2012-10-03T01:03:19Z

Z3333427: /* Normal Function */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
|[[File:Vomeronasal Organ position.jpg|thumb|right|200px|alt=Alt|''Vomeronasal Organ position''']]

Discovery of [[#Glossary|'''Vomeronasal organ''']] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|'''hypogonadism''']] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name="PMID15836430"><pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|'''epiblast''']], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of [[#Glossary|'''ectoderm''']]<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|'''cribriform plate''']]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia and midline anatomic defects) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for revealing the large number of genes involved in odour reception. <ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|300px|right|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|300px|thumb|right|Olfactory Epithelium]]
[http://www.example.com Nasal Cavity]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells. <ref name="PMID7143026"><pubmed>7143026</pubmed></ref>.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.<ref name="PMID17468753 "><pubmed>17468753 </pubmed></ref>.

[http://www.ncbi.nlm.nih.gov/books/NBK10896/ Olfactory epithelium]
==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|300px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined. The olfactory bulb is essential for olfaction as it transmits information from the olfactory epithelium and up to the brain. The bulb receives input from olfactory nerves which constitutes the axons of olfactory receptor neurons. <ref name="PMID12951145 "><pubmed>12951145</pubmed></ref>.

Structures known as glomeruli form by a number of olfactory axons joining together such that each glomerulus obtain information from olfactory neurons which have the identical odour receptors. These glomeruli structures are also surrounded by dendrites belonging to mitral cells which transmit electrical signals to the olfactory cortex in the brain.<ref name="PMID16269360"><pubmed>16269360</pubmed></ref>.

==== Cribiform plate ====

The cribiform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groove allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha. If the cribriform plate happens to get fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose. <ref name="PMID11226964"><pubmed>11226964</pubmed></ref>.

== Normal Function ==

===Olfactory Signal Transduction===

[[File:Olfaction_signal_transduction.JPG|380px|thumb|right]]

Olfactory Signal Transduction is initiated by any substance that emit molecules known as odours. The olfactory transduction is dependent upon the dissolving of these odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors in order for chemical signals to be converted into electrical signals. The transformation into electrical signal is essential for signal transduction for the brain to perceive the initial odourants as smell. <ref name="PMID18066954"><pubmed>18066954</pubmed></ref>.

When odorant molecules bind to receptors in olfactory epithelium, a G protein coupled receptors known as G(αolf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP (cAMP). In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions by binding to and opening cyclic nucleotide gated ion channel to travel through the membrane and enter the cell. <ref name="PMID19652915"><pubmed>19652915</pubmed></ref>. The main effect of ion entry into the cell is depolarisation, and activation of chloride channels resulting in greater depolarisation by the efflux of chloride ions. If the depolarization in the cell is great enough, an action potential is generated on the axon of the receptor cell and transferred to the brain through the olfactory bulb.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

Similar to other G-protein mediated pathways, the olfactory sensory neuron is exposed to negative feedback by the cAMP cascade activated by odours. The negative feedback loop has been discovered to be responsible for the adaption of odours and deactivation of response after exposure for a certain period of time. <ref name="PMID19804753"><pubmed>19804753</pubmed></ref>.

[http://www.youtube.com/watch?v=dIDBG-UPRUI&feature=related| Olfactory Signal Transduction]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
* All five facial swellings form initially surrounding the stomodeum.

* The [[#Glossary |'''frontonasal prominence''']] is the facial swelling which gives rise to [[#Glossary | '''olfactory placodes''']]. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>.

An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. Mesencephalic region produced neural crest cells which contributed to the frontonasal mass.<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>

* These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

* Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

* Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref name="PMID15454774"><pubmed>15454774</pubmed></ref>
||
[[File:week4.jpg|200px|thumb|right|Embryo at week 4]]
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

* As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

* The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit as the face folds, dividing the frontonasal prominence into the lateral and medial nasal processes.These pits deepen as the surrounding mesenchyme proliferates to form '''primordial nasal sacs''' which grow dorsally but remain ventral to the forebrain. <ref name="PMID15454774"><pubmed>15454774</pubmed></ref> These sacs are separated from the oral cavity via the '''oronasal membrane'''.

* '''Glial cells''': Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref>

||
[[File:Week5.jpg|200px|thumb|right|Embryo at week 5]]
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
* '''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

* The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and [[#Glossary |'''nasal septum''']].<ref name="PMID438867"><pubmed>438867</pubmed></ref>

* The oronasal membrane ruptures by the end of this week, allowing communication between the nasal and oral cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* '''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
The superior, middle, and inferior nasal conchae develop as the lateral walls of the nasal cavities proliferate and so elevate.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref name="PMID15454774"><pubmed>15454774</pubmed></ref>

* '''Vomeronasal Organ Primordium''': Visible as epithelial swellings on the lower medial aspect of the nasal pit.<ref name="PMID9712194"><pubmed>9712194</pubmed></ref>. The anterior part can be seen as an indentation and the posterior part can be seen as continuous epithelium with the nasal septum. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* [[#Glossary |'''Vomeronasal Organ''']]: The VNP's are no longer visible but are instead in the form of bilateral tubes with well delineated lumens, that open anteriorly into the nasal cavity.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref> The VNO epithelium is thicker than respiratory epithelium up until 12 weeks when the respiratory epithelium overtakes in thickness<ref name="PMID11117628"><pubmed>11117628</pubmed></ref>. The medial sides of the VNO's proliferate into thicker, microvillous sensory epithelium while the the lateral sides are thinner, receptor-free, ciliated epithelium. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

||
[[File:Week6.jpg|200px|thumb|right|Embryo at week 6]]
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
* '''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla.
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* '''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse to form the primary palate.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, [[#Glossary |'''Nasal fin.''']]<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* '''Secondary Palate''': Formed as the two palatine shelves extend medially and fuse at the midline at the primary palate.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The lining of the olfactory placode differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

- '''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

- '''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

- '''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

* At the end of the 7th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated [[#Glossary |'''cribriform plate''']]. <ref name="PMID15454774"><pubmed>15454774</pubmed></ref>

* [[#Glossary |'''Olfactory bulb''']] growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* [[#Glossary |'''Olfactory nerve''']] formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref>
As a result, the CNS olfactory tracts look stalk-like.

* '''Olfactory nerve''': the '''olfactory tract''' and bulb together.

* By this stage the olfactory nerve is divided into a medial and lateral plexus. The medial plexus receives the VNO axon strands which are directed towards the caudal part of the olfactory bulb. Meanwhile the lateral plexus receives axon elongation from the olfactory epithelium and is directed towards the lateral edge of the olfactory bulb. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* Migration of Gonadotropin Releasing hormone along the vomeronasal nerve between weeks 6 to 8- plays a part in hypothalamus development.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
[[File:Week7.jpg|200px|thumb|right|Embryo at week 7]]
|- bgcolor="#BCD4E6"
|''Week 8/Fetal development''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
* '''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* '''VNO:''' At this stage, the number of ciliated VNO epithelial cells increases into the late fetal period whilst the number of receptor cells decreases. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>
The degeneration of the VNO is noted by the closure of the duct and formation of a cyst like structure in the nasal septum. However, in most adults, the duct is left opened to a certain degree.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
||
[[#Anatomy of the Olfactory System |'''See normally developed sensory structures of olfaction''']]

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann Syndrome|'''Kallmann Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

------

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by narrowing or complete obliteration of the nasal aperture by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. The following models have been proposed to explain how choanal atresia may occur in the developing human.

<table>
{| width=100%
|-bgcolor="#FF9900 "
| width=20%|'''Risk Factor Model'''
| width=80%|'''Description'''
|-bgcolor="#FFFF99"
| ''' Embryonic'''
| Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence":
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter<ref name="PMID19328897"/>
* Abnormal persistence of mesoderm, resulting in adhesions in the nasochoanal region<ref name="PMID19328897"/>
* Misdirection of neural crest cell migration <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>
|-bgcolor="#FFCC66"
| '''Genetic'''
|
* A study <ref name="PMID3679682"><pubmed> 3679682</pubmed></ref> reported that 30% of children with choanal atresia had '''CHARGE Syndrome''' which stands for: Coloboma, Heart defect, Atresia Choanae, Retarded Growth and development, Genital hypoplasia, Ear anomalies or deafness <ref name="PMID19328897"/>.
* CHD7 gene on chromosome 8q12.1 found in 64% of CHARGE syndrome patients though its function is unknown. <ref name="PMID16155193"><pubmed>16155193</pubmed></ref>
|-bgcolor="#FFFF99"
| '''Molecular'''
|
* '''Thionamides and Hyperthyroidism''': A number of studies reported an increased incidence of choanal atresia in babies of hyperthyroid mothers treated with thionamides<ref name="PMID3688031"><pubmed>3688031</pubmed></ref><ref name="PMID9450891"><pubmed>9450891</pubmed></ref><ref name="PMID18698631"><pubmed>18698631</pubmed></ref>. The majority of hyperthyroid mothers had elevated levels of stimulating antibody for the thyrotropin receptor<ref name="PMID19328897"/>. Human studies and animal models have shown that elevated thyrotropin alters the expression of the growth factor FGF, FGF receptors and angiogenic factors which may play a role in development of choanal atresia<ref name="PMID12746216"><pubmed>18698631</pubmed></ref><ref name="PMID11397875"><pubmed>11397875</pubmed></ref>. However, further research is required in order to determine the exact mechanisms involved.

* '''Retinoic Acid''': Retinoic acid is the product of vitamin A metabolism by retinaldehyde dehydrogenase (Raldh)<ref name="PMID19328897"/>. Mouse models showed that an absence of Raldh causes choanal atresia, resulting in respiratory distress and death of Raldh3 knockout mutants at birth<ref name="PMID14623956"><pubmed>14623956</pubmed></ref>.
|}
</table>

====Clinical Features====

[[File:Choanal atresia computed tomography 01.jpg|300px|thumb|right|Computed Tomography of Choanal Atresia]] Neonates are obligate nose breathers, hence neonatal nasal obstruction as seen in choanal atresia is a serious deformity. In order to avoid severe hypoxia and death, immediate diagnosis and intervention are key<ref name="PMID11232465"><pubmed>11232465</pubmed></ref>. The severity of the clinical features of choanal atresia depends on the whether the obstruction is unilateral or bilateral <ref name="PMID19328897"/>.

'''Bilateral'''
* At birth present with ''asphyxia neonatorum'': pathological changes caused by hypoxia from affected respiration. A medical emergency requiring an oral airway tube or intubation then immediate surgical intervention<ref name="PMID19328897"/><ref name="PMID12567078"><pubmed>12567078</pubmed></ref>
* Obvious airway obstruction <ref name="PMID19328897"/>
* Stridor, a harsh vibrating sound when breathing <ref name="PMID19328897"/>
* Paradoxical cyanosis: cyanosis is present in the infant at rest but improves with exertion such as crying <ref name="PMID19328897"/>

'''Unilateral'''
* Not as life threatening as bilateral choanal atresia; more often diagnosed in childhood than in infancy <ref name="PMID19328897"/><ref name="PMID12567078"/>
* Mucoid rhinorrhea, constant mucous fluid discharge from nose <ref name="PMID19328897"/><ref name="PMID12567078"/>
* Dysosmia, distorted olfaction <ref name="PMID12567078"/>
* Obstructive sleep apnea <ref name="PMID12567078"/>

------

===Kallmann Syndrome===
====Introduction and Epidemiology====
[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|500px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]Kallmann syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb (OB) is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract. As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

'''Genetic Factors'''
In Kallmann syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations in six genes and the proteins they encode (see table below) have been attributed to Kallmann syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis of Kallmann Syndrome are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>. Note that CHD7 can also be mutated in Kallmann's syndrome patients, though these individuals tend to have additional features that are part of the CHARGE syndrome phenotype described in the section on [[#Choanal Atresia|'''Choanal Atresia''']]<ref name="PMID19021638"><pubmed>19021638</pubmed></ref>.

<table>
{| width=100%
|-bgcolor="#FF9900"
| width=9%|'''Gene'''
| width=20%|'''Mode of Inheritance'''
| width=50%|'''Role in Kallman’s Syndrome'''
|-bgcolor="#FFFF99"
| '''KAL1'''
| X-linked
| KAL1 normally encodes glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
|-bgcolor="#FFCC66"
| '''FGFR1 (KAL2)'''
| Autosomal-dominant <ref name="PMID20117945"/>
| FGFR1 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/> <ref name="PMID12627230"><pubmed>12627230</pubmed></ref>. When absent, Kallmann syndrome arises due to agenesis or digenesis of the olfactory bulb and failure of GnRH neuronal development and migration.
|-bgcolor="#FFFF99"
| '''FGF8'''
| Autosomal-dominant <ref name="PMID20117945"/>
| Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation. Absence produces similar phenotype to KAL2 mutation<ref name="PMID20117945"/>.
|-bgcolor="#FFCC66"
| '''PROKR2 (KAL3)'''
| Monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID20389090"><pubmed>20389090</pubmed></ref><ref name="PMID18826963"><pubmed>18826963</pubmed></ref>.
| Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"/>.. However, the exact role in Kallmann syndrome has yet to be clarified<ref name="PMID18826963"/>..
|-bgcolor="#FFFF99"
| '''PROK2 (KAL4)'''
| Hypothesised to have mendelian autosomal recessive transmission in addition to oligogenic transmission<ref name="PMID20389090"/>.
| Encodes the PROKR2 ligand<ref name="PMID18826963"/>. When PROK2 mutated, the ligand is not expressed preventing prokineticin receptor-2 activation; this produces similar effects to PROKR2 abnormalities.

|}
</table>

====Clinical Features====

Kallmann Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell<ref name="PMID22882983"/>. There exists additional characteristics that are not specific to Kallmann syndrome but may aid in correct diagnosis of this particular HH<ref name="PMID22882983"/>. The following characteristics of Kallmann syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* Cryptorchidism: Failure of one or both testes to migrate into the scrotum during male foetus development.
* Gynaecomastia: The development of abnormal mammary glands in males characterised by enlarged breasts.
* Amennorhoea: the absence of menstruation, in females

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification
* Unilateral renal [[#Glossary |'''aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* Pes cavus: Also called clawfoot, refers to a deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. <ref name="PMID16932275"/>
* Neurological symptoms
** Synkinesia: Patients can conduct voluntary movements, however, with accompanied involuntary muscular movements.
** Abnormalities in eye movement
** Cerebellar ataxia: Reduced control over muscle coordination arising from defects or damage to the cerebellum.
** Evoked horizontal nystagmus: fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.
** Sensorineural deafness
** Spatial attentional abnormalities
** Spastic paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>

===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmanb syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
[http://www.ncbi.nlm.nih.gov/pubmed/21543621 Forni PE et al.]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]][http://www.ncbi.nlm.nih.gov/pubmed/21943152 ''The dual origin of the peripheral olfactory system''] also investigated the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
[http://www.ncbi.nlm.nih.gov/pubmed/22906231 Shaker T. et al.] published a paper in August this year looking into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular section of the research looked to determine whether Neurog1 and Neurog2 were required for olfactory bulb development. A loss-of-function technique was utilised to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
[[File:Absence_of_CSFR1_Impacts_Normal_Development_of_Brain_Architecture.jpg|200px|thumb|left|'''Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development'''- Absence of CSF-1R results in perturbed brain architecture.]]A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cribiform Plate''': The inferior surface of the ethmoid bone which roofs the nasal cavities.

'''Ectoderm:''' The outermost layer of the trilaminar embryo. Differentiates to form structures including the epidermis and neural tissue.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Frontonasal Prominence''': An ectodermal expansive process that arises during the third week of embryonic development and forms the forehead and nasal bridge.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nasal Fin''': A plate-like ectodermal structure that forms between the medial and lateral prominences that thins to the form the oronasal membrane.

'''Nasal Septum''': Separates the left and right airways of the nose into nostrils. It is made up of the perpendicular plate of ethmoid bone, the vomer bone, cartilage and the crest of the maxillary and palatine bones.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Olfactory Placode''': A thickened area of ectoderm on the frontonasal prominence which contributes to the development of the olfactory sensory system.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones. A rudimentary organ in humans.

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

[http://kallmanns.org/ The Kallmann's Syndrome Organisation]

==Gallery==
<gallery>
Image:Vomeronasal_Organ_position.jpg
Image:Nasal_placode_diagram.jpeg
Image:Olfactory_bulb_and_epithelium.png
Image:Olfactory_epithelium.jpg
Image:New_olfactory_bulb.jpg
Image:Choanal_atresia_computed_tomography_01.jpg
Image:Normal_Neuronal_Migration_into_the_Olfactory_Bulb_Compared_to_Kallmann's_Syndrome.jpg
Image:Neural_crest-derived_cells_in_the_embryonic_olfactory_epithelium.jpg
Image:Absence_of_CSFR1_Impacts_Normal_Development_of_Brain_Architecture.jpg
Image:week4.jpg
Image:week5.jpg
Image:week6.jpg
Image:week7.jpg
</gallery>

{{External Links}}

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

File:Olfaction signal transduction.JPG

2012-10-03T01:00:54Z

Z3333427:

Olfaction signal transduction

"Signal transduction in the OSN. (A) Representation of the receptors, enzymes, and ion channels—present in the olfactory cilia—that transduce activity of the odorant receptor (OR) into changes in membrane potential and gene expression. Binding of an odorant to its cognate OR results in the activation of heterotrimeric G protein (Gαolf plus Gβγ). Activated Gαolf in turn activates type III adenylyl cyclase (AC3), leading to the production of cyclic AMP (cAMP) from ATP. cAMP gates or opens the cyclic nucleotide-gated (CNG) ion channel, leading to the influx of Na+ and Ca2+, depolarizing the cell. This initial depolarization is amplified through the activation of a Ca2+-dependent Cl− channel. In addition, cAMP activates protein kinase A (PKA), which can regulate other intracellular events, including transcription of cAMP-regulated genes. (B) Events in the nucleus of OSNs important for establishing and maintaining sensory neuron identity. Selection of a particular OR gene by the cell is thought to occur via interaction of a cis-regulatory locus control region with the proximal promoter of a single OR gene within a cluster of OR genes. This choice is stabilized—and the expression from all other OR genes in the genome is silenced—by an OR-dependent feedback loop, which ensures the expression of a single OR per sensory neuron. The mechanism underlying OR-mediated, OR gene silencing is at present not understood. OR-mediated activity also leads to transcriptional regulation of cAMP response element binding protein (CREB)–dependent gene expression via CREB's phosphorylation by PKA".

<pubmed>21041441</pubmed>

Published November 1, 2010 // JCB vol. 191 no. 3 443-452
The Rockefeller University Press, doi: 10.1083/jcb.201008163
© 2010 DeMaria and Ngai

This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

2012-09-28T09:14:11Z

Z3333427: /* Cribiform plate */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
| Discovery of [[#Glossary|Vomeronasal organ]] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link hypogonadism to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of epiblast, the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of ectoderm<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the cribriform plate<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|Kallmann's Syndrome]]. Frank Kallmann was a genetist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia, midline anatomic defect) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for their work on the olfactory system<ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribiform plate ====

The cribiform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribiform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

[http://www.youtube.com/watch?v=ABw68BsCMCs| Olfactory Signal Transduction]

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain and forebrain<ref name="PMID21882426"><pubmed>21882426</pubmed></ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon(forebrain) produced cells which migrated to the frontonasal mass while anterior neural ridge cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region(midbrain) produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of respiratory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of respiratory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

EFFECT OF AMNIOTIC FLUID ON THE DEVELOPMENT OF OLFACTION IN THE FETUS still to be ncluded!

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* [[#Glossary |'''Cryptorchidism''']] (males)
* [[#Glossary |'''Gynaecomastia''']] (males)
* Absence of menstruation, amennorhoea (femaleS)

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* [[#Glossary |'''Unilateral renal aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* [[#Glossary |'''Pes cavus''']] <ref name="PMID16932275"/>
* Neurological symptoms
** [[#Glossary |'''Synkinesia''']]
** Abnormalities in eye movement
** [[#Glossary |'''Cerebellar ataxia''']]
** Evoked horizontal [[#Glossary |'''nystagmus''']]
** Sensorineural deafness
** Spatial attentional abnormalities
** [[#Glossary |'''Spastic paraplegia''']]
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>
===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
A [http://www.ncbi.nlm.nih.gov/pubmed/21543621 paper]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]]Another [http://www.ncbi.nlm.nih.gov/pubmed/21943152 paper] also investigating the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
A [http://www.ncbi.nlm.nih.gov/pubmed/22906231 study] from August this year looked into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular part of the research looking to determine whether Neurog1 and Neurog2 were required for olfactory bulb development utilised a loss-of-function technique to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomernasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cryptorchidism:''' Failure of one or both testes to migrate into the scrotum during male foetus development.

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Gynaecomastia:''' The development of abnormal mammary glands in males characterised by enlarged breasts.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nystagmus:''' Refers to fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Pes cavus:''' A deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. Also referred to as clawfoot.

'''Spastic paraplegia:''' A hereditary paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.

'''Synkinesia:''' Refers to the ability to conduct voluntary movements, however, with accompanied involuntary muscular movements.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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