The Experts below are selected from a list of 1140 Experts worldwide ranked by ideXlab platform
Robert A. Hegele - One of the best experts on this subject based on the ideXlab platform.
-
Familial Partial Lipodystrophy presenting as metabolic syndrome
Journal of clinical lipidology, 2016Co-Authors: Darwin Chan, Adam D Mcintyre, Robert A. Hegele, Andrew C. Don-wauchopeAbstract:We report the first described case of a heterozygous p.R545H (c.1634 G > A) missense mutation in the LMNA gene with clinical features compatible with Dunnigan-type 2 Familial Partial Lipodystrophy (FPLD2). The case presented as metabolic syndrome to a specialist clinical service and highlights the overlap between FPLD2 and the metabolic syndrome. The associations with type 2 diabetes mellitus, fatty liver disease, polycystic ovarian syndrome, and hypertriglyceridemia are highlighted. The importance of evaluating patients for these associated conditions is discussed, and the potential mechanisms of disease are briefly outlined. The mutation has been previously reported in a heart failure database without a clinical description. The links between heart failure and the clinical condition are briefly considered.
-
a novel lipe nonsense mutation found using exome sequencing in siblings with late onset Familial Partial Lipodystrophy
Canadian Journal of Cardiology, 2014Co-Authors: Syed Mohd Farhan, John F Robinson, Adam D Mcintyre, Maria Giovanna Marrosu, Anna Ticca, Sara Loddo, Nicola Carboni, Francesco Brancati, Robert A. HegeleAbstract:Abstract Background Familial lipodystrophies are rare inherited disorders associated with redistribution of body fat and development of dyslipidemia, insulin resistance, and diabetes. We previously reported 2 siblings with unusual late-onset Familial Partial Lipodystrophy in whom heretofore known causative genes had been excluded. We hypothesized they had a mutation in a novel Lipodystrophy gene. Methods Our approach centred on whole exome sequencing of the patients' DNA, together with genetic linkage analysis and a bioinformatic prioritization analysis. All candidate variants were assessed in silico and available family members were genotyped to assess segregation of mutations. Results Our prioritization algorithm led us to a novel homozygous nonsense variant, namely p.Ala507fsTer563 in the hormone sensitive lipase gene encoding, an enzyme that is differentially expressed in adipocytes and steroidogenic tissues. Pathogenicity of the mutation was supported in bioinformatic analyses and variant cosegregation within the family. Conclusions We have identified a novel nonsense mutation in hormone sensitive lipase gene, which likely explains the Lipodystrophy phenotype observed in these patients.
-
Predicting Abdominal Adipose Tissue among Women with Familial Partial Lipodystrophy
Metabolism: clinical and experimental, 2009Co-Authors: Tisha R. Joy, Brooke A. Kennedy, Salam A. Al-attar, Brian K. Rutt, Robert A. HegeleAbstract:The objective of the study was to determine correlations between magnetic resonance imaging (MRI) measures of truncal adiposity (trunk fat percentage [TrF %MRI], visceral adipose tissue [VAT], and subcutaneous abdominal adipose tissue [SAT]), simple clinical measures (body mass index [BMI], waist circumference [WC], and waist-to-hip ratio [WHR]), and bioelectrical impedance analysis (BIA)–derived measures (total fat percentage [TF %] and TrF %BIA) in female patients with Familial Partial Lipodystrophy (FPLD). Our secondary aim was to generate and cross-validate predictive equations for VAT and SAT using these simple clinical and BIA-derived variables. Measures of truncal adiposity were measured using 1.5-T MRI (VAT, SAT, and TrF %MRI) and Tanita (Tokyo, Japan) 8-electrode body composition analyzer BC-418 (TrF %BIA) in 13 female FPLD patients. Pearson correlation coefficients were determined among the various adiposity parameters (BMI, WC, WHR, SAT, VAT, TrF %MRI, TrF %BIA, and TF %). Equations to estimate VAT and SAT were determined among 6 of the 13 FPLD subjects using multilinear regression analysis, and the best equations were then cross-validated in the remaining 7 subjects. Variables entered into the model included age, BMI, WC, WHR, TrF %BIA, and TF %. The TrF %MRI showed moderate correlation (r = 0.647, P = .02) with the TrF %BIA, but the discrepancy between the 2 variables increased with increasing truncal adiposity. The strongest correlate for TrF %MRI was BMI (r = 0.886, P < .0001). Visceral adipose tissue was poorly associated with simple clinical measures of BMI, WC, and WHR, but was inversely correlated with TF %, TrF %BIA, and SAT. The TF % was the strongest correlate for both SAT and VAT. Thus, the best regression equation for VAT included age, BMI, WC, and TF % (R2 = 1.0), whereas that for SAT only included TF % (R2 = 0.75). The corresponding standard error of the estimate for the predictive equations was approximately 0.03 % and 18.5 % of the mean value of VAT and SAT, respectively. In the cross-validation study, differences between predicted and observed values of SAT were larger than those of VAT. We conclude that, among female FPLD patients, (1) no simple clinical anthropometric measure correlates well with VAT, whereas BMI correlates well with SAT; (2) BIA measure of TF % most strongly correlated with both VAT and SAT; and (3) based on the cross-validation study, VAT but not SAT could be more reliably estimated using the regression equations derived.
-
prevalence of reproductive abnormalities among women with Familial Partial Lipodystrophy
Endocrine Practice, 2008Co-Authors: Tisha R. Joy, Robert A. HegeleAbstract:Objective: To compare the risk of having polycystic ovary syndrome (PCOS) or ovarian cysts among women with genetically confirmed Familial Partial Lipodystrophy (FPLD) with that in the general population of healthy women. Methods: Twenty-five women with FPLD who were 18 to 80 years old were interviewed regarding a history of PCOS or ovarian cysts (composite primary outcome) as well as for secondary outcomes of interest including men strual irregularities, hirsutism, gynecologic surgical proce dures, and fertility or obstetric complications. From the 2005 National Ambulatory Medical Care Survey, 3,326 women, aged 18 to 80 years (control subjects), were assessed for the presence of the primary outcome based on appropriate International Classification of Diseases, Ninth Revision, Clinical Modification codes. Results: Four of the 25 patients with FPLD (16%) had a history of PCOS or ovarian cysts, in comparison with 14 of the 3,326 control subjects (0.42%), resulting in an age- and body mass index-adjusted odds ratio of 40.6 (95% confidence interval, 12.1 to 136.7; P<.0001) among the patients with FPLD. Furthermore, 5 women with FPLD (20%) required at least 1 oophorectomy during their lifetime, and 6 (24%) had had hysterectomies at a young age ( ≤55 years). Conclusion: Women with genetically confirmed FPLD have an increased risk for PCOS and ovarian cysts, as well as early hysterectomies, in comparison with the general population. Therefore, timely involvement of gynecologists in the care of these patients is warranted. (EndocrPract.2008;14:000-000)
-
Prevalence of reproductive abnormalities among women with Familial Partial Lipodystrophy.
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, 2008Co-Authors: Tisha R. Joy, Robert A. HegeleAbstract:Objective: To compare the risk of having polycystic ovary syndrome (PCOS) or ovarian cysts among women with genetically confirmed Familial Partial Lipodystrophy (FPLD) with that in the general population of healthy women. Methods: Twenty-five women with FPLD who were 18 to 80 years old were interviewed regarding a history of PCOS or ovarian cysts (composite primary outcome) as well as for secondary outcomes of interest including men strual irregularities, hirsutism, gynecologic surgical proce dures, and fertility or obstetric complications. From the 2005 National Ambulatory Medical Care Survey, 3,326 women, aged 18 to 80 years (control subjects), were assessed for the presence of the primary outcome based on appropriate International Classification of Diseases, Ninth Revision, Clinical Modification codes. Results: Four of the 25 patients with FPLD (16%) had a history of PCOS or ovarian cysts, in comparison with 14 of the 3,326 control subjects (0.42%), resulting in an age- and body mass index-adjusted odds ratio of 40.6 (95% confidence interval, 12.1 to 136.7; P
Abhimanyu Garg - One of the best experts on this subject based on the ideXlab platform.
-
diagnostic value of anthropometric measurements for Familial Partial Lipodystrophy dunnigan variety
The Journal of Clinical Endocrinology and Metabolism, 2020Co-Authors: Chandna Vasandani, Hilal Sekizkardes, Rebecca J. Brown, Beverley Adamshuet, Abhimanyu GargAbstract:Context Familial Partial Lipodystrophy, Dunnigan variety (FPLD2) is a rare autosomal dominant disorder resulting from LMNA causal variants, which is characterized by loss of subcutaneous fat from the extremities and predisposition to metabolic complications. The diagnostic value of various anthropometric measurements for FPLD2 remains unknown. Objective To determine specificity and sensitivity of anthropometric measurements for the diagnosis of FPLD2. Methods We measured skinfold thickness and regional body fat by dual energy X-ray absorptiometry (DXA) in 50 adult females and 6 males with FPLD2 at UT Southwestern and compared their data with the sex- and age-matched controls from the National Health and Nutrition Examination Survey (NHANES) 1999-2010. We further compared data from 1652 unaffected females from the Dallas Heart Study and 23 females with FPLD2 from the National Institutes of Health with the NHANES data. Results The DXA-derived lower limb fat (%) had the best specificity (0.995) and sensitivity (1.0) compared with the upper limb fat, truncal fat, the ratio of lower limb to truncal fat, and triceps skinfold thickness for adult females with FPLD2. The lower limb fat below 1st percentile of NHANES females had a false-positive rate of 0.0054 and a false negative rate of 0. The diagnostic value of anthropometric parameters could not be determined for males with FPLD2 due to small sample size. Conclusions The lower limb fat (%) is the best objective anthropometric measure for diagnosing FPLD2 in females. Women with below the 1st percentile lower limb fat should undergo genetic testing for FPLD2, especially if they have metabolic complications.
-
Efficacy of Metreleptin Treatment in Familial Partial Lipodystrophy Due to PPARG vs LMNA Pathogenic Variants.
The Journal of Clinical Endocrinology & Metabolism, 2019Co-Authors: Hilal Sekizkardes, Elaine Cochran, Noemi Malandrino, Abhimanyu Garg, Rebecca J. BrownAbstract:Context Familial Partial Lipodystrophy (FPLD) is most commonly caused by pathogenic variants in LMNA and PPARG. Leptin replacement with metreleptin has largely been studied in the LMNA group. Objective To understand the efficacy of metreleptin in PPARG vs LMNA pathogenic variants and investigate predictors of metreleptin responsiveness. Design Subgroup analysis of a prospective open-label study of metreleptin in Lipodystrophy. Setting National Institutes of Health, Bethesda, Maryland. Participants Patients with LMNA (n = 22) or PPARG pathogenic variants (n = 7), leptin Intervention Metreleptin (0.08 to 0.16 mg/kg) for 12 months. Outcome Hemoglobin A1c (HbA1c), lipids, and medication use at baseline and after 12 months. Results Baseline characteristics were comparable in patients with PPARG and LMNA: HbA1c, 9.2 ± 2.3 vs 7.8 ± 2.1%; median [25th, 75th percentile] triglycerides, 1377 [278, 5577] vs 332 [198, 562] mg/dL; leptin, 6.3 ± 3.8 vs 5.5 ± 2.5 ng/mL (P > 0.05). After 12 months of metreleptin, HbA1c declined to 7.7 ± 2.4 in PPARG and 7.3 ± 1.7% in LMNA; insulin requirement decreased from 3.8 [2.7, 4.3] to 2.1 [1.6, 3.0] U/kg/d in PPARG and from 1.7 [1.3, 4.4] to 1.2 [1.0, 2.3] U/kg/d in LMNA (P 8%. Conclusion Metreleptin resulted in similar metabolic improvements in patients with LMNA and PPARG pathogenic variants. Our findings support the efficacy of metreleptin in patients with the two most common genetic causes of FPLD.
-
Whole-exome sequencing identifies ADRA2A mutation in atypical Familial Partial Lipodystrophy
JCI insight, 2016Co-Authors: Abhimanyu Garg, Shireesha Sankella, Chao Xing, Anil K. AgarwalAbstract:Despite identification of causal genes for various Lipodystrophy syndromes, the molecular basis of some peculiar lipodystrophies remains obscure. In an African-American pedigree with a novel autosomal dominant, atypical Familial Partial Lipodystrophy (FPLD), we performed linkage analysis for candidate regions and whole-exome sequencing to identify the disease-causing mutation. Affected adults reported marked loss of fat from the extremities, with excess fat in the face and neck at age 13–15 years, and developed metabolic complications later. A heterozygous g.112837956C>T mutation on chromosome 10 (c.202C>T, p.Leu68Phe) affecting a highly conserved residue in adrenoceptor α 2A (ADRA2A) was found in all affected subjects but not in unaffected relatives. ADRA2A is the main presynaptic inhibitory feedback G protein–coupled receptor regulating norepinephrine release. Activation of ADRA2A inhibits cAMP production and reduces lipolysis in adipocytes. As compared with overexpression of a wild-type ADRA2A construct in human embryonic kidney–293 cells and differentiated 3T3-L1 adipocytes, the mutant ADRA2A produced more cAMP and glycerol, which were resistant to the effects of the α2-adrenergic receptor agonist clonidine and the α2-adrenergic receptor antagonist yohimbine, suggesting loss of function. We conclude that heterozygous p.Leu68Phe ADRA2A mutation causes a rare atypical FPLD, most likely by inducing excessive lipolysis in some adipose tissue depots.
-
Increased skeletal muscle volume in women with Familial Partial Lipodystrophy, dunnigan variety
The Journal of clinical endocrinology and metabolism, 2013Co-Authors: Paul T Weatherall, Beverley Adams-huet, Abhimanyu GargAbstract:Introduction: Familial Partial Lipodystrophy, Dunnigan variety (FPLD), an autosomal dominant disorder caused by LMNA mutations, is characterized by fat loss from the extremities. However, it is unclear whether these patients appear muscular because of a lack of subcutaneous fat or have an actual increase in muscle mass. Therefore, we compared muscle mass and volume of selected muscles in women with FPLD and control subjects using dual-emission x-ray absorptiometry (DXA) and magnetic resonance imaging (MRI). Methods: Whole-body axial MRI and DXA scans were obtained on 39 women, aged 18 to 65 years, with FPLD and 17 healthy women matched for body mass index and age (group 1). Volumes of muscles in both the thighs, calves, and psoas were calculated from MRI scans and muscle mass in extremities were calculated from DXA. In addition, abdominal MRI and DXA scans were analyzed from 129 healthy, frequency-matched women (group 2). Comparisons between women with FPLD and control subjects were made using ANOVA, adju...
-
Comparison of Efficacy and Safety of Leptin Replacement Therapy in Moderately and Severely Hypoleptinemic Patients with Familial Partial Lipodystrophy of the Dunnigan Variety
The Journal of clinical endocrinology and metabolism, 2011Co-Authors: Vinaya Simha, Lalitha Subramanyam, Lidia S. Szczepaniak, Claudia Quittner, Beverley Adams-huet, Peter G. Snell, Abhimanyu GargAbstract:Context: Leptin replacement therapy improves metabolic complications in patients with Lipodystrophy and severe hypoleptinemia (SH), but whether the response is related to the degree of hypoleptinemia remains unclear. Objective: The aim of the study was to compare efficacy of leptin therapy in Familial Partial Lipodystrophy, Dunnigan variety (FPLD) patients with SH (serum leptin
Hartmut H.-j. Schmidt - One of the best experts on this subject based on the ideXlab platform.
-
Muscle and nerve pathology in Dunnigan Familial Partial Lipodystrophy.
Neurology, 2007Co-Authors: Simone Spuler, T. Kalbhenn, Joanna Zabojszcza, F.k.h. Van Landeghem, A. Lüdtke, Katrin Wenzel, M. Koehnlein, Markus Schuelke, L. Lüdemann, Hartmut H.-j. SchmidtAbstract:Objective: To characterize muscle and nerve pathology in Dunnigan Familial Partial Lipodystrophy (FPLD). Methods: We used conventional histology, immunohistochemistry, messenger RNA (mRNA) expression, gene sequencing, and clinical studies of 13 patients with neuromuscular involvement. Results: The clinical findings consisted of muscle hypertrophy (12/13), severe myalgias (9/13), and multiple nerve entrapment syndromes (8/13). Skeletal muscle histology demonstrated marked Type 1 and 2 muscle fiber hypertrophy and nonspecific myopathic changes, whereas numerous paranodal myelin swellings (tomacula) were found in sural nerve biopsies. We found that myostatin mRNA expression was reduced in patients with FPLD vs controls. We sequenced the myostatin gene in our subjects, but found no mutations. We then investigated whether or not SMAD, the intracellular mediator of myostatin signaling, might be impaired in patients with FPLD. We found that in FPLD muscle, a large number of SMAD molecules adhered to the nuclear membrane and were not found within the nucleus, compared with normal muscle or muscle from a patient with a non-FPLD lamin A/C disease. Conclusion: The myopathy and neuropathy associated with Dunnigan Familial Partial Lipodystrophy are distinct from other lamin A/C disorders. We hypothesize that the Lipodystrophy-associated mutation interferes with SMAD signaling, linking this type of Lipodystrophy to the phenotypically similar myostatin deficiency.
-
Long-term treatment experience in a subject with Dunnigan-type Familial Partial Lipodystrophy: efficacy of rosiglitazone.
Diabetic medicine : a journal of the British Diabetic Association, 2005Co-Authors: A. Lüdtke, Simone Spuler, Janine Genschel, Howard J. Worman, K. Heck, H. Mehnert, Hartmut H.-j. SchmidtAbstract:Dunnigan-type Familial Partial Lipodystrophy (FPLD) is caused by mutations in LMNA, the gene that encodes nuclear lamins A and C. FPLD is characterized by peripheral fat loss, excess central adiposity, insulin resistance, and hyperlipidaemia, which are difficult to treat. We present our 2 years' experience of treatment with rosiglitazone in a subject with FPLD. Insulin requirement decreased significantly from 240 IU/day to 76 IU/day (range 20-240 IU/day) and serum triglyceride concentration was lowered from 13.7 +/- 14.4 mmol/l to 4.5 +/- 4.3 mmol/l and remained stable. Mean HbA(1c) prior to rosiglitazone therapy was 9.4 +/- 1.32% and decreased to 7.4 +/- 0.6% during therapy with rosiglitazone. This case demonstrates the benefits of PPARgamma-agonists on glycaemic control and dyslipidaemia in a patient with FPLD. This in turn implies that PPARgamma may play a pathophysiological role in FPLD.
-
Consider Cardiomyopathy in Subjects With Familial Partial Lipodystrophy
Circulation, 2002Co-Authors: Hartmut H.-j. SchmidtAbstract:To the Editor: Hegele1 excellently described the presence of premature coronary artery disease in 8 out of 23 adult subjects (aged above 35 years) with Familial Partial Lipodystrophy (FPL) carrying LMNA mutations. His intriguing observations underline the striking similarity between FPL and the metabolic syndrome (also called syndrome X). The latter is known to result in premature coronary artery disease. In FPL, the phenotype of altered fatty tissue distribution and the prominence of the skeletal muscles, especially of the lower limbs, precedes the manifestation of dyslipidemia and diabetes mellitus. Dyslipidemia in turn seems to occur many years before diabetes mellitus may occur.2 However, it is remarkable, that Hegele reported on insulin resistance in all studied subjects, although 18/23 had dyslipidemia and 12/23 had diabetes mellitus. Does hyperinsulinemia and insulin resistance, respectively, precede dyslipidemia and diabetes mellitus in this selected cohort of patients? The observed coronary artery disease in FPL carrying LMNA mutations is presumably caused by the cardiovascular risk factors, …
-
Dyslipemia in Familial Partial Lipodystrophy caused by an R482W mutation in the LMNA gene.
The Journal of clinical endocrinology and metabolism, 2001Co-Authors: Hartmut H.-j. Schmidt, Janine Genschel, Peter Baier, Martina Schmidt, Johann Ockenga, Uwe J. F. Tietge, Marcus Pröpsting, Carsten Büttner, Michael P. Manns, Herbert LochsAbstract:Lipatrophic diabetes, also referred to as Familial Partial Lipodystrophy, is a rare disease that is metabolically characterized by hypertriglyceridemia and insulin resistance. Affected patients typically present with regional loss of body fat and muscular hypertrophic appearance. Variable symptoms may comprise pancreatitis and/or eruptive xanthomas due to severe hypertriglyceridemia, acanthosis nigricans, polycystic ovaria, and carpal tunnel syndrome. Mutations within the LMNA gene on chromosome 1q21.2 were recently reported to result in the phenotype of Familial Partial Lipodystrophy. The genetic trait is autosomal dominant. We identified a family with Partial Lipodystrophy carrying the R482W (Arg(482)Trp) missense mutation within LMNA. Here we present the lipoprotein characteristics in this family in detail. Clinically, the loss of sc fat and muscular hypertrophy especially of the lower extremities started as early as in childhood. Acanthosis and severe hypertriglyceridemia developed later in life, followed by diabetes. The characterization of the lipoprotein subfractions revealed that affected children present with hyperlipidemia. The presence and severity of hyperlipidemia seem to be influenced by age, apolipoprotein E genotype, and the coexistence of diabetes mellitus. In conclusion, dyslipemia is an early and prominent feature in the presented lipodystrophic family carrying the R482W mutation within LMNA.
Henian Cao - One of the best experts on this subject based on the ideXlab platform.
-
Familial Partial Lipodystrophy Phenotype Resulting from a Single-Base Mutation in Deoxyribonucleic Acid-Binding Domain of Peroxisome Proliferator-Activated Receptor-γ
The Journal of clinical endocrinology and metabolism, 2007Co-Authors: Houshang Monajemi, Henian Cao, Erik S.g. Stroes, Eric Kalkhoven, Lin Zhang, Ellen H. Jeninga, Mario Maas, C. B. Brouwer, Robert A. HegeleAbstract:Context: Familial Partial Lipodystrophy (FPLD) results from coding sequence mutations either in LMNA, encoding nuclear lamin A/C, or in PPARG, encoding peroxisome proliferator-activated receptor-γ (PPARγ). The LMNA form is called FPLD2 (MIM 151660) and the PPARG form is called FPLD3 (MIM 604367). Objective: Our objective was to investigate whether the clinical phenotype of this proband is due to mutation(s) in PPARγ. Design: This is a case report. Patient and Setting: A 31-yr-old female with the clinical phenotype of FPLD3, i.e. Lipodystrophy and early childhood diabetes with extreme insulin resistance and hypertriglyceridemia leading to recurrent pancreatitis, was assessed at an academic medical center. Results: The proband was heterozygous for a novel C→T mutation in the PPARG gene that led to the substitution of arginine 194 in PPARγ2 isoform, a conserved residue located in the zinc finger structure involved in DNA binding, by tryptophan (R194W). The mutation was absent from the genomes of 100 healthy ...
-
a lmna splicing mutation in two sisters with severe dunnigan type Familial Partial Lipodystrophy type 2
The Journal of Clinical Endocrinology and Metabolism, 2006Co-Authors: Chantal F Morel, Robert A. Hegele, Henian Cao, Mary Ann Thomas, Caroline Oneil, Geoffrey J Pickering, William D FoulkesAbstract:Context: To date, all cases of Familial Partial Lipodystrophy type 2 (FPLD2; Mendelian Inheritance in Man 151660) result from missense mutations in LMNA, which encodes nuclear lamin A/C (Mendelian Inheritance in Man 150330). Objective: The objective of the study was to carry out mutational analysis of LMNA in two sisters with a particularly severe FPLD2 phenotype. Design: This was a descriptive case report with molecular studies. Setting: The study was conducted at a referral center. Patients: We report two sisters of South Asian origin. The first presented with acanthosis nigricans at age 5 yr, diabetes with insulin resistance, hypertension and hypertriglyceridemia at age 13 yr, and Partial Lipodystrophy starting at puberty. Her sister and their mother had a similar metabolic profile and physical features, and their mother died of vascular disease at age 32 yr. Interventions: There were no interventions. Main Outcome Measures and Results: LMNA sequencing showed that the sisters were each heterozygous for...
-
Peroxisomal proliferator activated receptor-γ deficiency in a Canadian kindred with Familial Partial Lipodystrophy type 3 (FPLD3)
BMC medical genetics, 2006Co-Authors: Gordon A. Francis, Robin Casey, Jian Wang, Henian Cao, Todd Leff, Robert A. HegeleAbstract:Background Familial Partial Lipodystrophy (Dunnigan) type 3 (FPLD3, Mendelian Inheritance in Man [MIM] 604367) results from heterozygous mutations in PPARG encoding peroxisomal proliferator-activated receptor-γ. Both dominant-negative and haploinsufficiency mechanisms have been suggested for this condition.
-
Peroxisomal proliferator activated receptor-γ deficiency in a Canadian kindred with Familial Partial Lipodystrophy type 3 (FPLD3)
BMC Medical Genetics, 2006Co-Authors: Gordon A. Francis, Robin Casey, Jian Wang, Henian Cao, Todd Leff, Robert A. HegeleAbstract:Background Familial Partial Lipodystrophy (Dunnigan) type 3 (FPLD3, Mendelian Inheritance in Man [MIM] 604367) results from heterozygous mutations in PPARG encoding peroxisomal proliferator-activated receptor-γ. Both dominant-negative and haploinsufficiency mechanisms have been suggested for this condition. Methods We present a Canadian FPLD3 kindred with an affected mother who had loss of fat on arms and legs, but no increase in facial, neck, suprascapular or abdominal fat. She had profound insulin resistance, diabetes, severe hypertriglyceridemia and relapsing pancreatitis, while her pre-pubescent daughter had normal fat distribution but elevated plasma triglycerides and C-peptide and depressed high-density lipoprotein cholesterol. Results The mother and daughter were each heterozygous for PPARG nonsense mutation Y355X, whose protein product in vitro was transcriptionally inactive with no dominant-negative activity against the wild-type receptor. In addition the mutant protein appeared to be markedly unstable. Conclusion Taken together with previous studies of human PPARG mutations, these findings suggest that PPAR-γ deficiency due either to haploinsufficiency or to substantial activity loss due to dominant negative interference of the normal allele product's function can each contribute to the FPLD3 phenotype.
-
PPARG F388L, a Transactivation-Deficient Mutant, in Familial Partial Lipodystrophy
Diabetes, 2002Co-Authors: Robert A. Hegele, Henian Cao, Christy Frankowski, Suresh T. Mathews, Todd LeffAbstract:Autosomal dominant Familial Partial Lipodystrophy (FPLD) due to mutant LMNA encoding nuclear lamin A/C is characterized by adipose tissue repartitioning together with multiple metabolic disturbances, including insulin resistance and dyslipidemia. There is emerging evidence that some rare mutations in peroxisome proliferator-activated receptor-γ (PPAR-γ), encoded by PPARG, might be associated with human Lipodystrophy. We report a three-generation Canadian kindred ascertained based upon Partial Lipodystrophy, with a normal LMNA gene sequence. Candidate gene sequencing showed that all four affected subjects were heterozygous for a novel T→A mutation at PPARG nucleotide 1164 in exon 5 that predicted substitution of phenylalanine at codon 388 by leucine (F388L). The mutation was absent from normal family members and normal unrelated subjects, and altered a highly conserved residue within helix 8 of the predicted ligand-binding pocket of PPAR-γ. The mutant receptor had significantly decreased basal transcriptional activity and impaired stimulation by a synthetic ligand. The germline transmission of a transactivation-deficient mutation in PPARG suggests that autosomal dominant Partial Lipodystrophy is genetically heterogeneous. Our findings are consistent with the idea that mutant PPARG can underlie the Partial Lipodystrophy phenotype.
Milton C. Foss - One of the best experts on this subject based on the ideXlab platform.
-
Endoplasmic reticulum stress activation in adipose tissue induces metabolic syndrome in individuals with Familial Partial Lipodystrophy of the Dunnigan type
Diabetology & Metabolic Syndrome, 2018Co-Authors: Maria C. Foss-freitas, Rafael C. Ferraz, Luciana Z. Monteiro, Patricia M. Gomes, Ricardo Iwakura, Luiz Carlos C. Freitas, Milton C. FossAbstract:Background Familial Partial Lipodystrophy of the Dunnigan type is one of the most common inherited lipodystrophies variables. These individuals have important metabolic disorders that cause predisposition to various diseases. In this study we aimed to demonstrate the relation between the metabolic abnormalities, inflammatory profile and the expression of genes involved in the activation of the endoplasmic reticulum stress (ERS) in subjects with FPLD. Methods We evaluated 14 female FPLD patients and compared with 13 female healthy individuals. The subjects were paired with their respective BMI and age and categorized into two groups: Familial Partial Lipodystrophy of the Dunnigan type (FPLD) and control. Patients were fasted for 12 h before blood collection for measurement of HbA1c, glucose, insulin, lipids and inflammatory markers. Subcutâneous adipose tissue was collected by puncture aspiration of submental region during ambulatorial surgical aesthetic procedure. Results We demonstrate that patients with FPLD show increased HbA1c (p
-
Endoplasmic reticulum stress activation in adipose tissue induces metabolic syndrome in individuals with Familial Partial Lipodystrophy of the Dunnigan type.
Diabetology & metabolic syndrome, 2018Co-Authors: Maria Cristina Foss-freitas, Rafael C. Ferraz, Luciana Z. Monteiro, Patricia M. Gomes, Ricardo Iwakura, Luiz Carlos Conti De Freitas, Milton C. FossAbstract:Familial Partial Lipodystrophy of the Dunnigan type is one of the most common inherited lipodystrophies variables. These individuals have important metabolic disorders that cause predisposition to various diseases. In this study we aimed to demonstrate the relation between the metabolic abnormalities, inflammatory profile and the expression of genes involved in the activation of the endoplasmic reticulum stress (ERS) in subjects with FPLD. We evaluated 14 female FPLD patients and compared with 13 female healthy individuals. The subjects were paired with their respective BMI and age and categorized into two groups: Familial Partial Lipodystrophy of the Dunnigan type (FPLD) and control. Patients were fasted for 12 h before blood collection for measurement of HbA1c, glucose, insulin, lipids and inflammatory markers. Subcutâneous adipose tissue was collected by puncture aspiration of submental region during ambulatorial surgical aesthetic procedure. We demonstrate that patients with FPLD show increased HbA1c (p
-
endoplasmic reticulum stress activation in adipose tissue induces metabolic syndrome in individuals with Familial Partial Lipodystrophy of the dunnigan type
Diabetology & Metabolic Syndrome, 2018Co-Authors: Maria Cristina Fossfreitas, Rafael C. Ferraz, Luciana Z. Monteiro, Patricia M. Gomes, Ricardo Iwakura, Luiz Carlos Conti De Freitas, Milton C. FossAbstract:Familial Partial Lipodystrophy of the Dunnigan type is one of the most common inherited lipodystrophies variables. These individuals have important metabolic disorders that cause predisposition to various diseases. In this study we aimed to demonstrate the relation between the metabolic abnormalities, inflammatory profile and the expression of genes involved in the activation of the endoplasmic reticulum stress (ERS) in subjects with FPLD. We evaluated 14 female FPLD patients and compared with 13 female healthy individuals. The subjects were paired with their respective BMI and age and categorized into two groups: Familial Partial Lipodystrophy of the Dunnigan type (FPLD) and control. Patients were fasted for 12 h before blood collection for measurement of HbA1c, glucose, insulin, lipids and inflammatory markers. Subcutâneous adipose tissue was collected by puncture aspiration of submental region during ambulatorial surgical aesthetic procedure. We demonstrate that patients with FPLD show increased HbA1c (p < 0.01), fasting glucose (p < 0.002) and triglycerides (p < 0.005) while HDL/cholesterol (p < 0.001) was lower when compared to healthy individuals. We found that 64.2% FPLD patients had metabolic syndrome according to International Diabetes Federation definition. We also observe increased AUC of glucose (p < 0.001) and insulin during oGTT, featuring a frame of hyperglycemia and hyperinsulinemia, suggesting insulin resistance. Also we found hyperactivation of several genes responsible for ERS such as ATF-4 (p < 0.01), ATF-6 (p < 0.01), EIF2α3K (p < 0.005), CCT4 (p < 0.001), CHOP (p < 0.01), CALR (p < 0.001) and CANX (p < 0.005), that corroborate the idea that diabetes mellitus and metabolic syndrome are associated with direct damage to the endoplasmic reticulum homeostasis. Ultimately, we note that individuals with Lipodystrophy have an increase in serum interleukins, keys of the inflammatory process, as IL-1β, TNF-α and IL-6 (p < 0.05 all), compared with healthy individuals, which can be the trigger to insulin resistance in this population. Individuals with FPLD besides having typical dysfunctions of metabolic syndrome, show a hyperactivation of ERS associated with increased systemic inflammatory profile, which together may explain the complex clinical aspect of this diseases. Trial registration HCRP no 6711/2012
-
Body fat distribution in women with Familial Partial Lipodystrophy caused by mutation in the lamin A/C gene.
Indian journal of endocrinology and metabolism, 2012Co-Authors: Luciana Zaranza Monteiro, Maria Cristina Foss-freitas, Renan Magalhães Montenegro, Milton C. FossAbstract:Familial Partial Lipodystrophy (FPLD), Dunnigan variety, is an autosomal dominant disorder caused due to missense mutations in the lamin A/C (LMNA) gene encoding nuclear lamina proteins. Patients with FPLD are predisposed to metabolic complications of insulin resistance such as diabetes. We sought to evaluate and compare body fat distribution with dual-emission X-ray absorptiometry in women with and without FPLD and identify densitometric, clinical and metabolic features.
