scholarly journals Investigation of the pathogenic RFC1 repeat expansion in a Canadian and a Brazilian ataxia cohort: identification of novel conformations

2019 ◽  
Author(s):  
Fulya Akçimen ◽  
Jay P. Ross ◽  
Cynthia V. Bourassa ◽  
Calwing Liao ◽  
Daniel Rochefort ◽  
...  
Keyword(s):  
General Population ◽  
Late Onset ◽  
Genetic Diagnosis ◽  
The Novel ◽  
Adult Onset ◽  
Dynamic Nature ◽  
Common Cause ◽  
Cohort Identification ◽  
Repeat Expansions ◽  
Type Sequence

AbstractA homozygous pentanucleotide expansion in the RFC1 gene has been shown to be a common cause of late-onset ataxia. In the general population a total of four different repeat conformations have been observed: a wild type sequence AAAAG (11 repeats), and longer expansions of AAAAG, AAAGG and AAGGG sequences. However, in ataxia cases only the AAGGG expansion has been shown to be pathogenic. In this study, we assessed the prevalence and nature of RFC1 repeat expansions in three adult-onset ataxia cohorts: Brazilian (n = 23) and Canadian (n = 26) cases that tested negative for other known ataxia mutations, as well as a cohort of randomly selected Canadian cases (n = 128) without regard to a genetic diagnosis. We identified the homozygous AAGGG pathogenic expansion in only one Brazilian family with two affected siblings, and in one Canadian case. The RFC1 expansion may therefore not be a common cause of adult-onset ataxia in these populations. Interestingly we observed two new repeat motifs, AAGAG and AGAGG, which indicates the dynamic nature of the pentanucleotide expansion sequence. To assess the frequency of these two new repeat conformations in the general population we screened 163 healthy individuals. These novel motifs were more frequent in patients versus controls. While we cannot be certain that the homozygous genotypes of the novel expanded conformations are pathogenic, their occurrence should nonetheless be taken into consideration in future studies.

scholarly journals CANVAS: a late onset ataxia due to biallelic intronic AAGGG expansions

2020 ◽  
Author(s):  
Natalia Dominik ◽  
Valentina Galassi Deforie ◽  
Andrea Cortese ◽  
Henry Houlden
Keyword(s):  
Late Onset ◽  
Replication Factor C ◽  
Common Cause ◽  
Progressive Ataxia ◽  
The World ◽  
Recent Developments ◽  
C Subunit ◽  
Repeat Expansions ◽  
Visual Problems ◽  
Factor C

Abstract The ataxias are a group of disorders that manifest with balance, movement, speech and visual problems. They can arise due to dysfunction of the cerebellum, the vestibular system and/or the sensory neurons. Genetic defects are a common cause of chronic ataxia, particularly common are repeat expansions in this group of conditions. Co-occurrence of cerebellar ataxia with neuropathy and vestibular areflexia syndrome has been termed CANVAS. Although CANVAS is a rare syndrome, on discovery of biallelic expansions in the second intron of replication factor C subunit 1 (RFC1) gene, we and others have found the phenotype is broad and RFC1 expansions are a common cause of late-onset progressive ataxia. We aim to provide a review and update on recent developments in CANVAS and populations, where the disorder has been reported. We have also optimised a protocol for RFC1 expansion screening which is described herein and expanded phenotype after analysing late-onset ataxia patients from around the world.

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 Coronavirus, the great toilet paper panic and civilisation

Thesis Eleven ◽  
2021 ◽  
pp. 072551362110331
Author(s):  
Jon Stratton
Keyword(s):  
General Population ◽  
Federal Government ◽  
Perceived Threat ◽  
The Novel ◽  
Social Breakdown ◽  
Toilet Paper ◽  
Western Civilisation ◽  
Novel Coronavirus ◽  
Key Aspects ◽  
The Impact

Panic buying of toilet rolls in Australia began in early March 2020. This was related to the realisation that the novel coronavirus was spreading across the country. To the general population the impact of the virus was unknown. Gradually the federal government started closing the country’s borders. The panic buying of toilet rolls was not unique to Australia. It happened across all societies that used toilet paper rather than water to clean after defecation and urination. However, research suggests that the panic buying was most extreme in Australia. This article argues that the panic buying was closely linked to everyday notions of Western civilisation. Pedestal toilets and toilet paper are key aspects of civilisation and the fear of the loss of toilet paper is connected to anxiety about social breakdown, the loss of civilisation. This is the fear manifested in the perceived threat posed by the virus.

Maternally transmitted late-onset non-syndromic deafness is associated with the novel heteroplasmic T12201C mutation in the mitochondrial tRNAHis gene

2011 ◽  
Vol 48 (10) ◽  
pp. 682-690 ◽  
Author(s):  
X. Yan ◽  
X. Wang ◽  
Z. Wang ◽  
S. Sun ◽  
G. Chen ◽  
...  
Keyword(s):  
Late Onset ◽  
The Novel

A Cross-Sectional Observational Study on Neonatal Thrombocytopenia in a Teaching Hospital in Telangana

2021 ◽  
Vol 8 (06) ◽  
pp. 337-341
Author(s):  
Rajesh Khanna Pulmamidi ◽  
Ramya Madhuri Yendamuri
Keyword(s):  
Observational Study ◽  
Teaching Hospital ◽  
Neonatal Sepsis ◽  
Late Onset ◽  
Birth Asphyxia ◽  
Predisposing Factors ◽  
Maternal Factors ◽  
Cross Sectional ◽  
Common Cause ◽  
Neonatal Thrombocytopenia

BACKGROUND Neonatal thrombocytopenia is one of the most common haematological abnormalities in neonates occurring in 1 to 2 % of healthy term neonates. Various risk factors like sepsis, prematurity, and birth asphyxia are known to be associated with this condition. Maternal factors also predispose to this condition. Early detection and appropriate management is of utmost importance to prevent complications. The aim of the study is to evaluate the predisposing factors for neonatal thrombocytopenia in a teaching hospital. METHODS This was a cross sectional observational study done in the Department of Peadiatrics, MediCiti Institute of Medical Sciences, Medchal, Telangana, for a duration of one year i.e., from January 2019 to December 2019. A total of 60 neonates with thrombocytopenia were studied for onset of thrombocytopenia, severity based on platelet counts, aetiology and for contributing maternal factors. RESULTS Early onset thrombocytopenia (< 3 days of age) was seen in 46.6 % (28 / 60) and late onset thrombocytopenia (3 - 28 days) in 53.3 % (32 / 60). The most common cause for neonatal thrombocytopenia was neonatal sepsis 30 % (10 / 60), followed by birth asphyxia. Common maternal predisposing factors were pregnancyinduced hypertension and pregnancy-induced diabetes mellitus. CONCLUSIONS Neonatal thrombocytopenia is one of the most common clinical problems in neonates. It can be of early or late onset type and has fetal and maternal predisposing factors. Neonatal sepsis is one of the most common cause for neonatal thrombocytopenia followed by birth asphyxia which is a preventable cause. Early diagnosis and thorough evaluation are needed to prevent complications. KEYWORDS Neonatal Thrombocytopenia, Neonatal Sepsis

Characterising the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying MME mutations

2018 ◽  
Vol 55 (12) ◽  
pp. 814-823 ◽  
Author(s):  
Vincenzo Lupo ◽  
Marina Frasquet ◽  
Ana Sánchez-Monteagudo ◽  
Ana Lara Pelayo-Negro ◽  
Tania García-Sobrino ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Late Onset ◽  
Axonal Neuropathy ◽  
Genetic Diagnosis ◽  
Hereditary Neuropathy ◽  
Motor Neuropathy ◽  
Charcot Marie Tooth Disease ◽  
Hereditary Motor Neuropathy ◽  
Index Cases ◽  
Mode Of Inheritance

BackgroundMutations in the metalloendopeptidase (MME) gene were initially identified as a cause of autosomal recessive Charcot-Marie-Tooth disease type 2 (CMT2). Subsequently, variants in MME were linked to other late-onset autosomal dominant polyneuropathies. Thus, our goal was to define the phenotype and mode of inheritance of patients carrying changes in MME.MethodsWe screened 197 index cases with a hereditary neuropathy of the CMT type or distal hereditary motor neuropathy (dHMN) and 10 probands with familial amyotrophic lateral sclerosis (fALS) using a custom panel of 119 genes. In addition to the index case subjects, we also studied other clinically and/or genetically affected and unaffected family members.ResultsWe found 17 variants in MME in a total of 20 index cases, with biallelic MME mutations detected in 13 cases from nine families (three in homozygosis and six in compound heterozygosis) and heterozygous variants found in 11 families. All patients with biallelic variants had a similar phenotype, consistent with late-onset axonal neuropathy. Conversely, the phenotype of patients carrying heterozygous mutations was highly variable [CMT type 1 (CMT1), CMT2, dHMN and fALS] and mutations did not segregate with the disease.ConclusionMME mutations that segregate in an autosomal recessive pattern are associated with a late-onset CMT2 phenotype, yet we could not demonstrate that MME variants in heterozygosis cause neuropathy. Our data highlight the importance of establishing an accurate genetic diagnosis in patients carrying MME mutations, especially with a view to genetic counselling.

scholarly journals Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1-disease

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000011528
Author(s):  
Andreas Traschütz ◽  
Andrea Cortese ◽  
Selina Reich ◽  
Natalia Dominik ◽  
Jennifer Faber ◽  
...  
Keyword(s):  
Natural History ◽  
Late Onset ◽  
Premature Death ◽  
Cross Sectional ◽  
Treatment Trials ◽  
Disease Spectrum ◽  
Phenotypic Spectrum ◽  
Multisystemic Disease ◽  
Repeat Expansions ◽  
Cerebellar Type

Objective:To delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of RFC1-repeat expansions, recently identified as causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS).Methods:Multimodal RFC1 repeat screening (PCR, southern blot, whole-exome/genome (WES/WGS)-based approaches) combined with cross-sectional and longitudinal deep-phenotyping in (i) cross-European cohort A (70 families) with ≥2 features of CANVAS and/or ataxia-with-chronic-cough (ACC); and (ii) Turkish cohort B (105 families) with unselected late-onset ataxia.Results:Prevalence of RFC1-disease was 67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and 100% in ACC. RFC1-disease was also identified in Western and Eastern Asians, and even by WES. Visual compensation, sensory symptoms, and cough were strong positive discriminative predictors (>90%) against RFC1-negative patients. The phenotype across 70 RFC1-positive patients was mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia (28%) (=overlap with cerebellar-type multiple system atrophy [MSA-C]), postural instability (49%), slow vertical saccades (17%), and chorea and/or dystonia (11%). Ataxia progression was ∼1.3 SARA points/year (32 cross-sectional, 17 longitudinal assessments, follow-up ≤9 years [mean 3.1]), but also included early falls, variable non-linear phases of MSA-C-like progression (SARA 2.5-5.5/year), and premature death. Treatment trials require 330 (1-year-trial) and 132 (2-year-trial) patients in total to detect 50% reduced progression.Conclusions:RFC1-disease is frequent and occurs across continents, with CANVAS and ACC as highly diagnostic phenotypes, yet as variable, overlapping clusters along a continuous multisystemic disease spectrum, including MSA-C-overlap. Our natural history data help to inform future RFC1-treatment trials.Classification of Evidence:This study provides Class II evidence that RFC1-repeat expansions are associated with CANVAS and ACC.

scholarly journals Antenatally Diagnosed Posterior Urethral Valve: A Case Report

2016 ◽  
Vol 5 (1) ◽  
pp. 42-45
Author(s):  
Mahzabeen Islam ◽  
Masudur Rahman ◽  
Sankar Narayan Dey ◽  
Netay Kumer Sharma ◽  
Mir Naz Farzana
Keyword(s):  
Clinical Presentation ◽  
Antenatal Diagnosis ◽  
Late Onset ◽  
Obstructive Uropathy ◽  
Lower Abdominal Pain ◽  
Posterior Urethral Valve ◽  
Caesarian Section ◽  
Common Cause ◽  
Obstructive Lesion ◽  
Urethral Valve

Posterior urethral valve (PUV) are the most common congenital obstructive lesion of the urethra and a common cause of obstructive uropathy in infancy. Clinical presentation depends on the severity of the obstruction. In case of severe obstruction, the diagnosis is usually made antenatally. Here, we present a case of antenatally diagnosed PUV of a fetus of a lady in her 9th month of pregnancy with mild lower abdominal pain for several hours. On ultrasound (US) examination, we found 36.5±2 weeks of pregnancy with mild to moderate oligohydramnios. Fetal urinary bladder was over distended; both the kidneys were grossly hydronephrotic and PUV like echo lucent area was seen at the prostatic region (Key hole sign). Emergency caesarian section (CS) was done and US of the baby showed typical US finding of PUV. The prognosis of antenatal diagnosis of PUV in early pregnancy is poor. But in this case due to the late onset of symptoms and as immediate necessary steps were taken, the baby was totally cured. This case was reported to aware about importance of antenatal anomaly scan and to share our experience. CBMJ 2016 January: Vol. 05 No. 01 P: 42-45

scholarly journals Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): from clinical diagnosis towards genetic testing

2021 ◽  
Vol 33 (4) ◽  
pp. 301-310
Author(s):  
Andreas Thieme ◽  
Christel Depienne ◽  
Dagmar Timmann
Keyword(s):  
Cerebellar Ataxia ◽  
Chronic Cough ◽  
Late Onset ◽  
Neurological Diseases ◽  
Brain Mri ◽  
Genetic Research ◽  
Sensory Nerve ◽  
Repeat Expansions ◽  
Factor C ◽  
Pentanucleotide Repeat

Abstract The cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a late-onset and recessively inherited ataxia. For many years, CANVAS has been diagnosed based on the clinical phenotype. Only recently, a large biallelic pentanucleotide repeat expansion in the replication factor C subunit 1 (RFC1) gene has been identified as the underlying genetic cause for the large majority of CANVAS cases. Subsequently, other phenotypes such as ataxia with chronic cough, incomplete CANVAS and MSA-C-like phenotypes have been associated with biallelic RFC1 repeat expansions. Because of this heterogeneity it has been suggested to change the name of the disease to “RFC1 disease”. Chronic cough is characteristic and can precede neurological symptoms by years or decades. In the neurological examination signs of cerebellar, sensory, and vestibular ataxia are frequently observed. Nerve conduction studies usually show absent or markedly reduced sensory nerve action potentials. On brain MRI cerebellar degeneration and spinal cord alterations are common. In later disease stages more widespread neurodegeneration with additional involvement of the brainstem and basal ganglia is possible. As yet, the exact incidence of RFC1-associated neurological diseases remains uncertain although first studies suggest that RFC1-related ataxia is common. Moreover, the pathophysiological mechanisms caused by the large biallelic pentanucleotide repeat expansions in RFC1 remain elusive. Future molecular and genetic research as well as natural history studies are highly desirable to pave the way towards personalized treatment approaches.

A STUDY ON “ IMPACT ON MENTAL HEALTH DURING COVID CRISIS”

2021 ◽  
pp. 11-13
Author(s):  
Radhika Gupta ◽  
Deepshikha Deepshikha ◽  
Anjali Chauhan ◽  
Priyanka Priyanka ◽  
Manisha Bhatia ◽  
...  
Keyword(s):  
Mental Health ◽  
Anxiety Disorder ◽  
General Population ◽  
The Novel ◽  
Age Group ◽  
Individual Life ◽  
Corona Virus ◽  
Study Participants ◽  
The Impact

The pandemic spread by the novel corona virus identied in Wuhan China in the year 2019 has massive hit on every aspect of individual life. Like many other countries India had imposed nationwide complete lockdown on March 2020. Since India was facing Lockdown for the rst time in its history and the stringent measures taken to implement lockdown had effects on all aspect of society including physical as well as mental health of general population. The present study was conducted using online method to know the impact on mental health during COVID 19 pandemic. The prevalence of the anxiety disorder as per GAD 7 was 33.4% among the study participants and 19-30 yrs of age group of participants and females are more affected. People have tried different method to cope with the stress during this period.

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