Semin Respir Crit Care Med 2015; 36(02): 169-179
DOI: 10.1055/s-0035-1546748
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Primary Ciliary Dyskinesia

Jason Lobo
1   The Division of Pulmonary Diseases, University of North Carolina, Chapel Hill, North Carolina
,
Maimoona A. Zariwala
1   The Division of Pulmonary Diseases, University of North Carolina, Chapel Hill, North Carolina
,
Peadar G. Noone
1   The Division of Pulmonary Diseases, University of North Carolina, Chapel Hill, North Carolina
› Author Affiliations
Further Information

Publication History

Publication Date:
31 March 2015 (online)

Abstract

Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder of cilia structure, function, and biogenesis leading to chronic infections of the respiratory tract, fertility problems, and disorders of organ laterality. The diagnosis can be challenging, using traditional tools such as characteristic clinical features, ciliary function, and ultrastructural defects and newer screening tools such as nasal nitric oxide levels and genetic testing add to the diagnostic algorithm. There are 32 known PCD-causing genes, and in the future, comprehensive genetic testing may screen young infants before developing symptoms, thus improving survival. Therapies include surveillance of pulmonary function and microbiology, in addition to airway clearance, antibiotics, and early referral to bronchiectasis centers. As with cystic fibrosis (CF), standardized care at specialized centers using a multidisciplinary approach likely improves outcomes. In conjunction with the CF foundation, the PCD foundation, with experienced investigators and clinicians, is developing a network of PCD clinical centers to coordinate the effort in North America and Europe. As the network grows, clinical care and knowledge will improve.

 
  • References

  • 1 Noone PG, Leigh MW, Sannuti A , et al. Primary ciliary dyskinesia: diagnostic and phenotypic features. Am J Respir Crit Care Med 2004; 169 (4) 459-467
  • 2 Afzelius BA. A human syndrome caused by immotile cilia. Science 1976; 193 (4250) 317-319
  • 3 Eliasson R, Mossberg B, Camner P, Afzelius BA. The immotile-cilia syndrome. A congenital ciliary abnormality as an etiologic factor in chronic airway infections and male sterility. N Engl J Med 1977; 297 (1) 1-6
  • 4 Sturgess JM, Chao J, Wong J, Aspin N, Turner JA. Cilia with defective radial spokes: a cause of human respiratory disease. N Engl J Med 1979; 300 (2) 53-56
  • 5 Wakefield S, Waite D. Abnormal cilia in Polynesians with bronchiectasis. Am Rev Respir Dis 1980; 121 (6) 1003-1010
  • 6 Herzon FS, Murphy S. Normal ciliary ultrastructure in children with Kartagener's syndrome. Ann Otol Rhinol Laryngol 1980; 89 (1, Pt 1) 81-83
  • 7 Leigh MW, O'Callaghan C, Knowles MR. The challenges of diagnosing primary ciliary dyskinesia. Proc Am Thorac Soc 2011; 8 (5) 434-437
  • 8 Toskala E, Smiley-Jewell SM, Wong VJ, King D, Plopper CG. Temporal and spatial distribution of ciliogenesis in the tracheobronchial airways of mice. Am J Physiol Lung Cell Mol Physiol 2005; 289 (3) L454-L459
  • 9 Chilvers MA, Rutman A, O'Callaghan C. Functional analysis of cilia and ciliated epithelial ultrastructure in healthy children and young adults. Thorax 2003; 58 (4) 333-338
  • 10 Satir P, Christensen ST. Overview of structure and function of mammalian cilia. Annu Rev Physiol 2007; 69: 377-400
  • 11 Zariwala MA, Knowles MR, Omran H. Genetic defects in ciliary structure and function. Annu Rev Physiol 2007; 69: 423-450
  • 12 Mitchell B, Stubbs JL, Huisman F, Taborek P, Yu C, Kintner C. The PCP pathway instructs the planar orientation of ciliated cells in the Xenopus larval skin. Curr Biol 2009; 19 (11) 924-929
  • 13 Mitchell B, Jacobs R, Li J, Chien S, Kintner C. A positive feedback mechanism governs the polarity and motion of motile cilia. Nature 2007; 447 (7140) 97-101
  • 14 Sears PR, Thompson K, Knowles MR, Davis CW. Human airway ciliary dynamics. Am J Physiol Lung Cell Mol Physiol 2013; 304 (3) L170-L183
  • 15 Basu B, Brueckner M. Cilia multifunctional organelles at the center of vertebrate left-right asymmetry. Curr Top Dev Biol 2008; 85: 151-174
  • 16 Sagel SD, Davis SD, Campisi P, Dell SD. Update of respiratory tract disease in children with primary ciliary dyskinesia. Proc Am Thorac Soc 2011; 8 (5) 438-443
  • 17 Ferkol T, Leigh M. Primary ciliary dyskinesia and newborn respiratory distress. Semin Perinatol 2006; 30 (6) 335-340
  • 18 Brown DE, Pittman JE, Leigh MW, Fordham L, Davis SD. Early lung disease in young children with primary ciliary dyskinesia. Pediatr Pulmonol 2008; 43 (5) 514-516
  • 19 Santamaria F, Montella S, Tiddens HA , et al. Structural and functional lung disease in primary ciliary dyskinesia. Chest 2008; 134 (2) 351-357
  • 20 Green K, Buchvald FF, Marthin JK, Hanel B, Gustafsson PM, Nielsen KG. Ventilation inhomogeneity in children with primary ciliary dyskinesia. Thorax 2012; 67 (1) 49-53
  • 21 Kennedy MP, Noone PG, Leigh MW , et al. High-resolution CT of patients with primary ciliary dyskinesia. AJR Am J Roentgenol 2007; 188 (5) 1232-1238
  • 22 Jain K, Padley SP, Goldstraw EJ , et al. Primary ciliary dyskinesia in the paediatric population: range and severity of radiological findings in a cohort of patients receiving tertiary care. Clin Radiol 2007; 62 (10) 986-993
  • 23 Kennedy MP, Omran H, Leigh MW , et al. Congenital heart disease and other heterotaxic defects in a large cohort of patients with primary ciliary dyskinesia. Circulation 2007; 115 (22) 2814-2821
  • 24 Munro NC, Currie DC, Lindsay KS , et al. Fertility in men with primary ciliary dyskinesia presenting with respiratory infection. Thorax 1994; 49 (7) 684-687
  • 25 Engesaeth VG, Warner JO, Bush A. New associations of primary ciliary dyskinesia syndrome. Pediatr Pulmonol 1993; 16 (1) 9-12
  • 26 Lundberg JO, Weitzberg E, Nordvall SL, Kuylenstierna R, Lundberg JM, Alving K. Primarily nasal origin of exhaled nitric oxide and absence in Kartagener's syndrome. Eur Respir J 1994; 7 (8) 1501-1504
  • 27 Barbato A, Frischer T, Kuehni CE , et al. Primary ciliary dyskinesia: a consensus statement on diagnostic and treatment approaches in children. Eur Respir J 2009; 34 (6) 1264-1276
  • 28 Walker WT, Jackson CL, Lackie PM, Hogg C, Lucas JS. Nitric oxide in primary ciliary dyskinesia. Eur Respir J 2012; 40 (4) 1024-1032
  • 29 Leigh MW, Hazucha MJ, Chawla KK , et al. Standardizing nasal nitric oxide measurement as a test for primary ciliary dyskinesia. Ann Am Thorac Soc 2013; 10 (6) 574-581
  • 30 Santamaria F, de Santi MM, Grillo G, Sarnelli P, Caterino M, Greco L. Ciliary motility at light microscopy: a screening technique for ciliary defects. Acta Paediatr 1999; 88 (8) 853-857
  • 31 Olm MA, Kögler Jr JE, Macchione M, Shoemark A, Saldiva PH, Rodrigues JC. Primary ciliary dyskinesia: evaluation using cilia beat frequency assessment via spectral analysis of digital microscopy images. J Appl Physiol (1985) 2011; 111 (1) 295-302
  • 32 Stannard WA, Chilvers MA, Rutman AR, Williams CD, O'Callaghan C. Diagnostic testing of patients suspected of primary ciliary dyskinesia. Am J Respir Crit Care Med 2010; 181 (4) 307-314
  • 33 Altemeier WA, Liles WC, Villagra-Garcia A, Matute-Bello G, Glenny RW. Ischemia-reperfusion lung injury is attenuated in MyD88-deficient mice. PLoS ONE 2013; 8 (10) e77123
  • 34 Shoemark A, Dixon M, Corrin B, Dewar A. Twenty-year review of quantitative transmission electron microscopy for the diagnosis of primary ciliary dyskinesia. J Clin Pathol 2012; 65 (3) 267-271
  • 35 Chilvers MA, Rutman A, O'Callaghan C. Ciliary beat pattern is associated with specific ultrastructural defects in primary ciliary dyskinesia. J Allergy Clin Immunol 2003; 112 (3) 518-524
  • 36 O'Callaghan C, Rutman A, Williams GM, Hirst RA. Inner dynein arm defects causing primary ciliary dyskinesia: repeat testing required. Eur Respir J 2011; 38 (3) 603-607
  • 37 Jorissen M, Willems T. The secondary nature of ciliary (dis)orientation in secondary and primary ciliary dyskinesia. Acta Otolaryngol 2004; 124 (4) 527-531
  • 38 Olin JT, Burns K, Carson JL , et al; Genetic Disorders of Mucociliary Clearance Consortium. Diagnostic yield of nasal scrape biopsies in primary ciliary dyskinesia: a multicenter experience. Pediatr Pulmonol 2011; 46 (5) 483-488
  • 39 Morillas HN, Zariwala M, Knowles MR. Genetic causes of bronchiectasis: primary ciliary dyskinesia. Respiration 2007; 74 (3) 252-263
  • 40 Panizzi JR, Becker-Heck A, Castleman VH , et al. CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms. Nat Genet 2012; 44 (6) 714-719
  • 41 Genetic Disorders of Mucociliary Clearance Consortium(GDMCC). Available at: http://rarediseasesnetwork.epi.usf.edu/gdmcc/index.htm
  • 42 Merveille AC, Davis EE, Becker-Heck A , et al. CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs. Nat Genet 2011; 43 (1) 72-78
  • 43 Antony D, Becker-Heck A, Zariwala MA , et al; Uk10k. Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms. Hum Mutat 2013; 34 (3) 462-472
  • 44 Olbrich H, Schmidts M, Werner C , et al; UK10K Consortium. Recessive HYDIN mutations cause primary ciliary dyskinesia without randomization of left-right body asymmetry. Am J Hum Genet 2012; 91 (4) 672-684
  • 45 Olbrich H, Horváth J, Fekete A , et al. Axonemal localization of the dynein component DNAH5 is not altered in secondary ciliary dyskinesia. Pediatr Res 2006; 59 (3) 418-422
  • 46 Horani A, Druley TE, Zariwala MA , et al. Whole-exome capture and sequencing identifies HEATR2 mutation as a cause of primary ciliary dyskinesia. Am J Hum Genet 2012; 91 (4) 685-693
  • 47 Kott E, Duquesnoy P, Copin B , et al. Loss-of-function mutations in LRRC6, a gene essential for proper axonemal assembly of inner and outer dynein arms, cause primary ciliary dyskinesia. Am J Hum Genet 2012; 91 (5) 958-964
  • 48 Mazor M, Alkrinawi S, Chalifa-Caspi V , et al. Primary ciliary dyskinesia caused by homozygous mutation in DNAL1, encoding dynein light chain 1. Am J Hum Genet 2011; 88 (5) 599-607
  • 49 Boon M, Wallmeier J, Ma L , et al. MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia. Nat Commun 2014; 5: 4418
  • 50 Watson CM, Crinnion LA, Morgan JE , et al. Robust diagnostic genetic testing using solution capture enrichment and a novel variant-filtering interface. Hum Mutat 2014; 35 (4) 434-441
  • 51 Noone PG, Bennett WD, Regnis JA , et al. Effect of aerosolized uridine-5′-triphosphate on airway clearance with cough in patients with primary ciliary dyskinesia. Am J Respir Crit Care Med 1999; 160 (1) 144-149
  • 52 Kellett F, Robert NM. Nebulised 7% hypertonic saline improves lung function and quality of life in bronchiectasis. Respir Med 2011; 105 (12) 1831-1835
  • 53 Bilton D, Tino G, Barker AF , et al; B-305 Study Investigators. Inhaled mannitol for non-cystic fibrosis bronchiectasis: a randomised, controlled trial. Thorax 2014; 69 (12) 1073-1079
  • 54 Fuchs HJ, Borowitz DS, Christiansen DH , et al; The Pulmozyme Study Group. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med 1994; 331 (10) 637-642
  • 55 O'Donnell AE, Barker AF, Ilowite JS, Fick RB. Treatment of idiopathic bronchiectasis with aerosolized recombinant human DNase I. rhDNase Study Group. Chest 1998; 113 (5) 1329-1334
  • 56 Flume PA, O'Sullivan BP, Robinson KA , et al; Cystic Fibrosis Foundation, Pulmonary Therapies Committee. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2007; 176 (10) 957-969
  • 57 King PT, Holmes PW. Use of antibiotics in bronchiectasis. Rev Recent Clin Trials 2012; 7 (1) 24-30
  • 58 Murray MP, Govan JR, Doherty CJ , et al. A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2011; 183 (4) 491-499
  • 59 Barker AF, O'Donnell AE, Flume P , et al. Aztreonam for inhalation solution in patients with non-cystic fibrosis bronchiectasis (AIR-BX1 and AIR-BX2): two randomised double-blind, placebo-controlled phase 3 trials. Lancet Respir Med 2014; 2 (9) 738-749
  • 60 Haworth CS, Foweraker JE, Wilkinson P, Kenyon RF, Bilton D. Inhaled colistin in patients with bronchiectasis and chronic Pseudomonas aeruginosa infection. Am J Respir Crit Care Med 2014; 189 (8) 975-982
  • 61 Evans DJ, Bara AI, Greenstone M. Prolonged antibiotics for purulent bronchiectasis in children and adults. Cochrane Database Syst Rev 2007; (2) CD001392
  • 62 White L, Mirrani G, Grover M, Rollason J, Malin A, Suntharalingam J. Outcomes of Pseudomonas eradication therapy in patients with non-cystic fibrosis bronchiectasis. Respir Med 2012; 106 (3) 356-360
  • 63 Serisier DJ, Martin ML, McGuckin MA , et al. Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis: the BLESS randomized controlled trial. JAMA 2013; 309 (12) 1260-1267
  • 64 Altenburg J, de Graaff CS, Stienstra Y , et al. Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial. JAMA 2013; 309 (12) 1251-1259
  • 65 Wong C, Jayaram L, Karalus N , et al. Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet 2012; 380 (9842) 660-667
  • 66 Smit HJ, Schreurs AJ, Van den Bosch JM, Westermann CJ. Is resection of bronchiectasis beneficial in patients with primary ciliary dyskinesia?. Chest 1996; 109 (6) 1541-1544
  • 67 Christie JD, Edwards LB, Kucheryavaya AY , et al; International Society of Heart and Lung Transplantation. The Registry of the International Society for Heart and Lung Transplantation: 29th adult lung and heart-lung transplant report-2012. J Heart Lung Transplant 2012; 31 (10) 1073-1086
  • 68 Campbell R. Managing upper respiratory tract complications of primary ciliary dyskinesia in children. Curr Opin Allergy Clin Immunol 2012; 12 (1) 32-38
  • 69 Prulière-Escabasse V, Coste A, Chauvin P , et al. Otologic features in children with primary ciliary dyskinesia. Arch Otolaryngol Head Neck Surg 2010; 136 (11) 1121-1126
  • 70 Parsons DS, Greene BA. A treatment for primary ciliary dyskinesia: efficacy of functional endoscopic sinus surgery. Laryngoscope 1993; 103 (11, Pt 1): 1269-1272
  • 71 Ellerman A, Bisgaard H. Longitudinal study of lung function in a cohort of primary ciliary dyskinesia. Eur Respir J 1997; 10 (10) 2376-2379