RARE DISEASE
Acquired partial lipodystrophy
Acquired partial lipodystrophy
Acquired partial lipodystrophy
Synonyms: Barraquer-Simons syndrome, Progressive cephalothoracic lipodystrophy
Synonyms: Barraquer-Simons syndrome, Progressive cephalothoracic lipodystrophy
Synonyms: Barraquer-Simons syndrome, Progressive cephalothoracic lipodystrophy
Drug discovery
1
drug
With orphan designation
Overview
Acquired partial lipodystrophy (APL) is a rare adipose tissue disorder characterized by progressive, symmetric fat loss in the face, neck, arms, and upper trunk, often with lower-body sparing or lipohypertrophy. It typically emerges in childhood/adolescence, shows female predominance (4:1 ratio), and associates with C3 hypocomplementemia, C3-nephritic factor, and renal complications like C3 glomerulopathy [1][6][12]. Metabolic disturbances (insulin resistance, dyslipidemia) occur less frequently than in other lipodystrophies [1][4].
Therapies
Metabolic management: Insulin sensitizers (metformin), lipid-lowering agents (statins), and dietary modification [8][17]
Targeted therapies: Anti-complement agents (e.g., eculizumab) for C3 glomerulopathy; experimental adipose transplantation [6][12]
Adjunctive care: Psychological support and cosmetic interventions (fat grafting) [8][16]
Categories: rare endocrine diseases, rare skin diseases
Research Papers
167 drug discovery papers about Acquired partial lipodystrophy, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
167 drug discovery papers about Acquired partial lipodystrophy, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-01-01 | O-30 AUTOSOMAL RECESSIVE LIPE PATHOGENIC VARIANT-ASSOCIATED FAMILIAL PARTIAL LIPODYSTROPHY TYPE 6
Abstract Introduction Lipodystrophy is a rare and heterogeneous disorder characterized by selective loss or abnormal redistribution of adipose tissue, leading to metabolic complications such as insulin resistance, diabetes mellitus, hepatic steatosis, and dyslipidemia. Lipodystrophy is divided into 4 main groups: congenital generalized lipodystrophy (CGL), familial partial lipodystrophy (FPLD), acquired generalized lipodystrophy (AGL), and acquired partial lipodystrophy (APL). FPLD is caused by mutations is genes regulating adipocyte function and lipid metabolism, with six subtypes identified to date. Among these, type 6 (FPLD6) results from inactivating mutation in the LIPE gene, which encodes hormone-sensitive lipase (HSL). Here, we present a very rare case of autosomal recessive familial partial lipodystrophy type 6. Clinical Case A 34-year-old female was referred for evaluation of suspected Cushing’s syndrome. She was receiving hormone replacement therapy for primary ovarian insufficiency and had no other known medical conditions. She had gestational diabetes during her second pregnancy, managed with diet alone. Over three years she gained 29 kg (BMI 35.2 kg/m²). Family history revealed parental consanguinity. Physical examination revealed characteristic cushingoid features including a prominent buffalo hump, supraclavicular fat pads, and centripetal obesity. She had fat accumulation in the upper body while subcutaneous fat was markedly reduced in the extremities and breasts (Figure 1). Acanthosis nigricans was noted in the axillary and cervical regions. Additionally, she had undergone a cosmetic liposuction procedure targeting the deltoid and occipital regions. Low-dose dexamethasone testing excluded Cushing’s syndrome. Oral glucose tolerance test indicated insulin resistance; triglycerides were elevated, while leptin was normal. Laboratory results are summarized in Table 1. Whole-body DXA demonstrated markedly reduced fat mass in the upper and lower extremities, with central fat accumulation. This distribution was compatible with partial lipodystrophy. FibroScan revealed advanced hepatic steatosis (S3) without fibrosis (F0), consistent with nonalcoholic fatty liver disease (NAFLD). Genetic analysis identified a homozygous pathogenic LIPE gene variant (c.2182G>A), confirming the diagnosis of autosomal recessive familial partial lipodystrophy type 6. Treatment with metformin, SGLT-2 inhibitor, and fenofibrate was initiated, alongside lifestyle modification and genetic counseling. Conclusion FPLD6 is a very rare subtype of familial partial lipodystrophy. Unlike other subtypes, it is caused by LIPE mutations leading to defective lipolysis, and typically presents in adulthood rather than early life. It is further characterized by severe insulin resistance, dyslipidemia, and hepatic steatosis. In addition, the presence of subcutaneous lipomas distinguishes FPLD6 from other many forms and may lead to diagnostic confusion with multiple lipomatosis.Figure 1:a.Sagittal magnetic resonance imaging (MRI) of the neck and cervical spine region demonstrating abnormal fat distribution consistent with partial lipodystrophy b.Dual-energy X-ray absorptiometry (DEXA) scan demonstrating body composition c.Posterior view of the trunk showing loss of peripheral fat and abnormal fat deposition in the upper body Table 1:Biochemical parameters of the patientIR: insulin resistance
2025-10-01 | SUN-646 Immune Landscape and Clinical Characteristics of Patients with Acquired Partial and Generalized Lipodystrophy Syndromes
Abstract Disclosure: O. Besci: None. C.D. Uwandu: None. U. Cavdar: None. B. Akinci: None. D. Gilio: None. M.C. Foss de Freitas: None. K. Walkovich: None. E.A. Oral: Regeneron Pharmaceuticals, Rhythm Pharmaceuticals, Novo Nordisk, Amryt Pharmaceuticals, Ionis Pharmaceuticals Inc., Morphic Medical, Rejuvenate Bio, Fractyl Laboratories. Introduction: Acquired lipodystrophy syndromes (ALS) are characterized by loss of adipose tissue and associated metabolic abnormalities, manifesting in either partial (APL) or generalized forms (AGL). Increasing evidence of ALS links to autoimmunity, infections, malignancies, and associated treatments highlights the need for an understanding of the associated immune-mediated mechanisms. Objective: We sought to provide immune-related insights on ALS by correlating coexisting disorders with their underlying immune mechanisms and identifying patterns of phenotypic presentations via comprehensive case review and literature analysis. Methods: We retrospectively reviewed all cases from the University of Michigan (n = 30) and published cases (n = 462). We systematically searched PubMed for ALS studies published in English with full-text availability from 2004 to the present (last accessed: December, 2024) and reviewed references from comprehensive studies (1919-2004) to identify phenotypical descriptions matching the published diagnostic criteria for AGL and APL1,2. Barraquer-Simons syndrome and phenotypes resembling Dunnigan syndrome, with lipoatrophy in the extremities and fat retention in the face, neck, and abdomen, were classified as APL. Cases were categorized based on immune mechanisms and presenting phenotypes. Results: In our analysis of 492 patients with ALS, 32% (n=159) had AGL and 68% (n=333) had APL. ALS with autoimmune disorders was significantly more common in AGL compared to APL (39% vs 26%, p=0.004), as was ALS with regulatory T cell defects (7% vs. 1%, p<0.001), colitis (7% vs. 2%, p=0.01) and panniculitis (26% vs. 1%, p<0.001). ALS associated with malignancy, involving immune checkpoint inhibitors (7% vs. 1%, p<0.001), lymphoma (6% vs. <1%, p<0.001), and paraneoplastic syndromes (2% vs. <1%, p=0.04) predominantly exhibited the AGL phenotype, whereas prior exposure to HSCT/TBI was significantly associated with the APL phenotype (5% vs. <1%, p=0.01). While C3 deficiency was significantly more common in APL compared to AGL (39% vs 4%, p<0.001), C4 deficiency was more frequently observed in AGL than in APL (5% vs 1%, p=0.02). Conclusion: Our study highlights the diverse clinical manifestations of patients with APL and AGL, emphasizing ALS with autoimmune disorders, regulatory T-cell defects, lymphoma, panniculitis and colitis are predominantly linked to the AGL, while complement deficiencies and prior HSCT/TBI exposure are more frequently associated with APL. References: 1. Misra A, Garg A. Clinical features and metabolic derangements in acquired generalized lipodystrophy: case reports and review of the literature. Medicine (Baltimore). 2003. 2. Misra A, Peethambaram A, Garg A. Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: report of 35 cases and review of the literature. Medicine (Baltimore). 2004. Presentation: Sunday, July 13, 2025
2025-10-01 | SUN-645 Leptin- And Incretin-based Combination Therapy In Lipodystrophy: A Promising Metabolic Strategy?
Abstract Disclosure: M. Celik Guler: None. R. Meral: None. M. Lightbourne: None. O. Besci: None. A. Neidert: None. M.C. Foss de Freitas: None. R.J. Brown: Pfizer, Inc., Regeneron Pharmaceuticals, Chiesi Farmaceutici, Marea Therapeutics. E.A. Oral: Ionis Pharmaceuticals Inc., Novo Nordisk, Chiesi Farmaceutici, Rhythm Pharmaceuticals, Marea Therapeutics, Rejuvenate Bio, Fractyl, Morphic Medical, Regeneron Pharmaceuticals. Lipodystrophy syndromes (LD) are rare disorders characterized by partial or generalized loss of adipose tissue and significant metabolic disturbances. Metreleptin (ML) remains the cornerstone of treatment for generalized lipodystrophy (GL); however, its efficacy in partial lipodystrophy (PL) can be limited, highlighting the need for alternative or incremental therapies to achieve optimal metabolic control. We hypothesize that combining leptin-based therapies, such as ML or leptin receptor agonists like mibavademab (investigational product), with incretin-based agents may offer a promising therapeutic strategy to enhance metabolic outcomes in this population. We report 6 patients taking ML or mibavademab for clinical or compassionate use in whom incretin-based therapies were added to enhance metabolic control, with outcomes prospectively followed. P1 (25-year-old, congenital generalized lipodystrophy (CGL) type 1, treated with metreleptin for 2.5 years): following the addition of semaglutide for 8 months, HbA1c reduced from 8.7% to 5.6%, BMI from 24.7 to 21.9 kg/m², and triglycerides (TG) from 2261 to 33 mg/dL. P2 (36-year-old, acquired GL, treated with metreleptin for 18 years): after 9 months of tirzepatide treatment, HbA1c reduced from 9.1% to 6.5%, BMI from 19.5 to 17.6 kg/m², and TG from 1240 to 100 mg/dL. P3 (25-year-old, LMNA related GL (with T10I variant), treated with mibavademab for 4 years): after adding dulaglutide for 5 months, HbA1c reduced from 8.9% to 7.3%, with stable BMI (14.4 kg/m²) and no change in TG (265 to 273 mg/dL). P4 (44-year-old, familial partial lipodystrophy type 2 (FPLD2), treated with metreleptin for 3.5 years): after 17 months of tirzepatide therapy, HbA1c reduced from 6.6% to 5.1%, BMI from 18.2 to 16.2 kg/m², and TG from 298 to 104 mg/dL. P5 (23-year-old, atypical PL, previously treated with mibavademab for 5 years and 10 months): Following initiation of tirzepatide for 4 months, there was no change in HbA1c (10.1% to 10.5%) or BMI (27.1 to 27.3 kg/m²) but a 49% reduction in TG (1764 to 895 mg/dL) was observed. P6 (52-year-old, FPLD2, treated with metreleptin for 10 years): initiation of tirzepatide for 5 months led to reductions in HbA1c (6.8% to 5.7%), BMI (26.0 to 21.8 kg/m²), and TG (279 to 127 mg/dL). There were no unexpected adverse events with combination therapy, but patient P5 had an episode of pancreatitis at month 5 due to running out of her insulin and worsening glucose control. In summary, combined leptin-based and incretin-based therapies may enhance metabolic outcomes in lipodystrophy. Future randomized controlled trials are needed to evaluate the efficacy of incretin-based therapies either with or without leptin pathway treatments to confidently determine the extent of benefit of combination therapy in lipodystrophy. Presentation: Sunday, July 13, 2025
2025-09-02 | Clinical Guidance for Lipodystrophy Syndromes: From Diagnosis and Work-Up to Treatment
Clinical and metabolic assessments, along with genetic analyses, are essential for tailoring medical care and providing appropriate genetic counseling. Efforts are underway to develop more objective diagnostic tools using imaging techniques or novel biomarkers. Leptin therapy has been a significant breakthrough for generalized lipodystrophy treatment; however, more effective treatments are still needed for partial and acquired forms. While gene editing and transcript modification strategies are being explored for specific forms of lipodystrophy, reducing the burden on adipocytes by lowering caloric intake remains a fundamental approach across all forms of the condition. As supporting data emerge, agents that reduce caloric intake may become integral to treatment algorithms. This review offers practical guidance for clinicians managing patients with lipodystrophy, highlighting advances in diagnosis, treatment, and ongoing challenges in clinical care.
2024-01-04 | The blockade of the TGF-β pathway alleviates abnormal glucose and lipid metabolism of lipodystrophy not obesity.
Abstract TGF‐β is thought to be involved in the physiological functions of early organ development and pathological changes in substantial organ fibrosis, while studies around adipose tissue function and systemic disorders of glucolipid metabolism are still scarce. In this investigation, two animal models, aP2‐SREBP‐1c mice and ob/ob mice, were used. TGF‐β pathway showed up‐regulated in the inguinal white adipose tissue (iWAT) of the two models. SB431542, a TGF‐β inhibitor, successfully increased inguinal white adipocyte size by more than 1.5 times and decreased the weight of Peripheral organs including liver, Spleen and Kidney to 73.05%/62.18%/73.23% of pre‐administration weights. The iWAT showed elevated expression of GLUTs and lipases, followed by a recovery of circulation GLU, TG, NEFA, and GLYCEROL to the wild‐type levels in aP2‐SREBP‐1c mice. In contrast, TGF‐β inhibition did not have similar effects on that of ob/ob mice. In vitro, TGF‐β blocker treated mature adipocytes had considerably higher levels of glycerol and triglycerides than the control group, whereas GLUTs and lipases expression levels were unchanged. These findings show that inhibiting the abnormally upregulated TGF‐β pathway will only restore iWAT expansion and ameliorate the global metabolic malfunction of glucose and lipids in lipodystrophy, not obesity.
antibodies
2025-03-29 | Acquired partial lipodystrophy (Barraquer-Simons syndrome) with both-side axillary breasts: A case report.
Lipodystrophies are conditions characterized by a loss of subcutaneous fat, which can be congenital or acquired, and present in various patterns of fat distribution. Accurate diagnosis is essential for identifying comorbidities and ensuring appropriate multidisciplinary care and targeted treatments. A 34-year-old female experienced significant facial changes and increased abdominal fat over five years. She had lumps under her armpits discharging white fluid, with clinical findings of low hemoglobin and accessory breast tissue, which was surgically excised. Acquired generalized lipodystrophy is often overlooked, with over 250 documented cases. It typically presents in adolescence and involves symmetrical fat loss, with potential associations to autoimmune diseases and unique features in this case. This case emphasizes the complexities of acquired lipodystrophy, especially regarding accessory breast tissue. It highlights the need for thorough evaluations and increased awareness among healthcare providers for timely diagnosis and management.
2024-06-19 | Leptin replacement therapy in the management of lipodystrophy syndromes.
Lipodystrophy syndromes are rare diseases of genetic or acquired origin, characterized by quantitative and qualitative defects in adipose tissue. The metabolic consequences of lipodystrophy syndromes, such as insulin resistant diabetes, hypertriglyceridemia and hepatic steatosis, are frequently very difficult to treat, resulting in significant risks of acute and/or chronic complications and of decreased quality of life. The production of leptin by lipodystrophic adipose tissue is decreased, more severely in generalized forms of lipodystrophy, where adipose tissue is absent from almost all body fat depots, than in partial forms of the disease, where lipoatrophy affects only some parts of the body and can be associated with increased body fat in other anatomical regions. Several lines of evidence in preclinical and clinical models have shown that leptin replacement therapy could improve the metabolic complications of lipodystrophy syndromes. Metreleptin, a recombinant leptin analogue, was approved as an orphan drug to treat the metabolic complications of leptin deficiency in patients with generalized lipodystrophy in the USA or with either generalized or partial lipodystrophy in Japan and Europe. In this brief review, we will discuss the benefits and limitations of this therapy, and the new expectations arising from the recent development of a therapeutic monoclonal antibody able to activate the leptin receptor.
2013-03-06 | Choroidal Neovascularization in Acquired Partial Lipodystrophy
PurposeTo report a case of choroidal neovascularization (CNV) associated with acquired partial lipodystrophy (PLD). MethodsA 55-year-old woman with a known history of PLD presented with acute onset visual loss affecting her right eye and underwent investigations to diagnose the underlying pathology. ResultsFluorescein angiography and time-domain optical coherence tomography demonstrated the presence of intraretinal edema consistent with CNV. The patient was treated with intravitreal ranibizumab with excellent results, and her vision remains unimpaired 4 years posttreatment. ConclusionsChoroidal neovascularization is an angiogenic process that can occur following retinal pigment epithelium disruption of any cause. These vessels may then bleed into retinal tissue, with potentially devastating visual consequences. Although rare, PLD has been associated with retinal drusenoid lesions. This is the first case to report CNV in association with PLD, and highlights the importance of considering CNV in the differential diagnosis of acute visual loss in patients with drusenoid diseases such as PLD.
2009-08-01 | Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC.
Lipodystrophic syndromes are characterized by adipose tissue deficiency. Although rare, they are of considerable interest as they, like obesity, typically lead to ectopic lipid accumulation, dyslipidaemia and insulin resistant diabetes. In this paper we describe a female patient with partial lipodystrophy (affecting limb, femorogluteal and subcutaneous abdominal fat), white adipocytes with multiloculated lipid droplets and insulin-resistant diabetes, who was found to be homozygous for a premature truncation mutation in the lipid droplet protein cell death-inducing Dffa-like effector C (CIDEC) (E186X). The truncation disrupts the highly conserved CIDE-C domain and the mutant protein is mistargeted and fails to increase the lipid droplet size in transfected cells. In mice, Cidec deficiency also reduces fat mass and induces the formation of white adipocytes with multilocular lipid droplets, but in contrast to our patient, Cidec null mice are protected against diet-induced obesity and insulin resistance. In addition to describing a novel autosomal recessive form of familial partial lipodystrophy, these observations also suggest that CIDEC is required for unilocular lipid droplet formation and optimal energy storage in human fat.
2009-02-12 | Complement abnormalities in acquired lipodystrophy revisited.
Lipodystrophy is a heterogeneous condition characterized by an inherited or acquired deficiency in the number of adipocytes required for the storage of energy as triglycerides. Acquired lipodystrophy is frequently associated with other autoimmune disorders. One well-studied form is characterized by the selective loss of upper body fat in association with activation of the alternative complement pathway by C3 nephritic factor, low complement factor C3, and mesangiocapillary glomerulonephritis. We now describe an immunologically distinct form of acquired generalized lipodystrophy, with evidence of activation of the classical complement pathway (low C4) and autoimmune hepatitis. Patients and Research Design: Three unrelated patients with acquired lipodystrophy and low complement C4 levels are described. In vitro analysis of the complement pathway was undertaken to determine the reason for the low C4 complement levels. Biopsies were obtained from liver, bone marrow, and adipose tissue for histological analysis. All three patients manifested near-total lipodystrophy, chronic hepatitis with autoimmune features, and low C4 complement levels. Additional autoimmune diseases, including severe hemolytic anemia, autoimmune thyroid disease, and polyneuropathy, were variably present. Detailed studies of complement pathways suggested constitutive classical pathway activation. Although the previously described syndrome, which typically results in a cephalad pattern of partial lipodystrophy, results from activation of the alternative complement pathway, this form, in which lipodystrophy is generalized, is associated with activation of the classical pathway. Future therapeutic approaches to these disorders may benefit from being tailored to their distinct immunopathogenesis.
cell therapies
2025-05-30 | Surgical Management of Lipodystrophy in Barraquer-Simons Syndrome: Autologous Fat Redistribution and Reconstructive Strategies for Acquired Partial Lipodystrophy
Background: Barraquer-Simons Syndrome (BSS), a rare form of acquired partial lipodystrophy, is characterized by progressive adipose tissue loss in the cephalothoracic region, often with paradoxical fat accumulation in the lower body. This condition presents significant metabolic and aesthetic challenges, necessitating multidisciplinary management. Fat redistribution surgery (FRS) has emerged as a potential therapeutic approach to restore facial and upper body contour while addressing metabolic complications. Objective: This article reviews the surgical techniques, outcomes, and long-term efficacy of autologous fat grafting and liposuction-based fat redistribution in BSS patients, with a focus on optimizing functional and cosmetic results. Methods: A comprehensive literature review was conducted, analyzing case reports, clinical studies, and surgical outcomes in BSS patients undergoing fat redistribution procedures. Special emphasis was placed on patient selection, surgical planning, and postoperative metabolic implications. Results: Preliminary evidence suggests that autologous fat transfer from areas of lipohypertrophy (e.g., lower extremities) to atrophic regions (e.g., face, arms, and trunk) can improve both aesthetic and psychosocial outcomes. However, long-term fat graft retention remains variable, and metabolic stability post-surgery requires further investigation. Conclusion: Fat redistribution surgery offers a promising reconstructive option for BSS patients, though individualized surgical planning and close metabolic monitoring are essential. Further prospective studies are needed to standardize techniques and assess durability.
2024-09-27 | Successful fat transplant in a rare acquired lipodystrophy Barraquer–Simons syndrome
Lipodystrophies can be generalized and partial/localized lack of subcutaneous tissue, which are uncommon heterogeneous illnesses that can be hereditary or acquired. Acquired partial lipodystrophy’ (APL) is the new name for lipodystrophia progressiva, also known as Barraquer–Simons syndrome (BSS). It could come after a severe viral infection like the measles. Young people and children both experience it. Typically, BSS or APL starts between the ages of 5 and 15. The principal feature of BSS is cephalothoracic lipodystrophy, which affects the face, neck, arms, thorax, and upper abdomen in a cephalocaudal pattern. Alternate complement pathway activation and C3 hypocomplementemia with adipocyte lysis brought on by complement 3 nephritic factor (C3NeF) have been suggested as potential causes of fat loss in individuals with APL, even though the precise process is still mostly understood. Therapeutic options for lipodystrophy include fat fillers. Different types of autologous fat transplants are possible. Autologous free fat graft where a mass of tissue harvested from any discrete subcutaneous location and implanted at a recipient site. Dermofat grafts are made from tissue that has been removed from a region, allowing for the removal of full-thickness skin grafts and the primary closure of defects. The dermofat graft can be employed as a spacer between gliding tissues or as a filler. Omental flaps, which are revascularized fat flaps, can be utilized for microvascular transfer, soft-tissue filler for hemifacial atrophy, or to cover any significant skin defects. When fat is extracted, processed, and transplanted in liquid injectable form for a variety of purposes, it is known as free fat injection.
2020-02-14 | Safety and Localization of Mesenchymal Stromal Cells Derived from Human Adipose Tissue-Associated Hyaluronic Acid: A Preclinical Study
Millions of plastic surgeries are performed worldwide every year with the objective of correcting lipodystrophies stemming from lesions, tumor resections, birth defects, and AIDS-associated antiretroviral therapy. Besides that, a large number of clinical research have assessed the outcome of procedures that rely on combinations of dermal fillers and autologous cells. However, little is known about the safety of these combinations and the localization of the injected cells. The aim of this study was to test the toxicity of a solution containing 1% hyaluronic acid (HA) and adipose-derived stromal cells (ASCs) from the human adipose tissue and to assess the localization of the injected cells, with and without HA, labeled with technetium-99m. Rats received subcutaneous and intraperitoneal injections of a solution containing 1% HA/adipose-derived stromal cells isolated from the human fat tissue. The animals were then observed for up to forty-two days. The solution tested in this study did not result in systemic, biochemical, or anatomic alterations that could represent toxicity symptoms. The association of HA and ASCs labeled with technetium-99m remained at the site of the injection within a period of twenty-four hours, as demonstrated by a whole-body imaging software fusion of SPECT and CT. In conclusion, our study shows that the subcutaneous and intraperitoneal injection of HA associated with adipose-derived stromal cells (ASCs) is safe. The association of HA and ASCs did not induce local or systemic toxicity. Thus, the administration of volume equal to or less than 0.2 mL of the agent filler (1 × 106 ASC+HA 1%) should be considered for subsequent studies and may be an alternative to dermal fillers due to the expected lasting effects.
2018-12-10 | Visceral fat does not contribute to metabolic disease in lipodystrophy
Lipodystrophies are characterized by regional or generalized loss of adipose tissue and severe metabolic complications. The role of visceral adipose tissue (VAT) in the development of metabolic derangements in lipodystrophy is unknown. The study aim was to investigate VAT contribution to metabolic disease in lipodystrophy versus healthy controls.Analysis of correlations between VAT volume and biomarkers of metabolic disease in 93 patients and 93 age/sex-matched healthy controls.Patients with generalized lipodystrophy (n = 43) had lower VAT compared with matched controls, while those with partial lipodystrophy (n = 50) had higher VAT versus controls. Both groups with lipodystrophy had lower leg fat mass versus controls (p < 0.05 for all; unpaired t-test). In both generalized and partial lipodystrophy, there was no correlation between VAT and glucose, triglycerides or high-density lipoprotein cholesterol (p > 0.05 for all; Spearman correlation). In controls matched to patients with generalized or partial lipodystrophy, VAT correlated with glucose (R = 0.42 and 0.36), triglycerides (R = 0.36 and 0.60) and high-density lipoprotein cholesterol (R = -0.34 and -0.64) (p < 0.05 for all; Spearman correlation).In contrast to healthy controls, metabolic derangements in lipodystrophy did not correlate with VAT volume. These data suggest that, in lipodystrophy, impaired peripheral subcutaneous fat deposition may exert a larger effect than VAT accumulation on the development of metabolic complications. Interventions aimed at increasing functional subcutaneous adipose tissue may provide metabolic benefit.
2017-02-13 | Barraquer-Simons syndrome: a unique patient's perspective on diagnosis, disease progression and recontouring treatment.
This case report describes a female patient diagnosed with Barraquer-Simons syndrome, a rare form of acquired partial lipodystrophy characterised by symmetrical loss of adipose tissue from face, neck, upper extremities and the trunk with onset in early childhood. Initial symptoms were seen at the age of 8 years. Our patient did not show signs of renal impairment and this may be associated with the syndrome. Treatment of lipoatrophy in these patients is limited to cosmetic restoration, and autologous fat grafting has shown sustained positive effects with no or very little loss of volume at follow-ups. Furthermore, the treatment has resulted in considerable improvements in her quality of life and daily functioning. She has not experienced any adverse effects. Accurate and early diagnosis is important, and clinicians should consider early intervention for these patients. Autologous fat grafting is recommended as a safe procedure.
proteins
2026-07-09 | Case Report: Dramatic metabolic improvement with tirzepatide in a patient with acquired partial lipodystrophy following hematopoietic stem cell transplantation.
Acquired lipodystrophy is a rare disorder characterized by adipose tissue loss or dysfunction and is frequently associated with severe insulin resistance and metabolic complications. Metabolic complications of lipodystrophy have occasionally been reported after hematopoietic stem cell transplantation (HSCT), but their clinical features and optimal treatment strategies remain poorly defined. Tirzepatide, a dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, has recently emerged as a novel therapy for type 2 diabetes. We report a 37-year-old woman who underwent allogeneic HSCT at 12 years of age for relapsed acute lymphoblastic leukemia after a conditioning regimen including total body irradiation (TBI), high-dose cytarabine, and melphalan. She subsequently developed diabetes mellitus and fatty liver disease at 17 years of age. Although no apparent fat loss was initially recognized, lipodystrophy was clinically suspected based on severe insulin resistance and metabolic abnormalities disproportionate to her body habitus. Computed tomography at 37 years of age revealed region-specific fat loss extending from the lower back to the gluteal region. Glycemic control remained inadequate despite high-dose insulin therapy and sequential treatment with several GLP-1 receptor agonists. After initiation of tirzepatide, glycemic control improved dramatically, allowing complete discontinuation of insulin therapy. Body weight decreased modestly and hepatic steatosis improved. The high-molecular-weight (HMW)/total adiponectin ratio after treatment was elevated (64.0%), suggesting possible improvement in adipocyte secretory function. This case highlights acquired partial lipodystrophy developing after HSCT, supported by region-specific fat loss and characteristic metabolic abnormalities, and demonstrates a marked therapeutic response to tirzepatide. Dual incretin receptor agonism may represent a promising therapeutic strategy for severe insulin resistance associated with adipose tissue dysfunction, potentially through both weight-dependent and weight-independent mechanisms.
2026-02-17 | Lipodystrophies in Clinical Practice: A Case Series From a Local Health Unit in Portugal
Background Lipodystrophies are rare disorders characterized by loss of adipose tissue, leading to severe metabolic and multisystem complications. Data on real-world management remain limited, particularly in Portugal. Objectives The objective of this study is to describe the clinical, metabolic, genetic, and therapeutic characteristics of patients with confirmed or suspected lipodystrophy followed at a Portuguese Endocrinology Outpatient Clinic. Methods We conducted a retrospective observational study including 21 patients with clinical suspicion or diagnosis of lipodystrophy. Demographic, clinical, laboratory, imaging, and genetic data were collected. Results The cohort was predominantly female (90.5%) with a median age at diagnosis of 49 years. Sixteen patients (76.2%) had familial partial lipodystrophy (FPLD), two (9.5%) had congenital generalized lipodystrophy, two (9.5%) had acquired generalized lipodystrophy, and one presented a complex syndromic form. Diabetes mellitus was present in 71.4% of patients and hypertriglyceridemia in 52.4%. Metabolic liver disease occurred in both generalized and partial forms. Autoimmune disorders affected 31.6% of patients, and cardiac involvement was observed in 23.8%. Genetic testing identified pathogenic or likely pathogenic variants in BSCL2 and PPARG in three patients, while most FPLD cases remained genetically unexplained. Metreleptin therapy in three patients with generalized lipodystrophy improved glycemic control, triglycerides, liver enzymes, and proteinuria. Dual-energy X-ray absorptiometry imaging supported the phenotypic characterization of adipose tissue loss. Conclusions Detailed physical examination, genetic testing, imaging, and early therapeutic interventions are critical for management. These findings align with European registry data and highlight the need for increased awareness and systematic evaluation in real-world clinical practice.
2025-10-01 | MON-682 Acquired Generalized Lipodystrophy Treated With Metreleptin in a Patient With Total Body Irradiation and Chronic Graft-Versus-Host Disease
Abstract Disclosure: T. Moazezi: None. B. Salehian: None. Background: Acquired lipodystrophy, both partial and generalized, is a rare disease that can be seen in patients with a history of total-body irradiation (TBI) and hematopoietic stem cell transplantation (HSCT). The widespread metabolic complications that arise from this disorder warrant attention and treatment. Clinical Case: A 25-year-old female with a history of Non-Hodgkin Lymphoma status post TBI and HSCT in 2000 and 2004 complicated by chronic graft-versus-host disease (GVHD) presented with multiple endocrinopathies to the endocrinology clinic. She presented with type 2 diabetes mellitus with severe insulin resistance, severe hypertriglyceridemia, and non-alcoholic steatohepatitis. The patient weighed 36.7 kg with a BMI of 14.3 kg/m2. On physical exam, the patient had complete loss of subcutaneous fat mass in the chest, abdomen, upper and lower extremities, and palmar-plantar region; there was minimal appreciable subcutaneous fat in the face and supraclavicular region. Abdominal exam revealed visceral fat and hepatomegaly with percussion of the liver 5 cm below the costal margin. The quantitative adiponectin level was low at 3.1 ug/mL (2.0-19.3 ug/mL), and the diagnosis of acquired generalized lipodystrophy (AGL) was made. Laboratory work-up was notable for SGOT 50 U/L (15-46 U/L), SGPT 88 U/L (7-56 U/L), glucose of 435 mg/dL (80-128 mg/dL), hemoglobin A1c 14.4% (<=6.4%), C-peptide 9.7 ng/mL (0.8-3.5 ng/mL), fasting triglyceride 4268 mg/dL (<=150 mg/dL), total cholesterol 297 mg/dL (<=200 mg/dL), HDL 34 mg/dL (>=39 mg/dL), and LDL 32 mg/dL (<=100 mg/dL). Abdominal ultrasound with elastography showed hepatomegaly, fatty liver, mild-moderate fibrosis. The patient was treated with statin, fish oil, gemfibrozil, Humulin R U-500 insulin, insulin pump, pioglitazone, and multiple oral hypoglycemic agents, and her metabolic complications were refractory to these standard therapies. She was started on treatment with metreleptin by subcutaneous injection for treatment of AGL. The dose was titrated upwards as tolerated, and the patient had improvement in her metabolic parameters while on treatment, including improved insulin sensitivity and lipoprotein profile. Metreleptin was discontinued after two years due to significant pain at the injection site. She was referred to plastic surgery to assess for auto-transplantation of adipose tissue, which was not an option due to complete loss of subcutaneous adipose tissue. Conclusion: Childhood cancer survivors with a history of TBI and HSCT can develop acquired lipodystrophy with associated metabolic complications later in life. This case demonstrates the role of metreleptin in improving insulin sensitivity and lipoprotein profiles in a patient with AGL. Presentation: Monday, July 14, 2025
2025-10-01 | MON-622 Severe Insulin Resistance in a Patient with Generalized Lipodystrophy
Abstract Disclosure: D. Kaul: None. M. Paravastu: None. M. Shah: None. R. Patel: None. T. Yasmeen: None. M.H. Kazi: None. Introduction: Lipodystrophy is classified into two main types: generalized and partial, based on the extent of fat loss and further as genetic or acquired, depending on its underlying cause. The prevalence ranges from 1 in 1 million for familial partial lipodystrophy to 1 in 10 million for congenital generalized lipodystrophy. Its manifestation often includes severe metabolic disturbances, including dyslipidemia, insulin resistance, and increased risks of renal, hepatic, and cardiovascular diseases.Clinical Case: A 72-year-old female with type 2 diabetes, chronic kidney disease stage 3, and hyperlipidemia presented with hyperglycemia, severe weight loss, polydipsia, and polyuria. Her diabetes regimen included insulin degludec U-200 (76 units daily), insulin aspart (35 units with meals), and Trulicity (3 mg weekly). She reported missing several doses of insulin and had lost 78 lbs over the past year. On exam, she had generalized subcutaneous fat loss, weighing 54.1 kg with a BMI of 18.68 kg/m². Labs showed a glucose level of 614 mg/dL (normal range: 70-99 mg/dL), without evidence of diabetic ketoacidosis, HbA1c of 8.2% (normal range: 4.5-5.6%), C-peptide of 8.9 ng/mL (normal range: 0.8-3.9 ng/mL), and a triglyceride level of 36 mg/dL (normal range: <=149 mg/dL). Due to severe hyperglycemia, a continuous insulin infusion was started, requiring 931 units over 24 hours plus 100 units of insulin glargine. Given her phenotype and insulin resistance, lipodystrophy was suspected. Leptin was <0.4 ng/mL (normal range: 0.5-15.2 ng/mL), and Cushing syndrome was ruled out with a screening test, confirming generalized lipodystrophy. She was started on metreleptin and discharged with insulin degludec U-200 (90 units twice daily), insulin aspart (60 units three times daily), tirzepatide (2.5 mg weekly), and empagliflozin (25 mg daily).Discussion: Insulin resistance in lipodystrophy arises from the lack of functional adipose tissue, impairing the body’s ability to store excess energy as fat. This leads to ectopic fat deposition in the liver and muscle, disrupting insulin signaling. Leptin replacement therapy is a key treatment, as low leptin levels—due to reduced adipose tissue—contribute significantly to the metabolic abnormalities seen in lipodystrophy. Metreleptin, along with dietary modifications, is the first-line treatment, improving insulin sensitivity, reducing nonalcoholic steatohepatitis, alleviating cardiac hypertrophy, and lowering mortality. Though rare, lipodystrophy requires early recognition for appropriate screening and treatment. Presentation: Monday, July 14, 2025
2025-10-01 | SUN-644 Pharmacological Approaches in Lipodystrophy: Concomitant Medication and Metreleptin Therapy Use in the Participants of LD-Lync Study
Abstract Disclosure: M. Celik Guler: None. M.C. Foss de Freitas: None. M. Yosef: None. S. Khalatbari: None. M. Ashmus: None. D. Guler: None. D. Gilio: None. D. Kaba: None. A. Dill Gomes: None. C. Uwandu: None. M. Brush: None. R. Tuska: None. T. Neal: None. M. Hwang: None. B. Tracey: None. M. Okawa: None. B. Brite: None. C. Richison: None. I. Yildirim Simsir: None. B. Akinci: Chiesi Farmaceutici, Alnylam, Regeneron Pharmaceuticals, Marea Therapeutics, AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Sanofi, Bilim Ilac, ARIS, Servier. R.J. Brown: Pfizer, Inc., Regeneron Pharmaceuticals, Marea Therapeutics, Chiesi Farmaceutici. E.A. Oral: Chiesi Farmaceutici, Ionis Pharmaceuticals Inc., Regeneron Pharmaceuticals, Rhythm Pharmaceuticals, Marea Therapeutics, Novo Nordisk, Rejuvenate Bio, Fractyl, Morphic Medical. Background: Lipodystrophy (LD) syndromes are rare diseases characterized by subcutaneous adipose tissue deficiency and associated metabolic disorders, often requiring specialized pharmacological management. This study investigates the utilization of metreleptin and other metabolic therapies for managing complications across different LD subtypes. Methods: Data were analyzed from an ongoing prospective, multicenter registry study (LD Lync; NCT03087253, n=266, at the end of October 2023). Demographic information and medical history were collected at baseline and annual visits. Medication usage, including metreleptin, insulin, oral antidiabetics, and lipid-lowering therapies, was evaluated for prevalence and distribution across subgroups. Results: A total of 81 patients (30.5%) received at least one dose of metreleptin, either through clinical trials, expanded access or commercial use. This included 26 patients (70.2%) with congenital generalized lipodystrophy (CGL, n=37), ten patients (62.5%) with acquired generalized lipodystrophy (AGL, n=16), 37 patients (21.4%) with familial partial lipodystrophy (FPLD, n=173), two patients (8.0%) with acquired partial lipodystrophy (APL, n=25), and six patients categorized within the unclassified subgroup (n=15). Insulin use varied across subtypes, with the highest prevalence observed in the AGL (63%, 7/11) and FPLD (59%, 79/133), compared to the CGL (44%, 11/25) and the APL (35%, 5/14) subgroups, based on available data from documented cases. Metformin was the most commonly used antidiabetic agent, particularly in FPLD (n=101), followed by CGL (n=21), APL (n=10), and AGL (n=5). Thiazolidinediones (n=48), sodium-glucose cotransporter-2 inhibitors (n=47), injectable incretin therapies (n=40), and gliptins (n=16) were other commonly used antidiabetic drugs. Fenofibrate was used by 79 patients, with the highest prevalence observed in the CGL (48%) and FPLD (35%) subgroups. Statins, primarily atorvastatin (n=57) and rosuvastatin (n=25), were the most prescribed lipid-lowering agents, and were used by 100 patients overall, including 47.9% of those in the FPLD subgroup. Their use was infrequent in the CGL subgroup (n=3). Omega-3 derivatives were used by 53 patients (19%), while niacin and cholestyramine were used by only two patients. Despite extensive metabolic therapies, current metabolic control was suboptimal, especially in FPLD (mean ± SD: HbA1c 7.3% ± 1.9, low-density lipoprotein 97 ± 39 mg/dL, and TG 542 ± 730 mg/dL). Conclusion: This study highlights the heterogeneity in pharmacological management across lipodystrophy subtypes, reflecting their diverse metabolic profiles and needs. While metreleptin remains the cornerstone therapy for generalized lipodystrophy, there is a need for novel therapeutic options to achieve improved metabolic control and optimize treatment outcomes in partial lipodystrophy. Presentation: Sunday, July 13, 2025
other
2024-01-17 | Familial Screening for the Prevention of Rare Diseases: A Focus on Lipodystrophy in Southern Saudi Arabia
Abstract Background Lipodystrophy is a relatively rare, complex disease characterised by a deficiency of adipose tissue and can present as either generalised lipodystrophy (GLD) or partial lipodystrophy (PLD). The prevalence of this disease varies by region. This study aimed to identify the genetic variations associated with lipodystrophy in the southern part of Saudi Arabia. Methodology We conducted a retrospective study by recruiting nine patients from six families, recruiting the proband whole exome sequencing results or any other genetic test results, screening other family members using Sanger sequencing and analysing the carrier status of the latter. These patients were recruited from the Endocrinology and Diabetes Clinic at Jazan General Hospital and East Jeddah Hospital, both in the Kingdom of Saudi Arabia. Result Eight patients were diagnosed with GLD, and one was diagnosed with PLD. Of the six families, four were consanguineously married from the same tribe, while the remaining belonged to the same clan. The majority of GLD patients had an AGPAT2 c.158del mutation, but some had a BSCL2 c.942dup mutation. The single PLD case had a PPARG c.1024C > T mutation but no family history of the disease. In all families evaluated in this study, some family members were confirmed to be carriers of the mutation observed in the corresponding patient. Conclusion Familial screening of relatives of patients with rare, autosomal recessive diseases, such as lipodystrophy, especially when there is a family history, allows the implementation of measures to prevent the onset or reduced severity of disease and reduces the chances of the pathogenic allele being passed onto future generations. Creating a national registry of patients with genetic diseases and carriers of familial pathogenic alleles will allow the assessment of preventive measures and accelerate disease intervention via gene therapy.
2022-12-16 | Volanesorsen, an antisense oligonucleotide to apolipoprotein C-III, increases lipoprotein lipase activity and lowers triglycerides in partial lipodystrophy.
Partial lipodystrophy (PL) syndromes involve deficiency of adipose tissue, causing severe insulin resistance and hypertriglyceridemia. Apolipoprotein C-III (apoC-III) is elevated in PL and is thought to contribute to hypertriglyceridemia by inhibiting lipoprotein lipase (LPL). We hypothesized that volanesorsen, an antisense oligonucleotide to apoC-III, would decrease apoC-III, increase LPL activity, and lower triglycerides in PL. Five adults with PL enrolled in a 16-week placebo-controlled, randomized, double blind study of volanesorsen, 300 mg weekly, followed by 1-year open label extension. Within-subject effects of volanesorsen before and after 16 weeks of active drug are reported due to small sample size. From week 0 to 16, apoC-III decreased from median (25th, 75th %ile) 380 (246, 600) to 75 (26, 232) ng/mL, and triglycerides decreased from 503 (330, 1040) to 116 (86, 355) mg/dL while activation of LPL by subjects' serum increased from 21 (20, 25) to 36 (29, 42) nEq/mL*min. Although, A1c did not change, peripheral and hepatic insulin sensitivity (glucose disposal and suppression of glucose production during hyperinsulinemic clamp) increased and palmitate turnover decreased. After 32-52 weeks of volanesorsen, liver fat decreased. Common adverse events included injection site reactions and decreased platelets. In PL, volanesorsen decreased apoC-III and triglycerides, in part through an LPL dependent mechanism, and may improve insulin resistance and hepatic steatosis.
2015-12-31 | Defective differentiation of adipose precursor cells from lipodystrophic mice lacking perilipin 1.
Perilipin 1 (Plin1) localizes at the surface of lipid droplets to regulate triglyceride storage and hydrolysis in adipocytes. Plin1 defect leads to low adiposity in mice and partial lipodystrophy in human. This study investigated the roles of Plin1 in adipocyte differentiation. Plin1 null (-/-) mice showed plenty of multilocular adipocytes and small unilocular adipocytes in adipose tissue, along with lack of a subpopulation of adipose progenitor cells capable of in vivo adipogenesis and along with downregulation of adipogenic pathway. Before initiation of differentiation, adipose stromal-vascular cells (SVCs) from Plin1-/- mice already accumulated numerous tiny lipid droplets, which increased in number and size during the first 12-h induction but thereafter became disappeared at day 1 of differentiation. The adipogenic signaling was dysregulated despite protein level of PPARγ was near normal in Plin1-/- SVCs like in Plin1-/- adipose tissue. Heterozygous Plin1+/- SVCs were able to develop lipid droplets, with both the number and size more than in Plin1-/- SVCs but less than in Plin1+/+ SVCs, indicating that Plin1 haploinsufficiency accounts for attenuated adipogenesis. Aberrant lipid droplet growth and differentiation of Plin1-/- SVCs were rescued by adenoviral Plin1 expression and were ameliorated by enhanced or prolonged adipogenic stimulation. Our finding suggests that Plin1 plays an important role in adipocyte differentiation and provides an insight into the pathology of partial lipodystrophy in patients with Plin1 mutation.
small molecules
2026-01-01 | O-30 AUTOSOMAL RECESSIVE LIPE PATHOGENIC VARIANT-ASSOCIATED FAMILIAL PARTIAL LIPODYSTROPHY TYPE 6
Abstract Introduction Lipodystrophy is a rare and heterogeneous disorder characterized by selective loss or abnormal redistribution of adipose tissue, leading to metabolic complications such as insulin resistance, diabetes mellitus, hepatic steatosis, and dyslipidemia. Lipodystrophy is divided into 4 main groups: congenital generalized lipodystrophy (CGL), familial partial lipodystrophy (FPLD), acquired generalized lipodystrophy (AGL), and acquired partial lipodystrophy (APL). FPLD is caused by mutations is genes regulating adipocyte function and lipid metabolism, with six subtypes identified to date. Among these, type 6 (FPLD6) results from inactivating mutation in the LIPE gene, which encodes hormone-sensitive lipase (HSL). Here, we present a very rare case of autosomal recessive familial partial lipodystrophy type 6. Clinical Case A 34-year-old female was referred for evaluation of suspected Cushing’s syndrome. She was receiving hormone replacement therapy for primary ovarian insufficiency and had no other known medical conditions. She had gestational diabetes during her second pregnancy, managed with diet alone. Over three years she gained 29 kg (BMI 35.2 kg/m²). Family history revealed parental consanguinity. Physical examination revealed characteristic cushingoid features including a prominent buffalo hump, supraclavicular fat pads, and centripetal obesity. She had fat accumulation in the upper body while subcutaneous fat was markedly reduced in the extremities and breasts (Figure 1). Acanthosis nigricans was noted in the axillary and cervical regions. Additionally, she had undergone a cosmetic liposuction procedure targeting the deltoid and occipital regions. Low-dose dexamethasone testing excluded Cushing’s syndrome. Oral glucose tolerance test indicated insulin resistance; triglycerides were elevated, while leptin was normal. Laboratory results are summarized in Table 1. Whole-body DXA demonstrated markedly reduced fat mass in the upper and lower extremities, with central fat accumulation. This distribution was compatible with partial lipodystrophy. FibroScan revealed advanced hepatic steatosis (S3) without fibrosis (F0), consistent with nonalcoholic fatty liver disease (NAFLD). Genetic analysis identified a homozygous pathogenic LIPE gene variant (c.2182G>A), confirming the diagnosis of autosomal recessive familial partial lipodystrophy type 6. Treatment with metformin, SGLT-2 inhibitor, and fenofibrate was initiated, alongside lifestyle modification and genetic counseling. Conclusion FPLD6 is a very rare subtype of familial partial lipodystrophy. Unlike other subtypes, it is caused by LIPE mutations leading to defective lipolysis, and typically presents in adulthood rather than early life. It is further characterized by severe insulin resistance, dyslipidemia, and hepatic steatosis. In addition, the presence of subcutaneous lipomas distinguishes FPLD6 from other many forms and may lead to diagnostic confusion with multiple lipomatosis.Figure 1:a.Sagittal magnetic resonance imaging (MRI) of the neck and cervical spine region demonstrating abnormal fat distribution consistent with partial lipodystrophy b.Dual-energy X-ray absorptiometry (DEXA) scan demonstrating body composition c.Posterior view of the trunk showing loss of peripheral fat and abnormal fat deposition in the upper body Table 1:Biochemical parameters of the patientIR: insulin resistance
2025-10-01 | SUN-646 Immune Landscape and Clinical Characteristics of Patients with Acquired Partial and Generalized Lipodystrophy Syndromes
Abstract Disclosure: O. Besci: None. C.D. Uwandu: None. U. Cavdar: None. B. Akinci: None. D. Gilio: None. M.C. Foss de Freitas: None. K. Walkovich: None. E.A. Oral: Regeneron Pharmaceuticals, Rhythm Pharmaceuticals, Novo Nordisk, Amryt Pharmaceuticals, Ionis Pharmaceuticals Inc., Morphic Medical, Rejuvenate Bio, Fractyl Laboratories. Introduction: Acquired lipodystrophy syndromes (ALS) are characterized by loss of adipose tissue and associated metabolic abnormalities, manifesting in either partial (APL) or generalized forms (AGL). Increasing evidence of ALS links to autoimmunity, infections, malignancies, and associated treatments highlights the need for an understanding of the associated immune-mediated mechanisms. Objective: We sought to provide immune-related insights on ALS by correlating coexisting disorders with their underlying immune mechanisms and identifying patterns of phenotypic presentations via comprehensive case review and literature analysis. Methods: We retrospectively reviewed all cases from the University of Michigan (n = 30) and published cases (n = 462). We systematically searched PubMed for ALS studies published in English with full-text availability from 2004 to the present (last accessed: December, 2024) and reviewed references from comprehensive studies (1919-2004) to identify phenotypical descriptions matching the published diagnostic criteria for AGL and APL1,2. Barraquer-Simons syndrome and phenotypes resembling Dunnigan syndrome, with lipoatrophy in the extremities and fat retention in the face, neck, and abdomen, were classified as APL. Cases were categorized based on immune mechanisms and presenting phenotypes. Results: In our analysis of 492 patients with ALS, 32% (n=159) had AGL and 68% (n=333) had APL. ALS with autoimmune disorders was significantly more common in AGL compared to APL (39% vs 26%, p=0.004), as was ALS with regulatory T cell defects (7% vs. 1%, p<0.001), colitis (7% vs. 2%, p=0.01) and panniculitis (26% vs. 1%, p<0.001). ALS associated with malignancy, involving immune checkpoint inhibitors (7% vs. 1%, p<0.001), lymphoma (6% vs. <1%, p<0.001), and paraneoplastic syndromes (2% vs. <1%, p=0.04) predominantly exhibited the AGL phenotype, whereas prior exposure to HSCT/TBI was significantly associated with the APL phenotype (5% vs. <1%, p=0.01). While C3 deficiency was significantly more common in APL compared to AGL (39% vs 4%, p<0.001), C4 deficiency was more frequently observed in AGL than in APL (5% vs 1%, p=0.02). Conclusion: Our study highlights the diverse clinical manifestations of patients with APL and AGL, emphasizing ALS with autoimmune disorders, regulatory T-cell defects, lymphoma, panniculitis and colitis are predominantly linked to the AGL, while complement deficiencies and prior HSCT/TBI exposure are more frequently associated with APL. References: 1. Misra A, Garg A. Clinical features and metabolic derangements in acquired generalized lipodystrophy: case reports and review of the literature. Medicine (Baltimore). 2003. 2. Misra A, Peethambaram A, Garg A. Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: report of 35 cases and review of the literature. Medicine (Baltimore). 2004. Presentation: Sunday, July 13, 2025
2025-10-01 | SUN-645 Leptin- And Incretin-based Combination Therapy In Lipodystrophy: A Promising Metabolic Strategy?
Abstract Disclosure: M. Celik Guler: None. R. Meral: None. M. Lightbourne: None. O. Besci: None. A. Neidert: None. M.C. Foss de Freitas: None. R.J. Brown: Pfizer, Inc., Regeneron Pharmaceuticals, Chiesi Farmaceutici, Marea Therapeutics. E.A. Oral: Ionis Pharmaceuticals Inc., Novo Nordisk, Chiesi Farmaceutici, Rhythm Pharmaceuticals, Marea Therapeutics, Rejuvenate Bio, Fractyl, Morphic Medical, Regeneron Pharmaceuticals. Lipodystrophy syndromes (LD) are rare disorders characterized by partial or generalized loss of adipose tissue and significant metabolic disturbances. Metreleptin (ML) remains the cornerstone of treatment for generalized lipodystrophy (GL); however, its efficacy in partial lipodystrophy (PL) can be limited, highlighting the need for alternative or incremental therapies to achieve optimal metabolic control. We hypothesize that combining leptin-based therapies, such as ML or leptin receptor agonists like mibavademab (investigational product), with incretin-based agents may offer a promising therapeutic strategy to enhance metabolic outcomes in this population. We report 6 patients taking ML or mibavademab for clinical or compassionate use in whom incretin-based therapies were added to enhance metabolic control, with outcomes prospectively followed. P1 (25-year-old, congenital generalized lipodystrophy (CGL) type 1, treated with metreleptin for 2.5 years): following the addition of semaglutide for 8 months, HbA1c reduced from 8.7% to 5.6%, BMI from 24.7 to 21.9 kg/m², and triglycerides (TG) from 2261 to 33 mg/dL. P2 (36-year-old, acquired GL, treated with metreleptin for 18 years): after 9 months of tirzepatide treatment, HbA1c reduced from 9.1% to 6.5%, BMI from 19.5 to 17.6 kg/m², and TG from 1240 to 100 mg/dL. P3 (25-year-old, LMNA related GL (with T10I variant), treated with mibavademab for 4 years): after adding dulaglutide for 5 months, HbA1c reduced from 8.9% to 7.3%, with stable BMI (14.4 kg/m²) and no change in TG (265 to 273 mg/dL). P4 (44-year-old, familial partial lipodystrophy type 2 (FPLD2), treated with metreleptin for 3.5 years): after 17 months of tirzepatide therapy, HbA1c reduced from 6.6% to 5.1%, BMI from 18.2 to 16.2 kg/m², and TG from 298 to 104 mg/dL. P5 (23-year-old, atypical PL, previously treated with mibavademab for 5 years and 10 months): Following initiation of tirzepatide for 4 months, there was no change in HbA1c (10.1% to 10.5%) or BMI (27.1 to 27.3 kg/m²) but a 49% reduction in TG (1764 to 895 mg/dL) was observed. P6 (52-year-old, FPLD2, treated with metreleptin for 10 years): initiation of tirzepatide for 5 months led to reductions in HbA1c (6.8% to 5.7%), BMI (26.0 to 21.8 kg/m²), and TG (279 to 127 mg/dL). There were no unexpected adverse events with combination therapy, but patient P5 had an episode of pancreatitis at month 5 due to running out of her insulin and worsening glucose control. In summary, combined leptin-based and incretin-based therapies may enhance metabolic outcomes in lipodystrophy. Future randomized controlled trials are needed to evaluate the efficacy of incretin-based therapies either with or without leptin pathway treatments to confidently determine the extent of benefit of combination therapy in lipodystrophy. Presentation: Sunday, July 13, 2025
2025-09-02 | Clinical Guidance for Lipodystrophy Syndromes: From Diagnosis and Work-Up to Treatment
Clinical and metabolic assessments, along with genetic analyses, are essential for tailoring medical care and providing appropriate genetic counseling. Efforts are underway to develop more objective diagnostic tools using imaging techniques or novel biomarkers. Leptin therapy has been a significant breakthrough for generalized lipodystrophy treatment; however, more effective treatments are still needed for partial and acquired forms. While gene editing and transcript modification strategies are being explored for specific forms of lipodystrophy, reducing the burden on adipocytes by lowering caloric intake remains a fundamental approach across all forms of the condition. As supporting data emerge, agents that reduce caloric intake may become integral to treatment algorithms. This review offers practical guidance for clinicians managing patients with lipodystrophy, highlighting advances in diagnosis, treatment, and ongoing challenges in clinical care.
2024-01-04 | The blockade of the TGF-β pathway alleviates abnormal glucose and lipid metabolism of lipodystrophy not obesity.
Abstract TGF‐β is thought to be involved in the physiological functions of early organ development and pathological changes in substantial organ fibrosis, while studies around adipose tissue function and systemic disorders of glucolipid metabolism are still scarce. In this investigation, two animal models, aP2‐SREBP‐1c mice and ob/ob mice, were used. TGF‐β pathway showed up‐regulated in the inguinal white adipose tissue (iWAT) of the two models. SB431542, a TGF‐β inhibitor, successfully increased inguinal white adipocyte size by more than 1.5 times and decreased the weight of Peripheral organs including liver, Spleen and Kidney to 73.05%/62.18%/73.23% of pre‐administration weights. The iWAT showed elevated expression of GLUTs and lipases, followed by a recovery of circulation GLU, TG, NEFA, and GLYCEROL to the wild‐type levels in aP2‐SREBP‐1c mice. In contrast, TGF‐β inhibition did not have similar effects on that of ob/ob mice. In vitro, TGF‐β blocker treated mature adipocytes had considerably higher levels of glycerol and triglycerides than the control group, whereas GLUTs and lipases expression levels were unchanged. These findings show that inhibiting the abnormally upregulated TGF‐β pathway will only restore iWAT expansion and ameliorate the global metabolic malfunction of glucose and lipids in lipodystrophy, not obesity.
antibodies
2025-03-29 | Acquired partial lipodystrophy (Barraquer-Simons syndrome) with both-side axillary breasts: A case report.
Lipodystrophies are conditions characterized by a loss of subcutaneous fat, which can be congenital or acquired, and present in various patterns of fat distribution. Accurate diagnosis is essential for identifying comorbidities and ensuring appropriate multidisciplinary care and targeted treatments. A 34-year-old female experienced significant facial changes and increased abdominal fat over five years. She had lumps under her armpits discharging white fluid, with clinical findings of low hemoglobin and accessory breast tissue, which was surgically excised. Acquired generalized lipodystrophy is often overlooked, with over 250 documented cases. It typically presents in adolescence and involves symmetrical fat loss, with potential associations to autoimmune diseases and unique features in this case. This case emphasizes the complexities of acquired lipodystrophy, especially regarding accessory breast tissue. It highlights the need for thorough evaluations and increased awareness among healthcare providers for timely diagnosis and management.
2024-06-19 | Leptin replacement therapy in the management of lipodystrophy syndromes.
Lipodystrophy syndromes are rare diseases of genetic or acquired origin, characterized by quantitative and qualitative defects in adipose tissue. The metabolic consequences of lipodystrophy syndromes, such as insulin resistant diabetes, hypertriglyceridemia and hepatic steatosis, are frequently very difficult to treat, resulting in significant risks of acute and/or chronic complications and of decreased quality of life. The production of leptin by lipodystrophic adipose tissue is decreased, more severely in generalized forms of lipodystrophy, where adipose tissue is absent from almost all body fat depots, than in partial forms of the disease, where lipoatrophy affects only some parts of the body and can be associated with increased body fat in other anatomical regions. Several lines of evidence in preclinical and clinical models have shown that leptin replacement therapy could improve the metabolic complications of lipodystrophy syndromes. Metreleptin, a recombinant leptin analogue, was approved as an orphan drug to treat the metabolic complications of leptin deficiency in patients with generalized lipodystrophy in the USA or with either generalized or partial lipodystrophy in Japan and Europe. In this brief review, we will discuss the benefits and limitations of this therapy, and the new expectations arising from the recent development of a therapeutic monoclonal antibody able to activate the leptin receptor.
2013-03-06 | Choroidal Neovascularization in Acquired Partial Lipodystrophy
PurposeTo report a case of choroidal neovascularization (CNV) associated with acquired partial lipodystrophy (PLD). MethodsA 55-year-old woman with a known history of PLD presented with acute onset visual loss affecting her right eye and underwent investigations to diagnose the underlying pathology. ResultsFluorescein angiography and time-domain optical coherence tomography demonstrated the presence of intraretinal edema consistent with CNV. The patient was treated with intravitreal ranibizumab with excellent results, and her vision remains unimpaired 4 years posttreatment. ConclusionsChoroidal neovascularization is an angiogenic process that can occur following retinal pigment epithelium disruption of any cause. These vessels may then bleed into retinal tissue, with potentially devastating visual consequences. Although rare, PLD has been associated with retinal drusenoid lesions. This is the first case to report CNV in association with PLD, and highlights the importance of considering CNV in the differential diagnosis of acute visual loss in patients with drusenoid diseases such as PLD.
2009-08-01 | Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC.
Lipodystrophic syndromes are characterized by adipose tissue deficiency. Although rare, they are of considerable interest as they, like obesity, typically lead to ectopic lipid accumulation, dyslipidaemia and insulin resistant diabetes. In this paper we describe a female patient with partial lipodystrophy (affecting limb, femorogluteal and subcutaneous abdominal fat), white adipocytes with multiloculated lipid droplets and insulin-resistant diabetes, who was found to be homozygous for a premature truncation mutation in the lipid droplet protein cell death-inducing Dffa-like effector C (CIDEC) (E186X). The truncation disrupts the highly conserved CIDE-C domain and the mutant protein is mistargeted and fails to increase the lipid droplet size in transfected cells. In mice, Cidec deficiency also reduces fat mass and induces the formation of white adipocytes with multilocular lipid droplets, but in contrast to our patient, Cidec null mice are protected against diet-induced obesity and insulin resistance. In addition to describing a novel autosomal recessive form of familial partial lipodystrophy, these observations also suggest that CIDEC is required for unilocular lipid droplet formation and optimal energy storage in human fat.
2009-02-12 | Complement abnormalities in acquired lipodystrophy revisited.
Lipodystrophy is a heterogeneous condition characterized by an inherited or acquired deficiency in the number of adipocytes required for the storage of energy as triglycerides. Acquired lipodystrophy is frequently associated with other autoimmune disorders. One well-studied form is characterized by the selective loss of upper body fat in association with activation of the alternative complement pathway by C3 nephritic factor, low complement factor C3, and mesangiocapillary glomerulonephritis. We now describe an immunologically distinct form of acquired generalized lipodystrophy, with evidence of activation of the classical complement pathway (low C4) and autoimmune hepatitis. Patients and Research Design: Three unrelated patients with acquired lipodystrophy and low complement C4 levels are described. In vitro analysis of the complement pathway was undertaken to determine the reason for the low C4 complement levels. Biopsies were obtained from liver, bone marrow, and adipose tissue for histological analysis. All three patients manifested near-total lipodystrophy, chronic hepatitis with autoimmune features, and low C4 complement levels. Additional autoimmune diseases, including severe hemolytic anemia, autoimmune thyroid disease, and polyneuropathy, were variably present. Detailed studies of complement pathways suggested constitutive classical pathway activation. Although the previously described syndrome, which typically results in a cephalad pattern of partial lipodystrophy, results from activation of the alternative complement pathway, this form, in which lipodystrophy is generalized, is associated with activation of the classical pathway. Future therapeutic approaches to these disorders may benefit from being tailored to their distinct immunopathogenesis.
cell therapies
2025-05-30 | Surgical Management of Lipodystrophy in Barraquer-Simons Syndrome: Autologous Fat Redistribution and Reconstructive Strategies for Acquired Partial Lipodystrophy
Background: Barraquer-Simons Syndrome (BSS), a rare form of acquired partial lipodystrophy, is characterized by progressive adipose tissue loss in the cephalothoracic region, often with paradoxical fat accumulation in the lower body. This condition presents significant metabolic and aesthetic challenges, necessitating multidisciplinary management. Fat redistribution surgery (FRS) has emerged as a potential therapeutic approach to restore facial and upper body contour while addressing metabolic complications. Objective: This article reviews the surgical techniques, outcomes, and long-term efficacy of autologous fat grafting and liposuction-based fat redistribution in BSS patients, with a focus on optimizing functional and cosmetic results. Methods: A comprehensive literature review was conducted, analyzing case reports, clinical studies, and surgical outcomes in BSS patients undergoing fat redistribution procedures. Special emphasis was placed on patient selection, surgical planning, and postoperative metabolic implications. Results: Preliminary evidence suggests that autologous fat transfer from areas of lipohypertrophy (e.g., lower extremities) to atrophic regions (e.g., face, arms, and trunk) can improve both aesthetic and psychosocial outcomes. However, long-term fat graft retention remains variable, and metabolic stability post-surgery requires further investigation. Conclusion: Fat redistribution surgery offers a promising reconstructive option for BSS patients, though individualized surgical planning and close metabolic monitoring are essential. Further prospective studies are needed to standardize techniques and assess durability.
2024-09-27 | Successful fat transplant in a rare acquired lipodystrophy Barraquer–Simons syndrome
Lipodystrophies can be generalized and partial/localized lack of subcutaneous tissue, which are uncommon heterogeneous illnesses that can be hereditary or acquired. Acquired partial lipodystrophy’ (APL) is the new name for lipodystrophia progressiva, also known as Barraquer–Simons syndrome (BSS). It could come after a severe viral infection like the measles. Young people and children both experience it. Typically, BSS or APL starts between the ages of 5 and 15. The principal feature of BSS is cephalothoracic lipodystrophy, which affects the face, neck, arms, thorax, and upper abdomen in a cephalocaudal pattern. Alternate complement pathway activation and C3 hypocomplementemia with adipocyte lysis brought on by complement 3 nephritic factor (C3NeF) have been suggested as potential causes of fat loss in individuals with APL, even though the precise process is still mostly understood. Therapeutic options for lipodystrophy include fat fillers. Different types of autologous fat transplants are possible. Autologous free fat graft where a mass of tissue harvested from any discrete subcutaneous location and implanted at a recipient site. Dermofat grafts are made from tissue that has been removed from a region, allowing for the removal of full-thickness skin grafts and the primary closure of defects. The dermofat graft can be employed as a spacer between gliding tissues or as a filler. Omental flaps, which are revascularized fat flaps, can be utilized for microvascular transfer, soft-tissue filler for hemifacial atrophy, or to cover any significant skin defects. When fat is extracted, processed, and transplanted in liquid injectable form for a variety of purposes, it is known as free fat injection.
2020-02-14 | Safety and Localization of Mesenchymal Stromal Cells Derived from Human Adipose Tissue-Associated Hyaluronic Acid: A Preclinical Study
Millions of plastic surgeries are performed worldwide every year with the objective of correcting lipodystrophies stemming from lesions, tumor resections, birth defects, and AIDS-associated antiretroviral therapy. Besides that, a large number of clinical research have assessed the outcome of procedures that rely on combinations of dermal fillers and autologous cells. However, little is known about the safety of these combinations and the localization of the injected cells. The aim of this study was to test the toxicity of a solution containing 1% hyaluronic acid (HA) and adipose-derived stromal cells (ASCs) from the human adipose tissue and to assess the localization of the injected cells, with and without HA, labeled with technetium-99m. Rats received subcutaneous and intraperitoneal injections of a solution containing 1% HA/adipose-derived stromal cells isolated from the human fat tissue. The animals were then observed for up to forty-two days. The solution tested in this study did not result in systemic, biochemical, or anatomic alterations that could represent toxicity symptoms. The association of HA and ASCs labeled with technetium-99m remained at the site of the injection within a period of twenty-four hours, as demonstrated by a whole-body imaging software fusion of SPECT and CT. In conclusion, our study shows that the subcutaneous and intraperitoneal injection of HA associated with adipose-derived stromal cells (ASCs) is safe. The association of HA and ASCs did not induce local or systemic toxicity. Thus, the administration of volume equal to or less than 0.2 mL of the agent filler (1 × 106 ASC+HA 1%) should be considered for subsequent studies and may be an alternative to dermal fillers due to the expected lasting effects.
2018-12-10 | Visceral fat does not contribute to metabolic disease in lipodystrophy
Lipodystrophies are characterized by regional or generalized loss of adipose tissue and severe metabolic complications. The role of visceral adipose tissue (VAT) in the development of metabolic derangements in lipodystrophy is unknown. The study aim was to investigate VAT contribution to metabolic disease in lipodystrophy versus healthy controls.Analysis of correlations between VAT volume and biomarkers of metabolic disease in 93 patients and 93 age/sex-matched healthy controls.Patients with generalized lipodystrophy (n = 43) had lower VAT compared with matched controls, while those with partial lipodystrophy (n = 50) had higher VAT versus controls. Both groups with lipodystrophy had lower leg fat mass versus controls (p < 0.05 for all; unpaired t-test). In both generalized and partial lipodystrophy, there was no correlation between VAT and glucose, triglycerides or high-density lipoprotein cholesterol (p > 0.05 for all; Spearman correlation). In controls matched to patients with generalized or partial lipodystrophy, VAT correlated with glucose (R = 0.42 and 0.36), triglycerides (R = 0.36 and 0.60) and high-density lipoprotein cholesterol (R = -0.34 and -0.64) (p < 0.05 for all; Spearman correlation).In contrast to healthy controls, metabolic derangements in lipodystrophy did not correlate with VAT volume. These data suggest that, in lipodystrophy, impaired peripheral subcutaneous fat deposition may exert a larger effect than VAT accumulation on the development of metabolic complications. Interventions aimed at increasing functional subcutaneous adipose tissue may provide metabolic benefit.
2017-02-13 | Barraquer-Simons syndrome: a unique patient's perspective on diagnosis, disease progression and recontouring treatment.
This case report describes a female patient diagnosed with Barraquer-Simons syndrome, a rare form of acquired partial lipodystrophy characterised by symmetrical loss of adipose tissue from face, neck, upper extremities and the trunk with onset in early childhood. Initial symptoms were seen at the age of 8 years. Our patient did not show signs of renal impairment and this may be associated with the syndrome. Treatment of lipoatrophy in these patients is limited to cosmetic restoration, and autologous fat grafting has shown sustained positive effects with no or very little loss of volume at follow-ups. Furthermore, the treatment has resulted in considerable improvements in her quality of life and daily functioning. She has not experienced any adverse effects. Accurate and early diagnosis is important, and clinicians should consider early intervention for these patients. Autologous fat grafting is recommended as a safe procedure.
proteins
2026-07-09 | Case Report: Dramatic metabolic improvement with tirzepatide in a patient with acquired partial lipodystrophy following hematopoietic stem cell transplantation.
Acquired lipodystrophy is a rare disorder characterized by adipose tissue loss or dysfunction and is frequently associated with severe insulin resistance and metabolic complications. Metabolic complications of lipodystrophy have occasionally been reported after hematopoietic stem cell transplantation (HSCT), but their clinical features and optimal treatment strategies remain poorly defined. Tirzepatide, a dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, has recently emerged as a novel therapy for type 2 diabetes. We report a 37-year-old woman who underwent allogeneic HSCT at 12 years of age for relapsed acute lymphoblastic leukemia after a conditioning regimen including total body irradiation (TBI), high-dose cytarabine, and melphalan. She subsequently developed diabetes mellitus and fatty liver disease at 17 years of age. Although no apparent fat loss was initially recognized, lipodystrophy was clinically suspected based on severe insulin resistance and metabolic abnormalities disproportionate to her body habitus. Computed tomography at 37 years of age revealed region-specific fat loss extending from the lower back to the gluteal region. Glycemic control remained inadequate despite high-dose insulin therapy and sequential treatment with several GLP-1 receptor agonists. After initiation of tirzepatide, glycemic control improved dramatically, allowing complete discontinuation of insulin therapy. Body weight decreased modestly and hepatic steatosis improved. The high-molecular-weight (HMW)/total adiponectin ratio after treatment was elevated (64.0%), suggesting possible improvement in adipocyte secretory function. This case highlights acquired partial lipodystrophy developing after HSCT, supported by region-specific fat loss and characteristic metabolic abnormalities, and demonstrates a marked therapeutic response to tirzepatide. Dual incretin receptor agonism may represent a promising therapeutic strategy for severe insulin resistance associated with adipose tissue dysfunction, potentially through both weight-dependent and weight-independent mechanisms.
2026-02-17 | Lipodystrophies in Clinical Practice: A Case Series From a Local Health Unit in Portugal
Background Lipodystrophies are rare disorders characterized by loss of adipose tissue, leading to severe metabolic and multisystem complications. Data on real-world management remain limited, particularly in Portugal. Objectives The objective of this study is to describe the clinical, metabolic, genetic, and therapeutic characteristics of patients with confirmed or suspected lipodystrophy followed at a Portuguese Endocrinology Outpatient Clinic. Methods We conducted a retrospective observational study including 21 patients with clinical suspicion or diagnosis of lipodystrophy. Demographic, clinical, laboratory, imaging, and genetic data were collected. Results The cohort was predominantly female (90.5%) with a median age at diagnosis of 49 years. Sixteen patients (76.2%) had familial partial lipodystrophy (FPLD), two (9.5%) had congenital generalized lipodystrophy, two (9.5%) had acquired generalized lipodystrophy, and one presented a complex syndromic form. Diabetes mellitus was present in 71.4% of patients and hypertriglyceridemia in 52.4%. Metabolic liver disease occurred in both generalized and partial forms. Autoimmune disorders affected 31.6% of patients, and cardiac involvement was observed in 23.8%. Genetic testing identified pathogenic or likely pathogenic variants in BSCL2 and PPARG in three patients, while most FPLD cases remained genetically unexplained. Metreleptin therapy in three patients with generalized lipodystrophy improved glycemic control, triglycerides, liver enzymes, and proteinuria. Dual-energy X-ray absorptiometry imaging supported the phenotypic characterization of adipose tissue loss. Conclusions Detailed physical examination, genetic testing, imaging, and early therapeutic interventions are critical for management. These findings align with European registry data and highlight the need for increased awareness and systematic evaluation in real-world clinical practice.
2025-10-01 | MON-682 Acquired Generalized Lipodystrophy Treated With Metreleptin in a Patient With Total Body Irradiation and Chronic Graft-Versus-Host Disease
Abstract Disclosure: T. Moazezi: None. B. Salehian: None. Background: Acquired lipodystrophy, both partial and generalized, is a rare disease that can be seen in patients with a history of total-body irradiation (TBI) and hematopoietic stem cell transplantation (HSCT). The widespread metabolic complications that arise from this disorder warrant attention and treatment. Clinical Case: A 25-year-old female with a history of Non-Hodgkin Lymphoma status post TBI and HSCT in 2000 and 2004 complicated by chronic graft-versus-host disease (GVHD) presented with multiple endocrinopathies to the endocrinology clinic. She presented with type 2 diabetes mellitus with severe insulin resistance, severe hypertriglyceridemia, and non-alcoholic steatohepatitis. The patient weighed 36.7 kg with a BMI of 14.3 kg/m2. On physical exam, the patient had complete loss of subcutaneous fat mass in the chest, abdomen, upper and lower extremities, and palmar-plantar region; there was minimal appreciable subcutaneous fat in the face and supraclavicular region. Abdominal exam revealed visceral fat and hepatomegaly with percussion of the liver 5 cm below the costal margin. The quantitative adiponectin level was low at 3.1 ug/mL (2.0-19.3 ug/mL), and the diagnosis of acquired generalized lipodystrophy (AGL) was made. Laboratory work-up was notable for SGOT 50 U/L (15-46 U/L), SGPT 88 U/L (7-56 U/L), glucose of 435 mg/dL (80-128 mg/dL), hemoglobin A1c 14.4% (<=6.4%), C-peptide 9.7 ng/mL (0.8-3.5 ng/mL), fasting triglyceride 4268 mg/dL (<=150 mg/dL), total cholesterol 297 mg/dL (<=200 mg/dL), HDL 34 mg/dL (>=39 mg/dL), and LDL 32 mg/dL (<=100 mg/dL). Abdominal ultrasound with elastography showed hepatomegaly, fatty liver, mild-moderate fibrosis. The patient was treated with statin, fish oil, gemfibrozil, Humulin R U-500 insulin, insulin pump, pioglitazone, and multiple oral hypoglycemic agents, and her metabolic complications were refractory to these standard therapies. She was started on treatment with metreleptin by subcutaneous injection for treatment of AGL. The dose was titrated upwards as tolerated, and the patient had improvement in her metabolic parameters while on treatment, including improved insulin sensitivity and lipoprotein profile. Metreleptin was discontinued after two years due to significant pain at the injection site. She was referred to plastic surgery to assess for auto-transplantation of adipose tissue, which was not an option due to complete loss of subcutaneous adipose tissue. Conclusion: Childhood cancer survivors with a history of TBI and HSCT can develop acquired lipodystrophy with associated metabolic complications later in life. This case demonstrates the role of metreleptin in improving insulin sensitivity and lipoprotein profiles in a patient with AGL. Presentation: Monday, July 14, 2025
2025-10-01 | MON-622 Severe Insulin Resistance in a Patient with Generalized Lipodystrophy
Abstract Disclosure: D. Kaul: None. M. Paravastu: None. M. Shah: None. R. Patel: None. T. Yasmeen: None. M.H. Kazi: None. Introduction: Lipodystrophy is classified into two main types: generalized and partial, based on the extent of fat loss and further as genetic or acquired, depending on its underlying cause. The prevalence ranges from 1 in 1 million for familial partial lipodystrophy to 1 in 10 million for congenital generalized lipodystrophy. Its manifestation often includes severe metabolic disturbances, including dyslipidemia, insulin resistance, and increased risks of renal, hepatic, and cardiovascular diseases.Clinical Case: A 72-year-old female with type 2 diabetes, chronic kidney disease stage 3, and hyperlipidemia presented with hyperglycemia, severe weight loss, polydipsia, and polyuria. Her diabetes regimen included insulin degludec U-200 (76 units daily), insulin aspart (35 units with meals), and Trulicity (3 mg weekly). She reported missing several doses of insulin and had lost 78 lbs over the past year. On exam, she had generalized subcutaneous fat loss, weighing 54.1 kg with a BMI of 18.68 kg/m². Labs showed a glucose level of 614 mg/dL (normal range: 70-99 mg/dL), without evidence of diabetic ketoacidosis, HbA1c of 8.2% (normal range: 4.5-5.6%), C-peptide of 8.9 ng/mL (normal range: 0.8-3.9 ng/mL), and a triglyceride level of 36 mg/dL (normal range: <=149 mg/dL). Due to severe hyperglycemia, a continuous insulin infusion was started, requiring 931 units over 24 hours plus 100 units of insulin glargine. Given her phenotype and insulin resistance, lipodystrophy was suspected. Leptin was <0.4 ng/mL (normal range: 0.5-15.2 ng/mL), and Cushing syndrome was ruled out with a screening test, confirming generalized lipodystrophy. She was started on metreleptin and discharged with insulin degludec U-200 (90 units twice daily), insulin aspart (60 units three times daily), tirzepatide (2.5 mg weekly), and empagliflozin (25 mg daily).Discussion: Insulin resistance in lipodystrophy arises from the lack of functional adipose tissue, impairing the body’s ability to store excess energy as fat. This leads to ectopic fat deposition in the liver and muscle, disrupting insulin signaling. Leptin replacement therapy is a key treatment, as low leptin levels—due to reduced adipose tissue—contribute significantly to the metabolic abnormalities seen in lipodystrophy. Metreleptin, along with dietary modifications, is the first-line treatment, improving insulin sensitivity, reducing nonalcoholic steatohepatitis, alleviating cardiac hypertrophy, and lowering mortality. Though rare, lipodystrophy requires early recognition for appropriate screening and treatment. Presentation: Monday, July 14, 2025
2025-10-01 | SUN-644 Pharmacological Approaches in Lipodystrophy: Concomitant Medication and Metreleptin Therapy Use in the Participants of LD-Lync Study
Abstract Disclosure: M. Celik Guler: None. M.C. Foss de Freitas: None. M. Yosef: None. S. Khalatbari: None. M. Ashmus: None. D. Guler: None. D. Gilio: None. D. Kaba: None. A. Dill Gomes: None. C. Uwandu: None. M. Brush: None. R. Tuska: None. T. Neal: None. M. Hwang: None. B. Tracey: None. M. Okawa: None. B. Brite: None. C. Richison: None. I. Yildirim Simsir: None. B. Akinci: Chiesi Farmaceutici, Alnylam, Regeneron Pharmaceuticals, Marea Therapeutics, AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Sanofi, Bilim Ilac, ARIS, Servier. R.J. Brown: Pfizer, Inc., Regeneron Pharmaceuticals, Marea Therapeutics, Chiesi Farmaceutici. E.A. Oral: Chiesi Farmaceutici, Ionis Pharmaceuticals Inc., Regeneron Pharmaceuticals, Rhythm Pharmaceuticals, Marea Therapeutics, Novo Nordisk, Rejuvenate Bio, Fractyl, Morphic Medical. Background: Lipodystrophy (LD) syndromes are rare diseases characterized by subcutaneous adipose tissue deficiency and associated metabolic disorders, often requiring specialized pharmacological management. This study investigates the utilization of metreleptin and other metabolic therapies for managing complications across different LD subtypes. Methods: Data were analyzed from an ongoing prospective, multicenter registry study (LD Lync; NCT03087253, n=266, at the end of October 2023). Demographic information and medical history were collected at baseline and annual visits. Medication usage, including metreleptin, insulin, oral antidiabetics, and lipid-lowering therapies, was evaluated for prevalence and distribution across subgroups. Results: A total of 81 patients (30.5%) received at least one dose of metreleptin, either through clinical trials, expanded access or commercial use. This included 26 patients (70.2%) with congenital generalized lipodystrophy (CGL, n=37), ten patients (62.5%) with acquired generalized lipodystrophy (AGL, n=16), 37 patients (21.4%) with familial partial lipodystrophy (FPLD, n=173), two patients (8.0%) with acquired partial lipodystrophy (APL, n=25), and six patients categorized within the unclassified subgroup (n=15). Insulin use varied across subtypes, with the highest prevalence observed in the AGL (63%, 7/11) and FPLD (59%, 79/133), compared to the CGL (44%, 11/25) and the APL (35%, 5/14) subgroups, based on available data from documented cases. Metformin was the most commonly used antidiabetic agent, particularly in FPLD (n=101), followed by CGL (n=21), APL (n=10), and AGL (n=5). Thiazolidinediones (n=48), sodium-glucose cotransporter-2 inhibitors (n=47), injectable incretin therapies (n=40), and gliptins (n=16) were other commonly used antidiabetic drugs. Fenofibrate was used by 79 patients, with the highest prevalence observed in the CGL (48%) and FPLD (35%) subgroups. Statins, primarily atorvastatin (n=57) and rosuvastatin (n=25), were the most prescribed lipid-lowering agents, and were used by 100 patients overall, including 47.9% of those in the FPLD subgroup. Their use was infrequent in the CGL subgroup (n=3). Omega-3 derivatives were used by 53 patients (19%), while niacin and cholestyramine were used by only two patients. Despite extensive metabolic therapies, current metabolic control was suboptimal, especially in FPLD (mean ± SD: HbA1c 7.3% ± 1.9, low-density lipoprotein 97 ± 39 mg/dL, and TG 542 ± 730 mg/dL). Conclusion: This study highlights the heterogeneity in pharmacological management across lipodystrophy subtypes, reflecting their diverse metabolic profiles and needs. While metreleptin remains the cornerstone therapy for generalized lipodystrophy, there is a need for novel therapeutic options to achieve improved metabolic control and optimize treatment outcomes in partial lipodystrophy. Presentation: Sunday, July 13, 2025
other
2024-01-17 | Familial Screening for the Prevention of Rare Diseases: A Focus on Lipodystrophy in Southern Saudi Arabia
Abstract Background Lipodystrophy is a relatively rare, complex disease characterised by a deficiency of adipose tissue and can present as either generalised lipodystrophy (GLD) or partial lipodystrophy (PLD). The prevalence of this disease varies by region. This study aimed to identify the genetic variations associated with lipodystrophy in the southern part of Saudi Arabia. Methodology We conducted a retrospective study by recruiting nine patients from six families, recruiting the proband whole exome sequencing results or any other genetic test results, screening other family members using Sanger sequencing and analysing the carrier status of the latter. These patients were recruited from the Endocrinology and Diabetes Clinic at Jazan General Hospital and East Jeddah Hospital, both in the Kingdom of Saudi Arabia. Result Eight patients were diagnosed with GLD, and one was diagnosed with PLD. Of the six families, four were consanguineously married from the same tribe, while the remaining belonged to the same clan. The majority of GLD patients had an AGPAT2 c.158del mutation, but some had a BSCL2 c.942dup mutation. The single PLD case had a PPARG c.1024C > T mutation but no family history of the disease. In all families evaluated in this study, some family members were confirmed to be carriers of the mutation observed in the corresponding patient. Conclusion Familial screening of relatives of patients with rare, autosomal recessive diseases, such as lipodystrophy, especially when there is a family history, allows the implementation of measures to prevent the onset or reduced severity of disease and reduces the chances of the pathogenic allele being passed onto future generations. Creating a national registry of patients with genetic diseases and carriers of familial pathogenic alleles will allow the assessment of preventive measures and accelerate disease intervention via gene therapy.
2022-12-16 | Volanesorsen, an antisense oligonucleotide to apolipoprotein C-III, increases lipoprotein lipase activity and lowers triglycerides in partial lipodystrophy.
Partial lipodystrophy (PL) syndromes involve deficiency of adipose tissue, causing severe insulin resistance and hypertriglyceridemia. Apolipoprotein C-III (apoC-III) is elevated in PL and is thought to contribute to hypertriglyceridemia by inhibiting lipoprotein lipase (LPL). We hypothesized that volanesorsen, an antisense oligonucleotide to apoC-III, would decrease apoC-III, increase LPL activity, and lower triglycerides in PL. Five adults with PL enrolled in a 16-week placebo-controlled, randomized, double blind study of volanesorsen, 300 mg weekly, followed by 1-year open label extension. Within-subject effects of volanesorsen before and after 16 weeks of active drug are reported due to small sample size. From week 0 to 16, apoC-III decreased from median (25th, 75th %ile) 380 (246, 600) to 75 (26, 232) ng/mL, and triglycerides decreased from 503 (330, 1040) to 116 (86, 355) mg/dL while activation of LPL by subjects' serum increased from 21 (20, 25) to 36 (29, 42) nEq/mL*min. Although, A1c did not change, peripheral and hepatic insulin sensitivity (glucose disposal and suppression of glucose production during hyperinsulinemic clamp) increased and palmitate turnover decreased. After 32-52 weeks of volanesorsen, liver fat decreased. Common adverse events included injection site reactions and decreased platelets. In PL, volanesorsen decreased apoC-III and triglycerides, in part through an LPL dependent mechanism, and may improve insulin resistance and hepatic steatosis.
2015-12-31 | Defective differentiation of adipose precursor cells from lipodystrophic mice lacking perilipin 1.
Perilipin 1 (Plin1) localizes at the surface of lipid droplets to regulate triglyceride storage and hydrolysis in adipocytes. Plin1 defect leads to low adiposity in mice and partial lipodystrophy in human. This study investigated the roles of Plin1 in adipocyte differentiation. Plin1 null (-/-) mice showed plenty of multilocular adipocytes and small unilocular adipocytes in adipose tissue, along with lack of a subpopulation of adipose progenitor cells capable of in vivo adipogenesis and along with downregulation of adipogenic pathway. Before initiation of differentiation, adipose stromal-vascular cells (SVCs) from Plin1-/- mice already accumulated numerous tiny lipid droplets, which increased in number and size during the first 12-h induction but thereafter became disappeared at day 1 of differentiation. The adipogenic signaling was dysregulated despite protein level of PPARγ was near normal in Plin1-/- SVCs like in Plin1-/- adipose tissue. Heterozygous Plin1+/- SVCs were able to develop lipid droplets, with both the number and size more than in Plin1-/- SVCs but less than in Plin1+/+ SVCs, indicating that Plin1 haploinsufficiency accounts for attenuated adipogenesis. Aberrant lipid droplet growth and differentiation of Plin1-/- SVCs were rescued by adenoviral Plin1 expression and were ameliorated by enhanced or prolonged adipogenic stimulation. Our finding suggests that Plin1 plays an important role in adipocyte differentiation and provides an insight into the pathology of partial lipodystrophy in patients with Plin1 mutation.
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Drug Discovery Landscape
1 orphan drug designation for Acquired partial lipodystrophy, including 1 approved therapy.
1 orphan drug designation for Acquired partial lipodystrophy, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Metreleptin [Myalepta] | proteins | EMA | 2012-07-17 | 2018-08-01 | Chiesi Farmaceutici S.p.A. |
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