Unusual presentation of the immotile cilia syndrome in two children.
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Ciliary Motility Disorders↗
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Primary ciliary dyskinesia in the dog.
Electron microscopy was used to diagnose primary ciliary dyskinesia in a litter of English pointer dogs and in a golden retriever dog. A technique of membrane solubilization, fixation, and negative staining with glutaraldehyde tannic acid identified abnormally constructed central and B microtubules in respiratory cilia from dogs with primary ciliary dyskinesia. Shortened outer dynein arms commonly associated with primary ciliary dyskinesia actually represents the absence of a specific subset of the three most peripheral components of the whole outer dynein arm structure.
Animals↗
Ciliostasis and loss of cilia induced by Mycoplasma hyopneumoniae in porcine tracheal organ cultures.
In vivo- and in vitro-grown Mycoplasma hyopneumoniae organisms were inoculated onto newborn piglet tracheal organ cultures to provide a model for interaction of this organism with ciliated respiratory epithelium. Ciliostasis and loss of cilia in tracheal rings were induced by M. hyopneumoniae grown in vivo and with low-passage cultures when grown in vitro. Levels of calmodulin or dehydrogenase enzymes in tracheal ring epithelium were not altered even though ciliostasis and loss of cilia induced by M. hyopneumoniae were extensive. The capacity for inducing epithelial damage diminished with in vitro passage of the organism. Attempts to induce higher-passage cultures to attach to cilia, cause ciliostasis, or cause ciliary damage by supplementation of mycoplasmal medium with porcine lung extract failed. Epithelial damage induced by M. hyopneumoniae in tracheal rings was averted by using porcine immune serum or by separating the organisms from ciliated epithelium with a 0.1-microns-pore-size membrane. Attachment, or at least close association, of M. hyopneumoniae to ciliated epithelium appeared to be necessary to induce ciliostasis and loss of cilia in this model.
Animals↗
Resistance/susceptibility to lethal Sendai virus infection genetically linked to a mucociliary transport polymorphism.
Linkage was tested between a mucociliary transport polymorphism and resistance/susceptibility to lethal Sendai virus infection in segregant hybrid mice of C57BL/6J and DBA/2J parents. The distribution of paired phenotypes for tracheal mucociliary transport rates and susceptibility to lethal Sendai virus infection in 171 F1 X DBA/2J mice showed strong interaction of the parental phenotypes.
Animals↗
Hydrocephalus, situs inversus, chronic sinusitis, and male infertility in DNA polymerase lambda-deficient mice: possible implication for the pathogenesis of immotile cilia syndrome.
A growing number of DNA polymerases have been identified, although their physiological function and relation to human disease remain mostly unknown. DNA polymerase lambda (Pol lambda; also known as Pol beta2) has recently been identified as a member of the X family of DNA polymerases and shares 32% amino acid sequence identity with DNA Pol beta within the polymerase domain. With the use of homologous recombination, we generated Pol lambda(-/-) mice. Pol lambda(-/-) mice develop hydrocephalus with marked dilation of the lateral ventricles and exhibit a high rate of mortality after birth, although embryonic development appears normal. Pol lambda(-/-) mice also show situs inversus totalis and chronic suppurative sinusitis. The surviving male, but not female, Pol lambda(-/-) mice are sterile as a result of spermatozoal immobility. Microinjection of sperm from male Pol lambda(-/-) mice into oocytes gives rise to normal offspring, suggesting that the meiotic process is not impaired. Ultrastructural analysis reveals that inner dynein arms of cilia from both the ependymal cell layer and respiratory epithelium are defective, which may underlie the pathogenesis of hydrocephalus, situs inversus totalis, chronic sinusitis, and male infertility. Sensitivity of Pol lambda(-/-) cells to various kinds of DNA damage is indistinguishable from that of Pol lambda(+/+) cells. Collectively, Pol lambda(-/-) mice may provide a useful model for clarifying the pathogenesis of immotile cilia syndrome.
Animals↗
Mice deficient in the axonemal protein Tektin-t exhibit male infertility and immotile-cilium syndrome due to impaired inner arm dynein function.
The haploid germ cell-specific Tektin-t protein is a member of the Tektin family of proteins that form filaments in flagellar, ciliary, and axonemal microtubules. To investigate the physiological role of Tektin-t, we generated mice with a mutation in the tektin-t gene. The homozygous mutant males were infertile, while the females were fully fertile. Sperm morphology and function were abnormal, with frequent bending of the sperm flagella and marked defects in motility. In vitro fertilization assays showed that the defective spermatozoa were able to fertilize eggs. Electron microscopic examination showed that the dynein inner arm structure was disrupted in the sperm flagella of tektin-t-deficient mice. Furthermore, homozygous mutant mice had functionally defective tracheal cilia, as evidenced by altered dynein arm morphology. These results indicate that Tektin-t participates in dynein inner arm formation or attachment and that the loss of Tektin-t results in impaired motility of both flagella and cilia. Therefore, the tektin-t gene is one of the causal genes for immotile-cilium syndrome/primary ciliary dyskinesia.
Animals↗
How has research in the last five years changed my clinical practice?
UNLABELLED: The first instruction to examination candidates is to read and answer the question actually set. Doing so in this case leads to the following CONCLUSIONS: how research has changed my clinical practice includes the act of doing research, as well as reading about the work of others. Thus, this article refers to my own clinical practice (tertiary referral paediatric respiratory medicine in a setting where we do not service an accident and emergency department), rather than that of others. This means excluding important conditions such as acute croup and uncomplicated community acquired pneumonia. I should write about what has changed my practice, not what other people think I ought to have changed. So this will be a personal view, limited to research published in a peer review format at the time of writing. I shall also assume that change is an ongoing process, so I shall include change in progress, provided it is supported by published literature.
Asthma↗
Hydrocephalus and primary ciliary dyskinesia.
Primary ciliary dyskinesia was shown in a 12 year old boy with bronchiectasis who had developed hydrocephalus in the neonatal period. The possible relevance of his ciliary abnormality is discussed.
Child↗
Ciliary abnormalities in respiratory disease.
One hundred and sixty seven children, ranging in age from 5 weeks to 16 years, with chronic upper or lower respiratory tract problems, or both, were investigated for ciliary dyskinesia. Abnormal ciliary function was found in 18 cases all of whom had chronic lower respiratory disease and most of whom also had upper respiratory problems. Fifteen of the 18 cases had reduced ciliary beat frequencies (less than 10 Hz) associated with dyskinesia and the other three showed apparent absence of ciliated cells. Of the 15 cases with reduced ciliary beat frequencies, ciliary ultrastructure was normal in seven cases but abnormal with missing dynein arms and occasional abnormalities of microtubular arrangement in eight. Respiratory symptoms in the perinatal period were more common in children with abnormal ciliary function and present in all those with ultrastructural abnormalities or absence of ciliated cells compared with 34 (26%) of 132 children, in whom symptoms were recorded, with normal ciliary function. This study would suggest that all children with unexplained chronic respiratory disease, in particular those with symptoms starting in the perinatal period, should be investigated for ciliary dyskinesia.
Adolescent↗
Hydrocephalus, bronchiectasis, and ciliary aplasia.
A girl presented in the neonatal period with hydrocephalus, bronchiectasis, and ciliary aplasia. A common defect both in respiratory tract cilia and in ventricular ependyma cilia may explain the association of the two diseases.
Bronchi↗
Aetiology of chronic suppurative lung disease.
Forty one (1%) of 4000 children referred for respiratory disease had chronic suppurative lung disease not due to cystic fibrosis. Further investigations showed congenital malformations in six (15%), primary ciliary dyskinesia syndrome in seven (17%), 11 had immunological abnormalities (27%), and two bronchiectasis due to aspiration (5%). Therefore the underlying cause for the disease was found in 63%. Identification of predisposing causes may facilitate prevention of further bronchial damage.
Bronchi↗
Orientation of respiratory tract cilia in patients with primary ciliary dyskinesia, bronchiectasis, and in normal subjects.
A reproducible technique, utilising a graphics tablet and a personal computer for measuring ciliary orientation from electron micrographs of ciliated epithelium, was assessed. Ciliary deviation was measured in 47 normal subjects (mean ciliary deviation +/- 1 SD was 14.6 (3.3 degrees)), in eight patients with bronchiectasis and normal ciliary function (15.1 (6.5 degrees], and in seven patients with primary ciliary dyskinesia (38.7 (7.8 degrees); significantly greater than the first two groups). Measurements of ciliary deviation at the tip, base, and basal feet showed very little variation along the ciliary shaft in all three groups, suggesting that valid measurements of ciliary deviation can be made at any level of the cilium. Mean ciliary deviation in normal subjects was always less than 30 degrees; all patients with a mean ciliary deviation of greater than 30 degrees had recurrent respiratory tract disease. Four of seven patients with primary ciliary dyskinesia had ciliary disorientation; in one this was the only defect. Measurements of inter- and intraobserver variability using this method showed a maximum difference between observations of 4.1 degrees. It is suggested that ciliary orientation should be measured in patients suspected of having defective ciliary function or structure, or both.
Adolescent↗
Loci for primary ciliary dyskinesia map to chromosome 16p12.1-12.2 and 15q13.1-15.1 in Faroe Islands and Israeli Druze genetic isolates.
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Chromosome Mapping↗
A locus for primary ciliary dyskinesia maps to chromosome 19q.
Primary ciliary dyskinesia is an autosomal recessive condition characterised by chronic sinusitis, bronchiectasis, and subfertility. Situs inversus occurs in 50% of cases (Kartagener syndrome). It has an estimated incidence of 1 in 20 000 live births. The clinical phenotype is caused by defective ciliary function associated with a range of ultrastructural abnormalities including absent dynein arms, absent radial spokes, and disturbed ciliary orientation. The molecular genetic basis is unknown. A genome scan was performed in five Arabic families. Using GENEHUNTER, a maximal multipoint lod score (HLOD) of 4.4 was obtained on chromosome 19q13.3-qter at alpha (proportion of linked families) = 0.7. A 15 cM critical region is defined by recombinations at D19S572 and D19S218. These data provide significant evidence for a PCD locus on chromosome 19q and confirm locus heterogeneity.
Adult↗
RPGR mutation associated with retinitis pigmentosa, impaired hearing, and sinorespiratory infections.
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Adolescent↗
Freeze fracture study of airway epithelium from patients with primary ciliary dyskinesia.
BACKGROUND: The airway cilia of patients with primary ciliary dyskinesia (PCD) exhibit several anomalies when studied by transmission electron microscopy, but little is known about the ultrastructural organisation of ciliary membranes in these patients. Freeze fracture replication of airway epithelium from patients with PCD provides a means of achieving high resolution views of cell membrane structure. Ciliary necklaces are a specialised structural feature of ciliary membranes thought to serve as a timing mechanism for ciliary beat, and their characterisation in the cilia of patients with PCD may contribute new insights into the pathophysiology of this syndrome. METHODS: The nasal epithelium of three patients with PCD was freeze fractured and replicated with platinum and carbon shadowing. The resultant preparations were examined by transmission electron microscopy and the ciliary necklaces were compared with similar preparations of nasal biopsy specimens from normal healthy subjects. RESULTS: The ciliary necklaces of the three patients with PCD were normal with no overt differences from those of healthy individuals. CONCLUSIONS: The defective ciliary motility observed in patients with PCD does not appear to result from membrane dysfunction associated with overt disorganisation of ciliary necklace structure.
Ciliary Motility Disorders↗
Comparison of exhaled and nasal nitric oxide and exhaled carbon monoxide levels in bronchiectatic patients with and without primary ciliary dyskinesia.
BACKGROUND: Primary ciliary dyskinesia (PCD) is associated with chronic airway inflammation resulting in bronchiectasis. METHODS: The levels of exhaled nitric oxide (eNO), carbon monoxide (eCO) and nasal NO (nNO) from bronchiectatic patients with PCD (n=14) were compared with those from patients with non-PCD bronchiectasis without (n=31) and with cystic fibrosis (CF) (n=20) and from normal subjects (n=37) to assess the clinical usefulness of these measurements in discriminating between PCD and other causes of bronchiectasis. RESULTS: Exhaled NO levels were lower in patients with PCD than in patients with non-PCD non-CF bronchiectasis or healthy subjects (median (range) 2.1 (1.3-3.5) ppb v 8.7 (4.5-26.0) ppb, p<0.001; 6.7 (2.6-11.9) ppb, p<0.001, respectively) but not lower than bronchiectatic patients with CF (3.0 (1.5-7.5) ppb, p>0.05). Nasal levels of nNO were significantly lower in PCD patients than in any other subjects (PCD: 54.5 (5.0-269) ppb, non-PCD bronchiectasis without CF: 680 (310-1000) ppb, non-PCD bronchiectasis with CF: 343 (30-997) ppb, control: 663 (322-1343) ppb). In contrast, eCO levels were higher in all patient groups than in control subjects (PCD: 4.5 (3.0-24.0) ppm, p<0.01, other bronchiectasis without CF: 5.0 (3.0-15.0) ppm, p<0.001; CF: 5.3 (2.0-23.0) ppm, p<0.001 v 3.0 (0.5-5.0) ppm). Low values in both eNO and nNO readings (<2.4 ppb and <187 ppb, respectively) identified PCD patients from other bronchiectatic patients with a specificity of 98% and a positive predictive value of 92%. CONCLUSION: The simultaneous measurement of eNO and nNO is a useful screening tool for PCD.
Adult↗