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PubMed | University of Turku, University of Zürich, The Childrens Memorial Health Institute, General Hospital Slovenj Gradec and 21 more.
Type: | Journal: Orphanet journal of rare diseases | Year: 2015

Fabry disease (FD) is a lysosomal storage disorder resulting in progressive nervous system, kidney and heart disease. Enzyme replacement therapy (ERT) may halt or attenuate disease progression. Since administration is burdensome and expensive, appropriate use is mandatory. We aimed to define European consensus recommendations for the initiation and cessation of ERT in patients with FD.A Delphi procedure was conducted with an online survey (n=28) and a meeting (n=15). Patient organization representatives were present at the meeting to give their views. Recommendations were accepted with 75% agreement and no disagreement.For classically affected males, consensus was achieved that ERT is recommended as soon as there are early clinical signs of kidney, heart or brain involvement, but may be considered in patients of 16years in the absence of clinical signs or symptoms of organ involvement. Classically affected females and males with non-classical FD should be treated as soon as there are early clinical signs of kidney, heart or brain involvement, while treatment may be considered in females with non-classical FD with early clinical signs that are considered to be due to FD. Consensus was achieved that treatment should not be withheld from patients with severe renal insufficiency (GFR < 45 ml/min/1.73m(2)) and from those on dialysis or with cognitive decline, but carefully considered on an individual basis. Stopping ERT may be considered in patients with end stage FD or other co-morbidities, leading to a life expectancy of <1year. In those with cognitive decline of any cause, or lack of response for 1year when the sole indication for ERT is neuropathic pain, stopping ERT may be considered. Also, in patients with end stage renal disease, without an option for renal transplantation, in combination with advanced heart failure (NYHA class IV), cessation of ERT should be considered. ERT in patients who are non-compliant or fail to attend regularly at visits should be stopped.The recommendations can be used as a benchmark for initiation and cessation of ERT, although final decisions should be made on an individual basis. Future collaborative efforts are needed for optimization of these recommendations.

Othman A.A.,University of Zakho | Eissa A.A.,Duhok University | Markous R.D.,Inherited Health | Ahmed B.D.,PCR Unit | Al-Allawi N.A.S.,Duhok University
Asian Journal of Transfusion Science | Year: 2014

Background and Aim: Owing to the scarcity of data on hepatitis C virus (HCV) genotypes in Iraq and due to their epidemiological as well as therapy implications, this study was initiated aiming at determining these genotypes in Northern Iraq. Materials and Methods: A total of 70 HCV antibody positive multi transfused patients with hemoglobinopathies, who had detectable HCV ribonucleic acid, were recruited for genotyping using genotype-specific nested polymerase chain reaction. Results: The most frequent genotype detected was genotype 4 (52.9%) followed by 3a (17.1%), 1b (12.9%) and 1a (1.4%), while mixed genotypes (4 with either 3a or 1b) were detected in 7.1%. Conclusion: The predominance of genotype 4 is similar to other studies from surrounding Eastern Mediterranean Arab countries and to the only earlier study from central Iraq, however the significant high proportion of 3a and scarcity of 1a, are in contrast to the latter study and may be explainable by the differing population interactions in this part of Iraq. This study complements previous studies from Eastern Mediterranean region and demonstrates relative heterogeneity of HCV genotype distribution within Iraq and should trigger further studies in other parts of the country.

Coassin S.,Innsbruck Medical University | Schweiger M.,University of Graz | Kloss-Brandstatter A.,Innsbruck Medical University | Lamina C.,Innsbruck Medical University | And 10 more authors.
PLoS Genetics | Year: 2010

Recent studies demonstrated a strong influence of rare genetic variants on several lipid-related traits. However, their impact on free fatty acid (FFA) plasma concentrations, as well as the role of rare variants in a general population, has not yet been thoroughly addressed. The adipose triglyceride lipase (ATGL) is encoded by the PNPLA2 gene and catalyzes the rate-limiting step of lipolysis. It represents a prominent candidate gene affecting FFA concentrations. We therefore screened the full genomic region of ATGL for mutations in 1,473 randomly selected individuals from the SAPHIR (Salzburg Atherosclerosis Prevention program in subjects at High Individual Risk) Study using a combined Ecotilling and sequencing approach and functionally investigated all detected protein variants by in-vitro studies. We observed 55 novel mostly rare genetic variants in this general population sample. Biochemical evaluation of all non-synonymous variants demonstrated the presence of several mutated but mostly still functional ATGL alleles with largely varying residual lipolytic activity. About one-quarter (3 out of 13) of the investigated variants presented a marked decrease or total loss of catalytic function. Genetic association studies using both continuous and dichotomous approaches showed a shift towards lower plasma FFA concentrations for rare variant carriers and an accumulation of variants in the lower 10%-quantile of the FFA distribution. However, the generally rather small effects suggest either only a secondary role of rare ATGL variants on the FFA levels in the SAPHIR population or a recessive action of ATGL variants. In contrast to these rather small effects, we describe here also the first patient with "neutral lipid storage disease with myopathy" (NLSDM) with a point mutation in the catalytic dyad, but otherwise intact protein. © 2010 Coassin et al.

Grant S.,University of Manchester | Cross E.,University of Manchester | Wraith J.E.,Inherited Health | Jones S.,Inherited Health | And 4 more authors.
Journal of Inherited Metabolic Disease | Year: 2013

Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is a lysosomal storage disorder, caused by a deficiency in one of four enzymes involved in the catabolism of the glycosaminoglycan heparan sulphate. It is a degenerative disorder, with a progressive decline in children's intellectual and physical functioning. There is currently no cure for the disorder. To date there is a paucity of research on how this disorder impacts parents psychological functioning. Specifically, research in the area has failed to employ adequate control groups to assess if the impact of this disorder on parents psychological functioning differs from parenting a child with intellectual disability (ID). The current study examined child behaviour and parental psychological functioning in 23 parents of children with MPS III and 23 parents of children with ID. Parents completed postal questionnaires about their child's behaviour and abilities and their own psychological functioning. Parents of children with MPS III reported fewer behavioural difficulties as their child aged, more severe level of intellectual disability, and similar levels of perceived social support, coping techniques, stress, anxiety and depression levels as parents of children with ID. Both groups of parents scored above the clinical cut off for anxiety and depression. Parents of children with MPS III rated themselves as significantly less future-orientated and goal directed than parents of children with ID. Services should develop support packages for parents of children with MPS III that incorporate an understanding of the unique stressors and current-difficulty approach of this population. Future research should examine gender differences between parental psychological functioning, using mixed qualitative and quantitative approaches, and utilise matched developmental level and typically developing control groups. © 2012 SSIEM and Springer Science+Business Media Dordrecht.

Motwani M.,Salford Royal Hospital NHS Foundation Trust | Banypersad S.,Salford Royal Hospital NHS Foundation Trust | Woolfson P.,Salford Royal Hospital NHS Foundation Trust | Waldek S.,Inherited Health
Molecular Genetics and Metabolism | Year: 2012

Background: Although left ventricular hypertrophy (LVH) in Fabry disease (FD) can improve with enzyme-replacement therapy (ERT), the response is difficult to predict. Furthermore, the response of other cardiac features such as aortic dilatation and ECG changes are poorly understood. Methods: A local registry of 66 patients with FD was studied. ECG, echocardiogram and Fabry Outcome Survey-Mainz Severity Score Index (FOS-MSSI) data were compared between baseline and after long-term ERT (median 36. months). Results: In patients with LVH (n=42), left ventricular mass index (LVMI), maximal wall thickness (MWT), left ventricular end-diastolic diameter (LVEDD) and ejection fraction (EF) were all seen to improve after ERT (LVMI: 135±13 vs. 133±13g/m2, MWT: 17±6 vs. 16±5mm, LVEDD: 55±6 vs. 54±6mm; EF: 62±5 vs. 64±3%; p<0.05). In the entire patient group, PQ interval and P wave duration significantly increased with ERT (PQ: 131±13 vs. 144±13ms, P: 76±5 vs. 90±6ms; p values<0.001); QTc interval significantly decreased (418±18 vs. 410±15ms; p<0.001); and median FOS-MSSI score fell from 16 to 14 (p<0.001). On logistic-regression analysis, none of the recorded baseline features (age, gender, LVMI, MWT, LVEDD, aortic diameter, EF, PQ interval, P wave duration, QRS duration, QT interval, Romhilt-Estes score or FOS-MSSI) predicted improvements in LVH or FOS-MSSI with ERT (p>0.05). Conclusions: ERT improved LV morphology and function in patients with LVH - but there was no relationship between age, gender, FOS-MSSI or baseline ECG/TTE features and the response. ERT also normalised long QTc intervals, short PQ intervals and short P waves; and reduced disease burden (FOS-MSSI). © 2012 Elsevier Inc.

Davis S.K.,Cardiovascular Research Institute | Gebreab S.,Cardiovascular Research Institute | Quarells R.,Morehouse School of Medicine | Gibbons G.H.,Inherited Health | Gibbons G.H.,U.S. National Institutes of Health
Ethnicity and Disease | Year: 2014

Objective: To assess the associations of social determinants on cardiovascular health among White and Black residing in Stroke Belt (urban) and Stroke Buckle (rural) regions of the South. Design: A cross-sectional observational analysis based on a random digit-dial telephone survey of a representative sample of White and Black adults residing in urban and rural Georgia conducted from 2004-2005. Separate logistic regression analyses examined the effects of social determinants on cardiovascular health within and between White and Black women and within and between urban and rural residential location. The main outcome measure was poor cardiovascular health defined as ≤2 self-reported clinical cardiovascular disease risk factors (hypertension, diabetes, elevated cholesterol, overweight or obese). Social determinants were defined as socioeconomic status (SES), general daily stress, racial discrimination, and stress due to exposure to racial discrimination. Significance was established as a two-tailed P<.05. Results: A total of 674 White and Black women aged 18-90 years were included in the sample. Results showed Black women with lower SES had worse cardiovascular health than White women in both rural and urban areas (rural odds ratio [OR] 2.68; confidence interval [CI] 1.44, 4.90; P =.001; urban OR=2.92; CI=1.62, 5.23; P=.0003). White women reporting high or very high exposure to general daily stress where more likely to have worse cardiovascular health than White women reporting very little to no daily stress (OR =2.85; CI=1.49, 5.44; P=.001). Conclusion: Our findings demonstrate the importance of social determinants associated with cardiovascular health. Tailored cardiovascular risk reduction intervention is needed among lower SES Black women in Stroke Belt and Buckle regions of the South, as well as stress-reduction intervention among White women in the South.

Tahir T.A.,University of Wales | Eeles E.,University of Cardiff | Karapareddy V.,Mersey Care NHS trust | Muthuvelu P.,Betsi Cadwaladr University Local Health Board | And 5 more authors.
Journal of Psychosomatic Research | Year: 2010

Background: Delirium is a commonly occurring complex neuropsychiatric disorder. Evidence for its treatment based on randomized controlled trials (RCTs) is poor. Aims: To determine the efficacy and acceptability of quetiapine in the treatment of delirium. Method: A double-blind, RCT was conducted. A total of 42 patients were randomized to quetiapine or a placebo group. The primary outcome measure was the Delirium Rating Scale Revised 98. Other scales used were the Brief Psychiatric Rating Scale, Mini-Mental State Examination and Clinical Global Improvement. In order to account for missing data, a nonlinear mixed-effects model was used to estimate the difference between the two groups. Results: The quetiapine group improved more rapidly than the placebo group. Specifically, the quetiapine group recovered 82.7% faster (S.E. 37.1%, P=026) than the placebo group in terms of DRS-R-98 severity score. In terms of the DRS-R-98 noncognitive subscale, the quetiapine group improved 57.7% faster (S.E. 29.2%, P=048) than the placebo group. Conclusions: Quetiapine has the potential to more quickly reduce the severity of noncognitive aspects of delirium. This study was underpowered for treatment comparisons at specific points in time but nonetheless detected significant differences when analyzing the whole study period. While it is not possible to draw definitive conclusions, further larger studies exploring the use of quetiapine in other delirium populations seem justified. Larger increments in the dose of quetiapine may yield even stronger results. © 2010 Elsevier Inc.

PubMed | Inherited Health
Type: Evaluation Studies | Journal: Analytical and bioanalytical chemistry | Year: 2015

Although the phenylalanine/tyrosine ratio in blood has been the gold standard for diagnosis of phenylketonuria (PKU), the disadvantages of invasive sample collection and false positive error limited the application of this discriminator in the diagnosis of PKU to some extent. The aim of this study was to develop a new standard with high sensitivity and specificity in a less invasive manner for diagnosing PKU. In this study, an improved oximation-silylation method together with GC/MS was utilized to obtain the urinary metabolomic information in 47 PKU patients compared with 47 non-PKU controls. Compared with conventional oximation-silylation methods, the present approach possesses the advantages of shorter reaction time and higher reaction efficiency at a considerably lower temperature, which is beneficial to the derivatization of some thermally unstable compounds, such as phenylpyruvic acid. Ninety-seven peaks in the chromatograms were identified as endogenous metabolites by the National Institute of Standards and Technology (NIST) mass spectra library, including amino acids, organic acids, carbohydrates, amides, and fatty acids. After normalization of data using creatinine as internal standard, 19 differentially expressed compounds with p values of <0.05 were selected by independent-sample t test for the separation of the PKU group and the control group. A principal component analysis (PCA) model constructed by these differentially expressed compounds showed that the PKU group can be discriminated from the control group. Receiver-operating characteristic (ROC) analysis with area under the curve (AUC), specificity, and sensitivity of each PKU marker obtained from these differentially expressed compounds was used to evaluate the possibility of using these markers for diagnosing PKU. The largest value of AUC (0.987) with high specificity (0.936) and sensitivity (1.000) was obtained by the ROC curve of phenylacetic acid at its cutoff value (17.244mmol/mol creatinine), which showed that phenylacetic acid may be used as a reliable discriminator for the diagnosis of PKU. The low false positive rate (1-specificity, 0.064) can be eliminated or at least greatly reduced by simultaneously referring to other markers, especially phenylpyruvic acid, a unique marker in PKU. Additionally, this standard was obtained with high sensitivity and specificity in a less invasive manner for diagnosing PKU compared with the Phe/Tyr ratio. Therefore, we conclude that urinary metabolomic information based on the improved oximation-silylation method together with GC/MS may be reliable for the diagnosis and differential diagnosis of PKU.

PubMed | Clinic Hospital of Porto, Inherited Health, Kleijnen Systematic Reviews, Royal Childrens Hospital and 5 more.
Type: | Journal: Orphanet journal of rare diseases | Year: 2015

Morquio A (MPS IVA) is a rare disease characterised by a deficiency of N-acetylgalactosamine-6 sulfatase (GALNS) and presenting with short stature, abnormal gait, cervical spine instability and shortened lifespan.To prepare a systematic review of the prevalence of Morquio A in multiple countries and suggest recommendations for reporting rare diseases.Medline, Medline In-Process, Medline Daily Update, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, Health Technology Assessment Database and PROSPERO were searched from inception to October 2013 to identify relevant information on the epidemiology of Morquio A. Forty Patient Organisation Representatives (POR) and Key Opinion Leaders (KOL) across 24 countries were contacted for data. Observational studies were included and case reports were excluded. Searches were performed without date or language restriction. Two researchers independently screened and extracted data. Quality of study reporting was assessed using a checklist adapted from STROBE (STrengthening the Reporting of OBservational studies in Epidemiology). Point or birth prevalence was stratified according to diagnostic method and discussed narratively.In total 9,074 records were retrieved from searching and 25 studies were included for data extraction. Twenty out of 40 KOL and POR responded (50%) and 9 provided data (23%). Point prevalence of Morquio A was 1 per 926,000 in Australia, 1 per 1,872,000 in Malaysia and 1 per 599,000 in UK and Morquio (unclassified) was 1 per 323, 000 in Denmark. Birth prevalence of Morquio A (using recommended diagnostic methods) ranged from 1 per 71,000 in UAE to 1 per 500,000 in Japan. All results were compromised by poor study reporting and internal validity.The review highlighted that there is a misunderstanding of the definitions for prevalence and incidence in the field; that studies were poorly reported (diagnostic methods and patient characteristics) and that no suitable quality assessment tool exists. Overestimation and underestimation of prevalence data can occur. Bespoke reporting guidelines and a quality assessment tool specifically for prevalence of rare diseases are recommended.

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