scholarly journals Correlation between PABPN1 genotype and disease severity in oculopharyngeal muscular dystrophy

Neurology ◽  
2016 ◽  
Vol 88 (4) ◽  
pp. 359-365 ◽  
Author(s):  
Pascale Richard ◽  
Capucine Trollet ◽  
Tanya Stojkovic ◽  
Alix de Becdelievre ◽  
Sophie Perie ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Disease Severity ◽  
Severe Disease ◽  
Statistical Correlation ◽  
Age At Diagnosis ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Gene Encoding ◽  
Limb Weakness ◽  
Polyalanine Expansion ◽  
The Mean

Objective:Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant adult-onset disease characterized by progressive ptosis, dysphagia, and proximal limb weakness. The genetic cause is an expanded (GCN)n mutation in the PABPN1 gene encoding for the polyadenylate-binding protein nuclear 1. We hypothesized a potential correlation between the size of the (GCN)n expansion and the severity of the phenotype. To do this, we characterized the distribution of the genotypes as well as their correlation with age at diagnosis and phenotypical features in a large cohort of heterozygous and homozygous patients with OPMD in France with a confirmed molecular diagnosis of PABPN1.Methods:We explored 354 unrelated index cases recruited between 1999 and 2014 in several neuromuscular centers in France.Results:This cohort allowed us to characterize the frequency of mutated alleles in the French population and to demonstrate a statistical correlation between the size of the expansion and the mean age at diagnosis. We also confirmed that homozygous patients present with a more severe disease.Conclusions:It has been difficult to establish phenotype–genotype correlations because of the rare nature of this disease. Our work demonstrates that patients with OPMD with longer PABPN1 expansion are on average diagnosed at an earlier age than patients with a shorter expansion, confirming that polyalanine expansion size plays a role in OPMD, with an effect on disease severity and progression.

scholarly journals hnRNP A1 and A/B Interaction with PABPN1 in Oculopharyngeal Muscular Dystrophy

2003 ◽  
Vol 30 (3) ◽  
pp. 244-251 ◽  
Author(s):  
Xueping Fan ◽  
Christiane Messaed ◽  
Patrick Dion ◽  
Janet Laganiere ◽  
Bernard Brais ◽  
...  
Keyword(s):  
Cell Death ◽  
Muscular Dystrophy ◽  
Binding Proteins ◽  
Fetal Brain ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Hnrnp A1 ◽  
Intranuclear Inclusions ◽  
Limb Weakness ◽  
Dominant Form ◽  
Hnrnp Proteins

Background:Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by progressive ptosis, dysphagia and proximal limb weakness. The autosomal dominant form of this disease is caused by short expansions of a (GCG)6 repeat to (GCG)8-13 in the PABPN1 gene. The mutations lead to the expansion of a polyalanine stretch from 10 to 12-17 alanines in the N-terminus of PABPN1. The mutated PABPN1 (mPABPN1) induces the formation of intranuclear filamentous inclusions that sequester poly(A) RNA and are associated with cell death.Methods:Human fetal brain cDNA library was used to look for PABPN1 binding proteins using yeast two-hybrid screen. The protein interaction was confirmed by GST pull-down and co-immunoprecipitation assays. Oculopharyngeal muscular dystrophy cellular model and OPMD patient muscle tissue were used to check whether the PABPN1 binding proteins were involved in the formation of OPMD intranuclear inclusions.Results:We identify two PABPN1 interacting proteins, hnRNP A1 and hnRNP A/B. When co-expressed with mPABPN1 in COS-7 cells, predominantly nuclear protein hnRNP A1 and A/B co-localize with mPABPN1 in the insoluble intranuclear aggregates. Patient studies showed that hnRNP A1 is sequestered in OPMD nuclear inclusions.Conclusions:The hnRNP proteins are involved in mRNA processing and mRNA nucleocytoplasmic export, sequestering of hnRNPs in OPMD intranuclear aggregates supports the view that OPMD intranuclear inclusions are “poly(A) RNA traps”, which would interfere with RNA export, and cause muscle cell death.

scholarly journals Progress in Understanding the Pathogenesis of Oculopharyngeal Muscular Dystrophy

2003 ◽  
Vol 30 (1) ◽  
pp. 8-14 ◽  
Author(s):  
Xueping Fan ◽  
Guy A. Rouleau
Keyword(s):  
Muscular Dystrophy ◽  
Autosomal Dominant ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Intranuclear Inclusions ◽  
Intranuclear Inclusion ◽  
Limb Weakness ◽  
Dominant Form ◽  
Autosomal Dominant Form ◽  
Swallowing Difficulties

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by progressive eyelid drooping (ptosis), swallowing difficulties (dysphagia), and proximal limb weakness. The autosomal dominant form of this disease is caused by expansions of a (GCG)6 repeat to (GCG)8-13 in the PABPN1 gene. These mutations lead to the expansion of a polyalanine stretch from 10 to 12-17 alanines in the N-terminal domain of PABPN1. Mutated PABPN1 (mPABPN1) induces the formation of muscle intranuclear inclusions that are thought to be the hallmark of this disease. In this review, we discuss: 1) OPMD genetics and PABPN1 function studies; 2) diseases caused by polyalanine expansions and cellular polyalanine toxicity; 3) mPABPN1-induced intranuclear inclusion toxicity; 4) role of oligomerization of mPABPN1 in the formation and toxicity of OPMD intranuclear inclusions and; 5) recruitment of subcellular components to the OPMD inclusions. We present a potential molecular mechanism for OPMD pathogenesis that accounts for these observations.

scholarly journals Comparison of clinical rating scales in genetic frontotemporal dementia within the GENFI cohort

2021 ◽  
pp. jnnp-2021-326868
Author(s):  
Georgia Peakman ◽  
Lucy L Russell ◽  
Rhian S Convery ◽  
Jennifer M Nicholas ◽  
John C Van Swieten ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Disease Severity ◽  
Outcome Measures ◽  
Severe Disease ◽  
Genetic Group ◽  
Control Group ◽  
Sample Sizes ◽  
Genetic Groups ◽  
Mutation Carriers ◽  
The Mean

BackgroundTherapeutic trials are now underway in genetic forms of frontotemporal dementia (FTD) but clinical outcome measures are limited. The two most commonly used measures, the Clinical Dementia Rating (CDR)+National Alzheimer’s Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) and the FTD Rating Scale (FRS), have yet to be compared in detail in the genetic forms of FTD.MethodsThe CDR+NACC FTLD and FRS were assessed cross-sectionally in 725 consecutively recruited participants from the Genetic FTD Initiative: 457 mutation carriers (77 microtubule-associated protein tau (MAPT), 187 GRN, 193 C9orf72) and 268 family members without mutations (non-carrier control group). 231 mutation carriers (51 MAPT, 92 GRN, 88 C9orf72) and 145 non-carriers had available longitudinal data at a follow-up time point.ResultsCross-sectionally, the mean FRS score was lower in all genetic groups compared with controls: GRN mutation carriers mean 83.4 (SD 27.0), MAPT mutation carriers 78.2 (28.8), C9orf72 mutation carriers 71.0 (34.0), controls 96.2 (7.7), p<0.001 for all comparisons, while the mean CDR+NACC FTLD Sum of Boxes was significantly higher in all genetic groups: GRN mutation carriers mean 2.6 (5.2), MAPT mutation carriers 3.2 (5.6), C9orf72 mutation carriers 4.2 (6.2), controls 0.2 (0.6), p<0.001 for all comparisons. Mean FRS score decreased and CDR+NACC FTLD Sum of Boxes increased with increasing disease severity within each individual genetic group. FRS and CDR+NACC FTLD Sum of Boxes scores were strongly negatively correlated across all mutation carriers (rs=−0.77, p<0.001) and within each genetic group (rs=−0.67 to −0.81, p<0.001 in each group). Nonetheless, discrepancies in disease staging were seen between the scales, and with each scale and clinician-judged symptomatic status. Longitudinally, annualised change in both FRS and CDR+NACC FTLD Sum of Boxes scores initially increased with disease severity level before decreasing in those with the most severe disease: controls −0.1 (6.0) for FRS, −0.1 (0.4) for CDR+NACC FTLD Sum of Boxes, asymptomatic mutation carriers −0.5 (8.2), 0.2 (0.9), prodromal disease −2.3 (9.9), 0.6 (2.7), mild disease −10.2 (18.6), 3.0 (4.1), moderate disease −9.6 (16.6), 4.4 (4.0), severe disease −2.7 (8.3), 1.7 (3.3). Sample sizes were calculated for a trial of prodromal mutation carriers: over 180 participants per arm would be needed to detect a moderate sized effect (30%) for both outcome measures, with sample sizes lower for the FRS.ConclusionsBoth the FRS and CDR+NACC FTLD measure disease severity in genetic FTD mutation carriers throughout the timeline of their disease, although the FRS may be preferable as an outcome measure. However, neither address a number of key symptoms in the FTD spectrum, for example, motor and neuropsychiatric deficits, which future scales will need to incorporate.

scholarly journals Recent Progress in Oculopharyngeal Muscular Dystrophy

2021 ◽  
Vol 10 (7) ◽  
pp. 1375
Author(s):  
Satoshi Yamashita
Keyword(s):  
Muscular Dystrophy ◽  
Recent Progress ◽  
Trinucleotide Repeat ◽  
Late Onset ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Limb Weakness ◽  
Medical Needs ◽  
Therapeutic Benefits ◽  
Initial Symptoms ◽  
Swallowing Problems

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset intractable myopathy, characterized by slowly progressive ptosis, dysphagia, and proximal limb weakness. It is caused by the abnormal expansion of the alanine-encoding (GCN)n trinucleotide repeat in the exon 1 of the polyadenosine (poly[A]) binding protein nuclear 1 gene (11–18 repeats in OPMD instead of the normal 10 repeats). As the disease progresses, the patients gradually develop a feeling of suffocation, regurgitation of food, and aspiration pneumonia, although the initial symptoms and the progression patterns vary among the patients. Autologous myoblast transplantation may provide therapeutic benefits by reducing swallowing problems in these patients. Therefore, it is important to assemble information on such patients for the introduction of effective treatments in nonendemic areas. Herein, we present a concise review of recent progress in clinical and pathological studies of OPMD and introduce an idea for setting up a nation-wide OPMD disease registry in Japan. Since it is important to understand patients’ unmet medical needs, realize therapeutically targetable symptoms, and identify indices of therapeutic efficacy, our attempt to establish a unique patient registry of OPMD will be a helpful tool to address these urgent issues.

scholarly journals Oculopharyngeal muscular dystrophy (OPMD) and dementia in a 75-year-old female

2019 ◽  
Vol 12 (9) ◽  
pp. e230521
Author(s):  
Mhairi Kathryn Nisbet ◽  
Louise Marshall
Keyword(s):  
Muscular Dystrophy ◽  
Causal Link ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Limb Weakness ◽  
Cognitive Domains ◽  
Word Finding ◽  
Memory Problems ◽  
Swallowing Difficulties ◽  
With Memory

Oculopharyngeal muscular dystrophy (OPMD) is a relatively rare, adult-onset disorder characterised by proximal limb weakness, progressive eyelid drooping and swallowing difficulties. Preliminary research suggests there could be a link between OPMD and dementia; however, the current literature is relatively limited and inconsistent. This case study describes a 75-year-old female with OPMD, presenting to an older adults community mental health team with memory problems and word finding difficulties. A neuropsychological assessment was carried out. The results of her assessment were difficult to interpret; she demonstrated impairments in most cognitive domains tested and her presentation did not appear to reflect any typical dementia profile. It was thought she was most likely presenting with a dementia; however, the exact aetiology remains unclear. The dementia could be a result of OPMD, vascular changes or both. This report emphasises the need for further research into the possible causal link between OPMD and dementia/cognitive decline.

scholarly journals Alpha Fetoprotein as a Marker of Severe Disease and Foetal Outcome in Pregnancy Induced Hypertension

2019 ◽  
Vol 4 (03) ◽  
Author(s):  
Ayokunle Moses Olumodeji ◽  
Olumide Emmanuel Adewara ◽  
Olabisi Timothy Adeyemo ◽  
Segun Murtala Ghazali ◽  
Paul Olowoyo
Keyword(s):  
Birth Weight ◽  
Disease Severity ◽  
Severe Disease ◽  
Fetal Outcome ◽  
Maternal Serum ◽  
Alpha Fetoprotein ◽  
Pregnancy Induced Hypertension ◽  
Induced Hypertension ◽  
Foetal Outcome ◽  
The Mean

Background: Pregnancy-induced hypertension represents the most common medical complication of pregnancy and contributes significantly to maternal and neonatal morbidity and mortality. Many theories have been implicated in its genesis, crucial among which is the defective 2nd wave of trophoblastic invasion/placentation. Maternal serum alpha fetoprotein is a marker of placental abnormalities and may correlate with clinical features of significant management implications. This study evaluated the role of maternal Alpha-fetoprotein concentration as a marker of disease severity and foetal outcome in patients with pregnancy induced hypertension at the Federal Teaching Hospital, Ido-Ekiti, Ekiti state, Nigeria. Methodology: This was a prospective study in which 44 patients with PIH and 88 matched controls that satisfied the inclusion criteria were recruited using convenience sampling technique for cases and systematic random sampling for controls. Relevant socio-demographic, maternal medical and obstetric characteristics, alpha-fetoprotein levels and fetal outcome measures were obtained. A p-value of less than 0.05 was considered statistically significant. SPSS 20.0 statistical package (SPSS Inc, Chicago, IL, USA) was used for statistical analysis. Results: The prevalence of PIH in the study was 15.3%. The difference in the mean (±2SD) serum level of alpha fetoprotein (AFP) between the cases (207±156.2ng/ml) and control group (165.2±115.1ng/ml) was not statistically significant (p=0.079). The mean (±2SD) birth weight of babies born to women with PIH in this study was 2.7±0.6kg which was significantly lower (p<0.001; 95%CI 3.0 – 3.1)) than the mean birth weights of 3.2±0.4kg of babies of normotensive controls. The mean (± 2SD) Apgar scores at both 1 minute and 5 minutes were both significantly lower in the PIH group (6.7±1.8 and 8.4±1.5 respectively) than among the normotensive women (7.6±1.2 and 8.9±1.1 respectively). Thirty-one point eight percentage of babies born to women in the PIH group and 11.4% of babies of normotensive controls required admission into special care baby unit (SCBU) (Odds Ratio=1.17; 95%CI (0.24-5.76) Serum AFP had a reasonable negative correlation with both birth weight (r=-0.47, p=0.001) and Apgar score at 5 minute (r=-0.44, p=0.002). At 2 MoM serum AFP level, sensitivity and specificity for severe PIH were 36% and 90% respectively. Conclusion: Maternal serum AFP levels showed reasonable positive correlation with disease severity and adverse fetal outcome that warrants further investigation. Maternal serum AFP can be useful in identifying pregnant women with PIH at risk of having severe disease and adverse foetal outcome.

scholarly journals Does Thrombocytopenia Truly Correlate with COVID-19 Severity?

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Caroline Hana ◽  
Samar Aboulenain ◽  
Nakeya Dewaswala ◽  
Vijay Narendran
Keyword(s):  
Risk Factors ◽  
Platelet Count ◽  
Disease Severity ◽  
Retrospective Cohort ◽  
Severe Disease ◽  
Smoking History ◽  
Prognostic Impact ◽  
Disease Course ◽  
Platelet Counts ◽  
The Mean

Introduction: On March 11, 2020, the World Health Organization (WHO) declared SARS-CoV-19 a pandemic with about 114 countries affected. Many studies and metanalyses have investigated the risk factors associated with poor outcomes from COVID-19 infection. Different clinical as well as laboratory parameters have been shown to correlate with disease severity, including age, male gender, smoking history, presence of one or more co-morbidities, heart disease, hypertension, diabetes, obesity, and chronic lung disease. Among these risk factors, several studies suggest that a decreased platelet count is associated with more severe disease course. A lower platelets count was also observed to be associated with a poor prognosis. On the contrary, not all reports seem to show the same association. Objective: Our study is aimed at investigating the prognostic impact of the platelet count in patients admitted with COVID-19 infection and understanding its association with disease severity and mortality. Methodology: All patients admitted to JFK Medical center in Atlantis, Florida and diagnosed with COVID-19 from March 2020 to May 2020 were identified and included in this retrospective cohort. Certain demographic and clinical data were collected for each patient, including age, gender, comorbidities, complete blood count and blood chemistry values on admission. The following data was calculated: quick Sequential Organ Failure Assessment (qSOFA), the ratio of oxygen saturation to the fraction of inspired oxygen ratio (SpO2/FiO2) were calculated, presence or absence of adult respiratory distress syndrome (ARDS), and the outcome in terms of mortality. Data regarding the radiographic findings on chest X-ray (CXR) were determined to be normal, mild, moderate, or severe by a radiologist. Patients were identified as having severe disease if they met the following criteria: Admission to the intensive care unit (ICU) during hospitalization or met criteria for ARDS. Results: A total of 175 patients were identified. The mean age was 62.97 years(SD 17.9years), 97 patients (55.4%) were males, 36 (20.6%) had an ICU admission during their hospitalization, 18 (10.3%) met the criteria for ARDS, 131 (74.9%) had qSOFA of 0 with only 3 (1.7%) having qSOFA of 2. The majority of CXR findings were mild 66 out of valid 155 cases (37.7%) while 19.4% read as severe infiltrate. The mean platelets count on admission was 227.71 x 109/L (SD 104 x 109/L). 43 patients (24.6%) died in the hospital. Patients with severe disease versus non-severe disease did not differ significantly in the platelet count at admission. Platelet counts were also not associated with in-hospital mortality. No significant correlation was found between the platelets count and the qSOFA scale, the SpO2/FiO2 and the CXR findings (table 2). Conclusion: In our retrospective Cohort study, no significant association was found between the platelet count on admission and disease severity or mortality. Studies examining the risk factors for severe COVID-19 infection and mortality showed that thrombocytopenia is a significant risk factor.(13) Other studies showed that patients with significantly elevated platelets (&gt; 300 x 109/L) during treatment had longer average hospitalization days.(12). Finding practical and actionable indicators of disease severity can help clinicians guide patients with potentially worse outcomes to aggressive therapies that may lead to better outcomes when instituted earlier. More work should be done to clarify the role platelet counts can play in the prognostication of patients with COVID-19 infection. Our Study will be followed by further investigation of the correlation between day 3 platelet count and COVID-19 severity. We are also examining the validation of a scoring system involving the platelet count among other parameters to use as a predictor for disease course and outcome. Disclosures No relevant conflicts of interest to declare.

Unusual triplet expansion associated with neurogenic changes in a family with oculopharyngeal muscular dystrophy

2001 ◽  
Vol 21 (1) ◽  
pp. 45-52 ◽  
Author(s):  
Ralf Schober ◽  
Wolfram Kress ◽  
Friedrich Grahmann ◽  
Steffen Kellermann ◽  
Petra Baum ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Triplet Expansion

Vitamin D levels are not associated with non-alcoholic fatty liver disease severity in a Brazilian population

2020 ◽  
pp. 1-8
Author(s):  
Jeniffer Danielle M. Dutra ◽  
Quelson Coelho Lisboa ◽  
Silvia Marinho Ferolla ◽  
Carolina Martinelli M. L. Carvalho ◽  
Camila Costa M. Mendes ◽  
...  
Keyword(s):  
Vitamin D ◽  
Liver Disease ◽  
Fatty Liver ◽  
Disease Severity ◽  
Fatty Liver Disease ◽  
Hypovitaminosis D ◽  
Alcoholic Fatty Liver ◽  
Vitamin D Levels ◽  
The Mean ◽  
Alcoholic Fatty Liver Disease

Abstract. Some epidemiological evidence suggests an inverse correlation between non-alcoholic fatty liver disease (NAFLD) frequency and vitamin D levels. Likewise, a beneficial effect of vitamin D on diabetes mellitus (DM) and insulin resistance has been observed, but this is an unsolved issue. Thus, we aimed to investigate the prevalence of hypovitaminosis D in a NAFLD Brazilian population and its association with disease severity and presence of comorbidities. In a cross-sectional study, the clinical, biochemical and histological parameters of 139 NAFLD patients were evaluated according to two different cut-off points of serum 25-hydroxyvitamin D levels (20 ng/mL and 30 ng/mL). The mean age of the population was 56 ± 16 years, most patients were female (83%), 72% had hypertension, 88% dyslipidemia, 46% DM, 98% central obesity, and 82% metabolic syndrome. Serum vitamin D levels were < 30 ng/mL in 78% of the patients, and < 20 ng/mL in 35%. The mean vitamin D level was 24.3 ± 6.8 ng/mL. The comparison between the clinical, biochemical and histological characteristics of the patients according to the levels of vitamin D showed no significant difference. Most patients with NAFLD had hypovitaminosis D, but low vitamin D levels were not related to disease severity and the presence of comorbidities.

scholarly journals Genetic polymorphism for IFNγ +874T/A in patients with acute toxoplasmosis

2012 ◽  
Vol 45 (6) ◽  
pp. 757-760 ◽  
Author(s):  
Elizabeth de Souza Neves ◽  
André Luis Land Curi ◽  
Maira Cavalcanti de Albuquerque ◽  
Cassius Schnel Palhano-Silva ◽  
Laura Berriel da Silva ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Case Control Study ◽  
Severe Disease ◽  
Clinical Manifestations ◽  
Nucleotide Polymorphism ◽  
Gene Encoding ◽  
Single Nucleotide ◽  
Duration Of Disease ◽  
Acute Toxoplasmosis ◽  
Control Study

INTRODUCTION: A single nucleotide polymorphism (SNP) in the gene encoding gamma interferon influences its production and is associated with severity of infectious diseases. This study aimed to evaluate the association of IFNγ+874T/A SNP with duration of disease, morbidity, and development of retinochoroiditis in acute toxoplasmosis. METHODS: A case-control study was conducted among 30 patients and 90 controls. RESULTS: Although statistical associations were not confirmed, A-allele was more common among retinochoroiditis cases and prolonged illness, while T-allele was more frequent in severe disease. CONCLUSIONS: Despite few cases, the results could indicate a relation between IFNγ+874T/A single nucleotide polymorphism and clinical manifestations of toxoplasmosis.

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