Severe lung disease in children with cystic fibrosis missed in newborn screening.

BACKGROUND: Cystic fibrosis (CF) is now routinely diagnosed through newborn screening (NBS), but the tests employed in the USA have been evolving for two decades as missed cases become recognized and lab methods improve in association with more knowledge about CF genetics. New Jersey was among the first states to implement CF NBS in 2001 when it introduced the original two-tiered method that combined measurements of immunoreactive trypsinogen (IRT) with detection of the principal pathogenic variant (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. OBJECTIVE: With continuation of the IRT/DNA (F508del) algorithm for two decades and identification of screening false negative children, we decided to examine the condition of some missed cases with special attention to their respiratory status. METHODS: To strengthen the arguments for quality improvement in New Jersey's CF NBS program, we reviewed and evaluated false negative cases to determine the potential extent of preventable patient suffering as a consequence of delayed diagnoses. RESULTS: Five children with CF who had false negative screening results were studied in detail. In each case there was a different cause of the negative screening results. They all had clinically significant/severe lung disease, ranging from chronic cough with CF pathogens on respiratory culture at a young age to respiratory failure. CONCLUSION: This case series highlights the consequences of false negative screening results, which served as the impetus to upgrade New Jersey's CF NBS algorithm. Implemented changes include lowering the IRT cutoff to 70 ng/mL and expanding to a 139 variant CFTR panel. In 2023, a floating IRT cutoff is anticipated to be implemented.

Adolescent development and energy expenditure in females with cystic fibrosis.

BACKGROUND AND AIMS: Poor nutrition and growth status are common in people with cystic fibrosis (CF), and females often have a worse clinical course. Relationships between sexual maturity, nutrition, resting energy expenditure (REE), and pulmonary status in females with CF and pancreatic insufficiency (PI) were evaluated. METHODS: Pre- and post-menarcheal females with CF and PI (8-29 yr) were compared to healthy females. Z-scores for growth and body composition, anthropometry and DEXA were assessed. REE was measured in all subjects and pulmonary function in CF. RESULTS: Compared to healthy females (n=28, 14.6+/-4.1 yr), females with CF (n=16, 14.7+/-4.4 yr) had lower height Z (-0.1+/-0.9 versus -0.9+/-0.9, P=0.009) and muscle area Z (0.8+/-1.3 versus -0.4+/-1.2, P=0.007), and higher REE (100+/-10 versus 110+/-11% predicted, P=0.008). Difference in REE was more pronounced for post-menarcheal girls. REE adjusted for fat and fat-free mass was significantly higher with CF (+110 calories/day), and declined with menarcheal age in all subjects. FEV1 was positively associated with BMI Z score, and negatively associated with age at menarche. CONCLUSIONS: Height and muscle stores were reduced and REE elevated in subjects with CF compared to healthy controls. Poorer growth and nutritional status and delayed menarche were associated with poorer pulmonary function in CF and were likely related to the cumulative effect of energy imbalance on growth and body composition.

Altered terminal glycosylation and the pathophysiology of CF lung disease.

Altered terminal glycosylation, with increased fucosylation and decreased sialylation, is a hallmark of the cystic fibrosis (CF) glycosylation phenotype. The glycosylation phenotype of CF airway epithelial cells has been modulated by the expression of wtCFTR. Understanding the effects of mutant CFTR on glycosylation may provide further insight into the regulation of glycoconjugate processing as well as new approaches to the therapy of CF.

Alpha1,3fucosyltransferases in cystic fibrosis airway epithelial cells.

Cystic fibrosis (CF) has a glycophenotype of aberrant sialylation and/or fucosylation. The CF glycophenotype is expressed on membrane glycoconjugates of CF airway epithelial cells as increased fucosyl residues in alpha1,3/4 linkage to N-acetyl glucosamine, decreased fucosyl residues in alpha1,2 linkage to galactose and decreased sialic acid. To define the cause of this phenotype, the enzyme activity of alpha1,3fucosyltransferase (FucT) was examined in extracts of CF airway epithelial cells with a variety of low molecular weight substrates. Using Galbeta1,4GlcNAc as substrate, the activity was divided into 66% alpha1,3FucT and 34% alpha1,2FucT. mRNA expression examined with probes to FucTIII, IV, and VII showed that the highest expression of two CF cell lines was for FucTIV. Only one CF cell line expressed mRNA for FucTIII. The non CF airway epithelial cells had significant enzyme activity for alpha1,3FucT and strong mRNA expression for FucTIV. Thus as reported previously for alpha1,2FucT, the biochemical capacity for alpha1,3FucT was present in both the CF and non CF cells and can not be the cause of the CF glycophenotype. These results support the hypothesis that wild type CFTR acts in the Golgi and when mutated as in CF, faulty compartmentalization of terminal glycosyltransferases results, yielding the CF glycophenotype.