Generalized Lipodystrophy Research Articles

Immunogenicity of Metreleptin in Patients With Generalized Lipodystrophy

Immunogenicity of Metreleptin in Patients With Generalized Lipodystrophy

Comorbidities and Survival in Patients With Lipodystrophy: An International Chart Review Study.

Limited natural history data are available in patients with non-HIV-related lipodystrophy syndromes who never received disease-specific therapies, making interpretation of benefits of therapies in lipodystrophy syndromes challenging. We assessed the natural history of non-HIV-related generalized lipodystrophy (GL) and partial lipodystrophy (PL) in patients who have never received leptin or other lipodystrophy-specific therapies. We conducted an international chart review of 230 patients with confirmed GL or PL at five treatment centers who never received leptin or other lipodystrophy-specific therapies. Patients were observed from birth to loss to follow-up, death, or date of chart abstraction. Lifetime prevalence of diabetes/insulin resistance and select organ abnormalities, time to diabetes/insulin resistance, first organ abnormality, disease progression, and mortality were described. Diabetes/insulin resistance was identified in 58.3% of patients. Liver abnormalities were the most common organ abnormality (71.7%), followed by kidney (40.4%), heart (30.4%), and pancreatitis (13.0%). Kaplan-Meier estimates of mean (SE) time to first organ abnormality were 7.7 years (0.9) in GL and 16.1 years (1.5) in PL (P < 0.001). Mean time to diabetes/insulin resistance was 12.7 years (1.2) in GL and 19.1 years (1.7) in PL (P = 0.131). Mean time to disease progression was 7.6 years (0.8) and comparable between GL and PL subgroups (P = 0.393). Mean time to death was 51.2 years (3.5) in GL and 66.6 years (1.0) in PL (P < 0.001). This large-scale study provides comprehensive, long-term data across multiple countries on the natural history of non-HIV-related lipodystrophy.

Bowel perforation in a pediatric patient with congenital generalized lipodystrophy type 4

Abstract Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder that affects adipocyte development. Presentation varies based on type. A 12-year old female with CGL type 4, developed a sigmoid colon perforation in the setting of colonic wall hypertrophy after colonoscopy. She presented to the emergency room (ER) with several days of worsening abdominal pain and fevers. The initial evaluation was concerning for infectious versus inflammatory colitis. She was admitted for gastroenterology (GI) consultation for the complaint of abdominal pain. The patient had an established history of constipation management with laxatives. Full GI evaluation, including infectious panel as well as esophagogastroduodenoscopy (EGD) and colonoscopy, was negative. During the colonoscopy some difficulty with passage of the colonoscope past 25 cm was reported and therefore a gastroscope was used. She met criteria to start a clear liquid diet following the procedure. Two days after the colonoscopy, she had pneumoperitoneum on abdominal radiographs and was taken to the operating room for exploratory laparotomy. At the time of surgery, copious fibrinopurulent exudate was found throughout the abdominal cavity, as well as a thickened sigmoid colon/rectum and perforation with a contained abscess at the rectosigmoid junction. Sigmoid colectomy and end colostomy were performed. Pathologic examination demonstrated diffuse colonic wall thickening, a serosal defect that did not extended to the mucosa and several early diverticula. The pathology report stated that the presence of microscopic perforations could not be ruled out. The patient had an uneventful post-operative recovery. Congenital generalized lipodystrophy type 4 is a rare disease. We suspect an association between the muscular hypertrophy and the clinical presentation of bowel wall thickening and stricture. Given the rare nature of this disorder, clinicians that evaluate patients with CGL type 4 for constipation should have a suspicion for the possibility of colonic strictures. Rarely the condition can advance to perforation.

Description of a novel AGPAT2 gene mutation (R159C) responsible for congenital generalized lipoatrophy type 1 (Berardinelli-Seip Syndrome)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Acquired generalized lipodystrophy: a new cause of Anti-PD-1 immune-related diabetes

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

MON-129 An Unusual LMNA Mutation Causing a Complex Phenotype: When the Genetic Diagnosis Uncovers Novel Features

Background: Lipodystrophy syndromes are characterized by loss of body fat. Although classical Familial Partial Lipodystrophy (FPLD) and Congenital Generalized Lipodystrophy (CGL) have different clinical presentations, we have encountered a unique case where the distinction was quite challenging. Clinical Case: Our patient first presented to an endocrinologist at age 19 with secondary amenorrhea and hypothyroidism. After normalization of TSH, further investigation revealed central hypogonadism, hypertriglyceridemia (>3,000 mg/dL, normal<150mg/dL), xanthomas and fatty liver disease. By that time, she had adiposity changes such as lack of subcutaneous fat in the limbs and abdomen and prominent muscles. She believed she had those traits since early childhood. After puberty, she developed generalized muscle pain and was noted to have elevated CK. At 59 years old, she developed diabetes as well as liver fibrosis. These led to the diagnosis of lipodystrophy (initially classified as FPLD due to inheritance pattern). However, physical examination revealed acromegaloid features, BMI of 23.2 kg/m2, minimal fat palpable around the neck and minimal fullness of the supraclavicular fossa. The rest of the body was virtually devoid of subcutaneous fat tissue, consistent more with the CGL phenotype and inspection of older photos demonstrated progressive fat loss. She displayed prominent and hypertrophic muscles, phlebomegaly on limbs and trunk, umbilical hernia and acanthosis nigricans around the neck and armpits. Enlarged spleen and liver were also noted. There was labial hypertrophy with no cliteromegaly. Dual-Energy X-ray Absorptiometry (DEXA) showed total fat percentage of 22% and a "fat shadow” was obtained highlighting the generalized pattern of fat loss. Genetic analysis revealed a pathogenic variant (p. Arg541Pro) at exon 8 of the LMNA gene. Upon identification of the variant, her previously obtained muscle biopsy was reevaluated as muscular dystrophy. Cardiovascular investigations demonstrated first-degree atrioventricular block and non-sustained ventricular tachycardia on the ECG and fibrosis on cardiac MRI. Given her family history of sudden death, a dual-chamber implantable cardioverter-defibrillator was placed. When her HbA1c rose to 7.2% on Metformin monotherapy and her triglycerides exceeded 250 mg/dL on fibrates, we presented her case to her insurance company. She was approved for Metreleptin therapy even though she does not meet the consensus definition of generalized lipodystrophy. Conclusion: We present a unique case with lipodystrophy who had progressive fat loss from partial to generalized. Making the correct classification is important in the US where treatment with Metreleptin is approved only for generalized lipodystrophy. We also highlight a complex genotype-phenotype association of laminopathy that challenges the distinction between FPLD and CGL.

SAT-087 Familial Generalized Lipodystrophy in Two Siblings Due to Homozygous p.Arg545His LMNA Mutation

Background: Homozygous mutations in lamin A/C (LMNA) gene are extremely rare and have been reported to cause mandibuloacral dysplasia type A, Emery-Dreifuss muscular dystrophy-3, Charcot-Marie-Tooth axonal neuropathy type 2B1, progeroid syndrome and severe familial partial lipodystrophy. We report a novel syndrome of familial generalized lipodystrophy due to homozygous p.Arg545His LMNA mutation in two sisters. Clinical Cases: The proband, a 18.5-year-old Hispanic female, was diagnosed with speech delay at age 4 years; and developed lipodystrophy and acanthosis nigricans at age 10. She was diagnosed with diabetes and elevated serum aspartate and alanine aminotransferases at 11 years of age; and extreme hypertriglyceridemia (serum triglycerides >10,000 mg/dL), xanthomas and three episodes of acute pancreatitis at 14 years of age. Her liver biopsy showed hepatocytes with pleomorphic and enlarged mitochondria and variably enlarged glycogenated nuclei, with macro-vesicular and micro-vesicular steatosis in 2% of hepatocytes. At age 16, she had severe metabolic abnormalities despite low fat diet, metformin 1000 mg, insulin > 600 units, fish oil 4 g, gemfibrozil 600 mg, and lisinopril 10 mg per day. Subcutaneous metreleptin 2.5 mg/d was initiated which improved glycemic control, liver enzymes and triglycerides, with no further episode of acute pancreatitis. She currently takes metreleptin and insulin 140 units daily. She recently developed right hydrosalpinx, 1.8 cm posterior uterine fibroids, and 2.1 cm endometriosis. Her 17-year-old sister had speech delay in infancy, and recurrent pyelonephritis, and lost sc fat in early childhood. She developed hypothyroidism, elevated transaminases, and diabetes at age 10, 14, and 16 years, respectively. She had one episode of acute pancreatitis and an incidental 6.8 cm ovarian cyst was found at age 16 years. Both of them have generalized loss of sc fat, more from the extremities than from the trunk, thin lips with perioral pigmentation, dry skin, short 5th finger with clindodactyly, and bilateral ankle contractures. The proband also had bilateral knee contractures. They have no acro-osteolysis, buffalo hump, double chin, myopathy or neuropathy. Whole exome sequencing of both the patients revealed homozygous mutation chr1:156107470G>A, p.Arg545His (rs142191737, minor allele frequency 0.000038 in Latinos) in LMNA (http://gnomad.broadinstitute.org). The mother and a younger brother are both heterozygous for p.Arg545His variant and are healthy without any lipodystrophy. Conclusions: Homozygous p.Arg545His LMNA mutation results in a novel syndrome of childhood-onset familial generalized lipodystrophy with early onset diabetes, hypertriglyceridemia, and hepatic steatosis, speech delay and joint contractures. Metreleptin therapy may be helpful in improving metabolic derangements.

Promethin Is a Conserved Seipin Partner Protein.

Seipin (BSCL2/SPG17) is a key factor in lipid droplet (LD) biology, and its dysfunction results in severe pathologies, including the fat storage disease Berardinelli-Seip congenital lipodystrophy type 2, as well as several neurological seipinopathies. Despite its importance for human health, the molecular role of seipin is still enigmatic. Seipin is evolutionarily conserved from yeast to humans. In yeast, seipin was recently found to cooperate with the lipid droplet organization (LDO) proteins, Ldo16 and Ldo45, two structurally-related proteins involved in LD function and identity that display remote homology to the human protein promethin/TMEM159. In this study, we show that promethin is indeed an LD-associated protein that forms a complex with seipin, and its localization to the LD surface can be modulated by seipin expression levels. We thus identify promethin as a novel seipin partner protein.

Diagnosis of acquired generalized lipodystrophy in a single patient with T-cell lymphoma and no exposure to Metreleptin

BackgroundMetreleptin, 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 presentationA 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.ConclusionsCausal 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.

P398 Leptin controls immune cell composition and activity in acquired generalised lipodystrophy with combined Crohn’s disease

P398 Leptin controls immune cell composition and activity in acquired generalised lipodystrophy with combined Crohn’s disease

Berardinelli-Seip syndrome patient with novel AGPAT2 splicesite mutation and concomitant development of non-diabetic polyneuropathy

Berardinelli-Seip syndrome patient with novel AGPAT2 splicesite mutation and concomitant development of non-diabetic polyneuropathy

Novel metabolic disorders in skeletal muscle of Lipodystrophic Bscl2/Seipin deficient mice

Bscl2−/− mice recapitulate many of the major metabolic manifestations in Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) individuals, including lipodystrophy, hepatosteatosis, muscular hypertrophy, and insulin resistance. Metabolic defects in Bscl2−/− mice with regard to glucose and lipid metabolism in skeletal muscle have never been investigated. Here, we identified Bscl2−/− mice displayed reduced intramyocellular triglyceride (IMTG) content but increased glycogen storage predominantly in oxidative type I soleus muscle (SM). These changes were associated with increased incomplete fatty acid oxidation and glycogen synthesis. Interestingly, SM in Bscl2−/− mice demonstrated a fasting duration induced insulin sensitivity which was further confirmed by hyperinsulinemic-euglycemic clamp in SM of overnight fasted Bscl2−/− mice but reversed by raising circulating NEFA levels through intralipid infusion. Furthermore, mice with skeletal muscle-specific inactivation of BSCL2 manifested no changes in muscle deposition of lipids and glycogen, suggesting BSCL2 does not play a cell-autonomous role in muscle lipid and glucose homeostasis. Our study uncovers a novel link between muscle metabolic defects and insulin resistance, and underscores an important role of circulating NEFA in regulating oxidative muscle insulin signaling in BSCL2 lipodystrophy.

Female adipose tissue-specific Bscl2 knockout mice develop only moderate metabolic dysfunction when housed at thermoneutrality and fed a high-fat diet

Mutations affecting the BSCL2 gene cause the most severe form of congenital generalised lipodystrophy. Affected individuals almost completely lack adipose tissue and suffer from severe diabetes and metabolic complications. Likewise, mice lacking Bscl2 in all tissues have dramatically reduced adipose mass, glucose intolerance and hyperinsulinaemia. However, male adipose tissue-specific Bscl2 knockout mice fail to develop the metabolic dysfunction observed in Bscl2 null mice and BSCL2 deficient patients, despite a similar generalised lack of adipose tissues. Clinical reports indicate gender differences frequently exist in cases of lipodystrophy, with female patients more adversely affected than male patients. We therefore generated and characterised female mice lacking Bscl2 specifically in adipose tissue (Ad-B2(−/−)). We show that female Ad-B2(−/−) mice also develop early-onset lipodystrophy when fed a chow diet and are maintained under standard housing conditions (21 °C) or thermoneutrality (30 °C). Despite this, female Ad-B2(−/−) mice fail to develop severe metabolic dysfunction. Only when female Ad-B2(−/−) mice are maintained at thermoneutrality and fed a high-fat diet do subtle alterations to metabolic homeostasis manifest. This is despite a striking inability to expand adipose mass. Our findings provide further evidence that loss of Bscl2 in non-adipose tissues may contribute to the severity of metabolic dysfunction in this condition.

PSY11 - REAL-WORLD EXPERIENCE OF GENERALIZED LIPODYSTROPHY PATIENTS ENROLLED IN THE METRELEPTIN EARLY ACCESS PROGRAM: INITIAL RESULTS

To assess the real-world experience of patients with generalized lipodystrophy (GL) initiating treatment with metreleptin as part of an early access program (EAP). A retrospective data collection was conducted from three countries (Italy, Spain, and UK) for patients enrolled in the EAP. A descriptive analysis was performed on selected patient characteristics and response to metreleptin therapy, as measured through changes in triglycerides (TG) and HbA1c. 21 GL patients (Italy: 1, Spain: 11, UK: 9) were identified. Patients were diagnosed at a mean age of 3.7 years (75th-percentile: 3). 16 patients were diagnosed with congenital GL and 5 were diagnosed with acquired GL. Prior to metreleptin treatment, 100% of patients had TG >200 mg/dL and 72% of patients had HbA1c >8%. The duration of exposure to metreleptin varied across EAP patients, but was up to 14.6 years (mean 5.1, SD: 4.3). Following treatment, median % TG change between baseline and 12 months was a decrease of 70% (p<0.001) and mean HbA1c change was a 1.7 percentage point decrease (p=.010). 53% of patients (vs. 0% at baseline) achieved TG <200 mg/dL by month 12. 67% of patients (vs. 28% at baseline) achieved HbA1c <8% by month 12. No new safety signals emerged as data from the EAP was integrated with existing safety data. In the clinical trial, the most common treatment emergent adverse events (TEAEs) reported were decreased weight, abdominal pain, and hypoglycemia; drug-related treatment-emergent serious AEs affected <5%, and <10% of patients discontinued metreleptin due to drug-related TEAEs. Three deaths (none drug-related) were reported. Response to metreleptin in real-world EAP GL patients was consistent with clinical trial experience for registration (55% TG decrease and 2.0 percentage point HbA1c decrease). Ongoing research is needed to further characterize the burden of GL on patients and the impact of metreleptin.

"Fat Shadows" From DXA for the Qualitative Assessment of Lipodystrophy: When a Picture Is Worth a Thousand Numbers.

Lipodystrophy syndromes are a heterogeneous group of disorders associated with selective absence of fat. Currently, the diagnosis is established only clinically. 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. 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). 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.

Abstract P140: Leptin Supplementation Restores Endothelial Function and Vascular Adrenergic Tone via Direct Endothelial Mechanisms and Sympato-Activation, Respectively, in a Mouse Model of Congenital Lipodystrophy

Absence of adipose tissue in congenital generalized lipodystrophy (CGL) leads to metabolic and cardiovascular disease and reduced leptin levels. We tested the hypothesis that leptin supplementation restores endothelial function and reduces vascular adrenergic response respectively via acting directly on endothelial cells (EC) and desensitizing vascular adrenergic response, in CGL mice. Deletion of Berardinelli-Seip gene (Bscl2) was used to mimic the human pathology in mice. Bscl2-/- mice showed reduced adipose mass [% of fat: wild-type (WT): 8.6 ± 0.3 vs Bscl2-/-: 2.4 ± 0.1, P&lt;0.05], leptin levels [ng/mL: WT: 4.0 ± 0.3 vs Bscl2-/-: 0.3 ± 0.1, *P&lt;0.05], impaired aortic endothelium-dependent relaxation to acetylcholine (Ach): [% relaxation: WT: 71.9 ± 1 vs Bscl2-/-: 49.9 ± 2*, *P&lt;0.05], increased vascular contractility to phenylephrine (Phe), associated with upregulation of α-adrenergic receptors, high mean arterial pressure (MAP) and reduced heart rate (HR): [(mmHg: WT: 100.7 ± 5 vs Bscl2-/-: 109.5 ± 6*), (bpm: WT: 592.7 ± 9 vs Bscl2-/-: 542.9 ± 15*) *P&lt;0.05]. Moreover, Bscl2-/- mice shown increase in Nox1 gene expression and increases in vascular - O 2 and H 2 O 2 levels. Both chronic (in vivo) and acute (organ bath) leptin supplementation or NOX 1 inhibition (GKT771, 10μM) restored endothelial function in addition to reducing endothelial Nox1 expression and ROS production, which suggest a direct role for leptin in endothelial cells. EC leptin receptor deficiency induced an endothelial dysfunction in mice, which was restored by Nox1 inhibition, further supporting a direct role of leptin in endothelial cells. In parallel, leptin supplementation reduced vascular adrenergic tone and aortic α-adrenergic receptors and increased in HR without changing MAP. Our data show that leptin replacement restores endothelial function and reduces vascular adrenergic tone in mouse model of congenital lipodystrophy by acting directly in EC and desensitizing vascular adrenergic response, respectively. This highlight the importance of leptin in the maintenance of vascular homeostasis and presents leptin as a potential therapeutic avenue for the treatment of vascular diseases associated with low leptin levels.

Seipin regulates lipid homeostasis by ensuring calcium-dependent mitochondrial metabolism.

Seipin, the gene that causes Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2), is important for adipocyte differentiation and lipid homeostasis. Previous studies in Drosophila revealed that Seipin promotes ER calcium homeostasis through the Ca2+-ATPase SERCA, but little is known about the events downstream of perturbed ER calcium homeostasis that lead to decreased lipid storage in Drosophila dSeipin mutants. Here, we show that glycolytic metabolites accumulate and the downstream mitochondrial TCA cycle is impaired in dSeipin mutants. The impaired TCA cycle further leads to a decreased level of citrate, a critical component of lipogenesis. Mechanistically, Seipin/SERCA-mediated ER calcium homeostasis is important for maintaining mitochondrial calcium homeostasis. Reduced mitochondrial calcium in dSeipin mutants affects the TCA cycle and mitochondrial function. The lipid storage defects in dSeipin mutant fat cells can be rescued by replenishing mitochondrial calcium or by restoring the level of citrate through genetic manipulations or supplementation with exogenous metabolites. Together, our results reveal that Seipin promotes adipose tissue lipid storage via calcium-dependent mitochondrial metabolism.

Sleep Disorders in Patients with Congenital Generalized Lipodystrophy

Background and Aims: Sleep disorders are often associated with the several metabolic complications. Congenital generalized lipodystrophy (CGL) is associated with severe insulin resistance, diabetes, dyslipidemia and hepatic steatosis in non-obese individuals, but there are no data evaluating the presence of sleep disorders in this condition. The aim of this study was to describe the characteristics of sleep pattern in individuals with CGL and evaluate the presence of sleep disorders in these patients. Materials and Methods: A cross-sectional study with 8 patients with CGL. It was performed a polysomnography following the guidelines of the American Academy of Sleep Medicine. Results: There were 2 male and 6 female patients. The median age of these patients is 16,5 years old, ranging from 7 to 33 years old. All patients have hypertriglyceridemia and 6/8 had diabetes. Hepatic steatosis was observed in 4/8 cases (50%) and systemic arterial hypertension in 1/8 case (12,5%). Snore was observed in 7/8 (87,5%) of the sample. The diagnosis of obstructive sleep apnea syndrome was observed in 6/8 (75%) of the individuals, rapid eye movement sleep (REM) behavior disorder in 4/8 (50%), changes in sleep efficiency in 4/8 (50%), fragmented sleep in 8/8 (100%) and periodic leg movements in 7/8 (87,5%). There were no significant cardiovascular abnormalities in this study. Conclusion: The patients with CGL evaluated showed a high frequency of sleep disorders. These findings in a young no-obese population, but with severe metabolic abnormalities, suggest its negative impact in sleep quality of these patients, increasing the cardiovascular risk in this population. Disclosure V.O. Fernandes: None. C.P. Silva: None. A.D.R. Montenegro: None. C.M.M. Ponte: None. L.A.A. Batista: None. T.F. Pinto: None. I.T. Vasconcelos: None. L.A.S. Karbage: None. P.M. Fernandes: None. C.B. D'Alva: None. P.F.C. Bruin: None. R.M. Montenegro: None.

Ophthalmologic Findings in Congenital Generalized Lipodystrophy—A Possible Marker of Metabolic Disorders

Background and Aims: Metabolic disorders can present ophthalmologic changes. Congenital Generalized Lipodystrophy (CGL) is characterized by severe metabolic manifestations such as insulin resistance, diabetes and hypertriglyceridemia, but there are few data published about ophthalmologic findings in this condition. The purpose of this study is to describe ocular abnormalities in patients with CGL. Materials and Methods: It was a cross sectional study with 15 patients with CGL of both sex, aged between 2 and 29 years old. We evaluated the symptoms of surface eye disease and visual acuity. In the slit lamp, were evaluated the anterior segment of the eye, the break up time of the tear film with fluorescein and the corneal findings. Under mydriasis, the eye fundus examination was performed. Results: All subjects had dyslipidemia: 15/15 (100%) hypertriglyceridemia; 15/15 (100%) low HDL-c; 4/15 (26,7%) and high levels of LDL-c. Diabetes was presented in 7/15 (46,7%) cases. Symptoms of surface eye disease (blurred vision, pruritus, hyperemia or dry eye sensation) were presented in 9/15 (60%) patients and 8/15 (53%) had refractive errors: 5/8 (62,5%) astigmatism, 2/8 (25%) myopia and 1/8 (13%) myopia and astigmatism. In the slit lamp, 12/15 (80%) presented anterior blepharitis (seborrheic or meibomite), 13/15 (87%) decrease in the break up time of the tear (less than 8 seconds) and 5/15 (33,3%) keratitis. In the fundoscopy, 2/15 (13,3%) presented retinopathy (one with nonproliferative diabetic retinopathy and another presented proliferative diabetic retinopathy). Conclusion: These findings demonstrate high frequency of blepharites and its complications in patients with CGL, even in young subjects without diabetes. These data allow us to speculate that the presence of abnormalities in the anterior segment of the eye may be a marker of metabolic disorders as dyslipidemia and insulin resistance. Disclosure V.O. Fernandes: None. L.M.A. Gomes: None. A.D.R. Montenegro: None. C.M.M. Ponte: None. L.A.A. Batista: None. R.E.M. Aragão: None. J.V. Silva: None. R.M. Montenegro: None.

Insulin Resistance, Cardiovascular Autonomic Neuropathy, and Left Ventricular Hypertrophy in Patients with Congenital Generalized Lipodystrophy

Congenital generalized lipodystrophy (CGL) subjects have a high prevalence of cardiovascular autonomic neuropathy (CAN) and cardiac complications, including left ventricular hypertrophy (LVH). This study aimed to analyze insulin resistance (IR), CAN severity and LVH association. A cross sectional study with 10 CGL patients and 20 healthy controls. We evaluated clinical and laboratory data, echocardiogram parameters, 3 spectral analysis components - high frequency (HF), low frequency (LF), and very low frequency (VLF) - of heart rate variability (HRV), sympathetic-vagal balance, time domains of HRV, corrected QT interval (cQT), and 4 cardiovascular reflexes tests (postural hypotension test, orthostatic, respiratory, and valsalva coefficients - 2 abnormal tests: clinic CAN, 1 abnormal test: incipient CAN, and postural hypotension: advanced CAN). In CGL group 50% had CAN (40% clinic and 10% incipient) and 40% LVH. There was inverse correlation between LVMI and HF (p=0,007), IVS and HF (p=0,013), and positive correlation between IVS and HOMA-IR (p=0,042), and BP drop (p=0,010). These suggest that IR may be involved in the severity of CAN and cardiac autonomic dysfunction in the pathophysiology of cardiovascular complications in these disease. Disclosure V.O. Fernandes: None. C.M.M. Ponte: None. M.C. Gurgel: None. A.D.R. Montenegro: None. L.A.A. Batista: None. C.B.R. Liberato: None. C.B. D'Alva: None. R.M. Montenegro: None.