Familial Partial Lipodystrophy Research Articles

Cardiometabolic risk factors in women: what's sauce for the goose is not sauce for the gander.

The aim of this review was to discuss cardiometabolic risk factors that affect women. Recent calls to action to address cardiometabolic risk factors specific to women relate to increasing evidence of sex-specific differences in patient-related, drug-related, and socio-demographic factors leading to sub-optimal care of women. Certain aspects of common modifiable cardiovascular risk factors (e.g. smoking, hypertension, dyslipidaemia and diabetes) affect female individuals more adversely. Additionally, there are risk factors or enhancers that particularly affect cardiometabolic health in women [e.g. premature menopause, polycystic ovarian syndrome (PCOS), familial partial lipodystrophy, socio-cultural factors]. Understanding these risk factors may provide insight on how to improve cardiometabolic outcomes in women.

Hypertriglyceridemia Results From an Impaired Catabolism of Triglyceride-Rich Lipoproteins in PLIN1-Related Lipodystrophy.

Pathogenic variants in PLIN1-encoding PLIN1 (perilipin-1) are responsible for an autosomal dominant form of familial partial lipodystrophy (FPL) associated with severe insulin resistance, hepatic steatosis, and important hypertriglyceridemia. This study aims to decipher the mechanisms of hypertriglyceridemia associated with PLIN1-related FPL. We performed an in vivo lipoprotein kinetic study in 6 affected patients compared with 13 healthy controls and 8 patients with type 2 diabetes. Glucose and lipid parameters, including plasma LPL (lipoprotein lipase) mass, were measured. LPL mRNA and protein expression were evaluated in abdominal subcutaneous adipose tissue from patients with 5 PLIN1-mutated FPL and 3 controls. Patients with PLIN1-mutated FPL presented with decreased fat mass, insulin resistance, and diabetes (glycated hemoglobin A1c, 6.68±0.70% versus 7.48±1.63% in patients with type 2 diabetes; mean±SD; P=0.27). Their plasma triglycerides were higher (5.96±3.08 mmol/L) than in controls (0.76±0.27 mmol/L; P<0.0001) and patients with type 2 diabetes (2.94±1.46 mmol/L, P=0.006). Compared with controls, patients with PLIN1-related FPL had a significant reduction of the indirect fractional catabolic rate of VLDL (very-low-density lipoprotein)-apoB100 toward IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein; 1.79±1.38 versus 5.34±2.45 pool/d; P=0.003) and the indirect fractional catabolic rate of IDL-apoB100 toward LDL (2.14±1.44 versus 7.51±4.07 pool/d; P=0.005). VLDL-apoB100 production was not different between patients with PLIN1-related FPL and controls. Compared with patients with type 2 diabetes, patients with PLIN1-related FPL also showed a significant reduction of the catabolism of both VLDL-apoB100 (P=0.031) and IDL-apoB100 (P=0.031). Plasma LPL mass was significantly lower in patients with PLIN1-related FPL than in controls (21.03±10.08 versus 55.76±13.10 ng/mL; P<0.0001), although the LPL protein expression in adipose tissue was similar. VLDL-apoB100 and IDL-apoB100 indirect fractional catabolic rates were negatively correlated with plasma triglycerides and positively correlated with LPL mass. We show that hypertriglyceridemia associated with PLIN1-related FPL results from a marked decrease in the catabolism of triglyceride-rich lipoproteins (VLDL and IDL). This could be due to a pronounced reduction in LPL availability, related to the decreased adipose tissue mass.

Circulating exosomal circRNA-miRNA-mRNA network in a familial partial lipodystrophy type 3 family with a novel PPARG frameshift mutation c.418dup.

Familial Partial Lipodystrophy 3 (FPLD3) is a rare genetic disorder caused by loss-of-function mutations in the PPARG gene, characterized by a selective absence of subcutaneous fat and associated metabolic complications. However, the molecular mechanisms of FPLD3 remain unclear. In this study, we recruited a 17-year-old Chinese female with FPLD3 and her family, identifying a novel PPARG frameshift mutation (exon 4: c.418dup: p.R140Kfs*7) that truncates the PPARγ protein at the 7th amino acid, significantly expanding the genetic landscape of FPLD3. By performing next generation sequencing of circular RNAs (circRNAs), microRNAs (miRNAs), and mRNAs in plasma exosomes, we discovered 59 circRNAs, 57 miRNAs, and 299 mRNAs were significantly altered in the mutation carriers in the comparison of healthy controls. Integration analysis highlighted that the circ_0001597-miR-671-5p pair and 18 mRNAs might be incorporated into the metabolic regulatory networks of the FPLD3 induced by the novel PPARG mutation. Functional annotation suggested that these genes were significantly enriched in glucose and lipid metabolism related pathways. Among the circRNA-miRNA-mRNA network, we identified two critical regulators, EGR1, a key transcription factor known for its role in insulin signaling pathways and lipid metabolism, and AGPAT3, which gets involved in the biosynthesis of triglycerides and lipolysis. Circ_0001597 regulates the expression of these genes through miR-671-5p, potentially contributing to the pathophysiology of FPLD3. Overall, this study clarified a circulating exosomal circRNA-miRNA-mRNA network in a FPLD3 family with a novel PPARG mutation, providing evidence for exploring promising biomarkers and developing novel therapeutic strategies for this rare genetic disorder.

Case report: two novel PPARG pathogenic variants associated with type 3 familial partial lipodystrophy in Brazil

Introduction and aimType 3 Familial Partial Lipodystrophy (FPLD3) is a rare metabolic disease related to pathogenic PPARG gene variants. FPLD3 is characterized by a loss of fatty tissue in the upper and lower limbs, hips, and face. FPLD3 pathophysiology is usually associated with metabolic comorbidities such as type 2 diabetes, insulin resistance, hypertriglyceridemia, and liver dysfunction. Here, we clinically and molecularly characterized FPLD3 patients harboring novel PPARG pathogenic variants.Materials and methodsLipodystrophy-suspected patients were recruited by clinicians from an Endocrinology Reference Center. Clinical evaluation was performed, biological samples were collected for biochemical analysis, and DNA sequencing was performed to define the pathogenic variants associated with the lipodystrophic phenotype found in our clinically diagnosed FPLD subjects. Bioinformatics predictions were conducted to characterize the novel mutated PPARγ proteins.ResultsWe clinically described FPLD patients harboring two novel heterozygous PPARG variants in Brazil. Case 1 had the c.533T > C variant, which promotes the substitution of leucine to proline in position 178 (p.Leu178Pro), and cases 2 and 3 had the c.641 C > T variant, which results in the substitution of proline to leucine in the position 214 (p.Pro214Leu) at the PPARγ2 protein. These variants result in substantial conformational changes in the PPARγ2 protein.ConclusionTwo novel PPARG pathogenic variants related to FPLD3 were identified in a Brazilian FPLD cohort. These data will provide new epidemiologic data concerning FPLD3 and help understand the genotype-phenotype relationships related to the PPARG gene.

Bilateral developmental cataracts in a child with familial lipodystrophy

Bilateral developmental cataracts are usually caused due to hereditary metabolic disorder or intrauterine infections. Familial lipodystrophy type 7 has variable phenotypes with early-onset cataracts and lower limb spasticity, with most reports showing the onset of cataracts in the second decade of life. We report a rare case of bilateral congenital cataract in a child aged 3 years and 9 months with genetically proven familial partial lipodystrophy type 7. Bilateral developmental cataracts need complete physical examination and genetic analysis to detect unusual and rare causes like familial partial lipodystrophy.

Comprehensive analysis of morbidity and mortality patterns in familial partial lipodystrophy patients: insights from a population study.

There is a lack of information on the clinical and molecular presentation of familial partial lipodystrophy (FPLD), a rare genetic disorder characterized by partial subcutaneous fat loss. This study aimed to provide a comprehensive assessment of the clinical, metabolic, and genetic features of FPLD in the Brazilian population. In a multicenter cross-sectional investigation we evaluated patients with FPLD across five Brazilian reference centers for lipodystrophies. Diagnosis of FPLD was made by clinical evaluation and genetic confirmation. Data on genetic, clinical, and metabolic characteristics were captured. Statistical analysis involved the utilization of the Kruskal-Wallis test to identify differences. The study included 106 patients with genetic confirmation of FPLD. The mean age was 44 ± 15 years, and they were predominantly female (78.3%). LMNA pathogenic variants were identified in 85.8% of patients, PPARG in 10.4%, PLIN1 in 2.8%, and MFN2 in 0.9%. Diabetes mellitus (DM) was highly prevalent (57.5%), affecting 54 females (50.9%). Median triglycerides levels were 199 mg/dL (54-2724 mg/dL), severe hypertriglyceridemia (≥ 500 mg/dL) was found in 34.9% and pancreatitis in 8.5%. Metabolic-associated fatty liver disease (MAFLD) was observed in 56.6%, and cardiovascular disease in 10.4%. The overall mortality rate was 3.8%, due to cardiovascular events. This study presents an extensive cohort of Brazilian patients with FPLD, predominantly DM with several multisystem complications. A comprehensive characterization of lipodystrophy syndromes is crucial for effective patient management and care.

Combination of familial partial lipodystrophy (Dunnigan-Cobberling syndrome) with pulmonary sarcoidosis

Lipodystrophy syndromes are a heterogeneous group of extremely rare, inherited or acquired disorders that are characterized by total or partial fat loss or its improper redistribution. The prevalence of lipodystrophies is estimated to be 1:1,000,000 in the population, with approximately 1,000 cases currently described in the literature.Sarcoidosis is a multisystem disease of unknown etiology that is characterized by the formation of non-caseating epithelioid granulomas in the affected tissues. Despite the large number of studies, the etiology and pathogenesis of sarcoidosis still remain unknown. Most researchers allude to the possible autoimmune or immune-mediated genesis of the disease.This article presents a series of unique clinical cases of a combination of two rare diseases in one patient: sarcoidosis and familial partial lipodystrophy.

Lipomatoses

Lipomatoses are benign proliferation of adipose tissue. Lipomas (benign fat tumors) are the most common component of lipomatosis. They may be unique or multiple, encapsulated or not, subcutaneous or sometimes visceral. In some cases, they form large areas of non-encapsulated fat hypertrophy, with a variable degree of fibrosis. They can develop despite the absence of obesity. They may be familial or acquired. At difference with lipodystrophy syndromes, they are not associated with lipoatrophy areas, except in some rare cases such as type 2 familial partial lipodystrophy syndromes (FPLD2). Their metabolic impact is variable in part depending on associated obesity. They may have functional or aesthetic consequences. Lipomatosis may be isolated, be part of a syndrome, or may be visceral. Isolated lipomatoses include multiple symmetrical lipomatosis (Madelung disease or Launois-Bensaude syndrome), familial multiple lipomatosis, the painful Dercum's disease also called Adiposis Dolorosa or Ander syndrome, mesosomatic lipomatosis also called Roch-Leri lipomatosis, familial angiolipomatosis, lipedema and hibernomas. Syndromic lipomatoses include PIK3CA-related disorders, Cowden/PTEN hamartomas-tumor syndrome, some lipodystrophy syndromes, and mitochondrial diseases, especially MERRF, multiple endocrine neoplasia type 1, neurofibromatosis type 1, Wilson disease, Pai or Haberland syndromes. Finally, visceral lipomatoses have been reported in numerous organs and sites: pancreatic, adrenal, abdominal, epidural, mediastinal, epicardial… The aim of this review is to present the main types of lipomatosis and their physiopathological component, when it is known.

Identification of two novel LMNA variants causing familial partial lipodystrophy

Identification of two novel LMNA variants causing familial partial lipodystrophy

Comparison of metabolic and immunological profile of 2 types of familial partial lipodystrophy syndromes (PLIN1 and LMNA)

Comparison of metabolic and immunological profile of 2 types of familial partial lipodystrophy syndromes (PLIN1 and LMNA)

Diagnostic and referral pathways in patients with rare lipodystrophy and insulin-resistance syndromes: key milestones assessed from a national reference center

BackgroundRare syndromes of lipodystrophy and insulin-resistance display heterogeneous clinical expressions. Their early recognition, diagnosis and management are required to avoid long-term complications.ObjectiveWe aimed to evaluate the patients’ age at referral to our dedicated national reference center in France and their elapsed time from first symptoms to diagnosis and access to specialized care.Patients and methodsWe analyzed data from patients with rare lipodystrophy and insulin-resistance syndromes referred to the coordinating PRISIS reference center (Adult Endocrine Department, Saint-Antoine Hospital, AP-HP, Paris), prospectively recorded between 2018 and 2023 in the French National Rare Disease Database (BNDMR, Banque Nationale de Données Maladies Rares).ResultsA cohort of 292 patients was analyzed, including 208 women, with the following diagnosis: Familial Partial LipoDystrophy (FPLD, n = 124, including n = 67 FPLD2/Dunnigan Syndrome); Acquired lipodystrophy syndromes (n = 98, with n = 13 Acquired Generalized Lipodystrophy, AGL); Symmetric cervical adenolipomatosis (n = 27, Launois-Bensaude syndrome, LB), Congenital generalized lipodystrophy (n = 18, CGL) and other rare severe insulin-resistance syndromes (n = 25). The median age at referral was 47.6 years [IQR: 31–60], ranging from 25.2 (CGL) to 62.2 years old (LB). The median age at first symptoms of 27.6 years old [IQR: 16.8–42.0]) and the median diagnostic delay of 6.4 years [IQR: 1.3–19.5] varied among diagnostic groups. The gender-specific expression of lipodystrophy is well-illustrated in the FPLD2 group (91% of women), presenting with first signs at 19.3 years [IQR: 14.4–27.8] with a diagnostic delay of 10.5 years [IQR: 1.8–27.0].ConclusionThe national rare disease database provides an important tool for assessment of care pathways in patients with lipodystrophy and rare insulin-resistance syndromes in France. Improving knowledge to reduce diagnostic delay is an important objective of the PRISIS reference center.

Relationship of Fat Mass Ratio, a Biomarker for Lipodystrophy, With Cardiometabolic Traits.

Familial partial lipodystrophy (FPLD) is a heterogenous group of syndromes associated with a high prevalence of cardiometabolic diseases. Prior work has proposed DEXA-derived fat mass ratio (FMR) - defined as trunk fat percentage (trunk fat %) divided by leg fat percentage (leg fat %) - as a biomarker of FPLD, but this metric has not previously been characterized in large cohort studies. We set out to (1) understand the cardiometabolic burden of individuals with high FMR in up to 40,796 participants in the UK Biobank and 9,408 participants in the Fenland study, (2) characterize the common variant genetic underpinnings of FMR, and (3) build and test a polygenic predictor for FMR. Participants with high FMR were at higher risk for type 2 diabetes (OR = 2.30, p = 3.5 × 10-41) and MASLD/MASH (OR = 2.55, p = 4.9 × 10-7) in UK Biobank, and had higher fasting insulin (difference = +19.8 pmol/L, p = 5.7 × 10-36) and fasting triglycerides (difference = +36.1 mg/dL, p = 2.5 × 10-28) in the Fenland Study. Across FMR and its component traits, 61 conditionally independent variant-trait pairs were discovered, including 13 newly-identified pairs. A polygenic score for FMR was associated with increased risk of cardiometabolic diseases. This work establishes the cardiometabolic significance of high FMR - a biomarker for FPLD - in two large cohort studies and may prove useful in increasing diagnosis rates of patients with metabolically unhealthy fat distribution to enable treatment or a preventive therapy.

Clinical and imaging features of women with polygenic partial lipodystrophy: a case series.

Familial partial lipodystrophy (FPLD) is an inherited disorder of white adipose tissue that causes premature cardiometabolic disease. There is no clear diagnostic criteria for FPLD, and this may explain the under-detection of this condition. This pilot study aimed to describe the clinical features of women with FPLD and to explore the value of adipose tissue measurements that could be useful in diagnosis. In 8 women with FPLD and 4 controls, skinfold measurements, DXA and whole-body MRI were undertaken. Whole genome sequencing was negative for monogenic metabolic causes, but polygenic scores for partial lipodystrophy were elevated in keeping with FPLD type 1. The mean age of diagnosis of DM was 31 years in the FPLD group. Compared with controls, the FPLD group had increased HOMA-IR (10.3 vs 2.9, p = 0.028) and lower mean thigh skinfold thickness (19.5 mm vs 48.2 mm, p = 0.008). The FPLD group had lower percentage of leg fat and an increased ratio of trunk to leg fat percentage on DXA. By MRI, the FPLD group had decreased subcutaneous adipose tissue (SAT) volume in the femoral and calf regions (p < 0.01); abdominal SAT, visceral adipose tissue, and femoral and calf muscle volumes were not different from controls. Women with FPLD1 in Singapore have significant loss of adipose but not muscle tissue in lower limbs and have early onset of diabetes. Reduced thigh skinfold, and increased ratio of trunk to leg fat percentage on DXA are potentially clinically useful markers to identify FPLD1.

Efficacy and Safety of Glucagon-Like Peptide 1 Agonists in a Retrospective Study of Patients With Familial Partial Lipodystrophy.

Glucagon-like peptide 1 receptor agonists (GLP-1RA) are widely used for the management of diabetes mellitus (DM), but their efficacy in familial partial lipodystrophy (FPLD) is unknown. In this retrospective study, we evaluated the effect of GLP-1RA in patients with FPLD. We analyzed data, reported with SDs, from 14 patients with FPLD (aged 58 ± 12 years; 76.47% female) and 14 patients with type 2 DM (aged 58 ± 13 years; 71% female) before and 6 months after starting GLP-1RA. We observed reduction in weight (95 ± 23 to 91 ± 22 kg; P = 0.002), BMI (33 ± 6 to 31 ± 6 kg/m2; P = 0.001), HbA1c (8.2% ± 1.4% to 7.7% ± 1.4%; P = 0.02), and fasting glucose (186 ± 64 to 166 ± 53 mg/dL; P = 0.04) in patients with FPLD. The change in triglycerides after treatment was greater in the FPLD group compared with the DM group (P = 0.02). We noted acute pancreatitis in two case subjects with FPLD with longer therapy. Our study demonstrates the relative safety and effectiveness of GLP-1RA in patients with FPLD.

Effect of β-Estradiol on Adipogenesis in a 3T3-L1 Cell Model of Prelamin A Accumulation.

The accumulation of farnesylated prelamin A has been suggested as one of the mechanisms responsible for the loss of fat in type 2 familial partial lipodystrophy due to variants in the LMNA gene. In this rare disease, fat loss appears in women after puberty, affecting sex-hormone-dependent anatomical areas. This study investigated the impact of 17-β-estradiol on adipogenesis in murine preadipocytes subjected to a pharmacologically induced accumulation of farnesylated and non-farnesylated prelamin A. To induce the accumulation of non-farnesylated or farnesylated prelamin A, 3T3-L1 cells were treated with the farnesyltransferase inhibitor 277 or the methyltransferase inhibitor N-acetyl-S-farnesyl-l-cysteine methylester. Subsequently, the cells were induced to undergo adipocyte differentiation in the presence or absence of 17-β-estradiol. Prelamin A accumulation was assessed through immunofluorescence, while real-time PCR and Western blot techniques were used to quantify several adipogenic genes and evaluate protein levels, respectively. The results showed that 17-β-estradiol increased adipogenesis, although the combination of this hormone plus farnesylated prelamin A led to a reduction in the number of mature adipocytes and the expression of the different genes involved in adipogenesis. In conclusion, the influence of farnesylated prelamin A accumulation on adipogenesis manifested only in the presence of estradiol. These in vitro findings suggest a potential mechanism that could explain the characteristic phenotype in women suffering type 2 familial partial lipodystrophy.

Understanding Cardiac Alterations in Familial Partial Lipodystrophy: Insights from Echocardiography.

Understanding Cardiac Alterations in Familial Partial Lipodystrophy: Insights from Echocardiography.

Understanding Cardiac Alterations in Familial Partial Lipodystrophy: Insights from Echocardiography

Understanding Cardiac Alterations in Familial Partial Lipodystrophy: Insights from Echocardiography

Mineralocorticoid Receptor Antagonism Prevents Type 2 Familial Partial Lipodystrophy Brown Adipocyte Dysfunction.

Type-2 Familial Partial Lipodystrophy (FPLD2), a rare lipodystrophy caused by LMNA mutations, is characterized by a loss of subcutaneous fat from the trunk and limbs and excess accumulation of adipose tissue in the neck and face. Several studies have reported that the mineralocorticoid receptor (MR) plays an essential role in adipose tissue differentiation and functionality. We previously showed that brown preadipocytes isolated from a FPLD2 patient's neck aberrantly differentiate towards the white lineage. As this condition may be related to MR activation, we suspected altered MR dynamics in FPLD2. Despite cytoplasmic MR localization in control brown adipocytes, retention of MR was observed in FPLD2 brown adipocyte nuclei. Moreover, overexpression of wild-type or mutated prelamin A caused GFP-MR recruitment to the nuclear envelope in HEK293 cells, while drug-induced prelamin A co-localized with endogenous MR in human preadipocytes. Based on in silico analysis and in situ protein ligation assays, we could suggest an interaction between prelamin A and MR, which appears to be inhibited by mineralocorticoid receptor antagonism. Importantly, the MR antagonist spironolactone redirected FPLD2 preadipocyte differentiation towards the brown lineage, avoiding the formation of enlarged and dysmorphic lipid droplets. Finally, beneficial effects on brown adipose tissue activity were observed in an FPLD2 patient undergoing spironolactone treatment. These findings identify MR as a new lamin A interactor and a new player in lamin A-linked lipodystrophies.

SAT676 Severe Recurrent Pancreatitis In A Familial Partial Lipodystrophy Patient On Metreleptin

Abstract Disclosure: P. Sargin: None. M. Vinicky: None. A. Biglione: None. Lipodystrophy syndromes are congenital or acquired disorders characterized by either total or partial lipoatrophy and often unrecognized by clinicians due to their rarity. Patients with lipodystrophy may demonstrate severe complications of metabolic syndrome since lipids are deposited in non-adipose organs where they induce lipotoxicity resulting in insulin resistance, diabetes mellitus, hypertriglyceridemia, and hepatic steatosis. Familial Partial Lipodystrophy (FPLD) syndromes are one of the four major subtypes of lipodystrophy syndromes. These are heterogeneous, mostly autosomal dominant, and characterized by site-specific subcutaneous adipose tissue loss. The management of patients with FPLD can be challenging with life-threatening complications, heavy dependence on lifestyle modifications, limited treatment options and medication availability. One of the important complications seen in these patients is pancreatitis, related to high triglyceride levels. It can be recurrent and the episodes can be more severe compared to the general patient population. Metreleptin, the human leptin analogue, is the only disease-specific treatment for lipodystrophy syndromes and it has been shown to reduce the complications of leptin deficiency, but it is not currently approved for FPLD in the USA. Previous studies showed improvement of the complications of FPLD with its use. Our case is a 29-year-old woman who has Dunnigan type FPLD with a history of numerous bouts of pancreatitis while on fenofibrate, statin and omega-3-acid ethyl esters, later was on metreleptin for almost 3 years, presented to our hospital with typical symptoms of acute pancreatitis incited by severe hypertriglyceridemia (&amp;gt;1,500 mg/dL). Lipase levels were high at 27,501. Patient was treated with vigorous intravenous hydration, insulin and home metreleptin was continued at the hospital. Despite the initial improvement of the symptoms, on the 6th day of hospitalization, she developed worsening abdominal pain, nausea, and vomiting. CT angiogram of the abdomen showed 2.0 cm splenic artery pseudoaneurysm. Coiled embolization of the superior segmental branch of the splenic artery performed by interventional radiologist which was further complicated by splenic infarction. Her condition improved eventually, she was able to be discharged home. Importance of adherence to medications and special diet was discussed with the patient in length. This case report aims to bring attention to this rare disease and urgent need for further treatment options for these patients to prevent serious complications in this young patient population. Metreleptin is a daily injection which could be challenging to adherence and the consequence can be relapse of pancreatitis. Lack of other treatment options, treatment availability, physician awareness are barriers to optimize the treatment for these complex patients. Presentation: Saturday, June 17, 2023

SAT674 Lipodystrophy: A Hidden Culprit In Uncontrolled Diabetes

Abstract Disclosure: F. El Sayed: None. A. Banka: None. Introduction: Lipodystrophies are rare disorders with selective absence/accumulation of fat tissue. The “common” genetic forms include Congenital Generalized Lipodystrophy or Familial Partial Lipodystrophy (FPLD). Non-genetic factors like autoimmune disorders, chronic infections, or malnutrition can also contribute to a lipodystrophy phenotype. Clinical case: A 49-year-old female with diabetes mellitus, hypertriglyceridemia, gait disturbances, hypertension, hereditary hemorrhagic telangiectasias, asthma, presents with suspected lipodystrophy. She notes truncal obesity as a child, with progression as an adult and subsequent loss of volume from her arms and legs around age 30. Family history is significant for multiple family members with diabetes mellitus. On physical exam, the patient has a BMI of 22.86 kg/m2. She walks with a cane and has abdominal fat deposition, a dorsocervical fat pad, and reduced fat and muscle mass in her lower extremities. Her diabetes is poorly controlled with multiple complications including retinopathy, microalbuminuria, neuropathy, CVA, and CAD. Her medications include metformin, pioglitazone, detemir, aspart, and an insulin sliding scale for diabetes management, and rosuvastatin, fenofibrate, and omega-3-acid ethyl esters for hyperlipidemia. Her last A1C was 12.7%, and urine analysis was positive for glucosuria and ketonuria. Her lipid panel revealed high triglycerides (800s) and low HDL levels. Other pertinent labs include elevated GDF15 at 761 pg/mL. and lactate elevation at 3.4 mml/L. Given suspicion for hypercortisolism, she underwent a dexamethasone suppression test which was negative for Cushing’s disease. She subsequently underwent exome sequencing with mitochondrial deletion testing, which led to the diagnosis of FPLD. Discussion: FPLD results in loss of fat from the extremities starting around puberty, often leading to metabolic complications. Although both sexes are affected, women usually present with more severe disease. Currently, multiple genes are associated with FPLD, most commonly LMNA and PPARG which both follow autosomal dominant inheritance. Conclusion: Presently, there is no cure for lipodystrophy syndromes. However, in patients with diabetes and resistant metabolic syndrome features, a diagnosis of lipodystrophy should be considered. Further evaluation with genetic testing is warranted and has implications for family planning and medical management. Presentation: Saturday, June 17, 2023