ABCMdb

PMID: 25698453

Carter S, Kelly S, Caples E, Grogan B, Doyle J, Gallagher CG, McKone EF
Ivacaftor as salvage therapy in a patient with cystic fibrosis genotype F508del/R117H/IVS8-5T.
J Cyst Fibros. 2015 Jul;14(4):e4-5. doi: 10.1016/j.jcf.2015.01.010. Epub 2015 Feb 16., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC7 p.Gly551Asp ABCC7 p.Arg117His Case Report Ivacaftor as salvage therapy in a patient with cystic fibrosis genotype F508del/R117H/IVS8-5T S. Carter, S. Kelly, E. Caples, B. Grogan, J. Doyle, C.G. Gallagher, E.F. McKone Ìe; National Referral Centre for Adult Cystic Fibrosis, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland Received 12 January 2015; revised 23 January 2015; accepted 23 January 2015 Available online 16 February 2015 Abstract Ivacaftor is a novel CFTR potentiator that increases CFTR activity and improves clinical outcomes in cystic fibrosis (CF) patients with at least one copy of CFTR-G551D. Login to comment 1 ABCC7 p.Gly551Asp Clinical trials have shown an improvement in lung function, weight and CF pulmonary exacerbation in adults with CFTR-G551D leading to the approval of ivacaftor as a novel CF therapy [1]. Login to comment 2 ABCC7 p.Gly551Asp In vitro studies of ivacaftor have also shown significant improvements in CFTR chloride channel opening time in other non-G551D CFTR mutations suggesting that ivacaftor may be of benefit to patients with mutations other than gating mutations [2]. Login to comment 3 ABCC7 p.Arg117His R117H-CFTR is a relatively common CFTR mutation that demonstrates an in-vitro response to ivacaftor [2,3]. Login to comment 4 ABCC7 p.Arg117His A clinical trial has suggested that there may be a role for ivacaftor in older patients with R117H-CFTR although this trial did not include patients with very severe CF lung disease [4]. Login to comment 5 ABCC7 p.Arg117His In 2014, ivacaftor was approved in the United States as a treatment for CF subjects aged greater than 6 years old with a copy of R117H-CFTR. Login to comment 6 ABCC7 p.Arg117His We present a case demonstrating a substantial therapeutic effect of ivacaftor in a CF patient with genotype F508del/R117H and advanced lung disease. Login to comment 9 ABCC7 p.Arg117His Clinical Case MC, a 45 year old male with CF (F508del/R117H/IVS8-5T/ 9T), was diagnosed at the age of 16 years old. Login to comment 32 ABCC7 p.Arg117His Discussion R117H-CFTR is a CFTR mutation that is found in between 2% and 14% of CF patients worldwide. Login to comment 34 ABCC7 p.Arg117His R117H-CFTR results in impaired CFTR conductance with some preservation of CFTR function. Login to comment 35 ABCC7 p.Arg117His As a result, R117H-CFTR, when occurring on the opposite chromosome (in-trans) to a severe CFTR mutation, is associated with a milder CF phenotype with later age at diagnosis, older onset of pancreatic insufficiency and less severe lung disease than those with 2 severe CFTR mutations [5,6]. Login to comment 36 ABCC7 p.Arg117His The R117H-CFTR phenotype is quite variable with some of this variability explained by the presence of additional CFTR polymorphisms. Login to comment 38 ABCC7 p.Arg117His ABCC7 p.Arg117His An IVS8-5T repeat variant in-cis with R117H-CFTR is associated with a more reduced CFTR activity and a more severe phenotype compared to the patients who have R117H-CFTR in-cis with either the 7T or 9T variant [8,9]. Login to comment 39 ABCC7 p.Arg117His ABCC7 p.Arg117His The perception that R117H-CFTR only causes a mild phenotype has led to R117H-CFTR being reconsidered for inclusion in CF newborn screening programs [10]. Login to comment 40 ABCC7 p.Arg117His In countries where R117H-CFTR occurs predominantly on a background of IVS8-5T, such as the UK [11] and Ireland (Dr David Barton, personal communication), CF patients can have very severe disease as seen in this case. Login to comment 41 ABCC7 p.Arg117His These patients also may have a greater therapeutic benefit with drugs like ivacaftor as their CFTR expression is both reduced in function due to the impaired conductance seen with R117H-CFTR as well as reduced in quantity as a result of the IVS8-5T splicing variant. Login to comment 43 ABCC7 p.Arg117His ABCC7 p.Arg117His This is supported by the recent clinical trial results that show a benefit of ivacaftor in adult R117H patients with more severe disease who are more likely to have the R117H-IVS5T variants. Login to comment