Jessica E. Pittman

Clinical and genetic aspects of primary ciliary dyskinesia/kartagener syndrome

Primary ciliary dyskinesia is a genetically heterogeneous disorder of motile cilia. Most of the disease-causing mutations identified to date involve the heavy (dynein axonemal heavy chain 5) or intermediate (dynein axonemal intermediate chain 1) chain dynein genes in ciliary outer dynein arms, although a few mutations have been noted in other genes. Clinical molecular genetic testing for primary ciliary dyskinesia is available for the most common mutations. The respiratory manifestations of primary ciliary dyskinesia (chronic bronchitis leading to bronchiectasis, chronic rhino-sinusitis, and chronic otitis media) reflect impaired mucociliary clearance owing to defective axonemal structure. Ciliary ultrastructural analysis in most patients (>80%) reveals defective dynein arms, although defects in other axonemal components have also been observed. Approximately 50% of patients with primary ciliary dyskinesia have laterality defects (including situs inversus totalis and, less commonly, heterotaxy, and congenital heart disease), reflecting dysfunction of embryological nodal cilia. Male infertility is common and reflects defects in sperm tail axonemes. Most patients with primary ciliary dyskinesia have a history of neonatal respiratory distress, suggesting that motile cilia play a role in fluid clearance during the transition from a fetal to neonatal lung. Ciliopathies involving sensory cilia, including autosomal dominant or recessive polycystic kidney disease, Bardet-Biedl syndrome, and Alstrom syndrome, may have chronic respiratory symptoms and even bronchiectasis suggesting clinical overlap with primary ciliary dyskinesia.

ZMYND10 Is Mutated in Primary Ciliary Dyskinesia and Interacts with LRRC6

Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally, ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function.

Clinical features of childhood primary ciliary dyskinesia by genotype and ultrastructural phenotype

RATIONALE The relationship between clinical phenotype of childhood primary ciliary dyskinesia (PCD) and ultrastructural defects and genotype is poorly defined. OBJECTIVES To delineate clinical features of childhood PCD and their associations with ultrastructural defects and genotype. METHODS A total of 118 participants younger than 19 years old with PCD were evaluated prospectively at six centers in North America using standardized procedures for diagnostic testing, spirometry, chest computed tomography, respiratory cultures, and clinical phenotyping. MEASUREMENTS AND MAIN RESULTS Clinical features included neonatal respiratory distress (82%), chronic cough (99%), and chronic nasal congestion (97%). There were no differences in clinical features or respiratory pathogens in subjects with outer dynein arm (ODA) defects (ODA alone; n = 54) and ODA plus inner dynein arm (IDA) defects (ODA + IDA; n = 18) versus subjects with IDA and central apparatus defects with microtubular disorganization (IDA/CA/MTD; n = 40). Median FEV1 was worse in the IDA/CA/MTD group (72% predicted) versus the combined ODA groups (92% predicted; P = 0.003). Median body mass index was lower in the IDA/CA/MTD group (46th percentile) versus the ODA groups (70th percentile; P = 0.003). For all 118 subjects, median number of lobes with bronchiectasis was three and alveolar consolidation was two. However, the 5- to 11-year-old IDA/CA/MTD group had more lobes of bronchiectasis (median, 5; P = 0.0008) and consolidation (median, 3; P = 0.0001) compared with the ODA groups (median, 3 and 2, respectively). Similar findings were observed when limited to participants with biallelic mutations. CONCLUSIONS Lung disease was heterogeneous across all ultrastructural and genotype groups, but worse in those with IDA/CA/MTD ultrastructural defects, most of whom had biallelic mutations in CCDC39 or CCDC40.

Early lung disease in young children with primary ciliary dyskinesia

Primary ciliary dyskinesia (PCD) is an autosomal recessive disease in which ciliary dysfunction leads to chronic lung, sinus, and middle ear disease. PCD is often not diagnosed until late childhood due to its presumed rarity and the technical expertise necessary for diagnosis; as such, little is known about lung disease in young children with PCD. We report on 3 young children with PCD who had evidence of lung disease on infant pulmonary function testing, bronchoscopy, and/or computed tomography (CT) of the chest before 3 years of age. Pediatr Pulmonol. 2008; 43:514–516.

Multiple-Breath Washout as a Lung Function Test in Cystic Fibrosis. A Cystic Fibrosis Foundation Workshop Report

The lung clearance index (LCI) is a lung function parameter derived from the multiple-breath washout (MBW) test. Although first developed 60 years ago, the technique was not widely used for many years. Recent technological advances in equipment design have produced gains in popularity for this test among cystic fibrosis (CF) researchers and clinicians, particularly for testing preschool-aged children. LCI has been shown to be feasible and sensitive to early CF lung disease in patients of all ages from infancy to adulthood. A workshop was convened in January 2014 by the North American Cystic Fibrosis Foundation to determine the readiness of the LCI for use in multicenter clinical trials as well as clinical care. The workshop concluded that the MBW text is a valuable potential outcome measure for CF clinical trials in preschool-aged patients and in older patients with FEV1 in the normal range. However, gaps in knowledge about the choice of device, gas, and standardization across systems are key issues precluding its use as a clinical trial end point in infants. Based on the current evidence, there are insufficient data to support the use of LCI or MBW parameters in the routine clinical management of patients with CF.

Age of Pseudomonas aeruginosa acquisition and subsequent severity of cystic fibrosis lung disease

Pseudomonas aeruginosa (Pa) is associated with poor pulmonary outcomes in cystic fibrosis (CF), but the association between age of Pa infection and severity of subsequent lung disease has not been thoroughly investigated.

Cystic Fibrosis: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases

Cystic fibrosis (CF) is a life-limiting, monogenic disorder characterized by chronic sinopulmonary and gastrointestinal involvement. Progressive pulmonary disease leads to death in the majority of patients. Despite its well-defined molecular basis related to defects in the cystic fibrosis transmembrane conductance regulator anion transport channel, there are large gaps in our understanding of the origin of CF lung disease. Disease has been shown to be present in infancy, and there is mounting evidence that abnormalities begin in utero. Heterogeneity of clinical presentations and severity suggest that many factors involved in lung disease have yet to be fully elucidated. Although new advances in therapeutic treatments have shown promise in delaying disease progression, the prevention of pulmonary disease at its origin (primary prevention) should be a key goal of CF care. The objective of this workshop was to (1) review our understanding of the origins of CF lung disease, (2) determine gaps in the knowledge base that are most significant and most likely to enable prevention of CF lung disease, and (3) prioritize new research questions that will promote pulmonary health in both CF and other childhood lung diseases. The goal of this report is to provide recommendations for future research that will improve our understanding of pulmonary development in health and disease, improve outcome measures and biomarkers for early lung disease, and determine therapeutic targets and strategies to prevent the development of lung disease in children with CF.

The Evolution of Cystic Fibrosis Care

Cystic fibrosis (CF) is the most common life-limiting inherited illness of whites. Most of the morbidity and mortality in CF stems from impaired mucociliary clearance leading to chronic, progressive airways obstruction and damage. Significant progress has been made in the care of patients with CF, with advances focused on improving mucociliary clearance, minimizing inflammatory damage, and managing infections; these advances include new antimicrobial therapies, mucolytic and osmotic agents, and antiinflammatory treatments. More recently, researchers have targeted disease-causing mutations using therapies to promote gene transcription and improve channel function, which has led to impressive physiologic changes in some patients. As we develop more advanced, allele-directed therapies for the management of CF, it will become increasingly important to understand the specific genetic and environmental interactions that cause the significant heterogeneity of lung disease seen in the CF population. This understanding of CF endotypes will allow for more targeted, personalized therapies for future patients. This article reviews the genetic and molecular basis of CF lung disease, the treatments currently available, and novel therapies that are in development.

Improvement in pulmonary function following antibiotics in infants with cystic fibrosis

Recent studies have shown the presence of lung disease in even asymptomatic infants with cystic fibrosis (CF). While pulmonary function testing (PFT) is often used to follow progression of lung disease and guide treatment in older children with CF, little data is available on change in infant PFTs in young children with CF.

Variability of a closed, rebreathing setup for multiple breath wash-out testing in children†‡

The multiple breath wash‐out technique (MBW) that measures lung clearance index (LCI) and functional residual capacity (FRC) may be more sensitive than spirometry for identification of early obstructive airways disease. The open MBW setup using mass spectrometry referenced in previous publications is not readily available in the U.S. Our objective was to assess validity and sensitivity of a commercially available device that uses a closed (rebreathing) setup with photoacoustic spectroscopy for MBW testing.