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

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

The Lancet

Volume 337, Issue 8742, 16 March 1991, Pages 631-634

https://doi.org/10.1016/0140-6736(91)92449-C Get rights and content

Abstract

To assess the relation between genotype and severity of disease in cystic fibrosis (CF) the frequencies and extent of several features of its phenotypic expression were investigated in the 235 patients who attend the Danish CF Centre. 14 patients who attend irregularly and 3 who do not carry the ΔF508 mutation at all were excluded. The case-reports of the remaining 218 patients (aged 4 months to 41 years) were carefully evaluated, and they were all analysed for the ΔF508 mutation. 172 (79%) were homozygous for ΔF508 and 46 (20%) were heterozygous. The mutation therefore occurs on 89% of the chromosomes analysed. There were no significant differences between the homozygous and heterozygous groups in the proportions with meconium ileus at birth, liver involvement, or chronic Pseudomonas aeruginosa infection. However, significantly more of the homozygous patients had onset of symptoms before the age of 6 months (p<0·025); they were significantly younger at diagnosis (p=0·013) and centre referral (p=0·006); they required greater pancreatic enzyme substitution (p=0·0002) and had poorer lung function; and the calculated yearly incidence of chronic Ps aeruginosa infection and yearly mortality rates were greater than in heterozygous patients (p=0·0001).

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Cited by (149)

Disease burden in people with cystic fibrosis heterozygous for F508del and a minimal function mutation
2022, Journal of Cystic Fibrosis
Citation Excerpt :
The introduction of CFTR modulator (CFTRm) treatment has shifted focus from phenotype to genotype; therefore, treatment choice in some people with CF is now also determined by considering the molecular consequences of the CFTR defect associated with a given mutation in relation to the mechanisms of action of specific CFTRm regimens.[2] While the early-onset, multiorgan disease phenotype of people with CF who are homozygous for the F508del-CFTR mutation is relatively well understood,[3,4] the burden of CF has not been well characterized in people heterozygous for the F508del-CFTR mutation (F) and a minimal function CFTR mutation (MF), that is, those with F/MF genotypes. MF mutations either result in no production of CFTR protein or result in CFTR protein that is not responsive to tezacaftor (TEZ), ivacaftor (IVA), and TEZ/IVA in vitro.[5]
People with cystic fibrosis (CF) heterozygous for F508del-CFTR and a minimal function CFTR mutation (F/MF) that results in no CFTR protein or results in CFTR protein that is not responsive to tezacaftor, ivacaftor, and tezacaftor/ivacaftor in vitro comprise a sizeable percentage of the US CF population. This retrospective, cross-sectional, observational study aimed to characterize CF burden in this subpopulation.
People ≥2 years of age in the US CF Foundation Patient Registry with a CF diagnosis, F/MF genotype, and ≥1 encounters in 2017 were included. Descriptive analyses assessed lung function, nutritional parameters, microbiology, hospitalization and pulmonary exacerbation rates, and CF-related complications. Results were stratified by age group; select characteristics were summarized by percent predicted FEV₁ (ppFEV₁) and ethnicity.
5348 people met inclusion criteria. Rates of positive bacterial cultures, pulmonary exacerbations, and hospitalizations were generally higher in older age groups. Prevalence of prescribed symptomatic CF therapies was substantial and also generally higher in older age groups. ppFEV₁ was lower in older age groups. A greater percentage of adolescents and adults reported complications, including cirrhosis, osteoporosis, osteopenia, and sinus disease, than younger age groups. Increased prevalence of cultured Pseudomonas aeruginosa and prescribed chronic therapy was seen with decreasing ppFEV₁. In each age group, ppFEV₁ was slightly higher in the non-Hispanic cohort than in the Hispanic cohort.
People with F/MF genotypes have substantial disease burden that worsened in older age groups consistent with the progressive nature of CF, indicating need for additional treatment options in this subpopulation.
Real-world use of ivacaftor in Canada: A retrospective analysis using the Canadian Cystic Fibrosis Registry
2021, Journal of Cystic Fibrosis
: Ivacaftor is a CFTR potentiator with demonstrated efficacy in clinical trials and has been rapidly adopted within the CF community. Given the uptake of ivacaftor in eligible people, identifying a comparator group not on modulators to measure effectiveness is difficult. We evaluated health outcomes in individuals with G551D and non-G551D genotypes on ivacaftor using real-world longitudinal data.
: This population-based observational study compared clinical trajectories pre-post ivacaftor using the Canadian CF Registry from 2006 to 01–01 through 2018–12–31. Piece-wise linear mixed-effects models were used to compare lung function, nutritional status, pulmonary exacerbations, and Pseudomonas colonization pre- and post-ivacaftor. Multivariable models were used to adjust for confounding factors.
: Forced expiratory volume in 1 second (FEV1) increased significantly by 5.7 percent predicted (95% confidence interval (CI) 3.9, 7.5; p<0.001) after initiation of ivacaftor. FEV1 decline rate was attenuated to -0.30% (95% CI -0.9, 0.29; p = 0.32) predicted/year post-ivacaftor, compared with -0.75% (95% CI -1.12, -0.37; p<0.001) predicted/year pre-ivacaftor, although this difference did not reach statistical significance. BMI percentiles also increased post-ivacaftor (6.57 percentiles, 95% CI 3.91, 9.24; p<0.001). Pulmonary exacerbations showed a nonsignificant reduction of 18% (RR 0.82, 95% CI 0.61, 1.11; p = 0.19) and the odds of a positive sputum culture for Pseudomonas aeruginosa decreased in the post-ivacaftor period (odds ratio 0.44, 95% CI 0.30, 0.63; p<0.001).
: This real-world, observational study demonstrated improvement in health outcomes in a broad population of people with CF. Additional studies are needed to evaluate the impact of ivacaftor on quality of life and survival.
Elexacaftor–tezacaftor–ivacaftor: The new paradigm to treat people with cystic fibrosis with at least one p.Phe508del mutation
2021, Current Opinion in Pharmacology
Citation Excerpt :
Owing to the loss of a single phenylalanine at the 508th position in the sequence, the protein undergoes an incorrect folding process and is rapidly degraded in the endoplasmic reticulum, impairing normal protein trafficking to the cell surface and resulting in a severe reduction of CFTR activity. From a clinical point of view, patients with p.Phe508del homozygosity are younger and more symptomatic at diagnosis, require greater pancreatic enzyme substitution, and have poorer lung function, with greater incidence of chronic Pseudomonas aeruginosa infection and higher yearly mortality rates, than heterozygous patients [6,7]. CFTR modulators are a new class of drugs that partially enhance and restore CFTR function by increase in conductance of the CFTR channel (‘potentiators’ as ivacaftor [IVA]) or improvement of CFTR folding and trafficking to the cell surface (‘correctors’ including lumacaftor [LUM], tezacaftor [TEZ], and elexacaftor [ELX]).
Cystic fibrosis is the most common life-limiting genetic disease in the Caucasian population, with median predicted survival progressively improving up to 50 years, thanks to highly standardized multidisciplinary approach. Patients with p.Phe508del homozygosity usually have poorer lung function and higher mortality rates per year than other groups. By reason of that, this population has been among the most eligible target of the cystic fibrosis transmembrane conductance regulator (CFTR) modulators, a new class of drugs that can partially restore CFTR function by the correction of CFTR misfolding and trafficking to the cell surface. This narrative review summarizes the current preclinical and clinical evidence of the triple combination of elexacaftor–tezacaftor–ivacaftor, the new benchmark among highly effective CFTR modulators. It provides details on the efficacy and safety that led to drug regulation and approval and discusses future developments in clinical and translational research.
Lumacaftor/ivacaftor improves liver cholesterol metabolism but does not influence hypocholesterolemia in patients with cystic fibrosis
2021, Journal of Cystic Fibrosis
Cystic fibrosis (CF) patients have reduced intestinal absorption of sterols and, despite enhanced endogenous synthesis, low plasma cholesterol. Lumacaftor/ivacaftor CFTR protein modulator therapy is used to improve the clinical outcome of CF patients homozygous for F508del mutation (homo-deltaF508). Aim of the study is to evaluate the cholesterol metabolism and hepatobiliary injury/function in adult homo-deltaF508 patients, before and after lumacaftor/ivacaftor treatment. Baseline parameters in homo-deltaF508 patients were compared to those in CF patients compound heterozygous for F508del mutation and another severe mutation (hetero-deltaF508).
Cholesterol metabolism was evaluated measuring plasma phytosterols and cholestanol, as intestinal absorption markers, and lathosterol, as liver biosynthesis marker. We quantified serum vitamin E, as nutritional marker. We evaluated liver injury by aspartate aminotransferase (AST) and alanine transaminase (ALT), biliary injury by γ-glutamyltransferase (γGT) and AP, and the liver function by bilirubin and albumin.
Before the treatment, homo-deltaF508 patients (n = 20) had significantly lower cholesterol and vitamin E compared to hetero-deltaF508 (n = 20). Lumacaftor/ivacaftor treatment caused: 1) further reduction of cholesterol; 2) lathosterol reduction, suggesting a normalization of endogenous synthesis; 3) cholestanol and vitamin E increment, indicating an improvement of lipid digestion/absorption. Vitamin E difference (after-before treatment) was positively associated to treatment months. Alkaline phosphatase was also reduced.
These data suggest an effect of lumacaftor/ivacaftor on cholesterol metabolism and enterohepatic flux in CF patients. However, lumacaftor/ivacaftor does not promote the increase of cholesterol serum concentration that on the contrary declines. Further studies are needed to research the real mechanism causing this reduction.
Recent Progress in the Discovery and Development of Small-Molecule Modulators of CFTR
2018, Progress in Medicinal Chemistry
Cystic fibrosis (CF) is a genetic disorder driven by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. While different mutations lead to varying levels of disease severity, the most common CFTR F508del mutation leads to defects in protein stability, trafficking to the cell membrane and gating of chloride ions. Recently, advances in medicinal chemistry have led to the identification small-molecule drugs that result in significant clinical efficacy in improving lung function in CF patients. Multiple CFTR modulators are required to fix the various defects in the CFTR protein. Small-molecule potentiators increase the open-channel probability and improve the gating of ions through CFTR. Small-molecule correctors stabilize the protein fold of the mutant channel, facilitating protein maturation and translocation to the cellular membrane. Recent data suggest that triple-combination therapy consisting of a potentiator and two correctors that operate through distinct mechanisms will be required to deliver highly significant clinical efficacy for most CF patients. The progress in medicinal chemistry that has led to the identification of novel CFTR potentiators and correctors is presented in this chapter.
Cystic Fibrosis: What to Expect now in the Early Adult Years
2012, Paediatric Respiratory Reviews
As a testimony to advances in patient care, more individuals with cystic fibrosis are surviving into their adult years than ever before. The clinical epidemiology of this complex multi-organ disease is evolving and has changed dramatically over the past two to three decades. This article discusses the emergence of chronic disease-related co-morbidities such as CF-related diabetes, chronic kidney disease, bone disease, arthropathy, and depression. It also provides an overview of the many challenges confronted by adult CF care providers.

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ORIGINAL ARTICLESSeverity of cystic fibrosis in patients homozygous and heterozygous for ΔF508 mutation

Abstract

Lancet

Lancet

Lancet

Lancet

Cystic fibrosis

Am Rev Respir Dis

Identification of the cystic fibrosis gene: genetic analysis

Science

Identification of cystic fibrosis mutations

Pediatr Pulmonol

The relation between genotype and phenotype in cystic fibrosis—analysis of the most common mutation (ΔF508)

N Engl J Med

Gradient of distribution in Europe of the major CF mutation and of its associated haplotype

Hum Genet

Frequency of the ΔF508 mutation on cystic fibrosis chromosomes m Denmark

Hum Genet

Management of Pseudomonas aeruginosa lung infection in Danish cystic fibrosis patients

Acta Paediatr Scand

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