Severity of cystic fibrosis in patients homozygous and heterozygous for ΔF508 mutation

Johansen, H.; Nir, Marta; Høiby, Niels; Koch, Christian; Schwartz, Marianne

doi:10.1016/0140-6736(91)92449-c

Cited by 164 publications

(108 citation statements)

References 17 publications

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“…Esses dados estão de acordo com a literatura internacional, onde vários autores demonstraram que a mutação ∆F508 está associada à presença de insuficiência pancreática [9][10][11][12][13] .…”

Section: Discussionunclassified

Cystic fibrosis at a Brazilian center of excellence: clinical and laboratory characteristics of 104 patients and their association with genotype and disease severity

et al. 2004

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Objective: To identify the clinical, laboratory and radiographic characteristics of the cystic fibrosis patients under care at Universidade Estadual de Campinas (UNICAMP) in the last decade of the twentieth century, and to investigate the association of these characteristics with genotype and severity of the disease as measured by the Shwachman score.Methods: Descriptive, retrospective and cross-sectional study of the patients assisted at UNICAMP hospitals Cystic Fibrosis Clinic from July 1990 to July 2000. Results:One hundred and four patients were studied; 53.8% male; 93.3% Caucasian; 89.4% presented with respiratory symptoms; 59.6% presented with digestive symptoms; 5.8% had meconium ileus; 4.8% had diabetes. The mean age at onset of symptoms was 3 months, and the mean age at diagnosis was 2 years and 4 months. At diagnosis, 69.9 and 56.6% of the patients had weight and height below 10 th percentile, respectively; in 10.6%, sweat chloride was < 60 mEq/l. Staphylococcus aureus was found in 80.2%, Pseudomonas aeruginosa in 76.0%, and Burkholderia cepacia in 5.2%. ∆F508 homozygosis was observed in 18.75%, whereas 62.50% of the patients were ∆F508 heterozygous. A moderate/severe Shwachman score was found in 15.7%. Eighteen patients died in that period (17.3%). The mean age at death was 7 years and 8 months; median survival after diagnosis was 18 years and 4 months. Patients who have at least one ∆F508 mutation have more frequent alterations in fecal fat levels when compared to patients who do not have this mutation (p < 0.05). There were no differences in any parameter between ∆F508 homozygous and heterozygous patients. Conclusions:The clinical and laboratory characteristics of the 104 patients studied were similar to the characteristics described for patients in other countries. Exceptions are the higher age at diagnosis and lower survival. Our results support the recommendation for early diagnosis and the need for more treatment opportunities in the population of cystic fibrosis patients. ResumoObjetivo: Estudar as características clínicas, laboratoriais e radiográficas de pacientes fibrocísticos acompanhados na última década do século 20 na UNICAMP e verificar se existe associação com o genótipo e a gravidade da doença medida pelo escore de Shwachman.Métodos: Estudo descritivo, retrospectivo e de corte transversal dos pacientes fibrocísticos acompanhados na UNICAMP, que tiveram atendimento entre julho de 1990 e julho de 2000.Resultados: Foram estudados 104 pacientes: sexo masculino -53,8%; raça caucasóide -93,3%; comprometimento pulmonar -89,4%, comprometimento digestivo -59,6%; íleo meconial -5,8%; diabetes melito -4,8%; mediana da idade de início dos sintomas -3 meses; mediana da idade no diagnóstico -2 anos e 4 meses; 69,9 e 56,6% apresentavam peso e estatura abaixo do percentil 10, respectivamente, na época do diagnóstico; dosagem de cloro no suor < 60 mEq/l -10,6%; colonização: S. aureus -80,2%, P. aeruginosa -76,0%, B. cepacia -5,2%; ∆F508 homozigoto -18,75%, ∆F508heterozigoto -62,5%; escore de ...

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Section: Discussionunclassified

Cystic fibrosis at a Brazilian center of excellence: clinical and laboratory characteristics of 104 patients and their association with genotype and disease severity

et al. 2004

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“…1 The most common disease-causing lesion F508del-CFTR is observed on about 70% of Caucasian CF chromsomes. 2 Even though about half of the CF patients are homozygous for the same CFTR mutation, the clinical course of disease was noticed to be highly variable even among F508del-CFTR homozygous individuals 3 and also within F508del-CFTR homozygous sibling pairs 4 indicating that genes other than CFTR shape the phenotype of the monogenic disease CF.…”

Section: Introductionmentioning

confidence: 99%

Expression levels of FAS are regulated through an evolutionary conserved element in intron 2, which modulates cystic fibrosis disease severity

et al. 2008

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We have analyzed frequent naturally occurring variants in the autogene FAS in two independent cystic fibrosis (CF) patient populations. Analysis of FAS expression levels from intestinal epithelial biopsies from 16 unrelated F508del-CFTR homozygotes showed a correlation between FAS intron 2 SNP rs7901656 and signals for Affymetrix GeneChip U133 Plus 2.0 probeset 204781_s_at consistent with a dominant model (P ¼ 0.0009). Genotype and haplotype analysis at six informative SNPs spanning the FAS gene locus was carried out on 37 nuclear families representing extreme clinical phenotypes that were selected from the European CF Twin and Sibling Study population of more than 300 affected sibling pairs. Case-control comparison of the haplotype composed of rs2296603-rs7901656-rs1571019 encompassing intron 2 of FAS reached significance (P ¼ 0.0246). Comparative phylogenetic analysis and functional annotation of the FAS intron 2 sequence revealed a conserved non-coding sequence surrounding rs7901656 and predicted binding sites for four transcription factors whereby the binding site of c-Rel is altered by rs7901656. Taken together, these findings from two independent CF patient cohorts indicate that allelic variants within FAS intron 2 alter FAS gene expression and that these functional variants modulate the manifestation of CF disease.

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“…1 The di sease i s caused by mutati ons i n both chromosomal copi es of the cysti c fi brosi s transmembrane conductance regul ator (CFTR) gene. 2 The course of CF i s hi ghl y vari abl e w hen compari ng unrel ated pati ents w i th i denti cal CFTR mutati on genotypes, 3,4 or even CF si bl i ngs w ho carry the same CFTR al l el es and share several envi ronmental factors, such as soci oeconomi c status, general l i vi ng condi ti ons and therapeuti c measures. Thi s i ndi cates the i mpact of factors other than the CFTR genotype on the CF di sease phenotype.…”

Section: Introductionmentioning

confidence: 99%

Categories of ΔF508 homozygous cystic fibrosis twin and sibling pairs with distinct phenotypic characteristics

et al. 2000

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Cysti c fi br osi s (CF), the most common sever e autosomal r ecessi ve tr ai t among Caucasi ans, i s caused by mol ecul ar l esi ons i n the cysti c fi br osi s tr ansmembr ane conductance r egul ator gene (CFTR). The cour se of the mul ti -or gan di sease CF i s hi ghl y var i abl e, suggesti ng the i nfl uence of envi r onmental factor s and/or modul ati ng genes other than CFTR on the di sease phenotype. To evaluate the cause of CF disease variability, the European CF Twin and Sibling Study col l ected data on tw o cl i ni cal par ameter s most sensi ti ve for the cour se and pr ognosi s of CF, i e w ei ght pr edi cted for hei ght (w fh)% (r epr esentati ve for the nutr i ti onal status) and FEVPer c (r epr esentati ve for the pul monar y status) for a cohor t of 277 si bl i ng pai r s, 12 pai r s of di zygous tw i ns and 29 pai r s of monozygous tw i ns. Of these 318 CF tw i n and si b pai r s, 114 w er e r epor ted to be homozygous for the most fr equent CF di sease-causi ng l esi on, ∆F508. I ntr a-pai r di scor dance w as assessed by the i ntr a-pai r di ffer ences w i th w fh% and FEVPer c and by DELTA , a composi te par ameter defi ned by l i near combi nati on of w fh% and FEVPer c i n or der to descr i be di scor dance w i th r espect to the overall disease severity. Monozygous twins had a significantly lower DELTA than dizygous twins (P = 0.05) i ndi cati ng that CF di sease sever i ty i s modul ated by an i nher i ted component i n addi ti on to the CFTR gene i tsel f. Extr eme phenotypes ar e consi der ed to be mor e i nfor mati ve for the anal ysi s of any quanti tati ve tr ai t. Thus, w e ai med to quanti fy di sease sever i ty and i ntr a-pai r di scor dance i n or der to sel ect pai r s w i th the extr eme phenotypes DI S (di scor dant pati ent pai r s), CON + (concor dant and mi l dy affected pati ent pai r s) and CON -(concor dant and sever el y affected pati ent pairs). The algorithm reliably discriminated between pairs DIS, CON + and CON -among the cohor t of ∆F508 homozygotes. The sel ected pai r s fr om these categor i es demonstr ated non-over l appi ng pr oper ti es for w fh%, FEVPer c and the i ntr a-pai r di ffer ence of both par ameter s. Twin Research (2000) 3, 277-293. Keyw or ds: cysti c fi brosi s di sease severi ty, affected rel ati ve pai r, tw i n and si bl i ng study, extreme phenotypes, al gori thm based sel ecti on I ntr oducti on Cysti c fi brosi s (CF) i s know n as the most common severe autosomal recessi ve di sease w i thi n the Caucasi an popul ati on, exhi bi ti ng an i nci dence of 1 i n 2500 bi rths.1 The symptoms of the di sorder are caused by an i mpai red functi on of exocri ne gl ands i n many organs, but major mani festati ons i nvol ve the respi ratory and the gastroi ntesti nal tracts.1 The di sease i s caused by mutati ons i n both chromosomal copi es of the cysti c fi brosi s transmembrane conductance regul ator (CFTR) gene. 2 The course of CF i s hi ghl y vari abl e w hen compari ng unrel ated pati ents w i th i denti cal CFTR mutati on genotypes, 3,4 o...

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Severity of cystic fibrosis in patients homozygous and heterozygous for ΔF508 mutation

Cited by 164 publications

References 17 publications

Cystic fibrosis at a Brazilian center of excellence: clinical and laboratory characteristics of 104 patients and their association with genotype and disease severity

Cystic fibrosis at a Brazilian center of excellence: clinical and laboratory characteristics of 104 patients and their association with genotype and disease severity

Expression levels of FAS are regulated through an evolutionary conserved element in intron 2, which modulates cystic fibrosis disease severity

Categories of ΔF508 homozygous cystic fibrosis twin and sibling pairs with distinct phenotypic characteristics

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