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The impact of core 1,3-galactosyltransferase-specific molecular chaperon (COSMC) gene expression and methylation profile on clinical progression of IgA nephropathy (IgAN) is unclear. The aim of this study was to determine the clinical significance and the relation of the COSMC gene expression and methylation pattern with the progression of IgAN.Thirty-nine biopsy-confirmed IgAN patients, 11 healthy relatives and 20 healthy controls were recruited. The COSMC mRNA levels and methylation profile of COSMC gene promoter were measured using the quantitative real-time PCR. The galactose-deficient IgA1 (Gd-IgA1) levels were measured using ELISA in serum and cell culture supernatant. The effect of IL-4 and AZA on COSMC expression and methylation and the correlation of COSMC gene expression and methylation levels with baseline kidney function tests, histology and long-term outcomes were examined.The mean COSMC mRNA level was significantly lower, and serum Gd-IgA1 level was higher in IgAN patients compared with the control groups (p 0.001, and p = 0.001, respectively). The COSMC mRNA levels were correlated with intensity of hematuria (r = - 0.41, p = 0.009), serum creatinine level (r = - 0.37, p = 0.002) and eGFR (r = 0.36, p = 0.002). The COSMC methylation levels were correlated with age (r = 0.25, p = 0.04) and baseline eGFR (r = - 0.326, p = 0.006). Twenty IgAN patients (51.3%) reached to complete (5, 12.8%) or partial remission (15, 38.5%) after a median of 34.5 months (IQR, 13.75-71). In multivariable Cox regression analysis, COSMC mRNA expression (adjusted HR (aHR) 1.871, 95% CI 1.287-2.722, p = 0.001) and Oxford T score (aHR 0.355, 95% CI 0.146-0.859, p = 0.022) predicted the remission.COSMC mRNA level is a novel biomarker candidate to predict the remission in IgAN patients.

Context Leptin replacement with metreleptin improves glycemia and hypertriglyceridemia in severely hypoleptinemic patients with generalized lipodystrophy (GLD), but its effects are variable in partially leptin-deficient patients with partial lipodystrophy (PLD). Objective Compare 3 leptin assays (Study I); identify diagnostic performance of leptin assays to detect responders to metreleptin for each assay (Study II). Design Study I: cross-sectional analysis of average bias between leptin assays. Study II: retrospective analysis of diagnostic accuracy of potential leptin cut points to detect clinical responders to metreleptin. Setting National Institutes of Health; University of Michigan. Participants and Interventions Study I: Metreleptin-naïve patients with lipodystrophy (GLD, n = 33, PLD, n = 67) and healthy volunteers (n = 239). Study II: GLD (n = 66) and PLD (n = 84) patients treated with metreleptin for 12 months. Outcome Measures Leptin concentrations by Millipore radioimmunoassay (RIA), Millipore enzyme-linked immunosorbent assay (MELISA), and R&D Systems enzyme-linked immunosorbent assay (RDELISA). Response to metreleptin therapy was defined as either reduction ≥1.0% in A1c or ≥30% in serum triglycerides. Results RDELISA measured 3.0 ± 9.5 ng/mL higher than RIA; MELISA measured 11.0 ± 17.8 and 14.0 ±19.2 less than RIA and RDELISA, respectively. Leptin by RIA, MELISA, and RDELISA modestly predicted metreleptin response in GLD + PLD [receiver operating characteristic (ROC) area under the curve (AUC) 0.74, 0.69, and 0.71, respectively; P < 0.01 for all] with lower predictive power in PLD (ROC AUC 0.63, 0.61 and 0.65, respectively; P > 0.05 for all). The only reproducible cut point identified on sensitivity analyses was RIA leptin 7.2 ng/mL (sensitivity 56%; specificity 78%). Conclusions Three common leptin assays are not interchangeable, and a reliable cut point to select responders to metreleptin was not identified.

OBJECTIVE This study aimed to investigate the shortcoming of BMI as a measurement of adiposity in patients with familial partial lipodystrophy (FPLD). METHODS Two different matching procedures were used to compare 55 FPLD versus control patients with severe obesity (N = 548 patients) to study the relationship between body weight, fat distribution, and metabolic diseases, such as diabetes mellitus, hypertriglyceridemia, and nonalcoholic steatohepatitis. In MATCH1, the patients with FPLD were matched to controls with obesity (OCs) by truncal mass, and in MATCH2, the patients with FPLD were matched to OCs with respect to glucose control. RESULTS With MATCH1, the FPLD group had worse glycemic control (hemoglobin A1c 8.2% ± 1.6% vs. 5.9% ± 0.9%), higher triglycerides (884 ± 1,190 mg/dL vs. 139 ± 79 mg/dL), and lower leptin (20.5 ± 15.8 ng/mL vs. 41.9 ± 29.4 ng/mL, P

Objectives LMNA variants have been previously associated with cardiac abnormalities independent of lipodystrophy. We aimed to assess cardiac impact of familial partial lipodystrophy (FPLD) to understand the role of laminopathy in cardiac manifestations. Study design Retrospective cohort study. Methods Clinical data from 122 patients (age range: 13-77, 101 females) with FPLD were analysed. Mature human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with an LMNA variant were studied as proof-of-concept for future studies. Results Subjects with LMNA variants had a higher prevalence of overall cardiac events than others. The likelihood of having an arrhythmia was significantly higher in patients with LMNA variants (OR: 3.77, 95% CI: 1.45-9.83). These patients were at higher risk for atrial fibrillation or flutter (OR: 5.78, 95% CI: 1.04-32.16). The time to the first arrhythmia was significantly shorter in the LMNA group, with a higher HR of 3.52 (95% CI: 1.34-9.27). Non-codon 482 LMNA 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: 2.45-127.68 for atrial fibrillation or flutter; OR: 5.71, 95% CI: 1.37-23.76 for conduction disease). LMNA mutant hiPSC-CMs showed a higher frequency of spontaneous activity and shorter action potential duration. Functional syncytia of hiPSC-CMs displayed several rhythm alterations such as early afterdepolarizations, spontaneous quiescence and spontaneous tachyarrhythmia, and significantly slower recovery in chronotropic changes induced by isoproterenol exposure. Conclusions Our results highlight the need for vigilant cardiac monitoring in FPLD, especially in patients with LMNA variants who have an increased risk of developing cardiac arrhythmias. in addition, hiPSC-CMs can be studied to understand the basic mechanisms for the arrhythmias in patients with lipodystrophy to understand the impact of specific mutations., NIH Clinical and Translational Science AwardsUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [UL1TR000433]; Nutrition Obesity Research Centers [P30 DK089503]; NIH institutional grantUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [DK034933]; White Point Foundation of Turkey; Morton S. and Henrietta K. Sellner Professorship in Human Genetics, Infrastructure and data management support has been provided by the NIH Clinical and Translational Science Awards grant UL1TR000433, the Nutrition Obesity Research Centers grant P30 DK089503, and NIH institutional grant DK034933. Finally, the work was supported by generous gifts to the Lipodystrophy Fund at the University of Michigan made by the Sopha family, and the White Point Foundation of Turkey. JWI acknowledges support from the Morton S. and Henrietta K. Sellner Professorship in Human Genetics.

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.

Background Lipodystrophy is a group of heterogeneous syndromes characterized by selective loss of adipose tissue and metabolic abnormalities. The severity of pain and its possible relation to measures of quality of life (OoL) and psychoemotional and metabolic health have never been studied in-depth previously. Methods LD-Lync study is an international multi-center study collecting data on the natural history of different lipodystrophy syndromes. We have completed phase 1 of the study where only a single site (University of Michigan) entered data (n = 79 patients, M/F: 16/63, mean age: 46.13 ± 14.60, 56 with familial partial lipodystrophy). In this study, we sought to investigate the relationship of pain perception on QoL, psychoemotional and metabolic aspects of the disease. Brief Pain Inventory (BPI) was used to calculate pain severity (BPI-SS) and pain interference scores (BPI-IS). Results From the 77 who completed the questionnaires, 56 (72.73%) patients reported pain at different levels. Out of the 56, 29 (51.79%) patients had moderate/severe pain (BPI-SS ≥ 4). Patients with moderate/severe pain had “more impaired” QoL scores: physical functioning: 20 (15-50) vs. 80 (45-95), p = 0.002; limitation to physical health: 0 (0-25) vs. 75 (0-100), p = 0.002; energy/fatigue 15 (10-30) vs. 45 (20-60), p = 0.032; emotional well-being: 48 (32-60) vs. 72 (48-84), p = 0.029; social functioning: 33 (20-38) vs. 58 (35-70), p = 0.002; general health: 15 (10-25) vs. 35 (20-55), p = 0.005). Severe depression (PHQ-9 > 14) was more frequently detected among patients with moderate/severe pain (63.2% vs. 36.9%, p = 0.008). PHQ-9 score measuring depression was positively correlated with BPI-SS (r = 0.53, p < 0.001), and BPI-IS (r = 0.63, p < 0.001). Emotional burden score was also higher in patients reporting moderate/severe pain (4.0 (2.6-5.0) vs. 2.7 (1.6-3.3), p = 0.015). BPI-SS/BPI-IS scores correlated positively with disease distress (r = 0.33, p < 0.001, and r = 0.31, p = 0.010) and GAD7 scores measuring anxiety (r = 0.52, p < 0.001, and r = 0.50, p < 0.001). Anxiety (GAD7 > 10) was more prevalent among patients with moderate/severe pain (58.6% vs. 23.4%, p = 0.002). The presence of diabetes was associated with higher BPI-SS scores: 3.50 (1.50-5.00) vs. 0 (0-3.25), p = 0.030). Also, patients with HbA1c > 6.5% exhibited higher BPI-SS scores than those with an HbA1c less than 6.5%: 3.38 (1.38-5.00) vs. 1.25 (0-3.50), p = 0.030). Conclusion Our study reveals a high frequency of pain perception among patients with different types of lipodystrophy. Pain severity contributes to worsening in QoL, affects physical and emotional function, and relates to psychoemotional state in patients with lipodystrophy. In addition, the presence of diabetes and higher HbA1c may potentially modulate pain in patients with lipodystrophy. Further work is needed to elucidate the pathways that regulate pain in these patients and to address it effectively.

Summary A patient with atypical partial lipodystrophy who had a transient initial response to metreleptin experienced acute worsening of her metabolic state when neutralizing antibodies against metreleptin appeared. Because her metabolic status continued to deteriorate, a therapeutic trial with melanocortin-4 receptor agonist setmelanotide, that is believed to function downstream from leptin receptor in the leptin signaling system, was undertaken in an effort to improve her metabolic status for the first time in a patient with lipodystrophy. To achieve this, a compassionate use (investigational new drug application; IND) was initiated (NCT03262610). Glucose control, body fat by dual-energy X-ray absorptiometry and MRI, and liver fat by proton density fat fraction were monitored. Daily hunger scores were assessed by patient filled questionnaires. Although there was a slight decrease in hunger scales and visceral fat, stimulating melanocortin-4 receptor by setmelanotide did not result in any other metabolic benefit such as improvement of hypertriglyceridemia or diabetes control as desired. Targeting melanocortin-4 receptor to regulate energy metabolism in this setting was not sufficient to obtain a significant metabolic benefit. However, complex features of our case make it difficult to generalize these observations to all cases of lipodystrophy. It is still possible that melanocortin-4 receptor agonistic action may offer some therapeutic benefits in leptin-deficient patients. Learning points: A patient with atypical lipodystrophy with an initial benefit with metreleptin therapy developed neutralizing antibodies to metreleptin (Nab-leptin), which led to substantial worsening in metabolic control. The neutralizing activity in her serum persisted for longer than 3 years. Whether the worsening in her metabolic state was truly caused by the development of Nab-leptin cannot be fully ascertained, but there was a temporal relationship. The experience noted in our patient at least raises the possibility for concern for substantial metabolic worsening upon emergence and persistence of Nab-leptin. Further studies of cases where Nab-leptin is detected and better assay systems to detect and characterize Nab-leptin are needed. The use of setmelanotide, a selective MC4R agonist targeting specific neurons downstream from the leptin receptor activation, was not effective in restoring metabolic control in this complex patient with presumed diminished leptin action due to Nab-leptin. Although stimulating the MC4R pathway was not sufficient to obtain a significant metabolic benefit in lowering triglycerides and helping with her insulin resistance as was noted with metreleptin earlier, there was a mild reduction in reported food intake and appetite. Complex features of our case make it difficult to generalize our observation to all leptin-deficient patients. It is possible that some leptin-deficient patients (especially those who need primarily control of food intake) may still theoretically benefit from MC4R agonistic action, and further studies in carefully selected patients may help to tease out the differential pathways of metabolic regulation by the complex network of leptin signaling system.

Objective Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Renin-angiotensin-aldosterone-system (RAAS) inhibitors may increase the expression of angiotensin-converting enzyme 2, which is the receptor for SARSCoV-2 Spike protein. The consequences of using angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) during the COVID-19 pandemic are unknown. Methods A retrospective cohort study aiming to identify the odds of severe disease (defined as either hospitalization of ≥14 days, admission to the intensive care unit, or death) associated with exposure to ACEi or ARB was conducted. Adult patients (age ≥18 years) with COVID-19 admitted to the Istanbul Faculty of Medicine Corona Center between March 9 and May 11, 2020, were included. Chronic users of ACEi, ARB, or other antihypertensive drugs were matched according to age, sex, sick days before hospitalization, comorbidities, smoking, number of antihypertensive regimens, doxazosin use, furosemide use, and serum creatinine level. Odds ratios (OR) of having severe disease were calculated. Results In total, 611 patients were admitted with COVID-19, confirmed by either reverse-transcriptase polymerase chain reaction or computed tomography (CT). There were 363 males, and the age ranged from 18 to 98 years, with an average age of 57±15 years. Of these, 165 participants had severe disease (53 deaths, case fatality rate: 8.7%). Among those with hypertension (n=249), ARB exposure was compatible with decreased odds (OR=0.60, 95% CI: 0.27-1.36, p=0.31) of severe disease though not statistically significant, while ACEi exposure significantly reduced the risk of severe disease (OR=0.37, 95% CI: 0.15-0.87, p=0.03). ACEi exposure was associated with milder infiltrations seen on baseline CT, lower C-reactive protein and ferritin, higher monocytes, shorter hospitalization, and less requirement for specific empirical treatments (favipiravir and meropenem). Conclusion Our data suggest that exposure to ACEi drugs may have favorable effects in the context of COVID-19 pneumonia.

OBJECTIVE Lipodystrophy syndromes are a heterogeneous group of disorders associated with selective absence of fat. Currently, the diagnosis is established only clinically. RESEARCH DESIGN AND METHODS We developed a new method from DXA scans called a “fat shadow,” which is a color-coded representation highlighting only the fat tissue. We conducted a blinded retrospective validation study to assess its usefulness for the diagnosis of lipodystrophy syndromes. RESULTS We evaluated the fat shadows from 16 patients (11 female and 5 male) with generalized lipodystrophy (GL), 57 (50 female and 7 male) with familial partial lipodystrophy (FPLD), 2 (1 female and 1 male) with acquired partial lipodystrophy, and 126 (90 female and 36 male) control subjects. FPLD was differentiated from control subjects with 85% sensitivity and 96% specificity (95% CIs 72–93 and 91–99, respectively). GL was differentiated from nonobese control subjects with 100% sensitivity and specificity (95% CIs 79–100 and 92–100, respectively). CONCLUSIONS Fat shadows provided sufficient qualitative information to infer clinical phenotype and differentiate these patients from appropriate control subjects. We propose that this method could be used to support the diagnosis.

BACKGROUND: Sleeve gastrectomy (LSG) is now the predominant bariatric surgery performed yet there is limited long-term data comparing important outcomes between LSG and Roux-en-Y gastric bypass (RYGB). This study compares weight loss and impact on comorbidities of the two procedures. METHODS: We retrospectively evaluated weight, blood pressure, hemoglobin A1c, cholesterol, and medication use for hypertension, diabetes, and hyperlipidemia at 1–4 years post-operatively in 380 patients who underwent RYGB and 334 patients who underwent LSG at the University of Michigan from January 2008 to November 2013. Follow-up rates from 714 patients initially were 657 (92%), 556 (78%), 507 (71%), and 498 (70%) at 1–4 years post-operatively. RESULTS: Baseline characteristics were similar except for higher weight and BMI in LSG. There was greater weight loss with RYGB versus LSG at all points. Hemoglobin A1c and total cholesterol improved more in RYGB versus LSG at four years. There was greater remission of hypertension and discontinuation of all medications for hypertension and diabetes with RYGB at four years. CONCLUSIONS: Weight loss, reduction in medications for hypertension and diabetes, improvements in markers of diabetes and hyperlipidemia, and remission rates of hypertension were superior with RYGB versus LSG four years post-operatively. Choice of bariatric procedures should be tailored to surgical risk, comorbidities, and weight loss goals.

BACKGROUND. Recombinant leptin therapy reverses nonalcoholic steatohepatitis (NASH) in leptin-deficient lipodystrophy. We inquired if leptin therapy would improve nonalcoholic steatohepatitis in more common forms of this heterogeneous condition. METHODS. Nine male patients with relative leptin deficiency (level < 25th percentile of body mass index- and gender-matched United States population) and biopsy-proven NASH and 23 patients with partial lipodystrophy and NASH were recruited for two distinctive open-label trials. Participants received leptin therapy in the form of metreleptin for 12 months. The primary endpoints were the global nonalcoholic steatohepatitis scores from paired liver biopsies scored blindly. FINDINGS. Of 9 participants recruited in the relative leptin deficiency treatment study, 7 completed 12-months of therapy. Mean global NASH scores were reduced from 8 ± 3 to 5 ± 2 (range: from 1 to 6, P = 0.004). In the partial lipodystrophy study, 19 of 22 subjects completed 12 months of treatment, and 18 completed a second liver biopsy. Global NASH scores also reduced significantly from 6 ± 2 to 5 ± 2 (range: from −2 to 4, P = 0.008). In both studies, the predominant changes were in steatosis and hepatic injury scores. CONCLUSION. Our findings show that patients with NASH associated with both relative leptin deficiency and partial lipodystrophy have reductions in hepatic steatosis and injury in response to exogenous leptin therapy. Moreover, leptin deficiency may have regulatory effects in mediating fat deposition and ensuing injury in the liver. TRIAL REGISTRATION. ClinicalTrials.gov NCT00596934 and NCT01679197.

Background:Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare syndrome with unknown etiology. Metabolic abnormalities are not known to be part of the syndrome. We present one of the oldest cases reported in the literature, who developed severe metabolic abnormalities and hepatic disease suggesting that these features may be part of the syndrome.Case presentation:A 27-year-old woman, diagnosed with ROHHAD syndrome at age 15, who previously developed diabetes insipidus, growth hormone deficiency, hyperprolactinemia, and hypothyroidism in her first decade of life. This was followed by insulin resistance, NAFLD, liver fibrosis, and splenomegaly before age 14 years. Her regimen included a short course of growth hormone, and cyclic estrogen and progesterone. Her metabolic deterioration continued despite treatment with metformin. Interestingly, she had a favorable response to liraglutide therapy despite having a centrally mediated cause for her obesity. At age 26, a 1.6 cm lesion was found incidentally in her liver. Liver biopsy showed hepatocellular carcinoma which was successfully treated with radiofrequency ablation.Conclusion:Metabolic abnormalities, Insulin resistance and fatty liver disease are potentially part of the ROHHAD syndrome that may develop over time. GLP1 agonists were reasonably effective to treat insulin resistance and hyperphagia. Patients with ROHHAD may benefit from close follow up in regards to liver disease.Keywords:Atypical diabetes; GLP-1 agonists; Insulin resistance; Obesity; ROHHAD.

Familial partial lipodystrophy (FPLD) presents with an absence of adipose tissue in the extremities, with accumulation in the upper body. Metabolic abnormalities associated with FPLD include diabetes mellitus and/or severe insulin resistance, hypertriglyceridemia, and non-alcoholic steatohepatitis. FPLD patients have a disproportionately lower BMI compared to individuals with common obesity and similar metabolic derangements. However, the extent and degree of metabolic disease at comparable truncal mass, or the “equivalent” BMI between the groups with similar metabolic disease are not known. To determine a BMI reference or “equivalence”, we performed a retrospective case control study comparing “cases” of FPLD against “controls” with severe obesity while matching for co-morbidities or total trunk mass. Baseline data were gathered to perform two k:1 nearest neighbor case-control matches using matchControls function of R’s e1071 package. MATCH1 included matching of age, sex, and total trunk mass with the hypothesis that FPLD with similar trunk mass had worse metabolic parameters. MATCH2 was performed using age, sex, and presence of comorbidities (hypertension, hypertriglyceridemia (>300mg/dL), diabetes, fatty liver, heart disease, arthritis, depression and anxiety, smoking history) with the hypothesis that there would be a significant difference in weight or BMI between the two populations. Our populations consisted of 55 FPLD cases (46F/9M, Age = 47±12 years, Total trunk mass=45.3±11.6 Kg) and a pool of 549 non-FPLD controls (338F/211M, Age = 48±10 years). MATCH1 allowed for a 2:1 nearest neighbor match with 110 obese controls (92F/18M, p=1.00, Age=48±11 years, p=0.72; Total Trunk Mass= 46.8±10.9 Kg, p=0.36). FPLD had worse glycemic control (HbA1c= 8.2±1.6%, 5.9±0.9%, respectively, p=

Lipodystrophy syndromes are a heterogeneous cluster of rare diseases characterized by a paucity or abnormal distribution of fat which are also associated with insulin resistance and ectopic lipid deposition. Owing to the rarity of the syndromes, the natural history and exact evolution of clinical, and psychosocial aspects are largely unknown. In March, 2018 we launched a prospective data registry- the LD Lync. The registry will be expanded to multiple centers across the US to ensure maximum number of participants. Anticipated sample size is 500. The goal is to collect data on various aspects of lipodystrophy syndromes (LD) including demographic, morphometric, clinical, genetic, socioeconomic characteristics and novel patient related end points such as quality of life, hunger and pain scales, mood and anxiety, and eating habits. During the past 8 months, we initiated the pilot data collection at our center. As of this month, we collected data on 61 affected individuals (49F/12 M, mean±SD Age: 44±15, with 4 acquired generalized LD (AGL), 3 acquired partial LD (APL), 48 familial partial LD (FPLD), 1 congenital generalized LD (CGL), 5 atypical LD). The median (IQR) difference between symptoms onset and time of diagnosis was 14y (24). The prevalence (95%CI) of diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease were 83% (71-92), 81% (69-90), and 78% (67-89) respectively. In terms of significant organ manifestations, 10% (95%CI:2-18) had myocardial infarction, 3% (0-8) had heart failure, 23% (14-35) had pancreatitis, and 8% (1-16) had malignancy. The (Median: IQR) age of diagnosis of these diseases was heterogeneous: diabetes 31y (26), hypercholesterolemia 27y (20), hypertriglyceridemia 25y (17), fatty liver disease 33y (31), and myocardial infarction 50y (16) . Out of 60 patients, 70% (58-82) are on lipid lowering drugs, 77% (66-87) on glucose lowering drugs, 37% (24-49) on hormones, and 68% (57-80) on anti-hypertensives. Out of the 61 who completed the GAD-7, IPAQ-2002, Modified 13 item binge eating scale, SF-36 scale, PHQ-9, and the perceived financial burden scale, 33% (95% CI, 21-45) had minimal anxiety, 28.3% (17-40) had mild anxiety, 20% (10-30) had moderate anxiety, and 18% (8-28) had severe anxiety. On quality of life, with 100% being the perfect score, our patients had low scores mean(95%CI): 37%(34-40) on emotional wellbeing, 49% (43-55) on social functioning, 55% (48-62) on pain level, and 32% (27-37) on general health. On the financial impact of lipodystrophy: 46% (33-58) reported moderate or higher levels of burden. We conclude that the lipodystrophy syndromes present with a large burden not only in terms of known medical complications but also in socioeconomic and psychosocial aspects of life. Expansion of this registry to include multiple sites in the US and across the globe will improve our understanding of all aspects of these diseases.

Background Metreleptin, a recombinant methionyl -human -leptin, was approved to treat patients with generalized lipodystrophy (GL) in February 2014. However, leptin therapy has been associated with the development of lymphoma. We present a unique case of a patient with prior history of T cell lymphoma in remission, who was diagnosed with Acquired Generalized Lipodystrophy (AGL) during the following year after a clinical remission of her lymphoma without receiving leptin therapy. Case presentation A 33-year-old woman with a diagnosis of stage IV subcutaneous panniculitis like T-cell lymphoma in 2011, underwent chemotherapy. Shortly after completion therapy, she had a relapse and required more chemotherapy with complete response, followed by allogenic stem cell transplant on June 28, 2012. Since that time, she has been on observation with no evidence of disease recurrence. Subsequent to the treatment, she was found to have high triglycerides, loss of fat tissue from her entire body and diagnosis of diabetes. Constellation of these findings led to the diagnosis of AGL in 2013. Her leptin level was low at 3.4 ng/mL (182 pmol/mL). She is currently not receiving any treatment with Metreleptin for her AGL. Conclusions Causal association between exogenous leptin therapy and T-cell lymphoma still remains unclear. We hereby present a case of a young woman who was diagnosed with AGL after going into remission from T-cell lymphoma and who has never been treated with Metreleptin. Steroid therapy and chemotherapy might have masked the diagnosis of AGL in this patient. We believe that patients can develop these 2 conditions independent of each other.

Table S1. Autonomic testing available on subject. Table S2 Summary data abstracted from reported cases and respective references. (DOCX 79 kb)

Purpose of reviewThis article focuses on recent progress in understanding the genetics of lipodystrophy syndromes, the pathophysiology of severe metabolic abnormalities caused by these syndromes, and causes of severe morbidity and a possible signal of increased mortality associated with lipodystrophy. An updated classification scheme is also presented.Recent findingsLipodystrophy encompasses a group of heterogeneous rare diseases characterized by generalized or partial lack of adipose tissue and associated metabolic abnormalities including altered lipid metabolism and insulin resistance. Recent advances in the field have led to the discovery of new genes associated with lipodystrophy and have also improved our understanding of adipose biology, including differentiation, lipid droplet assembly, and metabolism. Several registries have documented the natural history of the disease and the serious comorbidities that patients with lipodystrophy face. There is also evolving evidence for increased mortality rates associated with lipodystrophy.SummaryLipodystrophy syndromes represent a challenging cluster of diseases that lead to severe insulin resistance, a myriad of metabolic abnormalities, and serious morbidity. The understanding of these syndromes is evolving in parallel with the identification of novel disease-causing mechanisms.

The purpose of this review is to summarize the therapeutic approach for lipodystrophy syndromes with conventional treatment options and metreleptin therapy in detail and to point out the current investigational treatments in development. The observation of leptin deficiency in patients with lipodystrophy and the potential of leptin replacement to rescue metabolic abnormalities in animal models of lipodystrophy were followed by the first clinical study of leptin therapy in patients with severe lipodystrophy. This and several other long-term studies demonstrated important benefits of recombinant human leptin (metreleptin) to treat metabolic abnormalities of lipodystrophy. These studies ultimately led to the recent FDA approval of metreleptin for the treatment of generalized lipodystrophy and EMA approval for both generalized and partial lipodystrophy. Additional research efforts in progress focus on novel treatment options, predominantly for patients with partial lipodystrophy. Current treatment of generalized lipodystrophy includes metreleptin replacement as an adjunct to diet and standard treatment approach for metabolic consequences of lipodystrophy. Beyond metreleptin, a number of different compounds and treatment modalities are being studied for the treatment of partial lipodystrophy.

Familial Partial Lipodystrophy (FPLD) is a rare genetic disorder with selective loss of adipose tissue from the periphery with an increase in ectopic fat leading to severe hepatic insulin resistance, and hypertriglyceridemia. ApoC-III is a secreted liver glycoprotein associated with hypertriglyceridemia and insulin resistance. We inquired the relationship between lipid and other metabolic parameters with morphometric characteristics (including those of ectopic fat deposition) and circulating apoC-III levels in a cohort of FPLD patients who were screened for enrollment into the BROADEN study, a global trial to study efficacy of volanesorsen (an antisense mRNA apoC-III inhibitor). 28 patients are included in these analyses (age range, 28 to 65, mean 45 years; M/F, 7/21; all but one Caucasian). Table 1 shows the significant relationships observed using linear regression analyses between circulating ApoC-III levels and investigated parameters. These results reiterate the tight relationship between triglyceride levels and ApoC-III levels, and further demonstrate that circulating ApoC-III levels also correlate with insulin resistance, and HbA1c as well as important left ventricle morphometric parameters. It is plausible to hypothesize that a strategy to lower apoC-III levels may have additional benefits beyond lowering triglyceride levels.Table 1: Relationship of metabolic and echocardiogram parameters in FPLDParametersR2p-valuenParametersR2p-valuenTriglycerides* vs. ApoC-III0.63 Disclosure R. Meral: None. A. Digenio: Employee; Self; Akcea Therapeutics. A.H. Neidert: None. J. Tami: Employee; Self; Ionis Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ionis Pharmaceuticals, Inc. E.A. Oral: Advisory Panel; Self; Aegerion Pharmaceuticals. Research Support; Self; Aegerion Pharmaceuticals, Akcea Therapeutics. Advisory Panel; Self; Akcea Therapeutics. Research Support; Self; Ionis Pharmaceuticals, Inc., AstraZeneca. Other Relationship; Self; Aegerion Pharmaceuticals.

Lipodystrophy (LD) syndromes are a heterogeneous group of disorders causing atypical diabetes, associated with selective absence of fat with diagnosis mostly depending on the clinical acumen of the physician. With niche therapies either approved or under investigation, development of objective diagnostic tools for these syndromes are urgently needed. Here we describe a new method using the built-in features of the enCore software v14.10 to render out non-fat tissues from Dual Energy X-ray Absorptiometry (DEXA) scans to derive a “fat-shadow” (Figure). We evaluated fat-shadows from 58 LD (50F:8M) patients and 91 non-LD patients (51F:40M). Among the LD, 3 had Generalized LD, 2 had Acquired Partial LD, and 53 had Familial Partial LD. Controls consisted of a mixed population of lean (12F:14M) or obese patients (39F:26M) with or without metabolic disease. There was substantial overlap in % body fat between the LD and non-LD groups (interquartile range: total, 22.2-39.8% vs. 33.6-45.9%; trunk, 27.0-46.8% vs. 39.1-50.2%; legs, 16.6-30.6% vs. 27.7-42.6%). However, fat-shadows obtained from patients with LD stood out due to the paucity of fat signal either in a generalized or regional manner compared to controls. Overall, fat-shadows provided sufficient qualitative information to infer clinical phenotype. We propose that these fat-shadows could be used for accurate documentation of fat distribution in LD. Disclosure R. Meral: None. B.J. Ryan: None. J.F. Horowitz: None. E.A. Oral: Advisory Panel; Self; Aegerion Pharmaceuticals. Research Support; Self; Aegerion Pharmaceuticals, Akcea Therapeutics. Advisory Panel; Self; Akcea Therapeutics. Research Support; Self; Ionis Pharmaceuticals, Inc., AstraZeneca. Other Relationship; Self; Aegerion Pharmaceuticals.

SummaryContext Partial lipodystrophy (PL) is associated with metabolic co-morbidities but may go undiagnosed as the disease spectrum is not fully described. Objective The objective of the study was to define disease spectrum in PL using genetic, clinical (historical, morphometric) and laboratory characteristics. Design Cross-sectional evaluation. Participants Twenty-three patients (22 with familial, one acquired, 78·3% female, aged 12–64 years) with PL and non-alcoholic fatty liver disease (NAFLD). Measurements Genetic, clinical and laboratory characteristics, body composition indices, liver fat content by magnetic resonance imaging (MRI), histopathological and immunofluorescence examinations of liver biopsies. Results Seven patients displayed heterozygous pathogenic variants in LMNA. Two related patients had a heterozygous, likely pathogenic novel variant of POLD1 (NM002691·3: c.3199 G>A; p.E1067K). Most patients had high ratios (>1·5) of percentage fat trunk to percentage fat legs (FMR) when compared to reference normals. Liver fat quantified using MR Dixon method was high (11·3 ± 6·3%) and correlated positively with haemoglobin A1c and triglycerides while leg fat by dual-energy X-ray absorptiometry (DEXA) correlated negatively with triglycerides. In addition to known metabolic comorbidities; chronic pain (78·3%), hypertension (56·5%) and mood disorders (52·2%) were highly prevalent. Mean NAFLD Activity Score (NAS) was 5 ± 1 and 78·3% had fibrosis. LMNA-immunofluorescence staining from select patients (including one with the novel POLD1 variant) showed a high degree of nuclear atypia and disorganization. Conclusions Partial lipodystrophy is a complex multi-system disorder. Metabolic parameters correlate negatively with extremity fat and positively with liver fat. DEXA-based FMR may prove useful as a diagnostic tool. Nuclear disorganization and atypia may be a common biomarker even in the absence of pathogenic variants in LMNA.

OBJECTIVES/SPECIFIC AIMS: Familial partial lipodystrophy (FPLD) is an inherited, rare syndrome characterized by selective absence of adipose tissue from extremities which is associated with severe insulin resistance, and metabolic dyslipidemia (with hypertriglyceridemia, and low HDL) Typically, 30%–50% of patients with FPLD demonstrate a pathogenic variant in Lamin A (LMNA) gene that is associated with inherited cardiomyopathy and arrhythmia syndromes. We inquired the prevalence of having abnormal ECGs and echocardiograms in FPLD and whether there is a difference in evaluated parameters with respect to genotype. METHODS/STUDY POPULATION: We conducted a retrospective review of an established a cohort of 58 patients (age range: 12–71, M/F 8/50) with FPLD. Demographic characteristics, genotype, fasting triglyceride, hemoglobin A1c, LDL, and HDL levels were collected; ECGs and echocardiograms were also interrogated. RESULTS/ANTICIPATED RESULTS: Out of 58 patients, 22 (38 %) displayed a pathogenic variant in the LMNA gene. In total, 71% of patients (41/58) had an abnormal ECG and echocardiogram; 40% (23/58) of the patients displayed an arrhythmia on the ECGs (13 in the patients with LMNA variants and 10 in the non-LMNA group). The likelihood of having an arrhythmia was significantly higher in the patients with LMNA variants versus those without (odds ratio of 3.4, CI: 1.1–10.6). DISCUSSION/SIGNIFICANCE OF IMPACT: The overall prevalence of abnormal ECHO and/or ECG is high at 45/58 (78 %) in FPLD. Patients with LMNA variants have a 3.4 times increased risk of developing cardiac arrhythmias compared to those without. We recommend vigilant, monitoring for cardiac disease in FPLD and for arrhythmias in patients with FPLD and LMNA variants.

Numerous studies indicate an inflammatory link between obesity and type 2 diabetes. The inflammatory kinases IKKɛ and TBK1 are elevated in obesity; their inhibition in obese mice reduces weight, insulin resistance, fatty liver and inflammation. Here we studied amlexanox, an inhibitor of IKKɛ and TBK1, in a proof-of-concept randomized, double-blind, placebo-controlled study of 42 obese patients with type 2 diabetes and nonalcoholic fatty liver disease. Treatment of patients with amlexanox produced a statistically significant reduction in Hemoglobin A1c and fructosamine. Interestingly, a subset of drug responders also exhibited improvements in insulin sensitivity and hepatic steatosis. This subgroup was characterized by a distinct inflammatory gene expression signature from biopsied subcutaneous fat at baseline. They also exhibited a unique pattern of gene expression changes in response to amlexanox, consistent with increased energy expenditure. Together, these data suggest that dual-specificity inhibitors of IKKɛ and TBK1 may be effective therapies for metabolic disease in an identifiable subset of patients.

Appendix 1. Antibodies used for immunohistochemistry. Histopathological examination using fresh frozen muscle biopsy specimen from the patient was performed using the immunostains for: MHC1, Lamin A/C, C5b9, CD163/CD4, CD3/CD20. The antibodies used and respective protocols are shown. Appendix 2 Sanger sequencing chromatogram completed by a CLIA certified laboratory. Data from Sanger sequencing was used to confirm the patient’s whole exome sequencing (WES) results. Similar to the WES data, Sanger sequencing chromatogram revealed a heterozygous c.29 C > T mutation in exon 1. In the figure, both the wild type and the patient’s data with this mutation are shown. (PDF 618 kb)

Appendix 1. Antibodies used for immunohistochemistry. Histopathological examination using fresh frozen muscle biopsy specimen from the patient was performed using the immunostains for: MHC1, Lamin A/C, C5b9, CD163/CD4, CD3/CD20. The antibodies used and respective protocols are shown. Appendix 2 Sanger sequencing chromatogram completed by a CLIA certified laboratory. Data from Sanger sequencing was used to confirm the patient’s whole exome sequencing (WES) results. Similar to the WES data, Sanger sequencing chromatogram revealed a heterozygous c.29 C > T mutation in exon 1. In the figure, both the wild type and the patient’s data with this mutation are shown. (PDF 618 kb)