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group_5_presentation_2_-_progeria [2018/03/02 15:11] bhattvj [History] |
group_5_presentation_2_-_progeria [2018/03/02 23:43] (current) bhattvj [Pathophysiology] |
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| HPGS affects all races; cases of progeria have been discovered in 45 different countries. However, 97% of affected patients are white. Males are affected 1 ½ times more often than females. The disease was thought to be autosomal recessive in the past, however observations made an autosomal recessive inheritance very unlikely and favour a sporadic, dominant mutation. The mutation results in life spans for progeria syndrome to be in the second/third decades of life, with the majority of patients dying of cardiovascular or cerebrovascular disease between 7 and 27 years of age (Sarkar and Shinton, 2001). | HPGS affects all races; cases of progeria have been discovered in 45 different countries. However, 97% of affected patients are white. Males are affected 1 ½ times more often than females. The disease was thought to be autosomal recessive in the past, however observations made an autosomal recessive inheritance very unlikely and favour a sporadic, dominant mutation. The mutation results in life spans for progeria syndrome to be in the second/third decades of life, with the majority of patients dying of cardiovascular or cerebrovascular disease between 7 and 27 years of age (Sarkar and Shinton, 2001). | ||
| - | <box 80%| > {{ :screen_shot_2018-03-02_at_4.02.11_am.png?300 |}}</box| Figure __: Number of children and countries that PRF has identified with cases of progeria over the years. > | + | <box 80%| > {{ :screen_shot_2018-03-02_at_4.02.11_am.png?300 |}}</box| Figure 3: Number of children and countries that PRF has identified with cases of progeria over the years. > |
| - | <box 80%| > {{ :screen_shot_2018-03-02_at_4.02.19_am.png?300 |}} </box| Figure ___: The 45 different countries that PRF has identified with cases of progeria as of January 1st, 2018. > | + | <box 80%| > {{ :screen_shot_2018-03-02_at_4.02.19_am.png?300 |}} </box| Figure 4: The 45 different countries that PRF has identified with cases of progeria as of January 1st, 2018. > |
| ==== Etiology ==== | ==== Etiology ==== | ||
| The cause of Progeria is known to be mutations of the Lamin A, or LMNA gene. These mutations have been found to be sporadic and new, rather than being inherited by their parents. In the sporadic cases leading to Progeria, an autosomal dominant mutation takes place. However, this does not occur when Progeria is inherited and is known as Werner’s syndrome (Sinha, Raghunath & Ghosh, 2018). What is known is the fact that the LMNA gene is responsible for creating a protein which helps keep a nuclei intact. Unfortunately, in individuals with Progeria, this does not occur as the LMNA is abnormal. Abnormal LMNA proteins, or Progerin, accumulates in the body and thus creates instability in cells. As a result, this leads to the abnormal aging process of children (Mayo Clinic, 2018). Interestingly, the LMNA mutations being the cause of Progeria was discovered in April 2003, and have claimed it has significant implications on treating the disease, aging, and cardiovascular disease as well (Progeria101/FAQ, 2018). | The cause of Progeria is known to be mutations of the Lamin A, or LMNA gene. These mutations have been found to be sporadic and new, rather than being inherited by their parents. In the sporadic cases leading to Progeria, an autosomal dominant mutation takes place. However, this does not occur when Progeria is inherited and is known as Werner’s syndrome (Sinha, Raghunath & Ghosh, 2018). What is known is the fact that the LMNA gene is responsible for creating a protein which helps keep a nuclei intact. Unfortunately, in individuals with Progeria, this does not occur as the LMNA is abnormal. Abnormal LMNA proteins, or Progerin, accumulates in the body and thus creates instability in cells. As a result, this leads to the abnormal aging process of children (Mayo Clinic, 2018). Interestingly, the LMNA mutations being the cause of Progeria was discovered in April 2003, and have claimed it has significant implications on treating the disease, aging, and cardiovascular disease as well (Progeria101/FAQ, 2018). | ||
| - | <box 80%| > {{ :image04.png?200 |}} </box| Figure : The mechanism of Progeria via mutation > | + | <box 80%| > {{ :image04.png?200 |}} </box| Figure 5: The mechanism of Progeria via mutation > |
| ==== Diagnosis/Symptoms ==== | ==== Diagnosis/Symptoms ==== | ||
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| CASE (X-Ray) of individual with HPGS. | CASE (X-Ray) of individual with HPGS. | ||
| - | <box 80%| > {{ :screen_shot_2018-03-02_at_4.06.11_am.png?300 |}} </box| Fig : shows small lower jaw with small ascending ramus and infantile obtuse angle (Rastogi & Mohan, 2008). > | + | <box 80%| > {{ :screen_shot_2018-03-02_at_4.06.11_am.png?300 |}} </box| Figure 6: shows small lower jaw with small ascending ramus and infantile obtuse angle. > |
| - | <box 80%| > {{ :screen_shot_2018-03-02_at_4.06.16_am.png?300 |}} </box| Fig : Enlarged skull, additional bone structures seen - wormian bones (Rastogi & Mohan, 2008) > | + | <box 80%| > {{ :screen_shot_2018-03-02_at_4.06.16_am.png?300 |}} </box| Figure 7: Enlarged skull, additional bone structures seen - wormian bones. > |
| - | <box 80%| > {{ :screen_shot_2018-03-02_at_4.06.22_am.png?300 |}} </box| Fig : both hands show acro-osteolysis - resorptions of distal bony phalanges (Rastogi & Mohan, 2008) > | + | <box 80%| > {{ :screen_shot_2018-03-02_at_4.06.22_am.png?300 |}} </box| Figure 8: both hands show acro-osteolysis - resorptions of distal bony phalanges. > |
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| + | <box 80%| > {{ :screen_shot_2018-03-02_at_4.06.29_am.png?300 |}} </box| Figure 9: The various physical characteristics and age-related symptoms of a child living with progeria. > | ||
| - | <box 80%| > {{ :screen_shot_2018-03-02_at_4.06.29_am.png?300 |}} </box| Figure ___: The various physical characteristics and age-related symptoms of a child living with progeria. > | ||
| ====== Pathophysiology ====== | ====== Pathophysiology ====== | ||
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| The main components of the nuclear lamina are type V intermediate filaments known as lamins that contain a central α- helical rod surrounded by globular N and C terminal domains; the C terminal region contains the nuclear localization sequences (Gonzalez, 2011). As proteins they form coiled- coil dimers that can associate head to tail. These protofilaments then create the final lamin filaments. Lamins can be classified into two types: A- type and B- type. A -type lamins are basic and type B is acidic. Type A are encoded by the LMNA gene with its two isoforms being Lamin A and C. B type lamins are therefore encoded by the LMNB1 and LMNB2 genes (Gonzalez, 2011). | The main components of the nuclear lamina are type V intermediate filaments known as lamins that contain a central α- helical rod surrounded by globular N and C terminal domains; the C terminal region contains the nuclear localization sequences (Gonzalez, 2011). As proteins they form coiled- coil dimers that can associate head to tail. These protofilaments then create the final lamin filaments. Lamins can be classified into two types: A- type and B- type. A -type lamins are basic and type B is acidic. Type A are encoded by the LMNA gene with its two isoforms being Lamin A and C. B type lamins are therefore encoded by the LMNB1 and LMNB2 genes (Gonzalez, 2011). | ||
| Lamin A is affected in Progeria so an understanding of the normal transcriptional and translational mechanisms of this protein is essential (Gonzalez, 2011). In cells containing the normal LMNA gene, prelamin A undergoes post- translational modifications before it is found in its mature Lamin A form. Firstly, the cysteine in the C – terminal CaaX motif is farnesylated by farnesyltransferase. Rce1, an endoprotease then cleaves the three terminal amino acids. Then the newly- available cysteine is then methylated by carboxyl methyltransferase, ICMT. Lastly to create mature Lamin A, 15 C- terminal residues that include the farnesylated and carbosymethylated C- terminal cysteine are cleaved by another endoprotease, Zmpste24/ FACE-1 (Gonzalez, 2011). | Lamin A is affected in Progeria so an understanding of the normal transcriptional and translational mechanisms of this protein is essential (Gonzalez, 2011). In cells containing the normal LMNA gene, prelamin A undergoes post- translational modifications before it is found in its mature Lamin A form. Firstly, the cysteine in the C – terminal CaaX motif is farnesylated by farnesyltransferase. Rce1, an endoprotease then cleaves the three terminal amino acids. Then the newly- available cysteine is then methylated by carboxyl methyltransferase, ICMT. Lastly to create mature Lamin A, 15 C- terminal residues that include the farnesylated and carbosymethylated C- terminal cysteine are cleaved by another endoprotease, Zmpste24/ FACE-1 (Gonzalez, 2011). | ||
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