Cytoskeleton and elastin disorders: Pathology review

What is discussed, and when

1. 6:00 – 9:00: Marfan syndrome
2. 9:00 – 12:00: Marfan syndrome
3. 12:00 – 15:00: Marfan syndrome
4. 15:00 – 18:00: Marfan syndrome
5. 18:00 – 19:50: Marfan syndrome

Notable quotes from "Cytoskeleton and elastin disorders: Pathology review"

• Therefore, fibbrillin's function results in decreased tissue growth. Okay. The first elastin related disorder is Marfan syndrome which is caused by a mutation in the gene…

  about Marfan syndrome · at 7:39

Who and what is mentioned in this episode?

Concepts & topics

• Marfan syndrome — Concept · 11 mentions · first at 7:44
• primary ciliary dyskinesia — Concept · 5 mentions
• alpha-1 antitrypsin deficiency — Concept · 2 mentions
• Cartagena syndrome — Concept · 2 mentions
• FBN1 — Concept · 1 mention

Full transcript with timestamps

0:03 A 10-year-old male named Thomas is brought to the clinic by his father because of a persistent fever as well as a productive cough with dark foul smelling sputum. Upon further questioning, his father states that since birth, Thomas has had multiple bouts of sinocitis and pneumonia which required antibiotics. Upon chest oscultation, you realize that the heart sounds are heard on the right side of the chest. You then decide to order a chest X-ray, which reveals that Thomas's heart is in fact located on the right side of the chest. Finally, you get a CT scan, which reveals abnormally dilated airways.

0:40 Right after Thomas, you meet Sarah, a 17-year-old female who comes into the clinic complaining that her joints frequently slip out of place. On physical examination, her height is at the 90th percentile and weight at the 60th percentile for her age. In addition, you notice that her fingers and toes are abnormally long. Upon chest oscultation, you hear a diastolic murmur in the aortic area. Enjoying our Osmosis videos? Unlock your full potential with an Osmosis subscription. Get unlimited access to every Osmosis feature and resource with a free 7-day trial.

1:21 Based on the initial presentation, Thomas seems to have some sort of a cytokeleletal disorder, whereas Sarah most likely has an elastin related disorder. Okay, before we start with cytokeleletal disorders, here's a bit of physiology real quick. The cytokeleton is an intracellular network of proteins which allows each cell to maintain its shape, but also to move, contract, divide, and absorb or secrete molecules. Now one of the protein structures in the cytokeleton is microtubules. These are tiny hollow rods found at the base of psyia which are hairike structures on the surface of epithelial cells lining the respiratory and reproductive tracts. Specifically each psyllium has microtubules arranged in a 9 plus2 pattern meaning there are nine microtubial dlets on the periphery as well as two single central microtubules.

2:16 Now in between the microtubules there's a dinian arm ATPAS protein which uses ATP to make microtubules slide past each other. This causes the psyllium to bend and thus move back and forth in a wavelike motion which is necessary to swipe out mucous secretions, debris and foreign particles or pathogens. This function is especially important in the middle ear, paranasal sinuses, airways and lungs. Additionally, in females, psyia transport a fertilized oam along the fallopian tube to the uterus where implantation occurs. On the other hand, in males, sperm cells have a similar but longer motile structure called flegellum, which allows them to propel along the female reproductive tract and fertilize the oam.

3:06 All right. Now the most high yield cytokeleletal disorder is primary siliary diskynesia which refers to a group of genetic disorders that occur due to a mutation in the gene coding for dinen arm ATPAS protein. For your exams remember that primary siliary disanesia is autotoal recessive meaning that an individual needs to inherit two copies of the mutated gene one from each parent to develop the condition. Now when the dinian arm ATPAS is not functioning normally celia won't be able to move effectively and swipe out mucus from the middle ear paranasal sinuses airways and lungs. As a consequence mucus builds up and traps foreign particles like dust and pathogens especially bacteria which start to multiply and cause infection. At the same time fertilized OAM or sperm cells won't be able to move along the reproductive tract. Symptoms of primary siliary disynesia include recurrent bacterial infections such as

4:10 otitis media which may lead to conductive hearing loss as well as respiratory tract infections such as chronic sinocitis and pulmonary infections. Over time this results in chronic lung inflammation which may cause the bronchi and bronchioles to get damaged and dilate leading to the development of bronchiacttois and that's a high yield fact. In the reproductive tract, both male and female fertility will be impaired. For your exams, keep in mind that individuals with primary siliary disynesia are also at an increased risk for ectopic pregnancy. That's because the defective celia won't be able to transport the fertilized OAM to the uterus. So, it may implant in the wall of the fallopian tube. Another high yield fact is that for unknown reasons primary siliary diskynesia can be associated with sitis inversus a condition in which chest and abdominal organs are positioned in a mirror image to their normal anatomical location. For

5:07 example, the heart is normally present on the left side of the chest but in situs inversus it would be on the right side and the high yield term used to describe this is dextrocardia. Now in a test question if primary siliary diskynesia presents with a clinical triad of chronic sinocitis bronchiacttois and sitis inversus it's called cartaginer syndrome and that's a high yield fact. Diagnosis of primary siliary disynesia starts by measuring nitrous oxide level in the nasal epithelium which would be marketkedly low. The diagnosis can then be confirmed with a biopsy from the nasal or bronchial epithelium which can be examined via transmission electron microscopy to detect the absence of dyn.

5:53 In addition, bronchiacttois or situs inversus can be identified via imaging tests such as x-rays or CT scan. Treatment of primary siliary diskynesia focuses on addressing complications like infections with antibiotics or managing bronchiacttois with daily chest physiootherapy which can help expel bronchial secretions. Finally, fertility issues can be treated with in vitro fertilization methods. All right, let's switch gears and talk about elastin related disorders. But first, a bit of physiology real quick. Within the extracellular matrix is a network that consists of several proteins and sugars which provide support for the surrounding cells. Zooming into this network, there's a glyoprotein called fibbrillin which along with other molecules like cellulose form strong ropelike structures called microfibbrals. These act as a scaffold for other proteins like elastin forming elastic fibers which are highly cross-

6:53 linked. This gives elastic fibers a rubber band-like quality which allows them to stretch and then spring back to their original shape. Tissues that have elastic fibers include the skin, arteries and lungs as well as the ligaments and in particular ligamentum flavom which supports the vertebrae. Now some tissues have microfib but no overlaying layer of elastin including tendons and the siliary zonules that hold the eyelids in place. As a result, these tissues are less stretchable but still have considerable tensile strength. Now, in addition to being part of microfibbrals, fibbrillin also sequesters and removes transforming growth factor beta or TGF beta which normally stimulates tissue growth.

7:39 Therefore, fibbrillin's function results in decreased tissue growth. Okay. The first elastin related disorder is Marfan syndrome which is caused by a mutation in the gene called FBN1 or fibbrillin 1 on chromosome 15 which encodes fibbrillin. For your exams bear in mind that Marfan syndrome is an autotoal dominant which means that a single mutated copy of the gene is sufficient to cause the disease. Now the FBN1 mutation results in either less abundant or dysfunctional fibrillain. This means that there are fewer functioning microfules in the extracellular matrix. So there's less integrity and elasticity of the skin, arteries, lungs, and the ligamentum flavom. At the same time, the lack of fibbrillin means that TGF beta doesn't get effectively sequestered leading to excessive and unregulated TGFBA signaling. This results in excessive tissue growth and particularly affects long bones like the femur.

8:41 Signs and symptoms of Marfan syndrome vary depending on the tissue affected. The most obvious physical features involve the skeleton since individuals are tall and have long arms and legs. For your exams, remember that this is called a morphanoid body habitus. They also have long thin fingers and toes which is called arachinodactyli. In addition, overgrowth of ribs can cause pectus excavatum where the chest sinks in or pectus carinatum where the chest points out. Other bone and joint features include scoliosis where the spine has a sideways curve as well as hyper mobile joints that can move beyond a normal range which may result in recurrent joint dislocations.

9:27 In the skin maran syndrome can cause stretch marks whereas in the lungs it can cause ble to form which are large airfield spaces. What's important to remember is that these boule are prone to rupture and may lead to pneumothorax where air collects in the plural space which impairs lung expansion. In the mouth, marfan syndrome causes a high arched pallet while in the eyes it causes weakness of the suspensory ligaments of the lens which may lead to lens dislocation usually in an upward and lateral direction. The most serious features of Marfan syndrome though are cardiovascular. The aorta often underos cystic medial necrosis which is when the tunica media or middle layer of the aortic wall degenerates. This makes the aorta susceptible to dilation and aneurysms or out pouchings of the vessel as well as dissection where the inima or inner wall develops a tear letting blood track into a false lumen in the vessel wall. And

10:28 that's important to bear in mind since it may lead to aortic rupture which is a full thickness tear that can cause internal bleeding and can be life-threatening. Now as the aorta dilates over time there's a risk for aortic valve insufficiency where blood leaks back into the left ventricle during diastily. Marfan syndrome may also lead to mitro valve prolapse which is when the mitro valve becomes floppy and bulges into the left atrium during cy. Now if a test question describes an individual with a morphanoid habitus pectus excavatum or pectis carinatum it's extremely important to differentiate marfan syndrome from homocyineuria.

11:11 This is an autotosomal recessive disorder most often caused by mutation involving the enzyme cysathionine beta which normally combines homocyine and serarine to create cysionine. In homoyineura cysionine beta is defective. So homocyine builds up in the body. Now unlike marfan syndrome homocyineura does not cause hyper mobile joints. Instead, the excess homocyine accumulates in the brain which causes neurons to undergo apoptosis or program cell death leading to neurodeeneration and intellectual disability. Homocyine also builds up in the blood where it binds to platelets causing them to stick to one another resulting in thrombosis as well as stick to endothelial cells lining the blood vessels. This leads to atherosclerosis or plaque buildup which narrows the arteries and could lead to eskeemia of their supplied tissues. As a consequence, homocyine ura can increase the risk of strokes, mocardial

12:13 infuctions and thrombbo emolism. But what's even more important to set it apart from Marfan syndrome is that in homocyine the lens is dislocated down and inward rather than up and outward. Now, if a test question mentions hyper mobile joints, scoliosis, and abnormalities involving the heart valves, make sure not to confuse Marfan syndrome with Aaylor Donlo syndrome, which is most often caused by an autotosomal dominant mutation that leads to a defective collagen protein. Now, the main difference with Marfan syndrome is that individuals with Elleronlo syndrome usually have normal height as well as hyperextensible skin. So, be sure to keep an eye out for these clues.

12:56 All right. To diagnose Marfan syndrome, echoc cardiography can be done to detect heart and aortic complications while a slit lamp examination can be performed to look for lens dislocation. Finally, diagnosis can be confirmed via genetic testing looking for FBN1 mutations. Treatment of Marfan syndrome depends on the associated clinical features. For example, medications like beta blockers and angotensin receptor blockers have been shown to slow aortic dilation, especially when used in combination. If the aorta gets too wide, it can be repaired surgically to prevent dissection or rupture. In addition, if an eye lens dislocates, it can be removed and replaced by an artificial lens.

13:43 The last elastin related disorder is alpha 1 antitriin deficiency which is an autotosomal co-ominant disorder caused by a mutation in the serpena 1 gene coding for the protein alpha 1 antitriin. Some of these mutations completely abolish the gene which means no alpha 1 antitriin is made while other mutations result in a misfolded and defective alpha 1 antitriin protein. Now normally in the lungs alpha 1 antitriin inactivates neutrfil elastace. This is a proteiase capable of breaking down elastin which gives elasticity and strength to lung tissues. So to allow lung expansion and elastic recoil when breathing.

14:26 But when there's a deficiency of alpha 1 antitriin this elastase remains excessively active and can damage the alvoli in the lungs. In addition, misfolded alpha 1 antitriin can build up in the liver damaging and killing hpatocytes. As a result, individuals develop cerosis, a process in which normal liver tissue is replaced with scar tissue. So the main symptoms of alpha 1 antitripen deficiency usually involve the lungs and liver. Starting with the lungs, individuals with panassinar emphyma typically experience shortness of breath, cough with sputum production, and wheezing, which is a whistling sound in the chest. In addition, because the lung loses much of its elastic recoil, it will be less able to propel the air in the alvoli to the outside, leading to air trapping and hyperinflation of the lungs. This causes individuals to develop panacinar emphyma which means that the whole asinus is affected and is

15:23 typically associated with a barrel-shaped chest. On the other hand, liver damage causes cerosis, a process in which normal liver tissue is replaced with scar tissue. Ultimately, cerosis can lead to a number of complications, including an inability to make coagulation factors as well as inability to remove toxins like ammonia from the blood. These toxins can build up and harm tissues like the brain causing hpatic and sephylopathy. Other complications include portal hypertension which can lead to esophageal veraces as well as an increased risk of hpatoscellular carcinoma.

16:03 So in a test question you should think of alpha 1 antitrip deficiency in a young person with cerosis and dispnnea without a history of smoking. For diagnosis of alpha 1 antitripen deficiency, blood tests can measure the low levels of alpha 1 antitriin and genetic testing can confirm the mutations. A chest X-ray or CT scan can be performed to look for hyperinflated lungs or evidence of damaged lung tissue. In addition, pulmonary function testing can be used to measure how quickly air exits the lung, which can be slower than normal. Finally, cerosis can be diagnosed with a liver ultrasound or liver biopsy.

16:47 In terms of treatment, intravenous infusions of normal alpha 1 antitripen protein may help slow or halt the progression of lung disease. In addition, supplemental oxygen is often needed as well. Finally, standard treatments for cerosis are also required such as laculose to prevent hpatic and encphylopathy. All right, as a quick recap, primary siliary disanesia is caused by a defective dynian arm atpace and this results in abnormal siliary motility in the respiratory and reproductive tracts. Manifestations include recurrent syopulmonary bacterial infections as well as decreased fertility and increased risk of ectopic pregnancy.

17:29 When primary siliary disanesia presents with a clinical triad of chronic sinocitis, bronchiactis and sitis inversus is called cartaginer syndrome. Next is marfan syndrome which is caused by mutations in the FBN1 gene. This leads to fewer fibbrin microfibals in certain connective tissues compromising their strength and elasticity and upregulating TGFBA signaling. The end result is an individual presenting with a morphanoid body habitus, so tall and thin, as well as scoliosis, hyper mobile joints, and stretch marks. Individuals with Marfan syndrome are at higher risk of pneumothorax and aortic aneurysm, dissection or rupture.

18:13 Finally, alpha 1 antitripin deficiency is caused by mutations that result in absent or defective alpha 1 antitriin which can cause excessive degradation of elastin in the lungs leading to panasinar emphyma and can build up in the liver causing cerosis. Okay, back to our cases. Thomas is the 10-year-old boy who presented with a persistent fever and productive cough with dark foul smelling sputum. His history of recurrent infections along with the imaging findings of cytoin versus bronchiacttois make up the characteristic clinical triad of cartaginer syndrome which is a type of primary siliary disynesia. Diagnosis was confirmed by taking a biopsy from his nasal epithelium which revealed absent dynian arms between the microtubules of psyia.

19:03 On the other hand, Sarah, the 17-year-old girl, came in with frequent joint dislocations. In addition, her diastolic murmur in the aortic area indicates aortic valve regurgitation. These two findings combined should make you think of either Marfan syndrome or Eller Danlo syndrome. However, the additional findings of a morphanoid body habitus as well as the arachnodactyl are characteristic of Marfan syndrome. Helping current and future clinicians focus, learn, retain, and thrive. Learn more.

Questions about this episode

What is discussed in "Cytoskeleton and elastin disorders: Pathology review"?

In order: 6:00 Marfan syndrome; 9:00 Marfan syndrome; 12:00 Marfan syndrome; 15:00 Marfan syndrome; 18:00 Marfan syndrome.

What is mentioned in this Osmosis from Elsevier episode?

5 people, works and ideas are mentioned, including Marfan syndrome, primary ciliary dyskinesia, alpha-1 antitrypsin deficiency, Cartagena syndrome, FBN1. Each one on this page links to its own page with every episode that mentions it.

How long is "Cytoskeleton and elastin disorders: Pathology review"?

The episode runs 20 min; the transcript is about 2,790 words in 24 timestamped sections.

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