Update in Primary Ciliary Dyskinesia

Abstract

The spectrum of ciliary disease has widened from a primary upper and lower respiratory tract problem with the appreciation of the key role of sensory cilia. Five disease causing mutations have been discovered, but given the complexity of cilia, many more are likely to be found in the future. Primary ciliary dyskinesia may present with upper or lower airway disease, or be diagnosed after the discovery of associated conditions such as heterotaxy, complex congenital heart disease, and severe esophageal disease. Screening tests include nasal nitric oxide and in vivo measurements of mucociliary transport. Definitive diagnosis is by ciliary biopsy with measurement of ciliary beat frequency and pattern, followed by electron microscopy. Ciliary culture may help distinguish primary ciliary dyskinesia from ciliary abnormalities secondary to infection. Increasingly, genetic testing is becoming available. Once diagnosed, the severity is assessed, and follow-up should be in clinics with expertise in all areas of the condition. The evidence base for current treatment is weak, with no randomized controlled trials; all therapies are directed at complications, not the underlying abnormality. Lower airway disease is treated with airway clearance, antibiotics, and encouragement of exercise. A conservative approach to chronic secretory otitis media is advised. Although in many cases the patient is stabilized by medical therapy, some will go on to lung transplantation. In the future, specific therapies to reverse the ciliary dysfunction may become available. (Clin Pulm Med 2009;16: 219 -225) T raditionally, cilia have been thought of as part of the initial stage of the mucociliary escalator, an essential airway defense mechanism. Dysfunction in this system underlies primary ciliary dyskinesia (PCD). It is now clear that cilia have wide importance during embryogenesis and in multiple organs. Defective ciliary function is implicated in polycystic hepatic and renal disease, hydrocephalus, biliary atresia, retinal degeneration, and rare syndromes such as Bardet-Biedl, Alstrom and Meckel-Gruber, and oro-facial-digital syndromes in addition to nephronophthisis. 1,2 Jeune asphyxiating thoracic dystrophy now appears to be a ciliopathy. 3 As well as the motile cilia responsible for airway defenses, sensory cilia are important in many aspects of embryonic development. Motile nodal cilia have long been known to be responsible for normal right-left orientation, but there are likely to be important roles for cilia also in the development of the kidney, neural tube, the cochlear apparatus, the central nervous system, and the limb bud. 1,2 Although this review focuses on motile cilia and PCD, ciliopathies are a truly multisystem issue. GENETICSPCD is an autosomal recessive inherited disorder, with an estimated incidence of 1:15-30,000, 4 although the requirement for specialized diagnostics and variability of disease symptoms means that this is likely to be an underestimate. PCD has a much higher incidence in certain consanguineous and isolated p...

Mutations in Radial Spoke Head Protein Genes RSPH9 and RSPH4A Cause Primary Ciliary Dyskinesia with Central-Microtubular-Pair Abnormalities

“…PCD is usually recessively inherited, and five PCD genes have been identified: DNAI1 (MIM 604366), DNAH5 (MIM 603335), DNAH11 (MIM 603339), DNAI2 (MIM 605483) 9 and TXNDC3 (MIM 607421) (reviewed by Bush et al 10 ). These encode axonemal dyneins and are associated with reduction or loss of axonemal outer dynein arms, which are the multisubunit axonemal ATPase complexes that generate the force for cilia motility and govern beat frequency.…”

Mutations in axonemal dynein assembly factor DNAAF3 cause primary ciliary dyskinesia

“…PCD (MIM 244400) affects 1:15-30,000 live births and arises from ultrastructural defects causing dysmotility of motile cilia/flagella in the respiratory epithelia, brain ependyma, embryonic node, oviduct and sperm. Ineffective airway mucociliary clearance usually manifests within the first year of life with recurrent infections, sinusitis, rhinitis and otitis media, causing a chronic respiratory condition, and progressing to permanent lung damage (bronchiectasis) 1 , 2 . Half of PCD patients have laterality defects reflecting randomized left-right organogenesis due to embryonic nodal cilia dysfunction, usually situs inversus totalis (Kartagener syndrome) with rarer incidence of complex heterotaxy defects often associated with congenital heart disease 3 , 4 , 5 .…”

Congenital problems of mucociliary clearance: primary ciliary dyskinesia

“…DNAH5 is thought to account for approximately 28% of PCD cases, with DNAI1 causing a further 2-10% (39,40) . The other genes have only been found in isolated or rare cases, so the genetic basis is unknown in over 60% of PCD cases (7) . Several other loci have also been identified,…”