scholarly journals Clinical Presentation of the c.3844T>C (p.Trp1282Arg, W1282R) Variant in Russian Cystic Fibrosis Patients

Genes ◽  
2020 ◽  
Vol 11 (10) ◽  
pp. 1137
Author(s):  
Nika V. Petrova ◽  
Nataliya Y. Kashirskaya ◽  
Stanislav A. Krasovskiy ◽  
Elena L. Amelina ◽  
Elena I. Kondratyeva ◽  
...  
Keyword(s):  
Lung Function ◽  
Severe Disease ◽  
Pancreatic Insufficiency ◽  
Clinical Manifestations ◽  
Chloride Concentration ◽  
Class I ◽  
Sweat Test ◽  
Microbial Infection ◽  
Sweat Chloride ◽  
In Trans

The goal was to study the phenotypic manifestations of c.3844T>C (p.Trp1282Arg, W1282R) variant, a CF-causing mutation, in patients from the Russian Federation. Clinical manifestations and complications (the age at CF diagnosis, sweat test, pancreatic status, lung function, microbial infection, body mass index (BMI), the presence of meconium ileus (MI), diabetes, and severe liver disease) were compared in four groups: group 1—patients carrying c.3844T>C and severe class I or II variant in trans; group 2—3849+10kbC>T/F508del patients; group 3—F508del/F508del patients; and group 4—patients with W1282R and “mild” variant in trans. Based on the analyses, W1282R with class I or II variant in trans appears to cause at least as severe CF symptoms as F508del homozygotes as reflected in the early age of diagnosis, high sweat chloride concentration, insufficient pancreatic function, and low lung function, in contrast to 3849+10kbC-T/F508del compound heterozygotes having milder clinical phenotypes. The W1282R pathogenic variant is seemed to lead to severe disease phenotype with pancreatic insufficiency similarly to the F508del homozygous genotype.

scholarly journals Lung function and disease severity in cystic fibrosis patients heterozygous for p.Arg117His

2017 ◽  
Vol 3 (1) ◽  
pp. 00056-2016 ◽  
Author(s):  
Michal Shteinberg ◽  
Damian G. Downey ◽  
Diane Beattie ◽  
John McCaughan ◽  
Alastair Reid ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Disease Severity ◽  
Pancreatic Insufficiency ◽  
Forced Expiratory Volume ◽  
Class I ◽  
Lung Function Decline ◽  
Diagnostic Features ◽  
Sweat Chloride ◽  
In Trans

Expression of p.Arg117His cystic fibrosis (CF) transmembrane conductance regulator is influenced by a polythymidine (poly-T) tract and a thymidine–guanine (TG) repeat on intron 9, which vary in length and affect exon 10 skipping.We compared clinical characteristics and the rate of progression of lung disease of CF patients carrying the p.Arg117His mutation with different intron 9 varying sequences (poly-T) and mutation classes in trans.Data were collected from patients in Northern Ireland, UK, including diagnostic features, sweat chloride, nutritional status, sputum microbiology, CF-related complications and lung function. Poly-T and TG repeats were determined by PCR. Forced expiratory volume in 1 s (FEV1) decline was determined from linear regression of FEV1 measurements of patients over time.We identified 62 patients with p.Arg117His, 55 with a class I/II mutation in trans and six with p.Arg117His/p.Gly551Asp. 42 patients had 5T and 13 had 7T. All patients had 12 TG repeats. Patients with p.Arg117His-5T had greater lung function decline, sweat chloride concentrations, pancreatic insufficiency and prevalence of Pseudomonas aeruginosa infection compared with patients with p.Arg117His-7T.Lung function decline and disease severity in p.Arg117His is determined by the poly-T tract length and identity of the mutation in trans. Patients with p.Arg117His-5T and a second class I/II mutation have a severity similar to p.Phe508del homozygous patients, although lung function decline is delayed to an older age. There may be linkage disequilibrium between p.Arg117His and 12 TG repeats.

scholarly journals Correlations Between Respiratory Manifestations And Nutritional Status In Children With Cystic Fibrosis

2020 ◽  
Vol 26 (2) ◽  
pp. 85-90
Author(s):  
Cuzic Viviana ◽  
Mihai Cristina Maria ◽  
Bălașa Adriana ◽  
Mihai Larisia ◽  
Pantazi Alexandru Cosmin
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Nutritional Status ◽  
Genetic Disease ◽  
Severe Disease ◽  
Pancreatic Insufficiency ◽  
Clinical Manifestations ◽  
Failure To Thrive ◽  
Sweat Test ◽  
Heterozygous Patient

Abstract Background: Cystic fibrosis is a multisystemic genetic disease with autosomal recessive transmission, with progressive clinical evolution and potentially fatal, predominantly found in the Caucasian population. It is characterized by chronic lung disease and malabsorption caused by exocrine pancreatic insufficiency. Objective: Screening of patients with persistent respiratory disease and malabsorption syndrome to diagnose cystic fibrosis and monitoring the correlation between respiratory manifestations and nutritional status. Methods: A retrospective study on 8 patients diagnosed with cystic fibrosis, from Department of Pediatrics - Constanta County Emergency Hospital, during the period from 2015 to 2018. Results: 8 patients were diagnosed by genetic test for 34 mutations and polymorphism of CFTR gene; 2 homozygous patients with ∆F508 mutation (second class of mutations) with severe disease, 2 heterozygous patients with ∆F508 mutation del 2,3; 2 heterozygous patients with ∆F508 and R553X mutations, 1 heterozygous patient with N1303K and 394delTT mutations, 1 heterozygous patient with 2183 AA96 and ∆F508 mutation; 7 out of 8 patients were diagnosed in the first year of life by performing the sweat test, with values higher than 120 mmol/L. Clinical manifestations at onset were represented by diarrhea and failure to thrive in 4 cases and in 4 cases respiratory manifestations were associated. More than half of cases had less than 6 months of age at first respiratory exacerbation, which was associated with failure to thrive. Analyzing the correlation between genotype and anthropometric indicators, it was observed that the weight was more affected than the height. The analysis between nutritional status and lung function revealed that obstructive respiratory dysfunction with low FEV1 was correlated with nutritional status. Conclusion: Cystic fibrosis is a severe genetic disease and it is important to diagnose early, because it has been observed that if the diagnosis is established late, the consequences will be severe and lung function will deteriorate earlier.

Test for the Concentration of Electrolytes in Cystic Fibrosis of the Pancreas Utilizing Pilocarpine by Iontophoresis, by Lewis E. Gibson and Robert E. Cooke,Pediatrics; 1959;24:545–549

PEDIATRICS ◽  
1998 ◽  
Vol 102 (Supplement_1) ◽  
pp. 230-231
Author(s):  
Victor Chernick
Keyword(s):  
Cystic Fibrosis ◽  
Filter Paper ◽  
Direct Injection ◽  
Heat Stroke ◽  
Chloride Concentration ◽  
Hot Water ◽  
Sweat Test ◽  
High Concentration ◽  
Sweat Chloride ◽  
Plastic Bag

Aim. To develop a method for stimulating sweating that is rapid, painless, and avoids the risk of heat stress. Background. Since the discovery that there is a high concentration of sodium and chloride in the sweat of patients with cystic fibrosis of the pancreas in 1953, the sweat test has been performed by placing the patient's body in a plastic bag with or without hot water bottles to stimulate sweating. This method is unsatisfactory because of complications such as hyperpyrexia and heat stroke. Direct injection of a cholinergic agent intradermally is painful and therefore not practical. Methods. A rheostat with a milliampere meter was constructed at a cost of ∼$7 that allowed the iontophoresis of pilocarpine into the skin using negative and positive (2-cm diameter) electrocardiography electrodes. The positive electrode was placed on the flexor surface of the arm over a filter paper soaked in 0.2 mL of 0.2% pilocarpine nitrate. Current (0.2 mA) was applied for 5 minutes and then sweat was collected onto a preweighed filter paper for 30 minutes. Sweat chloride was determined by a polarographic method. Sweat tests were performed on 25 patients with cystic fibrosis (CF), 17 asymptomatic relatives and 27 control patients. Patients with CF had sweat chloride concentration >80 mEq/L; relatives, 32.5 mEq/L (highest 57 mEq/L); and control subjects, 21.1 mEq/L (highest 60 mEq/L). Conclusions. The iontophoresis of pilocarpine into the skin is a rapid, painless, safe, and reliable method for stimulating sweating and facilitating the determination of sweat chloride concentration.

Uncertainty of sweat chloride testing: does the right hand know what the left hand is doing?

2008 ◽  
Vol 45 (6) ◽  
pp. 535-538 ◽  
Author(s):  
R J Mackay ◽  
C M Florkowski ◽  
P M George ◽  
C W Sies ◽  
S Woods
Keyword(s):  
Total Variation ◽  
Coefficient Of Variation ◽  
Age Groups ◽  
Chloride Concentration ◽  
Sweat Test ◽  
Left Hand ◽  
Sweat Chloride ◽  
The Difference ◽  
The Right ◽  
Analytical Variation

Although analytical variation in sweat electrolyte testing can be easily estimated, there is limited data on total variation. This study aims to evaluate the total variation of the sweat test by measuring the difference between sweat electrolyte values in specimens obtained simultaneously from two sites. Chloride is recommended in published guidelines as the only discriminant for the diagnosis of cystic fibrosis, and sodium may be measured as a guide to the adequacy of collection and analysis. Both are reported here. Sweat was collected in patients by the Gibson Cooke method from two sites simultaneously. Coefficient of variation in this laboratory is 4.1 and 5% for chloride and sodium, respectively. 295 patients had sufficient sweat collected from both sites for analysis. The values for chloride and sodium were compared between the two sites. The total coefficient of variation (CVt) calculated for the whole group between the two sites was 20.2% for chloride and 16.9% for sodium, and the standard deviations 4.3 mmol/L and 4.8 mmol/L, respectively. In patients with intermediate chloride concentrations; in different age groups; and when those tests with a difference between sodium and chloride concentration of more than 15 were excluded, minimal differences in these figures were observed. Use of strictly defined cut-off points to discriminate between normal and intermediate electrolyte values, and between intermediate and raised electrolyte values, does not reflect the variation in sweat electrolyte content found within an individual patient. This has important implications for reporting.

scholarly journals Long-Term Outcomes in Real Life of Lumacaftor–Ivacaftor Treatment in Adolescents With Cystic Fibrosis

2021 ◽  
Vol 9 ◽  
Author(s):  
Stéphanie Bui ◽  
Alexandra Masson ◽  
Raphaël Enaud ◽  
Léa Roditis ◽  
Gaël Dournes ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Real Life ◽  
Chloride Concentration ◽  
Electronic System ◽  
Antibiotic Use ◽  
Response To Treatment ◽  
Life Study ◽  
Sweat Chloride

Background: The combination of the CFTR corrector lumacaftor (LUM) and potentiator ivacaftor (IVA) has been labeled in France since 2015 for F508del homozygote cystic fibrosis (CF) patients over 12 years. In this real-life study, we aimed (i) to compare the changes in lung function, clinical (e.g., body mass index and pulmonary exacerbations) and radiological parameters, and in sweat chloride concentration before and after initiation of LUM/IVA treatment; (ii) to identify factors associated with response to treatment; and (iii) to assess the tolerance to treatment.Materials and Methods: In this tri-center, non-interventional, and observational cohort study, children (12–18 years old) were assessed prospectively during the 2 years of therapy, and retrospectively during the 2 years preceding treatment. Data collected and analyzed for the study were exclusively extracted from the medical electronic system records of the patients.Results: Forty adolescents aged 12.0–17.4 years at LUM/IVA initiation were included. The lung function decreased significantly during and prior to treatment and increased after LUM/IVA initiation, becoming significant after 2 years of treatment. LUM/IVA significantly improved the BMI Z-score and sweat chloride concentration. By contrast, there was no significant change in exacerbation rates, antibiotic use, or CT scan scores. Age at LUM/IVA initiation was lower in good responders and associated with greater ppFEV1 change during the 2 years of treatment. LUM/IVA was well-tolerated.Conclusion: In F508del homozygote adolescents, real-life long-term LUM/IVA improved the ppFEV1 trajectory, particularly in the youngest patients, nutritional status, and sweat chloride concentration but not exacerbation rates or radiological scores. LUM/IVA was generally well-tolerated and safe.

scholarly journals Stratifying infants with cystic fibrosis for disease severity using intestinal organoid swelling as a biomarker of CFTR function

2018 ◽  
Vol 52 (3) ◽  
pp. 1702529 ◽  
Author(s):  
Karin M. de Winter-de Groot ◽  
Hettie M. Janssens ◽  
Rick T. van Uum ◽  
Johanna F. Dekkers ◽  
Gitte Berkers ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Disease Severity ◽  
Gastrointestinal Disease ◽  
Pancreatic Insufficiency ◽  
Chloride Concentration ◽  
Individual Level ◽  
Outcome Parameters ◽  
Sweat Chloride ◽  
Intestinal Organoids ◽  
Residual Capacity

Forskolin-induced swelling (FIS) of intestinal organoids from individuals with cystic fibrosis (CF) measures function of the cystic fibrosis transmembrane conductance regulator (CFTR), the protein mutated in CF.We investigated whether FIS corresponds with clinical outcome parameters and biomarkers of CFTR function in 34 infants diagnosed with CF. Relationships with FIS were studied for indicators of pulmonary and gastrointestinal disease.Children with low FIS had higher levels of immunoreactive trypsinogen (p=0.030) and pancreatitis-associated protein (p=0.039), more often had pancreatic insufficiency (p<0.001), had more abnormalities on chest computed tomography (p=0.049), and had lower z-scores for maximal expiratory flow at functional residual capacity (p=0.033) when compared to children with high FIS values. FIS significantly correlated with sweat chloride concentration (SCC) and intestinal current measurement (ICM) (r= −0.82 and r=0.70, respectively; both p<0.001). Individual assessment of SCC, ICM and FIS suggested that FIS can help to classify individual disease severity.Thus, stratification by FIS identified subgroups that differed in pulmonary and gastrointestinal outcome parameters. FIS of intestinal organoids correlated well with established CFTR-dependent biomarkers such as SCC and ICM, and performed adequately at group and individual level in this proof-of-concept study.

Evaluation of a cystic fibrosis screening system incorporating a miniature sweat stimulator and disposable chloride sensor.

1986 ◽  
Vol 32 (5) ◽  
pp. 850-853 ◽  
Author(s):  
W J Warwick ◽  
N N Huang ◽  
W W Waring ◽  
A G Cherian ◽  
I Brown ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Chloride Concentration ◽  
Test System ◽  
Sweat Test ◽  
Sweat Chloride ◽  
The Subject ◽  
New System ◽  
Chloride Concentrations ◽  
Cystic Fibrosis Screening ◽  
Center Study

Abstract A new sweat test (CF Indicator; Medtronic, Inc.) for cystic fibrosis (CF) features a compact, portable configuration of electrodes that dispense pilocarpine for iontophoresis. A disposable chloride sensor patch absorbs a specified volume of sweat, in which the chloride concentration is immediately determined as less than 40, 40-60, or greater than 60 mmol/L. We assessed the performance of the system in a five-center study, in relation to the clinical diagnosis and to the Gibson-Cooke sweat test (GCST) as a control test. With sweat chloride concentrations of less than or equal to 40 mmol/L defined as normal and greater than 40 mmol/L as indicating persons at risk for CF, the new system showed 91% specificity and 100% sensitivity for CF, as compared with 92.8% and 100%, respectively, for the GCST. When we used sweat chloride concentrations of less than or equal to 60 mmol/L as probably normal and greater than 60 mmol/L as probably indicative of CF, the new system showed a 99.1% specificity and 98.6% sensitivity, vs 97.8% specificity and 97.9% sensitivity for the GCST test. In both procedures, occasionally insufficient sweat was collected, and this appeared related to the age of the subject. We conclude that the new sweat test system is potentially useful in physicians' offices, in clinics, and similar settings.

scholarly journals Forskolin-induced swelling of intestinal organoids predicts long-term cystic fibrosis disease progression

2021 ◽  
Author(s):  
D. Muilwijk ◽  
E. de Poel ◽  
P. van Mourik ◽  
S.W.F. Suen ◽  
A.M. Vonk ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Disease Progression ◽  
Pancreatic Insufficiency ◽  
Chloride Concentration ◽  
Predictive Biomarker ◽  
Sweat Chloride ◽  
Intestinal Organoids ◽  
Clinical Consequences ◽  
Related Liver Disease

ABSTRACTPatient-derived organoids hold great potential as predictive biomarker for disease expression or therapeutic response. Here, we used intestinal organoids to estimate individual cystic fibrosis transmembrane conductance regulator (CFTR) function of people with cystic fibrosis, a monogenic life-shortening disease associated with more than 2000 CFTR mutations and highly variable disease progression. In vitro CFTR function in CF intestinal organoids of 176 individuals with diverse CFTR mutations was quantified by forskolin induced swelling and was strongly associated with longitudinal changes of lung function and development of pancreatic insufficiency, CF-related liver disease and diabetes. This association was not observed when the commonly used biomarker of CFTR function sweat chloride concentration was used. The data strongly exemplifies the value of an organoid-based biomarker in a clinical disease setting and supports the prognostic value of forskolin induced swelling of intestinal organoids, especially for people with CF who have rare CFTR genotypes with unclear clinical consequences.

scholarly journals Two years of newborn screening for cystic fibrosis in North Macedonia: First experience

2021 ◽  
Vol 24 (1) ◽  
pp. 41-46
Author(s):  
S Fustik ◽  
V Anastasovska ◽  
D Plaseska-Karanfilska ◽  
A Stamatova ◽  
L Spirevska ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pilot Study ◽  
Newborn Screening ◽  
Chloride Concentration ◽  
Sweat Test ◽  
Sweat Chloride ◽  
Frequent Mutations ◽  
Cftr Mutations ◽  
The Republic ◽  
Cf Transmembrane Conductance Regulator

Abstract There is a widely accepted consensus on the benefits of newborn screening (NBS) for cystic fibrosis (CF) in terms of reduced disease severity, improved quality of life, lower treatment burden, and reduced costs. More and more countries in the world are introducing NBS for CF as a national preventive health program. Newborn screening for CF was introduced in the Republic of North Macedonia (RNM) in April, 2019, after a pilot study of 6 months in 2018. A two-step immunoreactive trysinogen (IRT-IRT) algorithm is performed, and then a sweat test for confirmation/exclusion of the CF diagnosis when the IRT values were both over the cutoff (70.0 and 45.0 ng/mL, respectively). In cases with confirmed diagnosis of CF (a sweat chloride concentration >60.0 mmol/L) or with intermediate sweat test results (a sweat chloride concentration of between 30.0 and 59.0 mmol/L), CF transmembrane conductance regulator (CFTR) mutation analysis is performed. By the end of 2020, over a period of 27 months, including the pilot study period, a total number of 43,139 newborns were screened for CF. Seventeen (0.039%) newborns were diagnosed with CF. In all newly discovered CF cases by screening, the diagnosis was confirmed by determination of the CFTR mutations. The most common CFTR mutation, F508del, was found with an overall incidence of 70.6%. Other more frequent mutations were G542X (11.8%) and N1303K (5.9%). Four mutations were found in one CFTR allele each: G1349D, G126D, 457TAT>G and CFTRdupexon22, with the last one being newly discovered with unknown consequences. An incredibly large difference was found in the incidence of the disease between the Macedonian and Albanian neonatal population, with almost four time higher prevalence among Albanians (1:4530 vs. 1:1284).

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