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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. > | ||
| + | |||
| + | <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. > |
| - | + | ||
| - | <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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| === Background === | === Background === | ||
| - | Both structural and functional abnormalities are common in patients with schizophrenia. The changes occur in several key brain systems, including prefrontal and medial temporal lobe regions, as well as in the cortex and in the connections between different cortical regions (Karlsgodt et al. 2010). Individuals with schizophrenia have smaller volume in the hippocampus, thalamus, amygdala, nucleus accumbens and intracranial space, and larger pallidum and ventricle volumes (McIntosh et al. 2011). At illness onset, prefrontal hypoactivity and hippocampal and subcortical hyperactivity represent a core illness pathophysiology (Gong et al. 2015). Over the course of the illness, changes in the brain progress and differ from the brain deficits at the onset of the illness, which has correlations with clinical symptoms (Gong et al. 2015). It is commonly seen in drug-free patients with schizophrenia that the functions and anatomic brain abnormalities overlapped in the default mode (DMN) and auditory networks (AN) however, the pattern of changes differed between the two (Gao et al. 2017). | + | The nuclear lamina is a filamentous protein layer that provides mechanical support to the inner nuclear membrane (Gonzalez, 2011). The functions of the nuclear lamina include nuclear positioning, chromatin organization, nuclear pore complex organization, nuclear envelope breakdown and reassembly during mitosis, DNA replication, DNA damage response and cell cycle progression, transcriptional control and apoptosis (Gonzalez, 2011). |
| - | Decreased grey matter was associated with decreased activation within the DMN, whereas it was associated with increased activation within the AN (Gao et al. 2017). Changes in grey matter have been most pronounced in the thalamo-cortical networks, whereas altered brain activity has been seen in fronto-parietal and default-mode networks (Gong et al. 2015). White and grey matter volumes are found to be 5-6% smaller in individuals with schizophrenia (Sigmundsson et al. 2001). Similarly, to the grey matter changes, white matter changes are present by the time of the first episode and are an indicator that the subject is at risk for the disorder (Karlsgodt et al. 2010). | + | 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). | ||
| - | <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) > | ||
| + | === Genetics === | ||
| - | <box 60%| > {{ :screen_shot_2018-02-01_at_7.24.04_pm.png?300 |}} </box| Figure 4: Coronal slide of the temporal lobe in control (A) and one of a patient with schizophrenia (B). Regions of interest in A include the grey matter of the superior temporal gyrus (right) as well as the amygdala- hippocampal complex (medial) which is almond- shaped. In Image B, the cerebrospinal fluid (CSF) surrounding the left superior temporal gyrus has increased compared to the control. Arrow points to tissue loss in the parahippocampal gyrus and increase in the temporal horn surrounding the amygdala- hippocampal complex. Retrieved from : http://www.nejm.org/doi/pdf/10.1056/NEJM199208273270905 | + | Hutchinson- Gilford Progeria syndrome is commonly caused by a single de novo silent mutation in codon 608 of the LMNA gene (Gonzalez, 2011). The mutation in HGPS is a nucleotide substitution from cytosine to thymine at position 1824 (Goldman et al., 2004). This substitution causes for the partial activation of a cryptic splice site (Goldman et al., 2004). It causes deletion of 150 nucleotides in exon 11 (Goldman et al., 2004). This causes for a 50 amino acid deletion near the C- terminus of the protein, which includes the Zmpste24 cleavage site (Pollex & Hegele 2004). This causes for a mutant prelamin A to remain farnesylated throughout the lifespan of the protein (Pollex & Hegele, 2004). The mutant protein that results from this is known as progerin (Pollex & Hegele, 2004). Around 80% of HGPS cases contain this mutation that is known as the LAΔ50 mutation. Evidence has suggested that transfection of progerin or a non-cleavable form of prelamin A causes for nuclear abnormalities (Pollex & Hegele, 2004). During mitosis, the abnormal association of progerin causes a delay in the onset and progression of cytokinesis and impairs the targeting of lamina components to the nucleus of daughter cells (Gonzalez, 2011). In addition, it can change the entry of the cell into S- phase mediated by hyperphosphorylation of the retinoblastoma gene product (pRB) by cyclin D1/cdk4 (Gonzalez, 2011). Progerin accumulation also causes abnormal chromosome segregation and binucleation (Gonzalez, 2011). It also promotes DNA- damage, changes in DNA repair, causes for genomic instability as well as interfering with nuclear architecture. This leads to premature cell death (Gonzalez, 2011). |
| - | Abnormalities of the left temporal lobe and thought disorder in schizophrenia > | + | |
| - | + | 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). | |
| - | === Neurotransmitter System Abnormalities === | + | |
| - | Currently, it is a common belief that both positive and negative symptoms are associated with neurotransmitter imbalances in patients’ brain (Frankenburg, 2018). Neurotransmitters are chemicals in the brain that are responsible for communication within the brain (Snyder, 2018). The neurotransmitters that may be imbalanced include: dopamine, serotonin, GABA and glutamate. In schizophrenic patients, dopamine is thought to be in excess in the brain, and as a result antipsychotic drugs are the gold standard medication to lower levels. Breaking down symptoms, positive symptoms are usually attributed to excess dopamine activity in the mesolimbic system (midbrain to the nucleus accumbens). Negative symptoms on the other hand are attributed to low dopamine activity in the mesocortical system (Ventral tegmentum to prefrontal cortex). Lastly, it is thought that lower glutamate levels are also found in schizophrenic patients, which produce psychotic symptoms (Frankenburg, 2018). | + | |
| - | === Inflammation and Immune Function === | + | === Genomic Instability === |
| - | Schizophrenia has been found to have many immunological effects. Observations have been made of a diffuse non-specific overactivation of the immunological response system, of a T-helper cell type 1 immune activation and of a T-helper cell type 2 immune activation in subgroups of schizophrenia patients (Strous et al. 2006). Cytokines play an important role in infection and inflammation and are crucial mediators between the brain and the immune system (Ptovin et al. 2008). An imbalance in inflammatory cytokines is common in individuals with schizophrenia leading to a decrease in Th1 and an increase in Th2 cytokine secretion (Ptovin et al. 2008). The cytokines exhibit a number of critical and overlapping regulating functions in the immunological system and interact in a highly complex fashion with a range of neurotransmitters including; increased levels of interleukin (IL) 2 and soluble IL-2 receptor, increased cerebrospinal fluid levels IL-4, increased levels of IL-6 and soluble IL-6 receptor, increased levels of IL-10, increased levels on tumor necrosis factor alpha, as well as decreased mitogen stimulated levels of interferon-y (Strous et al. 2006). | + | Hutchinson- Gilford Progeria syndrome is commonly caused by a single de novo silent mutation in codon 608 of the LMNA gene (Gonzalez, 2011). The mutation in HGPS is a nucleotide substitution from cytosine to thymine at position 1824 (Goldman et al., 2004). This substitution causes for the partial activation of a cryptic splice site (Goldman et al., 2004). It causes deletion of 150 nucleotides in exon 11 (Goldman et al., 2004). This causes for a 50 amino acid deletion near the C- terminus of the protein, which includes the Zmpste24 cleavage site (Pollex & Hegele 2004). This causes for a mutant prelamin A to remain farnesylated throughout the lifespan of the protein (Pollex & Hegele, 2004). The mutant protein that results from this is known as progerin (Pollex & Hegele, 2004). Around 80% of HGPS cases contain this mutation that is known as the LAΔ50 mutation. Evidence has suggested that transfection of progerin or a non-cleavable form of prelamin A causes for nuclear abnormalities (Pollex & Hegele, 2004). During mitosis, the abnormal association of progerin causes a delay in the onset and progression of cytokinesis and impairs the targeting of lamina components to the nucleus of daughter cells (Gonzalez, 2011). In addition, it can change the entry of the cell into S- phase mediated by hyperphosphorylation of the retinoblastoma gene product (pRB) by cyclin D1/cdk4 (Gonzalez, 2011). Progerin accumulation also causes abnormal chromosome segregation and binucleation (Gonzalez, 2011). It also promotes DNA- damage, changes in DNA repair, causes for genomic instability as well as interfering with nuclear architecture. This leads to premature cell death (Gonzalez, 2011). |
| - | There are three prominent lines in the overactivation of the immune system: 1. Elevated serum levels of the pleiotropic cytokine IL-6, released from astrocytes, lymphocytes, and macrophages; 2. Increased levels of serum IL-2 and soluble IL-2 receptor (sIL-2) levels have been commonly noted in the illness (Gaughran et al. 2998); 3. Decreased mitogen-stimulated IL-2 production by overloaded activated lymphocytes (Muller et al. 1999 & Ginestet et al. 19890 (Strous et al. 2006). The elevated levels of pro-inflammatory cytokines activate the kynurenine pathway, by which tryptophan is metabolized into kynurenic and quinolinic acids; these acids regulate NMDA receptor activity and may be involved in dopamine regulation (Strous et al. 2006). The kynurenine pathway, when dysfunctional, is commonly associated with a number of disorders one being schizophrenia. Dysregulation of molecules in individuals with schizophrenia is associated with inflammation/immune responses and centered around disrupted interactions between the central cholinergic system (Deng et al. 2013). | + | 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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| - | ====== Treatments ====== | + | ====== Current Treatments ====== |
| Unfortunately today there are no treatments for Progeria. Physicians and healthcare providers’ main goals right now are to delay or reduce symptoms. This can be achieved by: small doses of aspirin, preventative medications, physical and occupational therapy, nutrition and dental care. Common with Progeria, small doses of Aspirin attempt to reduce the risk of heart attacks and strokes. Preventative medications that can help lower cholesterol, blood pressure, and reduce the chance of getting a blood clot can all be prescribed if the individual seems to be at risk. Physical and occupational therapy can help an individual maintain healthy movement capability and nutrition and dental care for being overall healthy (Mayo Clinic, 2018). Progeria is commonly screened phenotypically or through medical history at the physician’s office. A genetic test for the LMNA mutations can be ordered if the physician deems this appropriate (Sinha, Raghunath & Ghosh, 2018). | Unfortunately today there are no treatments for Progeria. Physicians and healthcare providers’ main goals right now are to delay or reduce symptoms. This can be achieved by: small doses of aspirin, preventative medications, physical and occupational therapy, nutrition and dental care. Common with Progeria, small doses of Aspirin attempt to reduce the risk of heart attacks and strokes. Preventative medications that can help lower cholesterol, blood pressure, and reduce the chance of getting a blood clot can all be prescribed if the individual seems to be at risk. Physical and occupational therapy can help an individual maintain healthy movement capability and nutrition and dental care for being overall healthy (Mayo Clinic, 2018). Progeria is commonly screened phenotypically or through medical history at the physician’s office. A genetic test for the LMNA mutations can be ordered if the physician deems this appropriate (Sinha, Raghunath & Ghosh, 2018). | ||
| For potential future treatments, there are many different angles of approach. Genetics currently is a big area of research for this disease. Anything from early detection capability, to actual cures, genetics is a significant field to target. Additionally, there is also a lot of interest in reducing the severity of symptoms, common with individuals with Progeria. First, heart and blood vessel disease is a target of interest. Farnesyltransferase inhibitors (FTIs), which are drugs for treating cancer, are being investigated to whether they can help vasodilate blood vessels and reduce weight gain (Mayo Clinic, 2018). In 2012, 25 children with Progeria underwent a clinical trial that showed these results (Gordon et al., 2012). FTIs also have shown in mouse models to improve nuclear shape and reduce the negative effects of built up prelamin A. Lonafarnib, an FTI, certainly gives confidence for developing a potential cure to Progeria (Sinha, Raghunath & Ghosh, 2018). | For potential future treatments, there are many different angles of approach. Genetics currently is a big area of research for this disease. Anything from early detection capability, to actual cures, genetics is a significant field to target. Additionally, there is also a lot of interest in reducing the severity of symptoms, common with individuals with Progeria. First, heart and blood vessel disease is a target of interest. Farnesyltransferase inhibitors (FTIs), which are drugs for treating cancer, are being investigated to whether they can help vasodilate blood vessels and reduce weight gain (Mayo Clinic, 2018). In 2012, 25 children with Progeria underwent a clinical trial that showed these results (Gordon et al., 2012). FTIs also have shown in mouse models to improve nuclear shape and reduce the negative effects of built up prelamin A. Lonafarnib, an FTI, certainly gives confidence for developing a potential cure to Progeria (Sinha, Raghunath & Ghosh, 2018). | ||
| + | (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). | ||
| - | 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). | + | ===== References ===== |
| + | 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 | ||
| - | ===== References ===== | + | 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. |
| - | 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 | + | 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. |
| - | Coppedè, F. (2013). The epidemiology of premature aging and associated comorbidities. Clinical interventions in aging, 8, 1023. | + | 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. |
| - | 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. | + | |
| - | 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. | ||
| - | 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. | ||
| Gonzalez, J. (2011). A-type lamins and Hutchinson-Gilford progeria syndrome: pathogenesis and therapy. Frontiers In Bioscience, S3(1), 1133. | Gonzalez, J. (2011). A-type lamins and Hutchinson-Gilford progeria syndrome: pathogenesis and therapy. Frontiers In Bioscience, S3(1), 1133. | ||
| - | + | ||
| Gonzalo, S., & Kreienkamp, R. (2015). DNA repair defects and genome instability in Hutchinson–Gilford Progeria Syndrome. Current Opinion In Cell Biology, 34, 75-83. | Gonzalo, S., & Kreienkamp, R. (2015). DNA repair defects and genome instability in Hutchinson–Gilford Progeria Syndrome. Current Opinion In Cell Biology, 34, 75-83. | ||
| 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 | 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 | ||
| - | Kashyap, S., Shanker, V., & Sharma, N. (2014). Hutchinson–Gilford progeria syndrome: A rare case report. Indian dermatology online journal, 5(4), 478. | + | 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. | + | 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 | 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/ | Progeria 101/FAQ. (2018). The Progeria Research Foundation. Retrieved 14 February 2018, from https://www.progeriaresearch.org/progeria-101faq/ | ||
| - | Rastogi, R., & Mohan, S. C. (2008). Progeria syndrome: a case report. Indian journal of orthopaedics, 42(1), 97. | + | Rastogi, R., & Mohan, S. C. (2008). Progeria syndrome: a case report. Indian journal of orthopaedics, 42(1), 97. |
| - | 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 | + | |
| + | 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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