The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Leslie B Gordon - One of the best experts on this subject based on the ideXlab platform.
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Sulforaphane enhances progerin clearance in Hutchinson–Gilford progeria fibroblasts
2016Co-Authors: Diana Gabriel, Daniela Roedl, Leslie B Gordon, Karima DjabaliAbstract:Hutchinson–Gilford progeria syndrome (HGPS, OMIM 176670) is a rare multisystem childhood premature aging disorder linked to mutations in the LMNA gene. The most common HGPS mutation is found at position G608G within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A, and the truncated protein is called progerin. Progerin only undergoes a subset of the normal post-translational modifications and remains permanently farn-esylated. Several attempts to rescue the normal cellular pheno-type with farnesyltransferase inhibitors (FTIs) and other compounds have resulted in partial cellular recovery. Using proteomics, we report here that progerin induces changes in the composition of the HGPS nuclear proteome, including alter-ations to several components of the protein degradation path-ways. Consequently, proteasome activity and autophagy are impaired in HGPS cells. To restore protein clearance in HGPS cells, we treated HGPS cultures with sulforaphane (SFN), an antioxi-dant derived from cruciferous vegetables. We determined that SFN stimulates proteasome activity and autophagy in normal and HGPS fibroblast cultures. Specifically, SFN enhances progerin clearance by autophagy and reverses the phenotypic changes that are the hallmarks of HGPS. Therefore, SFN is a promising therapeutic avenue for children with HGPS. Key words: lamins; progeria; progerin; proteostasis; senes-cence; sulforaphane
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abstract 11518 diastolic left ventricular dysfunction is a common and early cardiac abnormality in Hutchinson gilford progeria syndrome
Circulation, 2015Co-Authors: Ashwin Prakash, Monica E Kleinman, Joseph M Massaro, Ralph B Dagostino, Leslie B Gordon, Marie Gerhardherman, Mark W Kieran, Leslie B SmootAbstract:Introduction: Hutchinson-Gilford progeria syndrome (HGPS) is associated with premature death due to cardiovascular events. However, little is known about the natural history of cardiac disease in t...
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Hutchinson gilford progeria syndrome
Handbook of Clinical Neurology, 2015Co-Authors: Nicole J Ullrich, Leslie B GordonAbstract:Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare, uniformly fatal, segmental "premature aging" disease in which children exhibit phenotypes that may give us insights into the aging process at both the cellular and organismal levels. Initial presentation in early childhood is primarily based on growth and dermatologic findings. Primary morbidity and mortality for children with HGPS is from atherosclerotic cardiovascular disease and strokes with death occurring at an average age of 14.6 years. There is increasing data to support a unique phenotype of the craniofacial and cerebrovascular anatomy that accompanies the premature aging process. Strokes in HGPS can occur downstream of carotid artery and/or vertebral artery occlusion, stenosis, and calcification, with prominent collateral vessel formation. Both large and small vessel disease are present, and strokes are often clinically silent. Despite the presence of multisystem premature aging, children with HGPS do not appear to have cognitive deterioration, suggesting that some aspects of brain function may be protected from the deleterious effects of progerin, the disease-causing protein. Based on limited autopsy material, there is no pathologic evidence of dementia or Alzheimer-type changes. In a transgenic mouse model of progeria with expression of the most common HGPS mutation in brain, skin, bone, and heart, there are distortions of neuronal nuclei at the ultrastructural level with irregular shape and severe invaginations, but no evidence of inclusions or aberrant tau in brain sections. Importantly, the nuclear distortions did not result in significant changes in gene expression in hippocampal neurons. This chapter will discuss both preclinical and clinical aspects of the genetics, pathobiology, clinical phenotype, clinical care, and treatment of HGPS, with special attention toward neurologic and cutaneous findings.
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impact of farnesylation inhibitors on survival in Hutchinson gilford progeria syndrome
Circulation, 2014Co-Authors: Leslie B Gordon, Monica E Kleinman, Joseph M Massaro, Ralph B Dagostino, Susan E Campbell, Joan F Brazier, Ted W Brown, Mark W KieranAbstract:Background—Hutchinson-Gilford progeria syndrome is an ultrarare segmental premature aging disease resulting in early death from heart attack or stroke. There is no approved treatment, but starting in 2007, several recent single-arm clinical trials administered inhibitors of protein farnesylation aimed at reducing toxicity of the disease-producing protein progerin. No study assessed whether treatments influence patient survival. The key elements necessary for this analysis are a robust natural history of survival and comparison with a sufficiently large patient population that has been treated for a sufficient time period with disease-targeting medications. Methods and Results—We generated Kaplan–Meier survival analyses for the largest untreated Hutchinson-Gilford progeria syndrome cohort to date. Mean survival was 14.6 years. Comparing survival for treated versus age- and sex-matched untreated cohorts, hazard ratio was 0.13 (95% confidence interval, 0.04–0.37; P<0.001) with median follow-up of 5.3 years f...
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initial cutaneous manifestations of Hutchinson gilford progeria syndrome
Pediatric Dermatology, 2014Co-Authors: F Jillian M D Rork, Leslie B Gordon, Mark W Kieran, T Jennifer M D Huang, M Monica D Kleinman, G Marilyn M D LiangAbstract:Hutchinson-Gilford progeria syndrome (HGPS) is a rare, uniformly fatal, premature aging disease with distinct dermatologic features. We sought to identify and describe the initial skin and hair findings as potential diagnostic signs of the disease. We performed a chart review of the structured initial intake histories of 39 individuals with HGPS enrolled in clinical trials from 2007 to 2010 at Boston Children's Hospital, limited to cutaneous history from birth to 24 months. Medical photographs were provided through the clinical trials and the Progeria Research Foundation Medical and Research Database at Brown University Center for Gerontology and Healthcare Research. All 39 patients reported skin and hair abnormalities within the first 24 months of life. Pathologies included sclerodermoid change, prominent superficial veins, dyspigmentation, and alopecia. The mean age of presentation for each finding was <12 months. The most frequently reported skin feature was sclerodermoid change, which commonly involved the abdomen and bilateral lower extremities. Prominent superficial vasculature manifested as circumoral cyanosis and pronounced veins on the scalp and body. Hypo- and hyperpigmentation were observed over areas of sclerodermoid change. Scalp alopecia progressed in a distinct pattern, with preservation of the hair over the midscalp and vertex areas for the longest period of time. HGPS has distinct cutaneous manifestations during the first 2 years of life that may be the first signs of disease. Awareness of these findings could expedite diagnosis.
Karima Djabali - One of the best experts on this subject based on the ideXlab platform.
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Sulforaphane enhances progerin clearance in Hutchinson–Gilford progeria fibroblasts
2016Co-Authors: Diana Gabriel, Daniela Roedl, Leslie B Gordon, Karima DjabaliAbstract:Hutchinson–Gilford progeria syndrome (HGPS, OMIM 176670) is a rare multisystem childhood premature aging disorder linked to mutations in the LMNA gene. The most common HGPS mutation is found at position G608G within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A, and the truncated protein is called progerin. Progerin only undergoes a subset of the normal post-translational modifications and remains permanently farn-esylated. Several attempts to rescue the normal cellular pheno-type with farnesyltransferase inhibitors (FTIs) and other compounds have resulted in partial cellular recovery. Using proteomics, we report here that progerin induces changes in the composition of the HGPS nuclear proteome, including alter-ations to several components of the protein degradation path-ways. Consequently, proteasome activity and autophagy are impaired in HGPS cells. To restore protein clearance in HGPS cells, we treated HGPS cultures with sulforaphane (SFN), an antioxi-dant derived from cruciferous vegetables. We determined that SFN stimulates proteasome activity and autophagy in normal and HGPS fibroblast cultures. Specifically, SFN enhances progerin clearance by autophagy and reverses the phenotypic changes that are the hallmarks of HGPS. Therefore, SFN is a promising therapeutic avenue for children with HGPS. Key words: lamins; progeria; progerin; proteostasis; senes-cence; sulforaphane
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Sulforaphane enhances progerin clearance in Hutchinson-Gilford progeria fibroblasts
Aging Cell, 2014Co-Authors: Diana Gabriel, Daniela Roedl, Karima DjabaliAbstract:Summary Hutchinson–Gilford progeria syndrome (HGPS, OMIM 176670) is a rare multisystem childhood premature aging disorder linked to mutations in the LMNA gene. The most common HGPS mutation is found at position G608G within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A, and the truncated protein is called progerin. Progerin only undergoes a subset of the normal post-translational modifications and remains permanently farnesylated. Several attempts to rescue the normal cellular phenotype with farnesyltransferase inhibitors (FTIs) and other compounds have resulted in partial cellular recovery. Using proteomics, we report here that progerin induces changes in the composition of the HGPS nuclear proteome, including alterations to several components of the protein degradation pathways. Consequently, proteasome activity and autophagy are impaired in HGPS cells. To restore protein clearance in HGPS cells, we treated HGPS cultures with sulforaphane (SFN), an antioxidant derived from cruciferous vegetables. We determined that SFN stimulates proteasome activity and autophagy in normal and HGPS fibroblast cultures. Specifically, SFN enhances progerin clearance by autophagy and reverses the phenotypic changes that are the hallmarks of HGPS. Therefore, SFN is a promising therapeutic avenue for children with HGPS.
Diana Gabriel - One of the best experts on this subject based on the ideXlab platform.
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Sulforaphane enhances progerin clearance in Hutchinson–Gilford progeria fibroblasts
2016Co-Authors: Diana Gabriel, Daniela Roedl, Leslie B Gordon, Karima DjabaliAbstract:Hutchinson–Gilford progeria syndrome (HGPS, OMIM 176670) is a rare multisystem childhood premature aging disorder linked to mutations in the LMNA gene. The most common HGPS mutation is found at position G608G within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A, and the truncated protein is called progerin. Progerin only undergoes a subset of the normal post-translational modifications and remains permanently farn-esylated. Several attempts to rescue the normal cellular pheno-type with farnesyltransferase inhibitors (FTIs) and other compounds have resulted in partial cellular recovery. Using proteomics, we report here that progerin induces changes in the composition of the HGPS nuclear proteome, including alter-ations to several components of the protein degradation path-ways. Consequently, proteasome activity and autophagy are impaired in HGPS cells. To restore protein clearance in HGPS cells, we treated HGPS cultures with sulforaphane (SFN), an antioxi-dant derived from cruciferous vegetables. We determined that SFN stimulates proteasome activity and autophagy in normal and HGPS fibroblast cultures. Specifically, SFN enhances progerin clearance by autophagy and reverses the phenotypic changes that are the hallmarks of HGPS. Therefore, SFN is a promising therapeutic avenue for children with HGPS. Key words: lamins; progeria; progerin; proteostasis; senes-cence; sulforaphane
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Sulforaphane enhances progerin clearance in Hutchinson-Gilford progeria fibroblasts
Aging Cell, 2014Co-Authors: Diana Gabriel, Daniela Roedl, Karima DjabaliAbstract:Summary Hutchinson–Gilford progeria syndrome (HGPS, OMIM 176670) is a rare multisystem childhood premature aging disorder linked to mutations in the LMNA gene. The most common HGPS mutation is found at position G608G within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A, and the truncated protein is called progerin. Progerin only undergoes a subset of the normal post-translational modifications and remains permanently farnesylated. Several attempts to rescue the normal cellular phenotype with farnesyltransferase inhibitors (FTIs) and other compounds have resulted in partial cellular recovery. Using proteomics, we report here that progerin induces changes in the composition of the HGPS nuclear proteome, including alterations to several components of the protein degradation pathways. Consequently, proteasome activity and autophagy are impaired in HGPS cells. To restore protein clearance in HGPS cells, we treated HGPS cultures with sulforaphane (SFN), an antioxidant derived from cruciferous vegetables. We determined that SFN stimulates proteasome activity and autophagy in normal and HGPS fibroblast cultures. Specifically, SFN enhances progerin clearance by autophagy and reverses the phenotypic changes that are the hallmarks of HGPS. Therefore, SFN is a promising therapeutic avenue for children with HGPS.
Mark W Kieran - One of the best experts on this subject based on the ideXlab platform.
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abstract 11518 diastolic left ventricular dysfunction is a common and early cardiac abnormality in Hutchinson gilford progeria syndrome
Circulation, 2015Co-Authors: Ashwin Prakash, Monica E Kleinman, Joseph M Massaro, Ralph B Dagostino, Leslie B Gordon, Marie Gerhardherman, Mark W Kieran, Leslie B SmootAbstract:Introduction: Hutchinson-Gilford progeria syndrome (HGPS) is associated with premature death due to cardiovascular events. However, little is known about the natural history of cardiac disease in t...
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impact of farnesylation inhibitors on survival in Hutchinson gilford progeria syndrome
Circulation, 2014Co-Authors: Leslie B Gordon, Monica E Kleinman, Joseph M Massaro, Ralph B Dagostino, Susan E Campbell, Joan F Brazier, Ted W Brown, Mark W KieranAbstract:Background—Hutchinson-Gilford progeria syndrome is an ultrarare segmental premature aging disease resulting in early death from heart attack or stroke. There is no approved treatment, but starting in 2007, several recent single-arm clinical trials administered inhibitors of protein farnesylation aimed at reducing toxicity of the disease-producing protein progerin. No study assessed whether treatments influence patient survival. The key elements necessary for this analysis are a robust natural history of survival and comparison with a sufficiently large patient population that has been treated for a sufficient time period with disease-targeting medications. Methods and Results—We generated Kaplan–Meier survival analyses for the largest untreated Hutchinson-Gilford progeria syndrome cohort to date. Mean survival was 14.6 years. Comparing survival for treated versus age- and sex-matched untreated cohorts, hazard ratio was 0.13 (95% confidence interval, 0.04–0.37; P<0.001) with median follow-up of 5.3 years f...
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initial cutaneous manifestations of Hutchinson gilford progeria syndrome
Pediatric Dermatology, 2014Co-Authors: F Jillian M D Rork, Leslie B Gordon, Mark W Kieran, T Jennifer M D Huang, M Monica D Kleinman, G Marilyn M D LiangAbstract:Hutchinson-Gilford progeria syndrome (HGPS) is a rare, uniformly fatal, premature aging disease with distinct dermatologic features. We sought to identify and describe the initial skin and hair findings as potential diagnostic signs of the disease. We performed a chart review of the structured initial intake histories of 39 individuals with HGPS enrolled in clinical trials from 2007 to 2010 at Boston Children's Hospital, limited to cutaneous history from birth to 24 months. Medical photographs were provided through the clinical trials and the Progeria Research Foundation Medical and Research Database at Brown University Center for Gerontology and Healthcare Research. All 39 patients reported skin and hair abnormalities within the first 24 months of life. Pathologies included sclerodermoid change, prominent superficial veins, dyspigmentation, and alopecia. The mean age of presentation for each finding was <12 months. The most frequently reported skin feature was sclerodermoid change, which commonly involved the abdomen and bilateral lower extremities. Prominent superficial vasculature manifested as circumoral cyanosis and pronounced veins on the scalp and body. Hypo- and hyperpigmentation were observed over areas of sclerodermoid change. Scalp alopecia progressed in a distinct pattern, with preservation of the hair over the midscalp and vertex areas for the longest period of time. HGPS has distinct cutaneous manifestations during the first 2 years of life that may be the first signs of disease. Awareness of these findings could expedite diagnosis.
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mechanisms of premature vascular aging in children with Hutchinson gilford progeria syndrome
Hypertension, 2012Co-Authors: Marie Gerhardherman, Monica E Kleinman, Leslie B Smoot, Nicole Wake, Mark W Kieran, David T Miller, Armin Schwartzman, Anita Giobbiehurder, Donna Neuberg, Leslie B GordonAbstract:Hutchinson-Gilford progeria syndrome is a rare, segmental premature aging syndrome of accelerated atherosclerosis and early death from myocardial infarction or stroke. This study sought to establish comprehensive characterization of the fatal vasculopathy in Hutchinson-Gilford progeria syndrome and its relevance to normal aging. We performed cardiovascular assessments at a single clinical site on the largest prospectively studied cohort to date. Carotid-femoral pulse wave velocity was dramatically elevated (mean: 13.00±3.83 m/s). Carotid duplex ultrasound echobrightness, assessed in predefined tissue sites as a measure of arterial wall density, was significantly greater than age- and sex-matched controls in the intima-media (P<0.02), near adventitia (P<0.003), and deep adventitia (P<0.01), as was internal carotid artery mean flow velocity (P<0.0001). Ankle-brachial indices were abnormal in 78% of patients. Effective disease treatments may be heralded by normalizing trends of these noninvasive cardiovascular measures. The data demonstrate that, along with peripheral vascular occlusive disease, accelerated vascular stiffening is an early and pervasive mechanism of vascular disease in Hutchinson-Gilford progeria syndrome. There is considerable overlap with cardiovascular changes of normal aging, which reinforces the view that defining mechanisms of cardiovascular disease in Hutchinson-Gilford progeria syndrome provides a unique opportunity to isolate a subset of factors influencing cardiovascular disease in the general aging population.
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disease progression in Hutchinson gilford progeria syndrome impact on growth and development
Pediatrics, 2007Co-Authors: Leslie B Gordon, Anita Giobbiehurder, Susan E Campbell, Kathleen M Mccarten, Jason T Machan, Scott D Berns, Mark W KieranAbstract:OBJECTIVES. Hutchinson-Gilford progeria syndrome is a rare and uniformly fatal segmental “premature aging” disease that affects a variety of organ systems. We sought to more clearly define the bone and weight abnormalities in patients with progeria as potential outcome parameters for prospective clinical trials. PATIENTS AND METHODS. We collected and analyzed longitudinal medical information, both retrospectively and prospectively, from a total of 41 children with Hutchinson-Gilford progeria syndrome spanning 14 countries, from the Progeria Research Foundation Medical and Research Database at the Brown University Center for Gerontology. RESULTS. In addition to a number of previously well-defined phenotypic findings in children with progeria, this study identified abnormalities in the eruption of secondary incisors lingually and palatally in the mandible and maxilla, respectively. Although bony structures appeared normal in early infancy, clavicular resorption, coxa valga, avascular necrosis of the femoral head, modeling abnormalities of long bones with slender diaphyses, flared metaphyses, and overgrown epiphyses developed. Long bones showed normal cortical thickness centrally and progressive focal demineralization peripherally. The most striking finding identified in the retrospective data set of 35 children was an average weight increase of only 0.44 kg/year, beginning at ∼24 months of age and persisting through life, with remarkable intrapatient linearity. This rate is >2 SD below normal weight gain for any corresponding age and sharply contrasts with the parabolic growth pattern for normal age- and gender-matched children. This finding was also confirmed prospectively. CONCLUSIONS. Our analysis shows evidence of a newly identified abnormal growth pattern for children with Hutchinson-Gilford progeria syndrome. The skeletal and dental findings are suggestive of a developmental dysplasia rather than a classical aging process. The presence of decreased and linear weight gain, maintained in all of the patients after the age of 2 years, provides the ideal parameter on which altered disease status can be assessed in clinical trials.
Donna Neuberg - One of the best experts on this subject based on the ideXlab platform.
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mechanisms of premature vascular aging in children with Hutchinson gilford progeria syndrome
Hypertension, 2012Co-Authors: Marie Gerhardherman, Monica E Kleinman, Leslie B Smoot, Nicole Wake, Mark W Kieran, David T Miller, Armin Schwartzman, Anita Giobbiehurder, Donna Neuberg, Leslie B GordonAbstract:Hutchinson-Gilford progeria syndrome is a rare, segmental premature aging syndrome of accelerated atherosclerosis and early death from myocardial infarction or stroke. This study sought to establish comprehensive characterization of the fatal vasculopathy in Hutchinson-Gilford progeria syndrome and its relevance to normal aging. We performed cardiovascular assessments at a single clinical site on the largest prospectively studied cohort to date. Carotid-femoral pulse wave velocity was dramatically elevated (mean: 13.00±3.83 m/s). Carotid duplex ultrasound echobrightness, assessed in predefined tissue sites as a measure of arterial wall density, was significantly greater than age- and sex-matched controls in the intima-media (P<0.02), near adventitia (P<0.003), and deep adventitia (P<0.01), as was internal carotid artery mean flow velocity (P<0.0001). Ankle-brachial indices were abnormal in 78% of patients. Effective disease treatments may be heralded by normalizing trends of these noninvasive cardiovascular measures. The data demonstrate that, along with peripheral vascular occlusive disease, accelerated vascular stiffening is an early and pervasive mechanism of vascular disease in Hutchinson-Gilford progeria syndrome. There is considerable overlap with cardiovascular changes of normal aging, which reinforces the view that defining mechanisms of cardiovascular disease in Hutchinson-Gilford progeria syndrome provides a unique opportunity to isolate a subset of factors influencing cardiovascular disease in the general aging population.
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Hutchinson gilford progeria is a skeletal dysplasia
Journal of Bone and Mineral Research, 2011Co-Authors: Catherine M Gordon, Brian D Snyder, Leslie B Gordon, Anita Giobbiehurder, Ara Nazarian, Nicolle Quinn, Susanna Y Huh, Donna NeubergAbstract:Hutchinson-Gilford progeria syndrome (HGPS) is a rare segmental premature aging disorder that affects bone and body composition, among other tissues. We sought to determine whether bone density and structural geometry are altered in children with HGPS and whether relationships exist among these parameters and measures of skeletal anthropometry, body composition, and nutrition. We prospectively enrolled 26 children with HGPS (ages 3.1 to 16.2 years). Outcomes included anthropometric data; bone age; areal bone mineral density (aBMD) and body composition by dual-energy X-ray absorptiometry (DXA); volumetric bone mineral density (vBMD), strength-strain index (SSI), and bone structural rigidity calculated from radial transaxial peripheral quantitative computed tomographic (pQCT) images; serum bone biomarkers and hormonal measures; and nutrition assessments. Children with HGPS had low axial aBMD Z-scores by DXA, which improved after adjustment for height age, whereas differences in radial vBMD by pQCT were less striking. However, pQCT revealed distinct abnormalities in both novel measures of bone structural geometry and skeletal strength at the radius compared with healthy controls. Dietary intake was adequate, confirming that HGPS does not represent a model of malnutrition-induced bone loss. Taken together, these findings suggest that the phenotype of HGPS represents a unique skeletal dysplasia.