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.

Differences of Subcutaneous Adipose Tissue Topography Between Type-2 Diabetic Men and Healthy Controls

2002 ◽  
Vol 227 (9) ◽  
pp. 794-798 ◽  
Author(s):  
Renate Horejsi ◽  
Reinhard Möller ◽  
Thomas R. Pieber ◽  
Sandra Wallner ◽  
Karl Sudi ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Body Fat ◽  
Subcutaneous Adipose Tissue ◽  
Subcutaneous Fat ◽  
Fat Distribution ◽  
Body Fat Distribution ◽  
Healthy Controls ◽  
Type 2 Dm ◽  
Subcutaneous Adipose

Men with noninsulin-dependent diabetes mellitus (type 2 DM) provide a different subcutaneous body fat distribution and a concentration of fatness on the upper trunk compared with healthy subjects. However, subcutaneous fat distribution is always measured in an inaccurate and/or very simplified way (e.g., by caliper), and to date, there exists no study reporting on the exact and complete subcutaneous adipose tissue distribution of type 2 DM men. A new optical device, the LIPOMETER, enables the nonivasive, quick, and safe determination of the thickness of subcutaneous adipose tissue layers at any given site of the human body. The specification of 15 evenly distributed body sites allows the precise measurement of subcutaneous body fat distribution, so-called subcutaneous adipose tissue topography (SAT-Top). SAT-Tops of 21 men with clinically proven type 2 DM (mean age of 57.5 ± 6.7 years) and 111 healthy controls of similar age (mean age 59.0 ± 5.4 years) were measured. In this paper, we describe the precise SAT-Top differences of these two groups and we present the multidimensional SAT-Top information condensed in a two-dimensional factor value plot. In type 2 DM men, especially in the upper trunk, SAT-Top is significantly increased (up to +50.7% at the neck) compared with their healthy controls. One hundred eleven of the 132 individuals (84.1%) are correctly classified (healthy or type 2 DM) by their subcutaneous fat pattern by stepwise discriminant analysis.

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 Familial partial lipodystrophy and proteinuric renal disease due to a missense c.1045C > T LMNA mutation

2017 ◽  
Vol 2017 ◽  
Author(s):  
Athanasios Fountas ◽  
Zoe Giotaki ◽  
Evangelia Dounousi ◽  
George Liapis ◽  
Alexandra Bargiota ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Renal Disease ◽  
Subcutaneous Adipose Tissue ◽  
Lower Limbs ◽  
List Type ◽  
Partial Loss ◽  
Partial Lipodystrophy ◽  
Familial Partial Lipodystrophy ◽  
Subcutaneous Adipose ◽  
Proteinuric Renal Disease

Summary Proteinuric renal disease is prevalent in congenital or acquired forms of generalized lipodystrophy. In contrast, an association between familial partial lipodystrophy (FPLD) and renal disease has been documented in very few cases. A 22-year-old female patient presented with impaired glucose tolerance, hyperinsulinemia, hirsutism and oligomenorrhea. On examination, there was partial loss of subcutaneous adipose tissue in the face, upper and lower limbs, bird-like facies with micrognathia and low set ears and mild acanthosis nigricans. Laboratory investigations revealed hyperandrogenism, hyperlipidemia, elevated serum creatine kinase and mild proteinuria. A clinical diagnosis of FPLD of the non-Dunnigan variety was made; genetic testing revealed a heterozygous c.1045C > T mutation in exon 6 of the LMNA gene, predicted to result in an abnormal LMNA protein (p.R349W). Electromyography and muscle biopsy were suggestive of non-specific myopathy. Treatment with metformin and later with pioglitazone was initiated. Due to worsening proteinuria, a renal biopsy was performed; histological findings were consistent with mild focal glomerular mesangioproliferative changes, and the patient was started on angiotensin-converting enzyme inhibitor therapy. This is the fourth report of FPLD associated with the c.1045C > T missense LMNA mutation and the second with co-existent proteinuric renal disease. Patients carrying this specific mutation may exhibit a phenotype that includes partial lipodystrophy, proteinuric nephropathy, cardiomyopathy and atypical myopathy. Learning points: Lipodystrophy is a rare disorder characterized by the complete or partial loss of subcutaneous adipose tissue, insulin resistance, diabetes mellitus and hyperlipidemia. Proteinuric renal disease is a prevalent feature of generalized lipodystrophy but rare in familial partial lipodystrophy. Patients carrying the c.1045C > T missense LMNA mutation (p.R349W) may present with familial partial lipodystrophy, proteinuric nephropathy, cardiomyopathy and atypical myopathy.

scholarly journals Variable Expressivity in Type 2 Familial Partial Lipodystrophy Related to R482 and N466 Variants in the LMNA Gene

2021 ◽  
Vol 10 (6) ◽  
pp. 1259
Author(s):  
David Araújo-Vilar ◽  
Sofía Sánchez-Iglesias ◽  
Ana I. Castro ◽  
Silvia Cobelo-Gómez ◽  
Álvaro Hermida-Ameijeiras ◽  
...  
Keyword(s):  
Body Composition ◽  
Skinfold Thickness ◽  
Pathogenic Variant ◽  
The Other ◽  
Metabolic Abnormalities ◽  
Lmna Gene ◽  
Partial Lipodystrophy ◽  
Variable Expressivity ◽  
Familial Partial Lipodystrophy

Patients with Dunnigan disease (FPLD2) with a pathogenic variant affecting exon 8 of the LMNA gene are considered to have the classic disease, whereas those with variants in other exons manifest the “atypical” disease. The aim of this study was to investigate the degree of variable expressivity when comparing patients carrying the R482 and N466 variants in exon 8. Thus, 47 subjects with FPLD2 were studied: one group of 15 patients carrying the N466 variant and the other group of 32 patients with the R482 variant. Clinical, metabolic, and body composition data were compared between both groups. The thigh skinfold thickness was significantly decreased in the R482 group in comparison with the N466 group (4.2 ± 1.8 and 5.6 ± 2.0 mm, respectively, p = 0.002), with no other differences in body composition. Patients with the N466 variant showed higher triglyceride levels (177.5 [56–1937] vs. 130.0 [55–505] mg/dL, p = 0.029) and acute pancreatitis was only present in these subjects (20%). Other classic metabolic abnormalities related with the disease were present regardless of the pathogenic variant. Thus, although FPLD2 patients with the R482 and N466 variants share most of the classic characteristics, some phenotypic and metabolic differences suggest possible heterogeneity even within exon 8 of the LMNA gene.

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.

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.

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