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The Journal of Pediatrics Mar 2021Ciliopathies are a collection of disorders related to cilia dysfunction. Cilia are specialized organelles that project from the surface of most cells. Motile and primary... (Review)
Review
Ciliopathies are a collection of disorders related to cilia dysfunction. Cilia are specialized organelles that project from the surface of most cells. Motile and primary (sensory) cilia are essential structures and have wide ranging functions. Our understanding of the genetics, pathophysiology, and clinical manifestations of motile ciliopathies, including primary ciliary dyskinesia (PCD), has rapidly advanced since the disease was linked to ciliary ultrastructural defects nearly five decades ago. We will provide an overview of different types of cilia, their role in child health and disease, focusing on motile ciliopathies, and describe recent advances that have led to improved diagnostics and may yield therapeutic targets to restore ciliary structure and function.
Topics: Cilia; Ciliary Motility Disorders; Humans
PubMed: 33242470
DOI: 10.1016/j.jpeds.2020.11.040 -
Clinics in Chest Medicine Mar 2022Primary ciliary dyskinesia (PCD) is a rare genetic disease leading to bronchiectasis in most patients. In addition to the lungs, PCD might affect multiple organ systems,... (Review)
Review
Primary ciliary dyskinesia (PCD) is a rare genetic disease leading to bronchiectasis in most patients. In addition to the lungs, PCD might affect multiple organ systems, and patients frequently have multiple clinical problems, which require multidisciplinary management. Diagnosis of PCD needs a combination of tests, many of which require expertise and expensive equipment. Measurement of nasal nitric oxide is the first test to consider when PCD is suspected. Detailed clinical history using available predictive scores in combination with information on functional and structural aspects of lung disease is important to identify which patients should be referred for further diagnostic testing.
Topics: Ciliary Motility Disorders; Humans; Nitric Oxide
PubMed: 35236553
DOI: 10.1016/j.ccm.2021.11.008 -
International Journal of Molecular... Sep 2021Primary ciliary dyskinesia (PCD) is a rare genetic ciliopathy in which mucociliary clearance is disturbed by the abnormal motion of cilia or there is a severe reduction... (Review)
Review
Primary ciliary dyskinesia (PCD) is a rare genetic ciliopathy in which mucociliary clearance is disturbed by the abnormal motion of cilia or there is a severe reduction in the generation of multiple motile cilia. Lung damage ensues due to recurrent airway infections, sometimes even resulting in respiratory failure. So far, no causative treatment is available and treatment efforts are primarily aimed at improving mucociliary clearance and early treatment of bacterial airway infections. Treatment guidelines are largely based on cystic fibrosis (CF) guidelines, as few studies have been performed on PCD. In this review, we give a detailed overview of the clinical studies performed investigating PCD to date, including three trials and several case reports. In addition, we explore precision medicine approaches in PCD, including gene therapy, mRNA transcript and read-through therapy.
Topics: Bacterial Infections; Ciliary Motility Disorders; Clinical Trials as Topic; Cystic Fibrosis; Humans; Lung; Respiratory Tract Infections
PubMed: 34575997
DOI: 10.3390/ijms22189834 -
Respiratory Medicine Apr 2023Cystic fibrosis (CF) and Primary ciliary dyskinesia (PCD) are both rare chronic diseases, inherited disorders associated with multiple complications, namely respiratory... (Review)
Review
Cystic fibrosis (CF) and Primary ciliary dyskinesia (PCD) are both rare chronic diseases, inherited disorders associated with multiple complications, namely respiratory complications, due to impaired mucociliary clearance that affect severely patients' lives. Although both are classified as rare diseases, PCD has a much lower prevalence than CF, particularly among Caucasians. As a result, CF is well studied, better recognized by clinicians, and with some therapeutic approaches already available. Whereas PCD is still largely unknown, and thus the approach is based on consensus guidelines, expert opinion, and extrapolation from the larger evidence base available for patients with CF. Both diseases have some clinical similarities but are very different, necessitating different treatment by specialists who are familiar with the complexities of each disease.This review aims to provide an overview of the knowledge about the two diseases with a focus on the similarities and differences between both in terms of disease mechanisms, common clinical manifestations, genetics and the most relevant therapeutic options. We hoped to raise clinical awareness about PCD, what it is, how it differs from CF, and how much information is still lacking. Furthermore, this review emphasises the fact that both diseases require ongoing research to find better treatments and, in particular for PCD, to fill the medical and scientific gaps.
Topics: Humans; Cystic Fibrosis; Kartagener Syndrome; Chronic Disease; Prevalence
PubMed: 36828173
DOI: 10.1016/j.rmed.2023.107169 -
Cellular and Molecular Life Sciences :... Jun 2020The core axoneme structure of both the motile cilium and sperm tail has the same ultrastructural 9 + 2 microtubular arrangement. Thus, it can be expected that... (Review)
Review
The core axoneme structure of both the motile cilium and sperm tail has the same ultrastructural 9 + 2 microtubular arrangement. Thus, it can be expected that genetic defects in motile cilia also have an effect on sperm tail formation. However, recent studies in human patients, animal models and model organisms have indicated that there are differences in components of specific structures within the cilia and sperm tail axonemes. Primary ciliary dyskinesia (PCD) is a genetic disease with symptoms caused by malfunction of motile cilia such as chronic nasal discharge, ear, nose and chest infections and pulmonary disease (bronchiectasis). Half of the patients also have situs inversus and in many cases male infertility has been reported. PCD genes have a role in motile cilia biogenesis, structure and function. To date mutations in over 40 genes have been identified cause PCD, but the exact effect of these mutations on spermatogenesis is poorly understood. Furthermore, mutations in several additional axonemal genes have recently been identified to cause a sperm-specific phenotype, termed multiple morphological abnormalities of the sperm flagella (MMAF). In this review, we discuss the association of PCD genes and other axonemal genes with male infertility, drawing particular attention to possible differences between their functions in motile cilia and sperm tails.
Topics: Animals; Cilia; Ciliary Motility Disorders; Humans; Infertility, Male; Male; Mutation; Spermatozoa
PubMed: 31781811
DOI: 10.1007/s00018-019-03389-7 -
Chest May 2021Primary ciliary dyskinesia (PCD) is a heterogeneous disease with a diverse clinical and genetic spectrum among populations worldwide. Few cases of pediatric PCD have...
BACKGROUND
Primary ciliary dyskinesia (PCD) is a heterogeneous disease with a diverse clinical and genetic spectrum among populations worldwide. Few cases of pediatric PCD have been reported from China.
RESEARCH QUESTION
What are the clinical and genotypic characteristics of children with PCD in China?
STUDY DESIGN AND METHODS
Clinical characteristics, laboratory findings, and genetic results obtained for 75 patients with PCD were reviewed retrospectively at a single center in China. Genetic sequencing was conducted using whole-exome screening.
RESULTS
Patient median age at diagnosis was 7.0 years (range, 2 months-14 years). Of 75 patients, 88% (66/75) had chronic wet cough, 77% (58/75) had recurrent sinusitis, 76% (57/75) had bronchiectasis, 40% (30/75) had neonatal respiratory distress, and 28% (21/75) had coexistent asthma. Notably, postinfectious bronchiolitis obliterans (PIBO) as first presentation was found in 8% of children (6/75). Genes with the highest incidence of mutations were DNAH11 (15/51), followed by DNAH5 (9/51), CCDC39 (5/51), DNAH1 (4/51), and CCNO (3/51). Four genes (DNAI1, HEATR2, RSPH9, and DNAAF3) each were respectively found in two patients, and seven genes (CCDC40, LRRC6, SPAG1, RSPH4A, ARMC4, CCDC114, and DNAH14, a novel gene) each were mutated once. No differences in classical clinical features were observed among patients with commonly observed PCD-associated genotypes. However, three of six PIBO patients carried DNAH1 mutations.
INTERPRETATION
Besides typical clinical features, PIBO was observed as the first presentation of pediatric PCD in China. An association of the novel gene DNAH14 with PCD was observed, expanding the PCD genotypic spectrum.
Topics: Adolescent; Child; Child, Preschool; China; Ciliary Motility Disorders; Dyneins; Female; Genotype; Humans; Infant; Male; Retrospective Studies
PubMed: 33577779
DOI: 10.1016/j.chest.2021.02.006 -
Nature Reviews. Nephrology Apr 2019Primary cilia project in a single copy from the surface of most vertebrate cell types; they detect and transmit extracellular cues to regulate diverse cellular processes... (Review)
Review
Primary cilia project in a single copy from the surface of most vertebrate cell types; they detect and transmit extracellular cues to regulate diverse cellular processes during development and to maintain tissue homeostasis. The sensory capacity of primary cilia relies on the coordinated trafficking and temporal localization of specific receptors and associated signal transduction modules in the cilium. The canonical Hedgehog (HH) pathway, for example, is a bona fide ciliary signalling system that regulates cell fate and self-renewal in development and tissue homeostasis. Specific receptors and associated signal transduction proteins can also localize to primary cilia in a cell type-dependent manner; available evidence suggests that the ciliary constellation of these proteins can temporally change to allow the cell to adapt to specific developmental and homeostatic cues. Consistent with important roles for primary cilia in signalling, mutations that lead to their dysfunction underlie a pleiotropic group of diseases and syndromic disorders termed ciliopathies, which affect many different tissues and organs of the body. In this Review, we highlight central mechanisms by which primary cilia coordinate HH, G protein-coupled receptor, WNT, receptor tyrosine kinase and transforming growth factor-β (TGFβ)/bone morphogenetic protein (BMP) signalling and illustrate how defects in the balanced output of ciliary signalling events are coupled to developmental disorders and disease progression.
Topics: Cell Differentiation; Cell Movement; Cilia; Ciliary Motility Disorders; Hedgehog Proteins; Homeostasis; Humans; Organogenesis; Signal Transduction
PubMed: 30733609
DOI: 10.1038/s41581-019-0116-9 -
The New England Journal of Medicine Apr 2011Diverse developmental and degenerative single-gene disorders such as polycystic kidney disease, nephronophthisis, retinitis pigmentosa, the Bardet–Biedl syndrome, the... (Review)
Review
Diverse developmental and degenerative single-gene disorders such as polycystic kidney disease, nephronophthisis, retinitis pigmentosa, the Bardet–Biedl syndrome, the Joubert syndrome, and the Meckel syndrome may be categorized as ciliopathies — a recent concept that describes diseases characterized by dysfunction of a hairlike cellular organelle called the cilium. Most of the proteins that are altered in these single-gene disorders function at the level of the cilium–centrosome complex, which represents nature’s universal system for cellular detection and management of external signals. Cilia are microtubule-based structures found on almost all vertebrate cells. They originate from a basal body, a modified centrosome, which is the organelle that forms the spindle poles during mitosis. The important role that the cilium–centrosome complex plays in the normal function of most tissues appears to account for the involvement of multiple organ systems in ciliopathies. In this review, we consider the role of the cilium in disease.
Topics: Centrosome; Cilia; Ciliary Motility Disorders; Eye Diseases; Genotype; Hedgehog Proteins; Humans; Kidney Diseases; Mutation; Phenotype; Signal Transduction; Ultrasonography
PubMed: 21506742
DOI: 10.1056/NEJMra1010172 -
Journal of Cellular and Molecular... Dec 2023More and more attention is paid to diseases such as internal transfer and brain malformation which are caused by the abnormal morphogenesis of cilia. These cilia-related... (Review)
Review
More and more attention is paid to diseases such as internal transfer and brain malformation which are caused by the abnormal morphogenesis of cilia. These cilia-related diseases are divided into two categories: ciliopathy resulting from defects of primary cilia and primary ciliary dyskinesia (PCD) caused by functional dysregulation of motile cilia. Cilia are widely distributed, and their related diseases can cover many human organs and tissues. Recent studies prove that primary cilia play a key role in maintaining homeostasis in the cardiovascular system. However, molecular mechanisms of cilia-related diseases remain elusive. Here, we reviewed recent research progresses on characteristics, molecular mechanisms and treatment methods of ciliopathy and PCD. Our review is beneficial to the further research on the pathogenesis and treatment strategies of cilia-related diseases.
Topics: Humans; Cilia; Ciliary Motility Disorders; Ciliopathies; Mutation
PubMed: 37830491
DOI: 10.1111/jcmm.17990 -
Acta Bio-medica : Atenei Parmensis Sep 2019Infertility due to genetic mutations that cause other defects, besides infertility, is defined as syndromic. Here we describe three of these disorders for which we... (Review)
Review
Infertility due to genetic mutations that cause other defects, besides infertility, is defined as syndromic. Here we describe three of these disorders for which we perform genetic tests. 1) Hypopituitarism is an endocrine syndrome characterized by reduced or absent secretion of one or more anterior pituitary hormones with consequent dysfunction of the corresponding peripheral glands. Deficiencies in all the hormones is defined as pan-hypopituitarism, lack of two or more hormones is called partial hypopituitarism, whereas absence of a single hormone is defined as selective hypopituitarism. Pan-hypopituitarism is the rarest condition, whereas the other two are more frequent. Several forms exist: congenital, acquired, organic and functional. 2) The correct functioning of the hypothalamic-pituitary-gonadal axis is fundamental for sexual differentiation and development during fetal life and puberty and for normal gonad function. Alteration of the hypothalamic-pituitary system can determine a condition called hypogonadotropic hypogonadism, characterized by normal/low serum levels of the hormones FSH and LH. 3) Primary ciliary dyskinesia is frequently associated with infertility in males because it impairs sperm motility (asthenozoospermia). Primary ciliary dyskinesia is a group of genetically and phenotypically heterogeneous disorders that show morpho-structural alterations of the cilia. Adult women with primary ciliary dyskinesia can be subfertile and have an increased probability of extra-uterine pregnancies. This is due to delayed transport of the oocyte through the uterine tubes.
Topics: Ciliary Motility Disorders; Female; Genetic Predisposition to Disease; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans; Hypogonadism; Hypopituitarism; Infertility; Male
PubMed: 31577259
DOI: 10.23750/abm.v90i10-S.8764