BACKGROUND: In questionable cystic fibrosis (CF), mild or monosymptomatic phenotypes frequently cause diagnostic difficulties despite detailed algorithms. CF transmembrane conductance regulator (CFTR)-mediated ion transport can be studied ex vivo in rectal biopsies by intestinal current measurement (ICM). OBJECTIVES: To describe reference values and validate ICM for the diagnostic classification of questionable CF at all patient ages. METHODS: ICM was performed in 309 rectal biopsies from 130 infants, children and adults including patients with known pancreatic-insufficient (PI)-CF (n=34), pancreatic-sufficient (PS)-CF (n=7), patients with an unclear diagnosis with mild CF symptoms, intermediate sweat test and/or CFTR mutation screening (n=61) and healthy controls (n=28). ICM was correlated to sweat chloride, extensive CFTR genotype and transcript analysis in the diagnostic group. The results were compared with previous ICM data in subjects with CF, congenital bilateral absence of the vas deferens, heterozygotes and controls. RESULTS: The cumulative chloride secretory response of DeltaI(sc,carbachol), DeltaI(sc,cAMP/forskolin) and DeltaI(sc,histamine) was the best diagnostic ICM parameter (cut-off 34 muA/cm(2) between patients with known PS-CF and controls), differentiating patients with questionable CF into PS-CF (n=6) and 'CF unlikely' (n=55) groups. Extensive genotype analysis detected two mutations (40% disease-causing) in 100% of individuals classified as PS-CF compared with 1.8% in those classified as 'CF unlikely'. CONCLUSIONS: This comprehensive investigation of CFTR function and genotype underlines the diagnostic value of ICM, especially for confirmation of CF in the absence of two disease-causing CFTR mutations, exclusion of CF despite intermediate sweat test and age groups unsuitable for nasal potential difference measurements. ICM is an important tool for functional assessment in CFTR mutations of unknown clinical relevance.
BACKGROUND: In questionable cystic fibrosis (CF), mild or monosymptomatic phenotypes frequently cause diagnostic difficulties despite detailed algorithms. CF transmembrane conductance regulator (CFTR)-mediated ion transport can be studied ex vivo in rectal biopsies by intestinal current measurement (ICM). OBJECTIVES: To describe reference values and validate ICM for the diagnostic classification of questionable CF at all patient ages. METHODS: ICM was performed in 309 rectal biopsies from 130 infants, children and adults including patients with known pancreatic-insufficient (PI)-CF (n=34), pancreatic-sufficient (PS)-CF (n=7), patients with an unclear diagnosis with mild CF symptoms, intermediate sweat test and/or CFTR mutation screening (n=61) and healthy controls (n=28). ICM was correlated to sweat chloride, extensive CFTR genotype and transcript analysis in the diagnostic group. The results were compared with previous ICM data in subjects with CF, congenital bilateral absence of the vas deferens, heterozygotes and controls. RESULTS: The cumulative chloride secretory response of DeltaI(sc,carbachol), DeltaI(sc,cAMP/forskolin) and DeltaI(sc,histamine) was the best diagnostic ICM parameter (cut-off 34 muA/cm(2) between patients with known PS-CF and controls), differentiating patients with questionable CF into PS-CF (n=6) and 'CF unlikely' (n=55) groups. Extensive genotype analysis detected two mutations (40% disease-causing) in 100% of individuals classified as PS-CF compared with 1.8% in those classified as 'CF unlikely'. CONCLUSIONS: This comprehensive investigation of CFTR function and genotype underlines the diagnostic value of ICM, especially for confirmation of CF in the absence of two disease-causing CFTR mutations, exclusion of CF despite intermediate sweat test and age groups unsuitable for nasal potential difference measurements. ICM is an important tool for functional assessment in CFTR mutations of unknown clinical relevance.
Authors: Marianne S Muhlebach; J P Clancy; Sonya L Heltshe; Assem Ziady; Tom Kelley; Frank Accurso; Joseph Pilewski; Nicole Mayer-Hamblett; Elizabeth Joseloff; Scott D Sagel Journal: J Cyst Fibros Date: 2016-10-27 Impact factor: 5.482
Authors: Marisa Sousa; Maria F Servidoni; Adriana M Vinagre; Anabela S Ramalho; Luciana C Bonadia; Verónica Felício; Maria A Ribeiro; Inna Uliyakina; Fernando A Marson; Arthur Kmit; Silvia R Cardoso; José D Ribeiro; Carmen S Bertuzzo; Lisete Sousa; Karl Kunzelmann; Antônio F Ribeiro; Margarida D Amaral Journal: PLoS One Date: 2012-10-17 Impact factor: 3.240
Authors: Eva K Roth; Stephanie Hirtz; Julia Duerr; Daniel Wenning; Irmgard Eichler; Hans H Seydewitz; Margarida D Amaral; Marcus A Mall Journal: PLoS One Date: 2011-08-31 Impact factor: 3.240
Authors: Elena Kondratyeva; Tatyana Bukharova; Anna Efremova; Yuliya Melyanovskaya; Natalia Bulatenko; Ksenia Davydenko; Alexandra Filatova; Mikhail Skoblov; Stanislav Krasovsky; Nika Petrova; Alexander Polyakov; Tagui Adyan; Elena Amelina; Vera Shadrina; Elena Zhekaite; Aysa Zodbinova; Alexander Chernyak; Rena Zinchenko; Sergei Kutsev; Dmitry Goldshtein Journal: Genes (Basel) Date: 2021-05-28 Impact factor: 4.096
Authors: Maria F Servidoni; Marisa Sousa; Adriana M Vinagre; Silvia R Cardoso; Maria A Ribeiro; Luciana R Meirelles; Rita B de Carvalho; Karl Kunzelmann; Antônio F Ribeiro; José D Ribeiro; Margarida D Amaral Journal: BMC Gastroenterol Date: 2013-05-20 Impact factor: 3.067
Authors: John P Clancy; Rhonda D Szczesniak; Melissa A Ashlock; Sarah E Ernst; Lijuan Fan; Douglas B Hornick; Philip H Karp; Umer Khan; James Lymp; Alicia J Ostmann; Amir Rezayat; Timothy D Starner; Shajan P Sugandha; Hongtao Sun; Nancy Quinney; Scott H Donaldson; Steven M Rowe; Sherif E Gabriel Journal: PLoS One Date: 2013-09-10 Impact factor: 3.240