomal Recessive Disorder ◽  
Compound Heterozygous ◽  
Enzyme Replacement ◽  
Whole Exome ◽  
Clinical Pictures

Pompe disease is an autosomal recessive disorder caused by a deficiency in the enzyme acid alpha-glucosidase. The late-onset form of Pompe disease (LOPD) is characterized by a slowly progressing proximal muscle weakness, often involving respiratory muscles. In LOPD, the levels of GAA enzyme activity and the severity of the clinical pictures may be highly variable among individuals, even in those who harbour the same combination of GAA mutations. The result is an unpredictable genotype–phenotype correlation. The purpose of this study was to identify the genetic factors responsible for the progression, severity and drug response in LOPD. We report here on a detailed clinical, morphological and genetic study, including a whole exome sequencing (WES) analysis of 11 adult LOPD siblings belonging to two Italian families carrying compound heterozygous GAA mutations. We disclosed a heterogeneous pattern of myopathic impairment, associated, among others, with cardiac defects, intracranial vessels abnormality, osteoporosis, vitamin D deficiency, obesity and adverse response to enzyme replacement therapy (ERT). We identified deleterious variants in the genes involved in autophagy, immunity and bone metabolism, which contributed to the severity of the clinical symptoms observed in the LOPD patients. This study emphasizes the multisystem nature of LOPD and highlights the polygenic nature of the complex phenotype disclosed in these patients.

Review Paper on Machine learning-based prediction of Corona Virus

2021 ◽  
Vol 9 (8) ◽  
pp. 2225-2229
Author(s):  
Miss. Aakansha P. Tiwari
Keyword(s):  
Machine Learning ◽  
Prediction Models ◽  
Clinical Symptoms ◽  
Contact Tracing ◽  
Test Results ◽  
Effective Contact ◽  
Machine Learning Approach ◽  
Binary Features ◽  
Simple Features ◽  
Medical Examiners

Abstract: Effective contact tracing of SARS-CoV-2 enables quick and efficient diagnosis of COVID-19 and might mitigate the burden on healthcare system. Prediction models that combine several features to approximate the danger of infection are developed. These aim to help medical examiners worldwide in treatment of patients, especially within the context of limited healthcare resources. They established a machine learning approach that trained on records from 51,831 tested individuals (of whom 4769 were confirmed to own COVID-19 coronavirus). Test set contained data from the upcoming week (47,401 tested individuals of whom 3624 were confirmed to own COVID-19 disease). Their model predicted COVID-19 test results with highest accuracy using only eight binary features: sex, age ≥60 years, known contact with infected patients, and also the appearance of 5 initial clinical symptoms appeared. Generally, supported the nationwide data publicly reported by the Israeli Ministry of Health, they developed a model that detects COVID-19 cases by simple features accessed by asking basic inquiries to the affected patient. Their framework may be used, among other considerations, to prioritize testing for COVID-19 when testing resources are limited and important. Keywords: Machine Learning, SARS-COV-2, COVID-19, Coronavirus.

Predicting progression in the late onset frontal lobe syndrome

2018 ◽  
Vol 31 (5) ◽  
pp. 743-748 ◽  
Author(s):  
Flora T. Gossink ◽  
Everard Vijverberg ◽  
Welmoed Krudop ◽  
Philip Scheltens ◽  
Max L. Stek ◽  
...  
Keyword(s):  
Frontal Lobe ◽  
Clinical Symptoms ◽  
Late Onset ◽  
Clinical Syndrome ◽  
Clinical Markers ◽  
Neuropsychological Profile ◽  
Stereotypical Behavior ◽  
Executive Deficits ◽  
Magnetic Resonance Imaging Mri ◽  
Frontal Lobe Syndrome

ABSTRACTA late onset frontal lobe syndrome (LOF) refers to a clinical syndrome with apathy, disinhibition, or stereotypical behavior arising in middle or late adulthood. Diagnostics are challenging, and both clinicians and patients need reliable predictors of progression to improve clinical guidance. In this longitudinal multicenter and genetically screened prospective study, 137 LOF patients with frontal behavior (FBI score≥11) and/or stereotypical behavior (SRI≥10) were included. Progression was defined as institutionalization, death, or progression of frontal or temporal atrophy at magnetic resonance imaging (MRI) after two years of follow up. Absence of progression at MRI in addition to stable or improved Mini Mental State Examination and Frontal Assessment Battery scores after two years was indicative for non-progression. The presence of stereotypy and a neuropsychological profile with executive deficits at baseline were found to be predictive for progression, while a history and family history with psychiatric disorders were predictors for non-progression. The combination of these clinical markers had a predictive value of 80.4% (p < 0.05). In patients presenting with late onset behavioral symptoms, an appraisal of the rate of deterioration can be made by detailed mapping of clinical symptoms. Distinction of progressive discourses from non-progressive or treatable conditions is to be gained.

scholarly journals Hemophagocytic Lymphohistiocytosis Gene Mutations in Adult Patients Presenting With CLIPPERS-Like Syndrome

2021 ◽  
Vol 8 (3) ◽  
pp. e970
Author(s):  
Guillaume Taieb ◽  
Elsa Kaphan ◽  
Claire Duflos ◽  
Christine Lebrun-Frénay ◽  
Valérie Rigau ◽  
...  
Keyword(s):  
Hemophagocytic Lymphohistiocytosis ◽  
Brain Mri ◽  
Gene Mutations ◽  
Adult Onset ◽  
Cytotoxic Lymphocyte ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Non Hodgkin Lymphoma ◽  
Treatable Condition ◽  
Perforin Expression

ObjectiveTo determine whether adult cases of Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) may be related to familial hemophagocytic lymphohistiocytosis (HLH) causes, we have screened patients with adult-onset CLIPPERS for mutations in primary HLH-associated genes.MethodsIn our cohort of 36 patients fulfilling the criteria for probable or definite CLIPPERS according to the CLIPPERS-2017 criteria, we conducted a first study on 12 patients who consented to genetic testing. In these 12 patients, systemic HLH criteria were searched, and genetic analysis of 8 genes involved in primary HLH was performed.ResultsFour definite and 8 probable CLIPPERS were enrolled (n = 12). Mutations involved in HLH were identified in 2 definite and 2 probable CLIPPERS (4/12). Three of them had biallelic PRF1 mutations with reduced perforin expression in natural killer cells. The remaining patient had biallelic UNC13D mutations with cytotoxic lymphocyte impaired degranulation. None of the mutated patients reached the criteria for systemic HLH. During follow-up, 3 of them displayed atypical findings for CLIPPERS, including emergence of systemic non-Hodgkin lymphoma (1/3) and confluent gadolinium-enhancing lesions on brain MRI (3/3).ConclusionsIn our patients presenting with adult-onset CLIPPERS, one-third have HLH gene mutations. This genetic treatable condition should be searched in patients with CLIPPERS, especially in those presenting with atypical findings.

Sign in / Sign up

Export Citation Format

Share Document