Mild Form Of Cystic Fibrosis Research Articles

142 Immunisation coverage in children with cystic fibrosis: a French multicenter survey

Objectives: To determine platelet aggregation capability for various variants of antigene system AB0 in patients with cystic fibrosis (CF). Methods: 55 CF children (homozygous and heterozygous on F508 del mutation) were enrolled. 46% girls and 54% boys had mild form of CF, 54% girls and 46% boys had severe form. We investigated the function of platelet aggregation with: thrombin, adenosinediphosphate (ADP) and arachidonic acid (AA). Results: Patients with severe form of CF most frequently (29%) had 0 (I); B (III) have not been revealed in this group, meanwhile 22.2% patients with mild form of CF had A (II) and AB (IV) have been revealed. Platelet aggregation with ADP has significant differences between blood groups A (II) and 0 (I), (p = 0.019). Values were ranged 2.5–97.5 percentile in patients with 0 (I) and 2.5−25 percentile in A (II). Data of aggregation with AA did not show significant differences between groups. Significant difference between homozygous F508 del and heterozygous F508 del patients was shown in aggregation with trombin (p = 0.03). There is a tendency to hyperaggregation in heterozygous patients meanwhile homozygous had both hypoaggregation and hyperaggregation. Difference on other tests between homozygous and heterozygous patients is not significant. Conclusion: First results of this study should be interpreted according to system ABO, severity of disease and genotype in patients with CF. These aspects play an important role for individual treatment.

141 Platelet aggregation capability in children with cystic fibrosis

Objectives: To determine platelet aggregation capability for various variants of antigene system AB0 in patients with cystic fibrosis (CF). Methods: 55 CF children (homozygous and heterozygous on F508 del mutation) were enrolled. 46% girls and 54% boys had mild form of CF, 54% girls and 46% boys had severe form. We investigated the function of platelet aggregation with: thrombin, adenosinediphosphate (ADP) and arachidonic acid (AA). Results: Patients with severe form of CF most frequently (29%) had 0 (I); B (III) have not been revealed in this group, meanwhile 22.2% patients with mild form of CF had A (II) and AB (IV) have been revealed. Platelet aggregation with ADP has significant differences between blood groups A (II) and 0 (I), (p = 0.019). Values were ranged 2.5–97.5 percentile in patients with 0 (I) and 2.5−25 percentile in A (II). Data of aggregation with AA did not show significant differences between groups. Significant difference between homozygous F508 del and heterozygous F508 del patients was shown in aggregation with trombin (p = 0.03). There is a tendency to hyperaggregation in heterozygous patients meanwhile homozygous had both hypoaggregation and hyperaggregation. Difference on other tests between homozygous and heterozygous patients is not significant. Conclusion: First results of this study should be interpreted according to system ABO, severity of disease and genotype in patients with CF. These aspects play an important role for individual treatment.

Mycobacterium avium and Mycobacterium abscessus complex target distinct cystic fibrosis patient subpopulations

BackgroundClinical observations suggest that Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABSC) may affect cystic fibrosis (CF) patients with different characteristics and risk factors, but this has never been demonstrated within a single prospective cohort. MethodsWe studied 50 MABSC-positive and 23 MAC-positive patients from a French prevalence study of non‐tuberculous mycobacteria (NTM) in CF. Risk factors specifically associated with MABSC and MAC were analyzed by nested case–control studies, with two NTM-negative controls matched by age, sex and center for each case. ResultsMAC-positive patients were significantly older than MABSC-positive patients (mean [SD] age, 23.1 [10.2] vs 17.4 [8.3] years, p=0.013), and were also older at CF diagnosis (mean [SD] age, 12.9 [16.1] vs 3.1 [7.7] years, p=0.015); they tended to be less frequent of the ΔF508/ΔF508 genotype (33.3 vs 61.1%, p=0.17) and to use pancreatic extracts less frequently (82.4 vs 97.6%, p=0.07). Risk factors identified by multivariate analysis were: i) in the MAC case–control study, an older age at CF diagnosis (p=0.004); ii) in the MABSC case–control study, at least one course of intravenous antibiotics (p=0.01) and more frequent isolation of Aspergillus (p=0.03). ConclusionsMAC affects adult patients with a mild form of CF, whereas MABSC affects younger patients with more severe CF and more frequent intravenous antimicrobial treatment.

Management of male infertility due to congenital bilateral absence of vas deferens should not ignore the diagnosis of cystic fibrosis

Microsurgical or percutaneous epididymal sperm aspiration and intracytoplasmic sperm injection (ICSI) are proposed to overcome male infertility due to congenital bilateral absence of vas deferens (CBAVD). CBAVD has been associated with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and consequently, genetic counselling has to be addressed before beginning ICSI procedure. However, management of male infertility due to CBAVD should not ignore a mild form of cystic fibrosis. We describe the case of cystic fibrosis late diagnosis performed in a 49-year-old infertile men with CBAVD. CFTR molecular testing detected two mutations F508del and A455E corresponding to a cystic fibrosis genotype. Pneumological evaluation revealed a severe obstructive respiratory disease, bronchiectasis and high sweat chloride levels. Symptoms consistent with a cystic fibrosis have to be identified in infertile men with CBAVD before beginning assisted reproductive procedures.

A Synonymous Mutation in the CFTR Gene Causes Aberrant Splicing in an Italian Patient Affected by a Mild Form of Cystic Fibrosis

Mutations within exons are responsible for aberrant splicing of pre-mRNA in several human disease genes and in some viral systems. Nonsense, missense, and even synonymous mutations can induce aberrant skipping of the mutant exon, producing nonfunctional proteins. In this paper, we describe the effect on the splicing efficiency of the synonymous variant 2811 G>T [Gly893Gly] detected in a patient of Italian descent affected by a mild form of cystic fibrosis, until now mentioned as sequence variation with unknown functional consequences. The study, performed through DNA as well as RNA analyses, shows that this mutation creates a new 5' splice site within exon 15, resulting in a transcript lacking 76 amino acid residues. Although this aberrant splicing causes a shorter exon 15, the downstream exonic sequence from exon 16 to the end of the open reading frame is in frame. This study indicates that apparently neutral polymorphism, which may be erroneously classified as nonpathogenic, may indeed led to aberrant splicing thereby resulting in defective protein.

Detection of an Apparent Homozygous 3120G>A Cystic Fibrosis Mutation on a Routine Carrier Screen

A 28-year-old Caucasian female with no personal or family history of cystic fibrosis (CF) presented for preconception counseling and screening. Cystic fibrosis transmembrane conductance regulator (CFTR) mutation analysis using the Inno-LiPa CFTR assay revealed lack of hybridization for both the wild-type and mutant oligonucleotides for 3120+1G>A. This region was sequenced, and an apparent homozygous 3120G>A mutation was detected. Additional testing revealed an abnormal sweat chloride (77 mmol/L). Review of systems was essentially unremarkable with an absence of sinus symptoms, occasional nonproductive cough, and no features of malabsorption. Physical examination, chest X-ray, and pulmonary function tests were within normal limits. Only two other patients (siblings) with homozygous 3120G>A mutations have been reported (http://www.genet.sickkids.on.ca/cftr/). Both siblings had pancreatic insufficiency, mild pulmonary symptoms, and abnormal sweat chloride levels. Our findings suggest that a homozygous mutation of a G>A conversion at 3120 is associated with abnormal CFTR function and either a mild form of CF or no overt symptoms of disease, emphasizing the difficulties in assigning genotype/phenotype correlation.

Identification of three novel mutations in the dystrophin gene detected by the heteroduplex/SSCA screening procedure. Mutations in brief no. 222. Online.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked neuromuscular disorders associated with alterations in the dystrophin gene. Analysis of 45 DMD/BMD patients has identified 18 patients with no deletion in the dystrophin gene. Heteroduplex analysis (HD), single strand conformation analysis (SSCA), and subsequent sequencing, identified five mutations and nine polymorphisms. Three out of the 5 mutations (780C>G, 2501-1g-->t, 9812 9813ins9800-9812) are first reported here. Furthermore we compare the relative efficiencies of the two alternatives methods (HD and SSCA) for screening sequence alterations.

CFTR mutations and IVS8-5T variant in newborns with hypertrypsinaemia and normal sweat test.

Neonates positive for immunoreactive trypsinogen assay (IRT) and negative for sweat test have formerly been found to carry the major cystic fibrosis (CF) mutation, delta F508, much more frequently than...

Hypofertility With Thick Cervical Mucus: Another Mild Form of Cystic Fibrosis?

To the Editor. —Male infertility due to congenital bilateral absence of the vas deferens (CBAVD) is frequently recognized as a mild form of cystic fibrosis (CF). 1,2 However, CF with primarily genital involvement may not be limited to males. Report of a Case. —We recently observed a 40-year-old woman with a medical history of infertility. She used oral contraceptives from 1974 to 1978. In 1975, she had electrocoagulation for ectropion. From 1981 to 1986, she had unprotected sexual intercourse but could not become pregnant. In 1986, she and her husband underwent investigations for infertility. Her husband's semen analysis was normal. Ovulation was confirmed by biphasic basal body temperature charts. Hysterosalpingogram was normal. The only consistent abnormality was found in postcoital tests. On 3 separate cycles, repetitive testing revealed tenacious mucus, which did not vary according to the time of cycle and contained no motile sperm. Testing for antisperm antibodies was

Hypofertility with thick cervical mucus: another mild form of cystic fibrosis?

Hypofertility with thick cervical mucus: another mild form of cystic fibrosis?

Birth After Preimplantation Diagnosis of the Cystic Fibrosis △F508 Mutation by Polymerase Chain Reaction in Human Embryos Resulting From Intracytoplasmic Sperm Injection With Epididymal Sperm

Men with congenital bilateral absence of the vas deferens (CBAVD) have been regarded as presenting a mild form of cystic fibrosis (CF). In this article, we report a case of male-factor infertility, in which both partners are carriers of the delta F508 mutation and the male partner has CBAVD. Microsurgical epididymal sperm aspiration (MESA) was performed to obtain spermatozoa; intracytoplasmic sperm injection (ICSI) was carried out on the oocytes since the motility of the spermatozoa was severely impaired; and embryo biopsy and a polymerase chain reaction (PCR) were carried out for preimplantation diagnosis of the CF delta F508 mutation. Single-blastomere analysis was performed and indicated that two embryos were affected (homozygous delta F508) and three embryos were carriers. After transfer of the latter three embryos, a singleton pregnancy was established. At amniocentesis, the delta F508 carrier status of the fetus with a 46, XY karyotype was confirmed. A healthy boy was born and the presence of vasa deferentia, bilaterally, was confirmed. The CF sweat test was also normal. Successful fertilization can be obtained by combination of MESA and ICSI in patients with CBAVD. Preimplantation diagnosis of CF is indicated. Pregnancy and birth of normal children can ensue in such patients.

Andrology: Cystic fibrosis mutations impair the fertilization rate of epididymal sperm from men with congenital absence of the vas deferens

One of the limiting factors for the successful treatment of male sterility due to congenital absence of the vas deferens (CAVD) is the low (< 20%) and extremely unpredictable rate of in-vitro fertilization of their epididymal spermatozoa. The recent demonstration that CAVD is a mild form of cystic fibrosis (CF) disease, almost exclusively involving the genital tract, has prompted us to investigate the hypothesis of whether there could be an association between particular CF genotype mutations and the in-vitro performance of epididymal sperm. In this study 63 patients with surgically confirmed diagnosis of CAVD undergoing microsurgical epididymal sperm aspiration (MESA) and in-vitro fertilization (IVF) were evaluated. The genetic screening was carried out on DNA extracted from peripheral lymphocytes and amplified by the polymerase chain reaction. A total of 12 mutations in the cystic fibrosis transmembrane regulator gene (CFTR), representing approximately 90% of the total known CF mutations, were tested. The presence or absence of mutations, as well as the type of mutation found, was correlated with the IVF and pregnancy rates. Of the 63 patients examined, 40 (64%) were positive to the CF screening and 23 were negative. In three cases no spermatozoa were found because of rete testis blockage. The difference in fertilization rates between patients testing positive and negative was highly significant (P = 0.000003), 13 versus 23%, respectively. In order to pinpoint which mutation could account for the most deleterious effect on the IVF results, we analysed these by keeping the patients separated by CF mutations.(ABSTRACT TRUNCATED AT 250 WORDS)