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Internal Medicine

Ciliopathies

Genetically heterogeneous group of disorders that are caused by mutations in genes with products that localize to the cilium–centrosome complex.


Physiology

Cilia structure:

Cilia are hair-like organelles projecting from the apical surface of polarized cells. Whether in single-celled organisms or in mammals, the form and function of cilia have been conserved over the course of evolution. Cilia are formed from the basal body, which is created through modification of the older of the two (mother) centrosomes. The basal body forms the central core of the cilium, the axoneme, which consists of a circular array of nine pairs of microtubules covered by a specialized membrane contiguous with the plasma membrane of the cell. Some cilia also contain a central pair of microtubules (“9+2” cilia), while other cilia lack the central pair (“9+0” cilia). In general, “9+2” cilia are motile while “9+0” cilia are primary, but overlap does occur.

Ciliary function:

Although this division is overly simplistic, as there is overlap between the features of motile and primary cilia.
  • Motile cilia: Respiratory epithelial function, fertility, and determination of left-right orientation
  • Primary (or sensory) cilia: Antennae for cells, sensing the extracullar environment and transducing signals back to the cell to facilitate its response. These functions are critically important in cell proliferation, differentiation, and maintenance.
Structures and functions of motile and non-motile cilia
Structures and functions of motile and non-motile cilia: All cilia extend from a basal body that typically consists of triplet microtubules, and subdistal and distal appendages. Distal appendages (also known as transition fibres) tether the basal body to the base of the ciliary membrane. Immediately distal to the basal body is the transition zone, which contains doublet microtubules that are connected to the ciliary membrane via Y-shaped structures. Axonemes (the ciliary backbone) are composed of doublet microtubules. In motile cilia, axonemes usually contain associated structures and proteins (for example, the central pair and axonemal dyneins) that are required for ciliary motility. Nodal cilia are an exception as they are motile but lack a central pair of microtubules. Cilia may contain additional subdomains, including singlet microtubules at the distal end, and regions with specific protein compositions or functions (for example, the inversin domain (INV; involved in signalling). Key cell signalling functions and roles in motility are summarized. | PKD, polycystin. | Reiter, J. F., & Leroux, M. R. (2017). Genes and molecular pathways underpinning ciliopathies. Nature reviews. Molecular cell biology, 18(9), 533–547. https://doi.org/10.1038/nrm.2017.60

Ciliary disorders

Ciliopathies cause a wide range of overlapping syndromes that include fibrocystic diseases of the kidney and liver as well as disparate abnormalities of other organ systems.

Dysfunctions in motile and/or non-motile cilia cause ciliopathies that encompass most human organ systems
Dysfunctions in motile and/or non-motile cilia cause ciliopathies that encompass most human organ systems: The figure shows the different organ systems or tissues that are affected in diverse ciliopathies, and the principle phenotypic manifestations of the disease in each organ. Ciliopathies that are caused primarily by defects in motile cilia are shown in orange, those that result from defects in non-motile (primary) cilia are shown in blue and those associated with defects in both types of cilia are shown in green. | NPHP, nephronophthisis; PKD, polycystic kidney disease. | Reiter, J. F., & Leroux, M. R. (2017). Genes and molecular pathways underpinning ciliopathies. Nature reviews. Molecular cell biology, 18(9), 533–547. https://doi.org/10.1038/nrm.2017.60

Motile ciliary disorders

Primary ciliary dyskinesia (PCD) “immotile cilia syndrome”:

Defects in the function of the motile cilia give rise to primary ciliary dyskinesia (PCD), or immotile cilia syndrome. PCD is the first human condition linked to abnormal ciliary function. Like other ciliopathies, PCD is genetically heterogeneous and patients demonstrate a spectrum of clinical manifestations with variable severity. Most patients demonstrate defective function of the outer dynein arms.
  • Respiratory tract: Abnormal ciliary movements cause impaired mucociliary clearance that results in recurrent and chronic oto-sinopulmonary infections.
  • Infertility: Sperm tail and fimbriae of fallopian tubes also have motile cilia therefore male and female infertility often results
  • Situs abnormalities: Abnormal thoracoabdominal orientation results since normal ciliary movement needed for the visceral rotation during embryogenesis

Primary (Sensory) Ciliary Disorders

Cilia line the ducts of the kidney and liver and have recently been shown to be integral to proper renal and hepatic development. The kidneys are the most commonly affected organs in ciliopathies, with effects ranging from mild urinary concentration defects in normal-appearing kidneys to cystic, dysplastic kidneys.

Polycystic kidney disease (PKD):

Inherited disorder characterized by cystic expansion of the kidneys producing progressive kidney enlargement and renal insufficiency, in addition to various extrarenal manifestations.
  • ARPKD: Abnormality of renal tubular (collecting duct) development
  • ADPKD: Abnormality of renal tubule homeostasis
  • Other renal abnormalities: Nephronophthisis, glomerulocystic disease, and medullary sponge kidney
Summary of ADPKD and ARPKD
Summary of ADPKD and ARPKD | Kwatra, S., Krishnappa, V., Mhanna, C., Murray, T.E., Novak, R., Sethi, S.K., Kumar, D., & Raina, R. (2017). Cystic Diseases of Childhood: A Review. Urology, 110, 184-191 .

Hepatic fibrocystic disease:

In both ARPKD and ADPKD, the liver is also involved with fibrocystic disease caused by ductal plate malformation (DPM), which manifests as characteristic liver pathologies
  • Congenital hepatic fibrosis (CHF) (in ARPKD)
  • Caroli syndrome
  • Polycystic liver disease
Hepatobiliary lesions in hepatorenal disease: a) Hepatobiliary lesions result from an architectural defect in the developing biliary tree. The normal ramifications of the portal venous system and the lattice-like network of associated biliary ducts (left) are disrupted owing to ductal plate malformation (DPM) (right), likely owing to a defect in terminal differentiation of cholangiocytes. b) The DPM results in marked cystic and fusiform dilatation of the intrahepatic biliary system (coronal T2-weighted image of the abdomen), nephromegaly with small cysts (arrowhead), cystic biliary disease (arrow) and marked splenomegaly (asterisk). c) The histopathological manifestation of the DPM is congenital hepatic fibrosis (section stained with haematoxylin and eosin), which is characterized by extensive fibrosis of the portal area (asterisk), ectatic, tortuous bile ducts (arrows) and hypoplasia of the portal vein (arrowhead). | Magnification is 40×. | Part a: Marchal G J, Desmet V J, Proesmans W C, et al. Caroli disease: high-frequency US and pathologic findings. | Part b, c: Bergmann, C., Guay-Woodford, L. M., Harris, P. C., Horie, S., Peters, D., & Torres, V. E. (2018). Polycystic kidney disease. Nature reviews. Disease primers, 4(1), 50. https://doi.org/10.1038/s41572-018-0047-y

Ciliopathy syndromes:

In addition, renal and hepatic fibrocystic disease may accompany abnormalities of other organ systems in ciliopathy syndromes:
  • Joubert syndrome
  • Meckel-Gruber syndrome
  • Orofaciodigital type 1 syndrome
  • Sensenbrenner syndrome
  • Jeune syndrome
Genetics and Clinical, Pathologic, and Imaging Features of Ciliopathies
Ciliary disorders affect a wide variety of tissues and organ systems. The genetic and phenotypic heterogeneity of these disorders explains the frequent overlap of cystic renal disease and tubulointerstitial fibrosis, hepatic cysts and fibrosis, retinal degeneration, CNS anomalies, skeletal anomalies, and laterality defects in the phenotypes of many human diseases | Note: AD = autosomal dominant, AR = autosomal recessive, MCKD = medullary cystic kidney disease. | From the Radiologic Pathology Archives: Pediatric Polycystic Kidney Disease and Other Ciliopathies: Radiologic-Pathologic Correlation Ellen M. Chung, Richard M. Conran, Jason W. Schroeder, Ivan R. Rohena-Quinquilla, and Veronica J. Rooks RadioGraphics 2014 34:1, 155-178

Motile ciliopathies are rare genetic diseases that result in defective beating of motile cilia on epithelial cells.
Motile ciliopathies are rare genetic diseases that result in defective beating of motile cilia on epithelial cells. | Motile ciliopathies. Nat Rev Dis Primers 6, 76 (2020). https://doi.org/10.1038/s41572-020-00219-0

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