scholarly journals Novel Heterozygous LMNA Variants Causing Familial Partial Lipodystrophy, Dunnigan Variety

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A35-A35
Author(s):  
Akhilesh Wadhwa ◽  
Chandna Vasandani ◽  
Abhimanyu Garg
Keyword(s):  
Autosomal Dominant ◽  
Subcutaneous Fat ◽  
Conduction System ◽  
Cardiac Conduction ◽  
Autosomal Dominant Disorder ◽  
Partial Lipodystrophy ◽  
Total Cohort ◽  
Causal Variants ◽  
Familial Partial Lipodystrophy ◽  
Relationship Of

Abstract Familial partial lipodystrophy (FPLD) is a rare, mostly autosomal dominant disorder characterized by selective loss of subcutaneous fat from the extremities. Patients with FPLD are predisposed to insulin resistance, dyslipidemia, diabetes mellitus, cardiac abnormalities (coronary heart disease [CHD], cardiomyopathy and conduction system disorders) and hepatic steatosis. FPLD2 (the Dunnigan variety) is the most common subtype which is caused by heterozygous variants in the lamin A/C (LMNA) gene. Over 50 LMNA causal variants have been reported in patients with FPLD2, with p.R482W and p.R482Q comprising ~75% of the families. We report 5 novel LMNA variants (c.722T>C, p.L241P; c.848A>G, p.N283S; c.1396A>G, p.N466D; c.1543A>G, p.K515E; c.1744C>A, p.R582S) in 5 families, where a female proband presented to us with moderately-severe FPLD, from among a total cohort of 264 FPLD2 families, with 259 families harboring other known pathogenic LMNA variants. The p.L241P variant was found in a 62-year-old female with a body mass index (BMI) of 28 kg/m2. She had hypertriglyceridemia. She is adopted and has two offsprings, who have not yet been examined and genotyped. The p.N283S variant was found in two males and two females from the same family (Age 40–74 y; BMI 18–45 kg/m2). Of these, only the 74-year-old female proband had clinical lipodystrophy, diabetes and hypertriglyceridemia. The other three subjects did not have lipodystrophy. Thus, this variant did not segregate with the phenotype of lipodystrophy in this family likely due to low penetrance or reduced clinical expressivity. The p.N466D variant was found in a 53-year-old female (BMI 26 kg/m2) who had diabetes and hypertriglyceridemia. The p.K515E variant was found in 4 females and 1 male who belonged to the same family (Age 29–62 y; BMI 19–26 kg/m2). All of them had lipodystrophy and hypertriglyceridemia and three of them had diabetes. The p.R582S variant was found in 3 males and one female who belonged to the same family (Age 19–76 y; BMI 16–30 kg/m2). All of them had lipodystrophy but only two of them had diabetes and hypertriglyceridemia. Eight of them had hypertension, three had CHD, one of them had acute pancreatitis and another one had a stroke. None of these patients had cardiomyopathy, cardiac conduction system defects or myopathy. In conclusion, we report genotype-phenotype relationship of 5 novel LMNA variants in patients presenting with FPLD2, with variable prevalence of diabetes, hypertriglyceridemia hypertension and CAD. None of these variants are associated with cardiomyopathy or myopathy or progeroid features. Our report adds to the allelic and clinical heterogeneity associated with LMNA variants.

scholarly journals Familial Partial Lipodystrophy: A Case Study and Review of Recent Literature

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A308-A309
Author(s):  
Ali Tipu ◽  
Farhad Hasan ◽  
Michael Grimes
Keyword(s):  
Adipose Tissue ◽  
Autosomal Dominant ◽  
Recent Literature ◽  
Subcutaneous Fat ◽  
Metabolic Abnormalities ◽  
Partial Lipodystrophy ◽  
Type 2 Dm ◽  
Familial Partial Lipodystrophy ◽  
Subcutaneous Adipose

Abstract Introduction: Familial partial lipodystrophy (FPLD) is a rare genetic disorder characterized by loss of subcutaneous adipose tissue, mainly from the extremities and gluteal region. FPLD is associated with a variety of metabolic abnormalities including severe hypertriglyceridemia (HTG), insulin resistance (IR), and hepatic steatosis. We present a case of FPLD and summarize recent literature on the metabolic features and their management in patients with this rare disease. Case: A 44 year old female with medical history of Type 2 DM, hypertension, hypothyroidism and recurrent pancreatitis from severe HTG was referred to our clinic. She was diagnosed with Type 2 DM in her 30s. Over the ensuing years she had significant IR requiring increasing doses of concentrated insulin (up to 250 units/day). She reported progressive loss of subcutaneous fat from extremities in the preceding 2–3 years. She had recurrent pancreatitis, including a recent hospitalization with TG>8000 mg/dL. On examination, she had typical features of FPLD including loss of subcutaneous adipose tissue from upper and lower extremities including gluteal region, visible skeletal muscles and veins in the extremities, and neck and truncal obesity (Fig. 1). Family history was significant for similar physical and metabolic manifestations in her father and brother. For HTG, she is treated with fibrates and high intensity statin. We avoided the use of fish oil in the patient, because she did not feel well when she was previously on this. Results of the genetic testing are pending. Discussion: FPLD is rare, predominantly autosomal dominant, disorder characterized phenotypically by variable loss of subcutaneous fat and metabolically by severe HTG and insulin resistance. The severity of metabolic derangements is proportional to the degree of the lipodystrophy. The proposed mechanism is limited capacity of adipose tissue to store fat leading to ectopic fat deposition, lipotoxicity and vascular inflammation. Diagnosis is often clinical, especially the loss of subcutaneous fat in the extremities and signs of IR, and is confirmed by genetic testing. Dunnigan syndrome is the most common type of FPLD, which occurs from an autosomal dominant missense mutation in lamin A/C (LMNA). Gene mutations encoding for PPAR-gamma, Akt2, CIDEC, perilipin and the ZMPSTE 24 enzyme are much less common. Treatment of FPLD is challenging, and mostly focuses on managing the metabolic abnormalities. Recent evidence suggests that fish oil may in fact worsen HTG when the main defect driving increased TG is impaired chylomicron clearance, which our patient had on lipid NMR profile. Metreleptin, a human leptin analog, has recently been approved for the management of FPLD with evidence of improved metabolic abnormalities. Recent data also suggests that GLP1 agonists and SGLT2 inhibitors improved glycemic control and reduced daily insulin requirements.

A genome-wide linkage scan for familial partial lipodystrophy susceptibility genes in a German kindreds

2007 ◽  
Vol 30 (4) ◽  
pp. 86
Author(s):  
M. Lanktree ◽  
J. Robinson ◽  
J. Creider ◽  
H. Cao ◽  
D. Carter ◽  
...  
Keyword(s):  
Subcutaneous Fat ◽  
Visceral Obesity ◽  
Fat Distribution ◽  
Dominant Negative ◽  
Molecular Forms ◽  
Partial Lipodystrophy ◽  
Genome Wide ◽  
A Genome ◽  
Familial Partial Lipodystrophy ◽  
Promoter Mutations

Background: In Dunnigan-type familial partial lipodystrophy (FPLD) patients are born with normal fat distribution, but subcutaneous fat from extremities and gluteal regions are lost during puberty. The abnormal fat distribution leads to the development of metabolic syndrome (MetS), a cluster of phenotypes including hyperglycemia, dyslipidemia, hypertension, and visceral obesity. The study of FPLD as a monogenic model of MetS may uncover genetic risk factors of the common MetS which affects ~30% of adult North Americans. Two molecular forms of FPLD have been identified including FPLD2, resulting from heterozygous mutations in the LMNA gene, and FPLD3, resulting from both heterozygous dominant negative and haploinsufficiency mutations in the PPARG gene. However, many patients with clinically diagnosed FPLD have no mutation in either LMNA or PPARG, suggesting the involvement of additional genes in FPLD etiology. Methods: Here, we report the results of an Affymetrix 10K GeneChip microarray genome-wide linkage analysis study of a German kindred displaying the FPLD phenotype and no known lipodystrophy-causing mutations. Results: The investigation identified three chromosomal loci, namely 1q, 3p, and 9q, with non-parametric logarithm of odds (NPL) scores >2.7. While not meeting the criteria for genome-wide significance, it is interesting to note that the 1q and 3p peaks contain the LMNA and PPARG genes respectively. Conclusions: Three possible conclusions can be drawn from these results: 1) the peaks identified are spurious findings, 2) additional genes physically close to LMNA, PPARG, or within 9q, are involved in FPLD etiology, or 3) alternative disease causing mechanisms not identified by standard exon sequencing approaches, such as promoter mutations, alternative splicing, or epigenetics, are also responsible for FPLD.

Myotonic Dystrophy

2018 ◽  
Author(s):  
Andrea Johnson
Keyword(s):  
Skeletal Muscle ◽  
Cognitive Impairment ◽  
Sleep Apnea ◽  
Myotonic Dystrophy ◽  
Pediatric Patients ◽  
Autosomal Dominant ◽  
Anesthetic Management ◽  
Cardiac Conduction ◽  
Autosomal Dominant Disorder ◽  
Skeletal Muscle Weakness

Myotonic dystrophy (DM) is a multisystemic autosomal dominant disorder. Individuals may present with symptoms at any age, but pediatric patients typically will present before 10 years of age. The clinical features of DM differ depending on the type of dystrophy and include skeletal muscle weakness, myotonia, sleep apnea, decreased gastrointestinal motility, insulin hypersecretion, cardiac conduction abnormalities, and occasionally cognitive impairment. Anesthetic management of the patient with DM should begin in the preoperative arena and should take into account the postoperative considerations and concerns for the patient with DM. This chapter will help the clinician develop an appropriate anesthetic plan and implement a safe and effective perioperative experience.

scholarly journals Inhibition of Angiopoietin-Like 3 (ANGPTL3) Reduces Adipose Tissue Insulin Resistance in Patients With Familial Partial Lipodystrophy

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A50-A51
Author(s):  
Maria Cristina Foss de Freitas ◽  
Baris Akinci ◽  
Adam Neidert ◽  
Rita Hench ◽  
Elif A Oral
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Body Fat ◽  
Fat Mass ◽  
Subcutaneous Fat ◽  
Hormonal Changes ◽  
Loss Of Function ◽  
Partial Lipodystrophy ◽  
Number Of Patients ◽  
Familial Partial Lipodystrophy

Abstract Familial partial lipodystrophy (FPLD) is a rare disease characterized by selective loss of peripheral subcutaneous fat, usually affecting the trunk and limbs, but preservation in other areas, such as the face and neck. It is usually associated with dyslipidemia and diabetes mellitus, and currently, there are no approved specific therapies for this disease in the US. Reductions in circulating levels of ANGPTL3 either by homologous loss-of-function mutations in humans or by pharmacological inhibition in rodents are associated with reductions in triglyceride (and other atherogenic lipid) levels and protect from atherosclerosis, making it an attractive target for patients with FPLD and metabolic dyslipidemia. We performed a proof-of-concept study to assess the early efficacy and safety of targeting ANGPTL3 via antisense oligonucleotide ISIS-703802 (vupanorsen) in a small number of patients with FPLD. Four patients with FPLD (3F/1M; age range: 39–48; 1 with LMNA R482Q, 1 with LMNA R584H, and 2 with no causative genetic variant), diabetes (HbA1c>6.5%) and hypertriglyceridemia (>250 mg/dL at screening) were included. Patients received the study drug at a subcutaneous dose of 20 mg weekly for 26 weeks. The primary endpoint was the change in triglycerides at week 27. Other end-points of interest measured at the same time points included insulin secretion, sensitivity, lipid and hormonal changes in response to a 5 hour long mixed meal test and body composition measured by dual energy absorptiometry (DEXA). Treatment resulted in a 59.9±26.3 (mean±SD) % of reduction in triglycerides, 54.7±9.8% of reduction in serum ANGPTL3 levels and 50.8±27.4% of reduction in ApoCIII. Treatment with vupanorsen led to a reduction of 209.3±120.4 in adipose tissue insulin resistance (ADIPO-IR) from a baseline of 470.3±114.3 and the area under the curve (AUC) for circulating free fatty acid levels were decreased by 32.1±21.4 mmol/L/min from a baseline of 215.8±55.2 mmol/L/min. Glucose AUC and triglyceride AUC also decreased after treatment (-14.0±5.2 and -60.1±26.5 mg/dL/min, respectively). Analyzing body fat distribution using DEXA, we observed that the fat mass index (FMI) and trunk mass index (TMI) did not change from baseline, but the ratio of total fat mass/ fat mass from limbs decreased by 10.7±12.2. These data show a tendency for redistribution of central body fat to limbs. There were numerous adverse events observed that were related to common serious complications associated with diabetes and FPLD. Although limited, these results suggest that targeting ANGPTL3 with vupanorsen in patients with FPLD may have a therapeutic role by addressing multiple problems.

scholarly journals SUN-556 Cardiac Phenotype in Familial Partial Lipodystrophy

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Abdelwahab Jalal Eldin ◽  
Baris Akinci ◽  
Andre Monteiro da Rocha ◽  
Rasimcan Meral ◽  
Ilgin Yildirim Simsir ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Stem Cell ◽  
Action Potential Duration ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Conduction System ◽  
Partial Lipodystrophy ◽  
Pathogenic Variants ◽  
Familial Partial Lipodystrophy ◽  
Induced Pluripotent

Abstract Background Pathogenic variants in Lamin A/C (LMNA) gene are the most common monogenic etiology in Familial Partial Lipodystrophy (FPLD) causing FPLD2. LMNA pathogenic variants have been previously associated with cardiomyopathy, familial arrhythmias or conduction system abnormalities independent of lipodystrophy. We aimed to assess cardiac impacts of FPLD, and to explore the extent of overlap between cardiolaminopathies and FPLD. Methods We conducted a retrospective review of an established cohort of 122 patients (age range: 13-77, M/F 21/101) with FPLD from Michigan (n = 83) and Turkey (n = 39) with an accessible cardiac evaluation. Also, functional syncytia of mature human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a FLPD2 patient was studied for assessment of autonomous rhythm and action potential duration with optical mapping using a voltage sensitive dye. Results In the whole study cohort, 95 (78%) patients had cardiac alterations (25% ischemic heart disease, 36% arrhythmia, 16% conduction abnormality, 20% prolonged QT interval, 11% cardiomyopathy, and 15% congestive heart failure). The likelihood of having an arrhythmia (OR; 3.95, 95% CI: 1.49-10.49) and conduction disease (OR: 3.324, 95% CI: 1.33-8.31) was significantly higher in patients with LMNA pathogenic variants. Patients with LMNA pathogenic variants were at high risk for atrial fibrillation/flutter (OR: 6.77, 95% CI: 1.27- 39.18). The time to first arrhythmia was significantly shorter in the LMNA group with a higher hazard rate of 3.04 (95% CI: 1.29-7.17, p = 0.032). Non-482 LMNA pathogenic variants were more likely to be associated with cardiac events (vs. 482 LMNA: OR: 4.74, 95% CI: 1.41- 15.98 for arrhythmia; OR: 17.67, 95% CI: 2.44- 127.68 for atrial fibrillation/flutter; OR: 5.71, 95% CI: 1.37- 23.76 for conduction disease. hiPSC-CMs from a FPLD2 patient had higher frequency of autonomous activity, and shorter Fridericia corrected action potential duration at 80% repolarization compared to control cardiomyocytes. Furthermore, FPLD2 functional syncytia of mature hiPSC-CMs presented several rhythm alterations such as early after-depolarizations, spontaneous quiescence and spontaneous tachyarrhythmia; none of those were observed in the control cell lines. Finally, FPLD2 hiPSC-CMs presented significantly slower recovery in chronotropic changes induced by isoproterenol exposure; which indicates disrupted beta-adrenergic response. Conclusion Our results suggest the need for vigilant cardiac monitoring in FPLD, especially in patients with FPLD2 who have an increased risk to develop cardiac arrhythmias and conduction system diseases. In addition, study of human induced pluripotent stem cell-derived cardiomyocytes may prove useful to understand the mechanism of cardiac disease and arrhythmias and to create precision therapy opportunities in the future.

scholarly journals Selective targeting of angiopoietin-like 3 (ANGPTL3) with vupanorsen for the treatment of patients with familial partial lipodystrophy (FPLD): results of a proof-of-concept study

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Maria C. Foss-Freitas ◽  
Baris Akinci ◽  
Adam Neidert ◽  
Victoria J. Bartlett ◽  
Eunju Hurh ◽  
...  
Keyword(s):  
Subcutaneous Fat ◽  
Area Under The Curve ◽  
Density Lipoprotein ◽  
Resistance Index ◽  
Lipoprotein Cholesterol ◽  
Proof Of Concept ◽  
Open Label ◽  
Partial Lipodystrophy ◽  
Concept Study ◽  
Familial Partial Lipodystrophy

Abstract Background Familial partial lipodystrophy (FPLD) is a rare disease characterized by selective loss of peripheral subcutaneous fat, associated with dyslipidemia and diabetes mellitus. Reductions in circulating levels of ANGPTL3 are associated with lower triglyceride and other atherogenic lipids, making it an attractive target for treatment of FPLD patients. This proof-of-concept study was conducted to assess the efficacy and safety of targeting ANGPTL3 with vupanorsen in patients with FPLD. Methods This was an open-label study. Four patients with FPLD (two with pathogenic variants in LMNA gene, and two with no causative genetic variant), diabetes (HbA1c ≥ 7.0 % and ≤ 12 %), hypertriglyceridemia (≥ 500 mg/dL), and hepatic steatosis (hepatic fat fraction, HFF ≥ 6.4 %) were included. Patients received vupanorsen subcutaneously at a dose of 20 mg weekly for 26 weeks. The primary endpoint was the percent change from baseline in fasting triglycerides at Week 27. Other endpoints analyzed at the same time point included changes in ANGPTL3, fasting lipids and lipoproteins, insulin secretion/sensitivity, postprandial lipids, and glycemic changes in response to a mixed meal test, HFF measured by MRI, and body composition measured by dual-energy absorptiometry (DEXA). Results Baseline mean ± SD fasting triglyceride level was 9.24 ± 4.9 mmol/L (817.8 ± 431.9 mg/dL). Treatment resulted in reduction in fasting levels of triglycerides by 59.9 %, ANGPTL3 by 54.7 %, and in several other lipoproteins/lipids, including very low-density lipoprotein cholesterol by 53.5 %, non-high-density lipoprotein cholesterol by 20.9 %, and free fatty acids (FFA) by 41.7 %. The area under the curve for postprandial triglycerides, FFA, and glucose was reduced by 60 %, 32 %, and 14 %, respectively. Treatment with vupanorsen also resulted in 55 % reduction in adipose tissue insulin resistance index, while other insulin sensitivity indices and HbA1c levels were not changed. Additional investigations into HFF and DEXA parameters suggested dynamic changes in fat partitioning during treatment. Adverse events observed were related to common serious complications associated with diabetes and FPLD. Vupanorsen was well tolerated, and there was no effect on platelet count. Conclusions Although limited, these results suggest that targeting ANGPTL3 with vupanorsen could address several metabolic abnormalities in patients with FPLD.

scholarly journals Diagnostic Challenge in PLIN1-Associated Familial Partial Lipodystrophy

2019 ◽  
Vol 104 (12) ◽  
pp. 6025-6032 ◽  
Author(s):  
Isabelle Jéru ◽  
Marie-Christine Vantyghem ◽  
Elise Bismuth ◽  
Pascale Cervera ◽  
Sara Barraud ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Polycystic Ovary ◽  
Liver Steatosis ◽  
Subcutaneous Fat ◽  
Diagnostic Challenge ◽  
Metabolic Complications ◽  
Partial Lipodystrophy ◽  
Patients With Diabetes ◽  
Familial Partial Lipodystrophy ◽  
Center For Rare Diseases

Abstract Context Heterozygous frameshift variants in PLIN1 encoding perilipin-1, a key protein for lipid droplet formation and triglyceride metabolism, have been implicated in familial partial lipodystrophy type 4 (FPLD4), a rare entity with only six families reported worldwide. The pathogenicity of other PLIN1 null variants identified in patients with diabetes and/or hyperinsulinemia was recently questioned because of the absence of lipodystrophy in these individuals and the elevated frequency of PLIN1 null variants in the general population. Objectives To reevaluate the pathogenicity of PLIN1 frameshift variants owing to new data obtained in the largest series of patients with FPLD4. Methods We performed histological and molecular studies for patients referred to our French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity for lipodystrophy and/or insulin resistance and carrying PLIN1 frameshift variants. Results We identified two heterozygous PLIN1 frameshift variants segregating with the phenotype in nine patients from four unrelated families. The FPLD4 stereotypical signs included postpubertal partial lipoatrophy of variable severity, muscular hypertrophy, acromegaloid features, polycystic ovary syndrome and/or hirsutism, metabolic complications (e.g., hypertriglyceridemia, liver steatosis, insulin resistance, diabetes), and disorganized subcutaneous fat lobules with fibrosis and macrophage infiltration. Conclusions These data suggest that some FPLD4-associated PLIN1 variants are deleterious. Thus, the evidence for the pathogenicity of each variant ought to be carefully considered before genetic counseling, especially given the importance of an early diagnosis for optimal disease management. Thus, we recommend detailed familial investigation, adipose tissue-focused examination, and follow-up of metabolic evolution.

Lamins and metabolism

2016 ◽  
Vol 131 (2) ◽  
pp. 105-111 ◽  
Author(s):  
Chayki Charar ◽  
Yosef Gruenbaum
Keyword(s):  
Cell Cycle Progression ◽  
Autosomal Dominant ◽  
Metabolic Diseases ◽  
Cell Metabolism ◽  
Accelerated Aging ◽  
Partial Lipodystrophy ◽  
The Metabolic Syndrome ◽  
Familial Partial Lipodystrophy ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Lamins are nuclear intermediate filaments (IFs) with important roles in most nuclear activities, including nuclear organization and cell-cycle progression. Mutations in human lamins cause over 17 different diseases, termed laminopathies. Most of these diseases are autosomal dominant and can be roughly divided into four major groups: muscle diseases, peripheral neuronal diseases, accelerated aging disorders and metabolic diseases including Dunnigan type familial partial lipodystrophy (FLPD), acquired partial lipodystrophy (APL) and autosomal dominant leucodystrophy. Mutations in lamins are also associated with the metabolic syndrome (MS). Cells derived from patients suffering from metabolic laminopathies, as well as cells derived from the corresponding animal models, show a disruption of the mechanistic target of rapamycin (mTOR) pathway, abnormal autophagy, altered proliferative rate and down-regulation of genes that regulate adipogenesis. In addition, treating Hutchinson–Gilford progeria syndrome (HGPS) cells with the mTOR inhibitor rapamycin improves their fate. In this review, we will discuss the ways by which lamin genes are involved in the regulation of cell metabolism.

scholarly journals Challenges in Managing Metabolic Complications in a Patient With Familial Partial Lipodystrophy Type 3

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A307-A308
Author(s):  
Kajal Shah ◽  
Marina Charitou
Keyword(s):  
Insulin Resistance ◽  
Subcutaneous Fat ◽  
Peroxisome Proliferator ◽  
Metabolic Complications ◽  
Peroxisome Proliferator Activated Receptor ◽  
Partial Lipodystrophy ◽  
Familial Partial Lipodystrophy ◽  
Type 3 ◽  
Pparγ Gene

Abstract Familial partial lipodystrophy (FPL) is a rare group of autosomal dominant genetic disorders which causes variable loss of subcutaneous fat from abdomen, thorax or extremities in addition to the numerous metabolic complications like insulin resistance, diabetes mellitus and dyslipidemia1. FPL type 3 was first characterized by Agarwal et al. in 20021, in which peroxisome proliferator-activated receptor-γ (PPARγ) gene was the molecular basis of this disorder. It is extremely rare and so far only 30 patients or so have been recognized with this mutation2. FPL3 is unique because it generally spares the loss of fat from trunk, face and neck region and also presents with more severe metabolic derangements. We report a case of a young female with PPARγ mutation leading to numerous metabolic complications. A 19 year old female with FPL3 was seen by adult endocrinology as a transition from pediatric endocrinology. She was found to have hypertriglyceridemia on routine labs done at the age of 11. Patient reported loss of subcutaneous fat from her extremities and eruptive xanthoma on flexor surfaces at the time of diagnosis along with a positive family history of hypertriglyceridemia induced pancreatitis and Myocardial infarction at the age of 40 in her father. Her triglyceride level has varied between 600 and 3000 (normal 20–149 mg/dl) over the years. FPL3 was diagnosed based on genetic testing. She was prescribed fenofibrate and fish oil, and statin was added thereafter. She developed type 2 diabetes and was started on metformin and pioglitazone. She was noted to have hypertension and was treated with amlodipine and lisinopril. She also was found to have Polycystic Ovarian Syndrome (PCOS) based on menstrual irregularities, hirsutism and ultrasound showing multiple ovarian cysts, and was treated with spironolactone. Her most recent labs show triglyceride level of 2400 mg/dl and HbA1c of 8.3. PPARγ gene mutation in FPL3 leads to insulin resistance and hence patients often develop hypertriglyceridemia, type 2 diabetes, PCOS and hypertension. In terms of treatment options, we are still limited to pioglitazone, metformin, statins and fish oil. Often these are not sufficient in addressing the complexity of metabolic derangements in these patients who have an increased risk of cardiovascular events at a young age. Further research about agents targeting this gene in particular would be beneficial. 1. Agarwal et al. A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab. 2002 Jan; 87(1):408–411. 2. Garg A. Lipodystrophies: Genetic and Acquired Body Fat Disorders. J Clin Endocrinol Metab. 2011;96(11): 3313–3325.

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