Daniela Zemkova

Polymorphisms in the mannose binding lectin gene affect the cystic fibrosis pulmonary phenotype

ystic fibrosis is a common lethal autosomal recessive disease affecting whites with an incidence of about 1 in 2500. The median lifespan is approximately 30 years. Chronic obstruction and infection of the respiratory tract, pancreatic insufficiency, elevated sweat electrolyte concentration, and male infertility characterise this disease. Clinical manifestations are attributed to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, 1 which encodes an epithelial chloride channel. 2 Certain phenotypes of cystic fibrosis, such as pancreatic insufficiency, are highly associated with the CFTR genotype. Pulmonary symptoms are highly variable, even among patients from the same family. 3 Other genetic factors, as well as environmental factors, thus affect the cystic fibrosis disease phenotype. In association studies, evidence has been found that mannose binding lectin (MBL) protein affects cystic fibrosis disease. 45 MBL protein is an important mediator component of the innate immune defense system, which functions as an opsonin and complement activator. It is part of a family of proteins called collectins, because they contain collagen-like regions and lectin domains. Through the lectin domain, they bind to carbohydrate structures presented by a wide range of pathogenic bacteria, viruses, fungi, and parasites. Mannose binding lectin protein is synthesised in the liver by hepatocytes and secreted in the blood, and circulates as dimers or hexamers composed of subunits containing three identical polypeptides. 67

Association of tumour necrosis factor alpha variants with the CF pulmonary phenotype

Background: The pulmonary phenotype in patients with cystic fibrosis (CF), even in those with the same CF transmembrane conductance regulator (CFTR) genotype, is variable and must therefore be influenced by secondary genetic factors as well as environmental factors. Possible candidate genes that modulate the CF lung phenotype may include proinflammatory cytokines. One such protein is tumour necrosis factor α (TNFα), a member of the immune system. Methods: Three polymorphic loci in the promoter (−851c/t, −308g/a, −238g/a) and one polymorphic locus in intron 1 (+691g ins/del) of the TNFα gene were typed by a single nucleotide primer extension assay in CF patients and healthy controls. Spirometric data and first age of infection with Pseudomonas aeruginosa were collected retrospectively from patients’ medical records. Results: An association was found between the TNFα +691g ins/del polymorphic locus and severity of CF lung disease. Patients heterozygous for +691g ins and +691g del were more likely to have better pulmonary function (mean (SD) forced expiratory volume in 1 second (FEV1) 79.7 (12.8)% predicted) than patients homozygous for +691g ins (mean (SD) FEV1 67.5 (23.0)% predicted; p = 0.008, mean difference 12.2%, 95% CI 3.5 to 21.0). Also, patients heterozygous for +691g ins and +691g del were more likely to have an older first age of infection with P aeruginosa (mean (SD) 11.4 (6.0) years) than patients homozygous for +691g ins (mean (SD) 8.3 (4.6) years; p = 0.018, mean difference 3.1 years, 95% CI 0.5 to 5.6). An association was also found with the −851c/t polymorphic locus. In the group of patients with more severe FEV1% predicted, a higher proportion of patients were homozygous for the −851c allele than in the other group of patients (p = 0.04, likelihood ratio χ2, odds ratio = 2.4). Conlusion: TNFα polymorphisms are associated with the severity of CF lung disease in Czech and Belgian patients with CF.

Insulin-like growth factor-I and insulin-like growth factor-binding protein-3 in cystic fibrosis: a positive effect of antibiotic therapy and hyperalimentation

Patients with cystic fibrosis (CF) are underweight and growth retarded. This study tested the link between serum insulin‐like growth factor‐I (IGF‐I) and insulin‐like growth factor‐binding protein‐3 (IGFBP‐3) levels and body height, nutritional status, pulmonary function tests and activity of inflammation in 92 subjects with CF (age 2.1–18.8 y). It also analysed the effect of short‐term antibiotic treatment and hyperalimentation on IGF‐I and IGFBP‐3 levels in 33 subjects (age 3.6–33.7 y) on 41 occasions. Both IGF‐I (‐1.19 ±0.17 SD) and IGFBP‐3 levels (‐0.66 ±0.12 SD; both p 0.0001 vs 0) were decreased in cross‐sectional measurements. Their standardized values were inversely proportional to age (IGF‐I: r= ‐0.23, p= 0.03; IGFBP‐3: r= ‐0.29, p= 0.005) and positively correlated with SDS of height (IGF‐I: r= 0.40, p 0.0001; IGFBP‐3: r= 0.36, p= 0.0005) and of mid‐arm circumference (IGF‐I: r= 0.39, p= 0.0001; IGFBP‐3: r= 0.38, p= 0.0002), and with pulmonary function tests. After a short‐term course of intensive antibiotic therapy and hyperalimentation, IGF‐I normalized (from ‐0.66 ± 0.20 to 0.00 ± 0.25 SD; pľ 0 0001) and IGFBP‐3 increased (from ‐0.78 ± 0.15 to ‐0.53 ± 0.16 SD; p= 0.002). IGFBP‐3 correlated inversely with erythrocyte sedimentation rate (r= ‐0.40, p= 0.01).

Low-dose insulin therapy in patients with cystic fibrosis and early-stage insulinopenia prevents deterioration of lung function: a 3-year prospective study.

Abstract Cystic fibrosis related diabetes (CFRD) is an insulinopenic condition. We aimed to detect insulinopenia early and to evaluate the impact of low dose insulin on nutritional status and forced expiratory volume in first second (FEV1). Out of 142 cystic fibrosis patients (CFpts) older than 10 years, 28 with abnormal oral glucose tolerance test in spite of normal fasting glycemia were found to have decreased first phase insulin release and started low dose insulin therapy (median age 15.4 years). Sex and age matched CFpts with normal glucose tolerance (NGT) were observed for comparison. Whereas nutritional status improved following 3 years of insulin administration, FEV1 stabilized in insulin-treated insulinopenic subjects (73.8±4.3% vs. 73.5±4.4%), but decreased in the parallel group with NGT who remained without insulin treatment (71.1±3.8% vs. 61.0±4.0%; p=0.001). We conclude that low dose insulin improves nutritional status and stabilizes pulmonary functions. Regular estimation of stimulated insulin secretion in CFpts may allow optimizing treatment.

The importance of advanced parental age in the origin of neurofibromatosis type 1.

Von Recklinghausen neurofibromatosis (NF1) is an autosomal dominant disorder with a prevalence about 1/3,000 (1/2,000–1/5,000 in various population‐based studies). About 30–50% of cases are sporadic, resulting from a new mutation. NF1 is fully penetrant by mid‐childhood, stigmata, and medical problems (neurological, dermatological, endocrine, ophthalmological, oncological) are highly variable. Advanced paternal age (APA) has been known to increase the risk of new germline mutations that contribute to the presence of a variety of genetic diseases in the human population. The trend in developed countries has been toward higher parental age due to various reasons. In a cross‐sectional study, in two university hospital centers, data on parental age of 103 children (41 female) born between 1976 and 2005 with sporadic NF1 were analyzed. Parental age at birth was compared with the Czech general population matched to birth year. The mean NF1 sporadic case paternal age at birth was 32.0 years (95% CI 30.7–33.3 years) compared with 28.8 years (95% CI 28.6–29.1 years) in the general population (P < 0.001). The mean maternal age at birth was 27.4 years (95% CI 26.3–28.5 years) compared with 25.8 years (95% CI 25.5–26.0 years) in the general population (P < 0.05). The case‐control difference in the fathers age was higher than it was for the mothers age. Sporadic NF1 cases accounted for 35.6% of our entire NF1 cohort. We confirmed an association of advanced parental and particularly paternal age with the occurrence of sporadic NF1.

Impaired Growth during Childhood in Patients with Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) leads to recurrent/chronic respiratory infections, resulting in chronic inflammation and potentially in chronic pulmonary disease with bronchiectasis. We analyzed longitudinal data on body length/height and body mass index (BMI) for 29 children and young adults with PCD aging 1.5–24 years (median, 14.5) who had been diagnosed at the age of 0.5–17 years (median, 8). Of these, 10 carried pathogenic mutations in either DNAH5 or DNAI1. In children with PCD, body length/height progressively decreased from +0.40 ± 0.24 SDS (the 1st birthday), +0.16 ± 0.23 SDS (3 years old), and −0.13 ± 0.21 SDS (5 years old) to −0.54 ± 0.19 SDS (7 years old; P = 0.01 versus 0), −0.67 ± 0.21 SDS (9 years old; P = 0.005 versus 0), −0.52 ± 0.24 SDS (11 years old; P = 0.04 versus 0), and −0.53 ± 0.23 SDS (13 years old; P = 0.03 versus 0). These results reflect low growth rates during the childhood growth period. Thereafter, heights stabilized up to the age of 17 years. The growth deterioration was not dependent on sex or disease severity but was more pronounced in DNAH5 or DNAI1 mutation carriers. BMI did not differ from population standards, which suggests that nutritional deficits are not the cause of growth delay. We conclude that PCD leads to chronic deprivation with significant growth deterioration during childhood.