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group_5_presentation_2_-_progeria [2018/03/02 01:07] saeedkf |
group_5_presentation_2_-_progeria [2018/03/02 23:43] (current) bhattvj [Pathophysiology] |
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| ====== Progeria ====== | ====== Progeria ====== | ||
| - | {{ :nintchdbpict000287654150.jpg?300 |}} Retrieved from: http://fcscortland.org/schizophrenia | + | |
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| In 1886, the syndrome was first reported by Hutchinson of a 6-year-old boy whose overall appearance was that of an old man. Hutchinson described the case as “congenital absence of hair and its appendages” (DeBusk, 1972). It was a year later that Gilford described a second patient with similar clinical findings. To date, there are only 100 patients with HGPS that have been described in literature (Kashyap et al., 2014). These two boys were further described in 1897 and 1904 by Gildford, who was the one to proposal the term “progeria” and described the post-mortem characteristics (DeBusk, 1971). Little research was done on the disease until the 1990’s due to the rarity of the disease, causing it to be frequently diagnosed erroneously in patients with some of the features such as alopecia and skin of aged appearance (DeBusk, 1972). However, there are three features present in early life; mid-facial cyanosis, skin resembling scleroderma, and glyphic nasal tip, which all facilitate an early diagnosis of HGPS (DeBusk, 1972). | In 1886, the syndrome was first reported by Hutchinson of a 6-year-old boy whose overall appearance was that of an old man. Hutchinson described the case as “congenital absence of hair and its appendages” (DeBusk, 1972). It was a year later that Gilford described a second patient with similar clinical findings. To date, there are only 100 patients with HGPS that have been described in literature (Kashyap et al., 2014). These two boys were further described in 1897 and 1904 by Gildford, who was the one to proposal the term “progeria” and described the post-mortem characteristics (DeBusk, 1971). Little research was done on the disease until the 1990’s due to the rarity of the disease, causing it to be frequently diagnosed erroneously in patients with some of the features such as alopecia and skin of aged appearance (DeBusk, 1972). However, there are three features present in early life; mid-facial cyanosis, skin resembling scleroderma, and glyphic nasal tip, which all facilitate an early diagnosis of HGPS (DeBusk, 1972). | ||
| + | <box 80%| > {{ :screen_shot_2018-03-02_at_3.52.29_am.png?300 |}} </box| | ||
| + | Figure 1: Dr. Jonathan Hutchinson was the first doctor to describe a case of progeria in 1886. | ||
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| + | <box 80%| > {{ :screen_shot_2018-03-02_at_3.52.34_am.png?300 |}} </box| Figure 2: Dr. Hastings Gilford described the second case of progeria in 1887. He was the individual to purpose the term progeria and describe the post-mortem characteristics. > | ||
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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 3: Number of children and countries that PRF has identified with cases of progeria over the years. > | ||
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| + | <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 ==== | + | ==== Diagnosis/Symptoms ==== |
| The only way to diagnose is once the symptoms become visible. There are no early diagnostic techniques. | The only way to diagnose is once the symptoms become visible. There are no early diagnostic techniques. | ||
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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| 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| 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| Figure 8: both hands show acro-osteolysis - resorptions of distal bony phalanges. > | ||
| - | ====Symptoms==== | + | <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. > |
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| - | <box 80%| > {{ :screen_shot_2018-01-25_at_12.36.51_pm.png?300 |}} </box| Figure 2: Temporal profile of developing schizophrenia symptoms. > | + | |
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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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| - | <box 60%| > {{ :screen_shot_2018-02-01_at_7.37.00_pm.png?300 |}} </box| Figure 3: MRI coronal view from 2 sets of monozygotic twins discordant for Schizophrenia showing a small enlargement of the lateral ventricles in affected twins (B and D) compared to unaffected twins (A and C) > | ||
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| Additional heterozygous mutations for atypical Progeria patients have also been revealed. R644C affects the C- terminus, E578V also in the C- terminus and T10I within the N- terminal globular domain seen in Seip syndrome (Pollex & Hegele, 2004). The most common hypothesis for the inheritance of this disorder is sporadic autosomal dominant (Pollex & Hegele, 2004). | Additional heterozygous mutations for atypical Progeria patients have also been revealed. R644C affects the C- terminus, E578V also in the C- terminus and T10I within the N- terminal globular domain seen in Seip syndrome (Pollex & Hegele, 2004). The most common hypothesis for the inheritance of this disorder is sporadic autosomal dominant (Pollex & Hegele, 2004). | ||
| - | <box 45%| > {{ :27591717_10155315219240003_2136198995_n.png?300 |}} </box| Figure 5: Complex interactions between cholinergic receptors, muscarinic M2 receptor, α4 ß2 nicotinic receptor and the α4 ß4 nicotinic receptor and the cytokines; tumor necrosis factor α, interleukin 1ß and interleukin 6.> | ||
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| (a is Progerin cell, d is a healthy cell - treated with FTI - Capell reference) | (a is Progerin cell, d is a healthy cell - treated with FTI - Capell reference) | ||
| - | <box 60%| > {{ :lonafarnib.svg.png?200 |}} </box| Figure : Chemical structure of Lonafarnib, the compound that prevents farnesyl transferase from acting on pathways leading to progeria > | ||
| ======Conclusion====== | ======Conclusion====== | ||
| + | With the description of the history, diagnosis, symptoms, risks, pathophysiology, etiology, epidemiology, and treatments there are clear outlines of progeria however further research is required. The future implications of progeria details a focus on increasing the lifespan of diagnosed individuals. Although there are not specific treatments available, the future developments are promising. With the use of models and genetics, the advancements to create a clinical trial are near (Swahari and Nakamura, 2016). | ||
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| + | ===== References ===== | ||
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| + | Capell, B., Erdos, M., Madigan, J., Fiordalisi, J., Varga, R., & Conneely, K. et al. (2018). Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome. PNAS. Retrieved 24 February 2018, from http://www.pnas.org/content/102/36/12879 | ||
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| + | Coppedè, F. (2013). The epidemiology of premature aging and associated comorbidities. Clinical interventions in aging, 8, 1023. DeBusk, F. L. (1972). The Hutchinson-Gilford progeria syndrome: report of 4 cases and review of the literature. The Journal of pediatrics, 80(4), 697-724. | ||
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| + | De Sandre-Giovannoli, A., Bernard, R., Cau, P., Navarro, C., Amiel, J., Boccaccio, I., … & Lévy, N. (2003). Lamin a truncation in Hutchinson-Gilford progeria. Science, 300(5628), 2055-2055. | ||
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| + | Goldman, R., Shumaker, D., Erdos, M., Eriksson, M., Goldman, A., & Gordon, L. et al. (2004). Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proceedings Of The National Academy Of Sciences, 101(24), 8963-8968. | ||
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| + | Gonzalez, J. (2011). A-type lamins and Hutchinson-Gilford progeria syndrome: pathogenesis and therapy. Frontiers In Bioscience, S3(1), 1133. | ||
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| + | Gonzalo, S., & Kreienkamp, R. (2015). DNA repair defects and genome instability in Hutchinson–Gilford Progeria Syndrome. Current Opinion In Cell Biology, 34, 75-83. | ||
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| + | Gordon, L., Kleinman, M., Miller, D., Neuberg, D., Giobbie-Hurder, A., & Gerhard-Herman, M. et al. (2012). Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome. Proceedings Of The National Academy Of Sciences, 109(41), 16666-16671. http://dx.doi.org/10.1073/pnas.1202529109 | ||
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| + | Kashyap, S., Shanker, V., & Sharma, N. (2014). Hutchinson–Gilford progeria syndrome: A rare case report. Indian dermatology online journal, 5(4), 478. | ||
| + | Pollex, R., & Hegele, R. (2004). Hutchinson-Gilford progeria syndrome. Clinical Genetics, 66(5), 375-381. | ||
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| + | Progeria - Symptoms and causes. (2018). Mayo Clinic. Retrieved 14 February 2018, from https://www.mayoclinic.org/diseases-conditions/progeria/symptoms-causes/syc-20356038 | ||
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| + | Progeria 101/FAQ. (2018). The Progeria Research Foundation. Retrieved 14 February 2018, from https://www.progeriaresearch.org/progeria-101faq/ | ||
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| + | Rastogi, R., & Mohan, S. C. (2008). Progeria syndrome: a case report. Indian journal of orthopaedics, 42(1), 97. | ||
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| + | Sangita Devi, A., Thokchom, S., & Mamata Devi, A. (2017). Children Living with Progeria. Nursing & Care Open Access Journal, 3(4). http://dx.doi.org/10.15406/ncoaj.2017.03.00077 | ||
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| + | Sarkar, P. K., & Shinton, R. A. (2001). Hutchinson-Guilford progeria syndrome. Postgraduate medical journal, 77(907), 312-317. | ||
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| + | Sinha, J., Raghunath, M., & Ghosh, S. (2018). Progeria: A rare genetic premature ageing disorder. PubMed Central (PMC). Retrieved 14 February 2018, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140030/ | ||
| + | Swahari, V., & Nakamura, A. (2016). Speeding up the clock: The past, present and future of progeria. Development, growth & differentiation, 58(1), 116-130. | ||
