RARE DISEASE
Familial partial lipodystrophy
Familial partial lipodystrophy
Familial partial lipodystrophy
Synonyms: FPLD
Synonyms: FPLD
Synonyms: FPLD
Drug discovery
2
drugs
With orphan designations
Overview
Familial partial lipodystrophy (FPLD) is a rare genetic disorder characterized by progressive subcutaneous fat loss in limbs/buttocks and ectopic fat deposition in the face, neck, or trunk. Associated with severe insulin resistance, hypertriglyceridemia, diabetes, hepatic steatosis, and cardiovascular complications. Most forms follow autosomal dominant inheritance, often linked to LMNA or PPARG mutations. Diagnosis is clinical and genetic, with management focusing on metabolic complications [1][10][14].
Burden
High rates of diabetes (∼80%), hypertriglyceridemia (60–90%), pancreatitis, and premature atherosclerosis [1][5][14].
Reduced quality of life due to body image concerns and psychiatric comorbidities (e.g., depression) [3][7].
Increased cardiovascular mortality; lifespan often reduced by 10–20 years [7][14][15].
Therapies
Lifestyle: Low-fat, high-fiber diets; structured exercise to reduce ectopic fat [3][16].
Pharmacologic: Metformin, fibrates, and insulin for metabolic control; metreleptin (leptin analog) for severe insulin resistance/hypertriglyceridemia [1][3][16].
PPARγ agonists (e.g., pioglitazone) may benefit PPARG mutation carriers [12][16].
Categories: rare endocrine diseases, rare genetic diseases, rare skin diseases
Research Papers
238 drug discovery papers about Familial partial lipodystrophy, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
238 drug discovery papers about Familial partial lipodystrophy, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2024-06-14 | 1470-P: Modeling Familial Partial Lipodystropy Type 2 (LMNAp.R482W) Utilizing iPSC-Derived Adipocytes
Familial partial lipodystrophy type 2 (FPLD2) is a genetic syndrome characterized by loss of adipose tissue in the trunk and limbs and accumulation of supraclavicular fat. The most common genetic cause of FPLD2 is a pathogenic variant in the lamin A gene (LMNA; c.1444C>T; p.R482W). Our goal was to model FPLD2 in an induced pluripotent stem cell (iPSC) line. CRISPR/Cas9 gene editing was used to knock-in the heterozygous LMNA p.R482W variant into AN1.1 control iPSCs. Wild type and mutant iPSCs underwent a 2-stage differentiation process, first to mesenchymal cells then to adipocytes. Functional studies included 2-deoxyglucose (2-DG) uptake and mitochondrial stress testing. Adipocytes also underwent flow cytometry, RNA sequencing, and microscopy. We observed that both wild-type and mutant clones successfully differentiated to adipocytes after 26 days in adipogenic differentiation media. Adipogenic differentiation was diminished in mutant cells. Basal and insulin-stimulated uptake of 2-DG was impaired in mutant cells. Mitochondrial stress testing in mutant cells demonstrated decreased oxygen consumption rate (OCR), which was driven by a significant decrease in maximal respiration and coupling efficiency. RNA sequencing showed that the mutant cells had significant reduction in the expression of key adipogenic genes including ADIPOQ, CD36, ITIH5, CHCR7, LIPE, ITGA7, and OMD. Preliminary results from flow cytometry and high content microscopy both demonstrated decreased lipid droplet accumulation in the mutant cell lines. Our results show that an iPSC-based model system can recapitulate the adipose tissue dysfunction seen in FPLD2. We propose that this system is a useful model for studying pharmaceuticals aimed at restoring the metabolic function of adipose tissue in FPLD2. Additionally, our work suggests that iPSC-derived adipocytes may be used to study novel candidate disease genes in individuals with atypical lipodystrophy. Disclosure A. Borrego Alvarez: None. K. Liu: None. M.R.S. Gobble: None. M. Grupe: None. L. Mohammed Ali: None. W.J. Buchser: None. D. Baldridge: None. S.I. Stone: None. Funding UL1TR002345 Clinical and Translational Research Funding Program. This project is funded through the Pilot Translational and Clinical Studies function of the WU ICTS.
2023-08-28 | From scarcity to solutions: Therapeutic strategies to restore adipose tissue functionality in rare disorders of lipodystrophy
Abstract Aims Lipodystrophy is a rare disorder characterised by abnormal or deficient adipose tissue formation and distribution. It poses significant challenges to affected individuals, including the development of severe metabolic complications like diabetes and fatty liver disease. These conditions are often chronic, debilitating and life‐threatening, with limited treatment options and a lack of specialised expertise. This review aims to raise awareness of lipodystrophy disorders and highlights therapeutic strategies to restore adipose tissue functionality. Methods Extensive research has been conducted, including both historical and recent advances. We have examined and summarised the literature to provide an overview of potential strategies to restore adipose tissue functionality and treat/reverse metabolic complications in lipodystrophy disorders. Results A wealth of basic and clinical research has investigated various therapeutic approaches for lipodystrophy. These include ground‐breaking methods such as adipose tissue transplantation, innovative leptin replacement therapy, targeted inhibition of lipolysis and cutting‐edge gene and cell therapies. Each approach shows great potential in addressing the complex challenges posed by lipodystrophy. Conclusions Lipodystrophy disorders require urgent attention and innovative treatments. Through rigorous basic and clinical research, several promising therapeutic strategies have emerged that could restore adipose tissue functionality and reverse the severe metabolic complications associated with this condition. However, further research and collaboration between academics, clinicians, patient advocacy groups and pharmaceutical companies will be crucial in transforming these scientific breakthroughs into effective and viable treatment options for individuals and families affected by lipodystrophy. Fostering such interdisciplinary partnerships could pave the way for a brighter future for those battling this debilitating disorder.
2020-12-04 | Generation of an integration-free induced pluripotent stem cell line (PUMCHi001-A) from a patient with familial partial lipodystrophy type 2 (FPLD2) carrying a heterozygous p.R349W (c.1045C > T) mutation in the LMNA gene.
Familial partial lipodystrophy type 2 (FPLD2) is a rare autosomal dominant metabolic disorder caused by heterozygous mutations in the LMNA gene, which encodes for the lamin A/C. A human induced pluripotent stem cell (iPSC) line was generated from peripheral blood mononuclear cells (PBMCs) of a 30 year-old male patient with FPLD2 who had a heterozygous p.R349W (c.1045C > T) mutation in the LMNA gene using non-integrating episomal vector technique. This iPSC line offers a useful resource to investigate pathogenic mechanisms in FPLD2, as well as a cell-based model for drug development to treat FPLD2.
2020-03-19 | Relapsing and Progressive Complications of Severe Hypertriglyceridemia: Effective Long-Term Treatment with Double Filtration Plasmapheresis
Severe hypertriglyceridemia (HTG) is associated with major complications such as acute or relapsing pancreatitis (AP) and atherosclerotic cardiovascular disease (ASCVD). Rapid elimination of triglyceride (TG)-rich lipoproteins (LP) with double filtration plasmapheresis (DFPP) without need for substitution has been found to be effective for the acute, short-term treatment of HTG-induced AP. Data on the long-term use of DFPP to prevent HTG-associated complications are scarce.To evaluate the use and efficacy of regular DFPP treatment in clinical practice for preventing recurrence of HTG-associated complications in thera-py refractory patients.Retrospective multicenter study in patients with severe symptomatic drug and diet refractory HTG with regular DFPP treatment. Patients' incidence of HTG-associated pancreatic or cardiovascular complications was compared before treatment and with regular DFPP treatment.Ten patients (3 female) were identified with baseline maximal TG concentrations of 2,587-28,090 mg/dL (median 5,487 mg/dL; interquartile range [IQR] 4,340-12,636). The mean observation period was 3.9 ± 3.4 years before and 3.8 ± 3.0 years after commencement of DFPP. In 5 patients, severe HTG was related to chylomicronemia, 2 patients had familial partial lipodystrophy Dunnigan, and 1 patient had additional LP(a)-hyperlipoproteinemia. The main HTG-associated complication was recurrent AP in 8 patients, including 1 patient treated during pregnancy. Two patients presented severe progressive ASCVD. With long-term DFPP treatment, the annual rate of HTG-associa-ted pancreatic or cardiovascular complications declined from median 1.4 (IQR 0.7-2.6) to 0 (IQR 0.0-0.4; p < 0.005). The absolute number of events was reduced by 77%. In 6 patients (60%) episodes of AP did not occur, nor was progression of ASCVD detected clinically or by routine imaging techniques. DFPP was effective in the elimination of TG-rich LP from plasma, and was safe and well-tolerated.Long-term, regular DFPP treatment resulted in stabilization of patients with severe HTG and related recurrent AP or progression of ASCVD, who were refractory to conventional dietary and drug therapy.
2011-06-13 | Could Metabolic Syndrome, Lipodystrophy, and Aging Be Mesenchymal Stem Cell Exhaustion Syndromes?
One of the most important and complex diseases of modern society is metabolic syndrome. This syndrome has not been completely understood, and therefore an effective treatment is not available yet. We propose a possible stem cell mechanism involved in the development of metabolic syndrome. This way of thinking lets us consider also other significant pathologies that could have similar etiopathogenic pathways, like lipodystrophic syndromes, progeria, and aging. All these clinical situations could be the consequence of a progressive and persistent stem cell exhaustion syndrome (SCES). The main outcome of this SCES would be an irreversible loss of the effective regenerative mesenchymal stem cells (MSCs) pools. In this way, the normal repairing capacities of the organism could become inefficient. Our point of view could open the possibility for a new strategy of treatment in metabolic syndrome, lipodystrophic syndromes, progeria, and even aging: stem cell therapies.
small molecules
2026-06-22 | First diagnosis of familial partial lipodystrophy syndrome type 3 during pregnancy associated with a novel heterozygous PPARG variant and a concurrent ABCC8 variant: a case report
Familial partial lipodystrophy (FPLD) is a rare genetic syndrome characterised by persistent, selective loss of adipose tissue and is closely associated with severe metabolic disturbances. Pregnancy in women with FPLD is associated with a high risk for both mother and foetus, while clinical experience remains very limited. Evidence from case reports and small series is essential for risk stratification, multidisciplinary management, and optimization of maternal and foetal health. Here, we report the case of a woman at 18 weeks of gestation with very severe hypertriglyceridaemia complicated by acute pancreatitis. The patient had a history of young-onset diabetes mellitus, hypertension, polycystic ovary syndrome (PCOS) and previously known hypertriglyceridaemia, accompanied by characteristic loss of gluteofemoral and lower limb adipose tissue, raising the clinical suspicion of FPLD. Molecular genetic analysis was performed using next-generation sequencing-based gene panel diagnostics. Variants were described according to Human Genome Variation Society (HGVS) nomenclature and classified according to the American College of Medical Genetics and genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. We made the initial diagnosis of severe FPLD3 syndrome and detected a novel heterozygous c.380A>C, p.(Glu127Ala) variant in the peroxisome proliferator-activated receptor gamma gene ( PPARG ), classified as likely pathogenic and considered causative for the patient´s phenotype. In addition, a heterozygous variant of uncertain significance c.328G>A, p.(Ala110Thr) in the ATP-binding cassette transporter sub-family C member 8 gene ( ABCC8 ), was detected. High-dose intensive insulin therapy in combination with metformin and omega-3 fatty acids resulted in a marked reduction in triglyceride levels, normalised blood glucose levels until delivery and avoided further episodes of pancreatitis. Early recognition of FPLD is crucial, particularly in high-risk settings such as pregnancy. Intensive, multidisciplinary metabolic management can stabilize severe metabolic complications and may enable favourable maternal and foetal outcomes.
2026-06-05 | Molecular insight into the activator and deactivator mutations of peroxisome proliferator-activated receptor gamma.
The nuclear receptor known as peroxisome proliferator-activated receptor gamma (PPARγ) is essential for inflammation, lipid metabolism, glucose homeostasis, and adipogenesis. The function of PPARγ can be significantly impacted by mutations that either activate or deactivate the receptor. Deactivating variants can act as dominant-negative forms that sequester coactivators, impair ligand recognition, destabilize the activation function-2 (AF-2) surface, or favor corepressor binding. They are frequently found in the ligand-binding or DNA-binding domains. Metabolic disorders like severe insulin resistance and familial partial lipodystrophy type 3 are caused by these mutations. Activating mutations provide mechanistic insights into receptor overactivation by stabilizing helix 12 and the AF-2 surface, improving coactivator recruitment, and promoting ligand-independent transcription. These variations change the equilibrium between inactive and active states, modify coactivator binding, and reshape conformational ensembles, as demonstrated by molecular dynamics simulations. The design of selective modulators for precision therapy that target PPARγ is guided by an understanding of these molecular mechanisms, which also help classify mutations as dominant-negative or drug-rescuable.
2026-04-27 | Familial partial lipodystrophy type 2 associated with a novel LMNA variant (c.604G>C; p.Glu202Gln): a Colombian family case series.
Familial partial lipodystrophy type 2 (FPLD2) is a rare autosomal dominant laminopathy caused by LMNA gene variants. It is characterized by progressive gluteofemoral lipoatrophy and severe metabolic derangements, including insulin resistance and metabolic dysfunction-associated steatotic liver disease. Three Colombian women (two sisters and a daughter) underwent standardized clinical phenotyping, dual-energy X-ray absorptiometry (DXA), cardiometabolic laboratory testing, and next-generation sequencing-based testing for lipodystrophy-related genes with copy-number variant analysis. All patients carried the heterozygous LMNA variant c.604G>C (p.Glu202Gln). Patients 1 and 2 exhibited classic Dunnigan phenotypes with diabetes and severe hypertriglyceridemia (up to 1,471 mg/dL), as well as imaging evidence of metabolic dysfunction-associated steatotic liver disease. Patient 3 (age 27) presented an evolving phenotype with central adiposity, clinically reported lower-limb fat loss, and insulin resistance (homeostatic model assessment for insulin resistance [HOMA-IR], 4), without hepatic steatosis on abdominal ultrasound. Management optimization in Patients 1 and 2 using contemporary combination therapy, including glucagon-like peptide-1 receptor agonist-based treatment and sodium-glucose cotransporter-2 inhibitors, was followed by sustained improvement in glycemia (HbA1c 11.1% to 7.6% in Patient 1) and triglycerides. In Patient 3, liraglutide was discontinued due to poor tolerability and limited weight response, and she was transitioned to semaglutide in February 2026. This case series expands the phenotypic spectrum of LMNA-associated FPLD2 and supports a disease association for the p.Glu202Gln variant despite its current classification as a variant of uncertain significance. It demonstrates that modern cardiometabolic therapies can be implemented in middle-income settings; however, the absence of functional data, population frequency metrics, and genetic testing in unaffected relatives limits the strength of variant interpretation.
2026-03-19 | Lamin A/C in health, laminopathies, and familial partial lipodystrophy 2.
Familial partial lipodystrophy 2 (FPLD2) is a rare disease characterized by selective adipose tissue loss, expansion, and dysfunction, caused by pathogenic variants in LMNA encoding nuclear lamins A and C. Here, we synthesize current evidence on how nuclear shape abnormalities, impaired mechanosensing, blocked adipogenesis, chromatin remodeling, and altered lamin-binding partner interactions may contribute to FPLD2 pathology. Emerging data highlight chromatin and transcriptional dysregulation of lipogenic, mitochondrial, and inflammatory genes as central drivers, with other mechanisms acting in complementary ways. We also discuss depot-specific transcriptional remodeling that may explain differential adipose loss and expansion in FPLD2. Understanding how these mechanistic pathways converge across FPLD2 and other laminopathies may reveal new therapeutic targets to preserve adipose function.
2026-02-27 | A Novel PPARG R212W Variant Causes Familial Partial Lipodystrophy Type 3: Clinical Presentation and Functional Characterization.
Familial partial lipodystrophy type 3 (FPLD3) is a rare autosomal dominant disorder caused by mutations in peroxisome proliferator-activated receptor gamma(PPARG), which encodes the key adipogenic transcription factor peroxisome proliferator-activated receptor gamma(PPARγ). Clinical diagnosis is challenging due to phenotypic overlap with common metabolic syndromes. We identified a novel PPARG variant in a Chinese family and performed comprehensive functional characterization to elucidate its pathogenic mechanism. The proband, a 15-year-old boy presenting with atypical fat distribution, severe insulin resistance, hypertriglyceridemia, and pancreatitis, underwent clinical evaluation and whole-exome sequencing. The identified variant was confirmed by Sanger sequencing. Its functional impact was assessed through in silico modeling, luciferase reporter assays, protein stability analysis (cycloheximide chase), and evaluation of mitochondrial function (JC-1 staining) and adipocyte gene expression in cellular models. A heterozygous PPARG c.634C>T (p.Arg212Trp, R212W) variant was identified and segregated with the phenotype. Functional studies revealed that the R212W mutant exhibits a partial loss of transcriptional activity (~40% of wild-type) while retaining ligand sensitivity. Crucially, we demonstrated that the mutant protein has significantly reduced stability due to accelerated degradation. In adipocyte models, R212W expression led to impaired mitochondrial membrane potential, depleted cellular ATP levels, and downregulated expression of key metabolic genes (glucose transporter 4[GLUT4], adiponectin[ADIPOQ], fatty acid binding protein 4[FABP4], lipoprotein lipase[LPL], perilipin 1[PLIN1]). These functional deficits were partially rescued by treatment with the PPARγ agonist rosiglitazone. We report a novel pathogenic PPARG R212W variant associated with FPLD3. Our data extend beyond a simple loss-of-function model by establishing a multi-faceted pathogenic mechanism involving protein destabilization, mitochondrial dysfunction, and cellular bioenergetic failure. The partial rescue by rosiglitazone suggests a potential therapeutic avenue. This study underscores the importance of integrating clinical phenotyping with deep functional analysis to diagnose and understand rare monogenic lipodystrophies.
proteins
2026-03-23 | Evaluating the therapeutic impact of tirzepatide in people with partial lipodystrophy.
Lipodystrophy syndromes (LD) are a group of rare conditions characterized by the generalized or partial absence and/or dysfunction of adipocytes. Due to the lack of fat storage capacity, excess lipid accumulates in other tissues, leading to severe insulin resistance. At present, effective therapeutic options remain limited, with metreleptin currently the only specific licensed treatment. To this end, we evaluated the therapeutic impact of tirzepatide in people with partial lipodystrophy (PLD). This was a single-center, retrospective, observational study, including all patients with PLD treated with tirzepatide between January 2022 and September 2025. Forty patients with PLD were included FPLD1 like = 26 (65%), FPLD2 = 4 (10%), FPLD3 = 7 (17.5%), FPLD7 = 1 (2.5%), APLD = 1 (2.5%), unclassified = 1 (2.5%). 87.5% (n = 35) were female with a median age of 47 years (IQR 39-59) and a median BMI of 31.5 kg/m2 (IQR 27.3 to 35.5). After a median 9.5 month follow-up (IQR 7 to 11), marked reductions were seen in body weight from 91.0 kg (IQR 75.0 to 106.0) to 82.8 kg (IQR 69.0 to 93.4; P < .0001), in HbA1c from 65 mmol/mol (IQR 54.5 to 85) to 52 mmol/mol (IQR 39 to 62; P < .0001) and in serum triglycerides from 2.80 mmol/L (IQR 1.6 to 3.7) to 1.83 mmol/L (IQR 1.0 to 2.9; P = .0005). Daily insulin requirements fell from 177.5 IU (IQR 101.3 to 213.8) to 58.0 IU (IQR 0 to 112.5; P = .0028). In patients with partial lipodystrophy, tirzepatide use resulted in substantial statistically significant reductions in weight, glycemic control, serum triglycerides, and daily insulin requirement. We recommend further prospective studies to support these findings and to evaluate its impact earlier in the course of the disorder.
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
2025-07-24 | A clinical case of pregnancy of a patient with a combination of two orphan diseases: familial partial lipodystrophy type 4 and HNF1A-MODY on the background of therapy with recombinant human methionyl leptin
Lipodystrophies are a group of orphan diseases (according to different sources, the prevalence of the disease varies from 1 to 5 cases per 1,000,000 population), which can be either hereditary or acquired. Diseases of this group represent a symptom complex characterized by varying degrees of loss of adipose tissue: complete (generalized lipodystrophy) or partial (partial lipodystrophy), as well as abnormal distribution of subcutaneous fat, provided that there is no influence of alimentary factors and catabolic conditions. Lipodystrophies are characterized by metabolic changes: dyslipidemia, carbohydrate metabolism disorders, insulin resistance, metabolically associated fatty liver disease. Separately, it is worth mentioning reproductive disorders, such as polycystic ovary syndrome, infertility, miscarriage, and others. A decrease in the body’s fat content leads to a decrease in the production of the hormone leptin, which affects the hypothalamic neurons that regulate hunger and satiety, and increases energy expenditure by stimulating thermogenesis. Hypoleptinemia is the main cause of metabolic disorders associated with lipodystrophy. Currently, a recombinant analogue of human leptin has been registered — metreleptin (methionyl leptin), which improves the quality of life of patients by achieving compensation for metabolic disorders, reducing hyperphagia, and also having a beneficial effect on fertility. HNF1A-MODY is diabetes mellitus with an autosomal dominant type of inheritance associated with heterozygous variants of the HNF1A gene, which is involved in the differentiation and functioning of the pancreas. The disease is characterized by onset at a young age, prevalence of postprandial hyperglycemia, presence of glucosuria, progressive course with a high risk of developing micro- and macrovascular complications, effectiveness of therapy with sulfonylurea drugs with the emergence of the need for insulin therapy over time. This article presents the first clinical case in Russia demonstrating the pregnancy of a patient with a combination of two orphan diseases: familial partial lipodystrophy type 4 and MODY 3 (list of rare (orphan) diseases of the Ministry of Health of Russia, dated February 6, 2023), who received pathogenetic treatment with metreleptin before confirmation of the fact of pregnancy.
2025-07-07 | Liraglutide use in pediatric type 2 familial partial lipodystrophy caused by LMNA mutation: a case report.
Type 2 familial partial lipodystrophy (FPLD2), or Dunnigan syndrome, is a rare genetic disorder characterized by selective subcutaneous fat loss, metabolic complications, and insulin resistance due to LMNA gene mutations. This case report describes the clinical presentation and treatment of a Chinese family with FPLD2, highlighting liraglutide's role in glycemic and lipid control. The index patient is a 14-year-old girl, presenting with fat accumulation in the neck, loss of subcutaneous fat on the face, arms, legs, and trunk, and metabolic complications including diabetes mellitus with insulin resistance, hepatomegaly, and dyslipidemia. The diagnosis of FPLD2 was confirmed by the identification of a heterozygous mutation c.1456 A > G (p. Lys486Glu) in exon 8 of the LMNA gene. The patient was initially treated with a diabetic diet, metformin, and insulin therapy, but glycemic control was only achieved after introducing liraglutide, resulting in satisfactory control within two months. The variable manifestations of FPLD2 within the family (the proband, her father, and elder sister), all carrying the same LMNA mutation are presented, highlighting the complexity of this genetic disorder. The fast clinical response to liraglutide in our patient suggests a potential therapeutic role for Glucagon-like peptide-1 receptor agonists in the management of metabolic complications in FPLD2. This case report underscores the importance of recognizing the variable expressivity of FPLD2 and the potential role of liraglutide in managing glycemic and lipid in pediatric patients. It also highlights the need for further research to explore novel therapeutic strategies for the metabolic complications associated with FPLD2.
2025-04-10 | Leptin acutely increases hepatic triglyceride secretion in patients with lipodystrophy.
Metreleptin ameliorates hepatic steatosis partially independent of its anorexic action. We previously showed that metreleptin increases hepatic very low-density lipoprotein triglycerides (VLDL1-TG) export in rodents and healthy humans requiring intact hepatic autonomic innervation. The primary aim of this study was to investigate whether metreleptin has anti-steatotic properties in patients with lipodystrophy by increasing VLDL1-TG export. In addition, we present a case of generalized lipodystrophy undergoing metreleptin treatment after liver transplantation, a model for hepatic autonomic denervation. In this randomized, placebo-controlled, crossover trial (EudraCT 2017-003014-22) we assessed the acute effects of a single metreleptin injection in 10 patients (8 females, 2 males; mean age ± SD: 49 ± 14 yrs; 9 familial partial and 1 generalized lipodystrophy) on hepatic VLDL1-TG secretion and hepatocellular lipid content (HCL) measured via an intravenous fat emulsion test and 1H-magnetic resonance spectroscopy, respectively. We found that a single injection of metreleptin increased hepatic VLDL1-TG secretion by 75 % (mean difference ± SD: +219 ± 149 mg/h metreleptin vs. placebo; p = 0.001), without significant changes in HCL within 3 h (mean difference ± SD: -8 ± 14 % metreleptin vs. placebo, p = 0.14). Metreleptin therapy in a patient with generalized lipodystrophy following liver transplantation failed to ameliorate hepatic steatosis despite improving glucose and lipid metabolism. Leptin acutely increases hepatic VLDL1-TG secretion in patients with lipodystrophy, likely contributing to metreleptin's body weight-independent anti-steatotic effects. The case report suggests that intact autonomic liver innervation may be required for this action, warranting further research.
gene therapies
2026-02-19 | Variable Expressivity in Type 2 Familial Partial Lipodystrophy Related to a Pathogenic LMNA Variant R482: Maternal Transmission to Non-Identical Twins.
Familial partial lipodystrophy type 2 (FPLD2), or Dunnigan syndrome, is a rare autosomal dominant disorder caused by mutations in the lamin A (LMNA) gene, most frequently involving the p.R482W variant. It is characterized by regional loss of subcutaneous fat and severe metabolic abnormalities, particularly dyslipidemia, insulin resistance, and hepatic steatosis. We report a family with three individuals -mother and two siblings- carrying the same pathogenic LMNA c.1444C>T (p.R482W) variant but exhibiting distinct clinical and biochemical profiles. The proband (patient 1) is a 29-year-old male, presented with moderate metabolic disturbances, including hypertriglyceridemia, low levels of high density lipoprotein-cholesterol (HDL-C), and hepatic steatosis, accompanied by physical features such as dorsocervical fat accumulation and winged neck. His dizygotic female twin (patient 2) exhibited a more severe phenotype with triglycerides levels approached 700 mg/dL, insulin resistance, and polycystic ovarian morphology (PCOM). Their 68-year-old mother, also a carrier, showed only mild dyslipidemia and unstable angina. The comparison of dizygotic twins and their mother carrying the same LMNA variant provides a unique opportunity to illustrate how sex, age, and hormonal status modulate metabolic severity in FPLD2. These findings reinforce the clinical relevance of family-based evaluation and early metabolic surveillance, even in mildly affected or asymptomatic carriers.
2026-01-01 | Unraveling the Natural History of Lipodystrophy Syndromes: Insights from the Prospective LD-LYNC Study:
Supplemental Table 1. Distribution of total number of probands and relatives across study sites.Supplemental Table 2. Overview of possible underlying etiologies or coexisting diseases in patients with acquired lipodystrophy syndromes.Supplemental Table 3. Metabolic and other uncommon complications of patients with lipodystrophy stratified by the centers.Supplemental Table 4. Features of glomerulonephritis in patients with lipodystrophy.Supplemental Table 5. Previous diagnosis of malignancy in patients with lipodystrophy.Supplemental Table 6. Comparison of the clinical characteristics and comorbidities of patients with acquired and congenital or familial lipodystrophy syndromes.Supplemental Table 7. Comparison of laboratory parameters based on metreleptin treatment status in females.Supplemental Table 8. Comparison of laboratory parameters based on metreleptin treatment status in males.Supplemental Table 9. Longitudinal laboratory results by lipodystrophy typeSupplemental Figure 1. Kaplan–Meier Estimates Incorporating Prospectively Observed Incident Events.Kaplan–Meier estimates of time to diagnosis for major comorbidities across lipodystrophy subgroups. Updated survival models incorporate both retrospectively reported age-of-onset data collected at enrollment and incident events observed prospectively after study entry. Participants were censored at their most recent follow-up visit. Panels show diabetes-free (A, B), hypertriglyceridemia (HighTG)-free (C, D), pancreatitis-free (E, F), metabolic dysfunction-associated steatotic liver disease (MASLD)-free (G, H), heart disease-free (I, J), and hospitalization-free (K, L) survival probabilities over time (years). The y-axis represents survival probability, and the x-axis represents age in years. GL, generalized lipodystrophy; PL, partial lipodystrophy; CGL, congenital generalized lipodystrophy; FPLD, familial partial lipodystrophy; MASLD, metabolic dysfunction-associated steatotic liver disease; HighTG, hypertriglyceridemia.Supplemental Figure 2. Longitudinal Trajectories of Laboratory Parameters in Generalized and Partial Lipodystrophy.Spaghetti plots illustrating individual longitudinal trajectories of key metabolic laboratory parameters in participants with generalized lipodystrophy (GL) and partial lipodystrophy (PL) during prospective follow-up. Each line represents a single participant with repeated measurements obtained from baseline through subsequent annual visits. Panels depict (A) HbA1c (%), (B) triglycerides (mg/dL), (C) HDL (mg/dL), (D) LDL (mg/dL), (E) total cholesterol (mg/dL), and (F) alanine aminotransferase (ALT, U/L). Time is shown in years since study enrollment.
2025-03-25 | A case of familial partial lipodystrophy type 2 masquerading as Cushing syndrome: Explaining an atypical phenotype by whole-exome sequencing.
Familial partial lipodystrophy type 2 is a rare disease, particularly when it is caused by nonclassical gene variants. A high index of suspicion is essential for a timely diagnosis. We present the case of a 32-year-old woman, referred to evaluation of a possible Cushing syndrome, which was clinically and biochemically ruled out. Yet, due to the finding of a rather abnormal fat distribution during physical examination, the diagnosis of lipodystrophy was cogitated. Whole-exome sequencing revealed a missense variant of exon 11 R582H of the gene encoding Laminin A (rs57830985,c.1745G>A, p.Arg582His). The patient presented some clinical and biochemical characteristics discordant with those previously reported in patients harboring other classical variants of this gene.
2025-03-21 | Hyperandrogenism as a clinical manifestation of familial partial lipodystrophy type 2 in an adolescent female patient
We present a case report of a girl with significant hyperandrogenism with accompanying metabolic disorders. In the physical examination, attention was drawn to tall stature, excessive body mass with a muscular build, broad shoulders and a narrow pelvis, low timbre of voice, acne lesions, enlarged mandible, hirsutism (19 points on the Ferriman-Gallwey scale), and elevated blood pressure. Substantial hyperandrogenemia was noted, with a significantly increased testosterone level and elevated levels of adrenal androgens. Based on steroid metabolome analysis from 24-hour urine collection, congenital adrenal hyperplasia was ruled out. Dyslipidemia and impaired glucose tolerance with hyperinsulinism in the oral glucose tolerance test were found. Magnetic resonance imaging of the abdomen and pelvis revealed a fatty liver and overgrowth of muscles and mesentery with adipose tissue. Whole exome sequencing was performed, revealing the presence of a known, pathogenic molecular variant, c.1394G > A, in the LMNA gene, associated with the occurrence of familial partial lipodystrophy.
2025-01-02 | I suffer from several serious diseases”. The Dunnigan-type of familial partial lipodystrophy: a multiple-symptom disorder caused by genetic mutation
DOI: 10.20452/pamw.16918, Published online: January 02, 2025, Authors: Magdalena Płonka-Stępień1,2, Jerzy Hohendorff1, Łukasz Pawliński1, Barbara Katra1, Maciej T. Małecki1
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2024-09-03 | Circulating exosomal circRNA-miRNA-mRNA network in a familial partial lipodystrophy type 3 family with a novel PPARG frameshift mutation c.418dup.
Familial partial lipodystrophy 3 (FPLD3) is a rare genetic disorder caused by loss-of-function mutations in the PPARG gene, characterized by a selective absence of subcutaneous fat and associated metabolic complications. However, the molecular mechanisms of FPLD3 remain unclear. In this study, we recruited a 17-yr-old Chinese female with FPLD3 and her family, identifying a novel PPARG frameshift mutation (exon 4: c.418dup: p.R140Kfs*7) that truncates the PPARγ protein at the seventh amino acid, significantly expanding the genetic landscape of FPLD3. By performing next-generation sequencing of circular RNAs (circRNAs), microRNAs (miRNAs), and mRNAs in plasma exosomes, we discovered 59 circRNAs, 57 miRNAs, and 299 mRNAs were significantly altered in the mutation carriers compared with the healthy controls. Integration analysis highlighted that the circ_0001597-miR-671-5p pair and 18 mRNAs might be incorporated into the metabolic regulatory networks of the FPLD3 induced by the novel PPARG mutation. Functional annotation suggested that these genes were significantly enriched in glucose- and lipid metabolism-related pathways. Among the circRNA-miRNA-mRNA network, we identified two critical regulators, early growth response-1 (EGR1), a key transcription factor known for its role in insulin signaling pathways and lipid metabolism, and 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3), which gets involved in the biosynthesis of triglycerides and lipolysis. Circ_0001597 regulates the expression of these genes through miR-671-5p, potentially contributing to the pathophysiology of FPLD3. Overall, this study clarified a circulating exosomal circRNA-miRNA-mRNA network in a FPLD3 family with a novel PPARG mutation, providing evidence for exploring promising biomarkers and developing novel therapeutic strategies for this rare genetic disorder.NEW & NOTEWORTHY Through the establishment of a ceRNA regulatory networks in a novel PPARG frameshift mutation c.418dup-induced FPLD3 pedigree, this study reveals that circ_0001597 may contribute to the pathophysiology of FPLD3 by sequestering miR-671-5p to regulate the expression of EGR1 and AGPAT3, pivotal genes situated in the triglyceride (TG) synthesis and lipolysis pathways. Current findings expand our molecular understanding of adipose tissue dysfunction, providing potential blood biomarkers and therapeutic avenues for lipodystrophy and associated metabolic complications.
2023-01-23 | APOC-III: a Gatekeeper in Controlling Triglyceride Metabolism
Abstract Purpose of Review Apolipoprotein C-III (ApoC-III) is a widely known player in triglyceride metabolism, and it has been recently recognized as a polyhedric factor which may regulate several pathways beyond lipid metabolism by influencing cardiovascular, metabolic, and neurological disease risk. This review summarizes the different functions of ApoC-III and underlines the recent findings related to its multifaceted pathophysiological role. Recent Findings The role of ApoC-III has been implicated in HDL metabolism and in the development of atherosclerosis, inflammation, and ER stress in endothelial cells. ApoC-III has been recently considered an important player in insulin resistance mechanisms, lipodystrophy, diabetic dyslipidemia, and postprandial hypertriglyceridemia (PPT). The emerging evidence of the involvement of ApoC-III in the in the pathogenesis of Alzheimer’s disease open the way to further study if modification of ApoC-III level slows disease progression. Furthermore, ApoC-III is clearly linked to cardiovascular disease (CVD) risk, and progression of coronary artery disease (CAD) as well as the calcification of aortic valve and recent clinical trials has pointed out the inhibition of ApoC-III as a promising approach to manage hypertriglyceridemia and prevent CVD. Summary Several evidences highlight the role of ApoC-III not only in triglyceride metabolism but also in several cardio-metabolic pathways. Results from recent clinical trials underline that the inhibition of ApoC-III is a promising therapeutical strategy for the management of severe hypertriglyceridemia and in CVD prevention.
2022-09-09 | Severe loss of adipose tissue in a Vietnamese lipodystrophy patient caused by LMNA p.G465D mutation: a first clinical characterization and two-year follow-up.
Familial partial lipodystrophy type 2 is the most well-known subtype of lipodystrophy. We describe for the first time the phenotype of a case with lipodystrophy, who carried heterozygous mutation c.G1394A (p.G465D) in the LMNA gene. A 17-year-old girl was diagnosed with FPLD2 due to severe loss of subcutaneous fat in the extremities, buttocks and metabolic complications. However, there was no accumulation of fat over her face and neck, which is remarkably different from the FPLD2 clinical phenotypes. Two years of surveillance showed the challenge due to unable control of insulin resistance, glucose and lipid metabolism. Whole exome sequencing revealed the heterozygous mutation c.1394G>A at exon 11 of LMNA gene (p.G465D). Our case displayed an atypical phenotype of FPLD2 with metabolic anomalies, not cardiovascular diseases. The difficulties of medical management in this case pointed out the urgent need for more effective treatment for individuals suffering from this rare disease.
2021-08-03 | Selective Targeting of Angiopoietin-like 3 (ANGPTL3) with Vupanorsen for the Treatment of Patients with Familial Partial Lipodystrophy (FPLD): Results of a Proof-of-Concept Study
Abstract Background: Familial partial lipodystrophy (FPLD) is a rare disease characterized by selective loss of peripheral subcutaneous fat associated with dyslipidemia and diabetes mellitus. Reductions in circulating levels of ANGPTL3 are associated with lower triglyceride and other atherogenic lipids, making it an attractive target for treatment of FPLD patients. This proof-of-concept study was conducted to assess the efficacy and safety of targeting ANGPTL3 with vupanorsen in patients with FPLD. Methods: This was an open-label study. Four patients with FPLD (two with pathogenic variants in LMNA gene, and two with no causative genetic variant), diabetes (HbA1c≥7.0% and ≤12%), hypertriglyceridemia (≥500 mg/dL), and hepatic steatosis (hepatic fat fraction, HFF≥6.4%) were included. Patients received vupanorsen subcutaneously at a dose of 20 mg weekly for 26 weeks. The primary endpoint was the percent change from baseline in fasting triglycerides at Week 27. Other endpoints analyzed at the same time point included changes in ANGPTL3, fasting lipids and lipoproteins, insulin secretion/sensitivity, postprandial lipid and glycemic changes in response to a mixed meal test, HFF measured by MRI, and body composition measured by dual energy absorptiometry (DEXA). Results: Baseline mean ± SD fasting triglyceride level was 9.24 ± 4.9 mmol/L (817.8 ± 431.9 mg/dL). Treatment resulted in reduction in fasting levels of triglyceride by 59.9%, ANGPTL3 by 54.7%, and in several other lipoproteins/lipids including very low- density lipoprotein cholesterol by 53.5%, non-high-density lipoprotein cholesterol by 20.9%, and free fatty acids (FFA) by 41.7%. The area under the curve for postprandial triglycerides, FFA, and glucose were reduced by 60%, 32%, and 14%, respectively. Treatment with vupanorsen also resulted in 55% reduction in adipose tissue insulin resistance index, while other insulin sensitivity indices and HbA1c levels were not changed. Additional investigations in HFF and in DEXA parameters suggested dynamic changes in fat partitioning during treatment. Adverse events observed were related to common serious complications associated with diabetes and FPLD, vupanorsen was well tolerated, and there was no effect on platelet count. Conclusions: Although limited, these results suggest that targeting ANGPTL3 with vupanorsen could address several metabolic abnormalities in patients with FPLD. Clinical Trial: NCT03514420
2021-03-17 | Development of Antisense Oligonucleotide Gapmers for the Treatment of Dyslipidemia and Lipodystrophy.
Although technological advances in molecular genetics over the last few decades have greatly expedited the identification of mutations in many genetic diseases, the translation of the genetic mechanisms into a clinical setting has been quite challenging, with a minimum number of effective treatments available. The advancements in antisense therapy have revolutionized the field of neuromuscular disorders as well as lipid-mediated diseases. With the approval of splice-switching antisense oligonucleotide (AO) therapy for nusinersen and eteplirsen for the treatment of spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD), several modified AOs are now being evaluated in clinical trials for the treatment of a number of disorders. In order to activate RNase H-mediated cleavage of the target mRNA, as well as to increase the binding affinity and specificity, gapmer AOs are designed that have a PS backbone flanked with the modified AOs on both sides. Mipomersen (trade name Kynamro), a 2'-O-methoxyethyl (MOE) gapmer, was approved by the Food and Drug Administration (FDA) for the treatment of homozygous familial hypercholesterolemia (HoFH) in 2013. Volanesorsen, another 20-mer MOE gapmer has shown to be successful in lowering the levels of triglycerides (TGs) in several lipid disorders and has received conditional approval in the European Union for the treatment of Familial chylomicronemia syndrome (FCS) in May 2019 following successful results from phase II/III clinical trials. This chapter focuses on the clinical applications of gapmer AOs for genetic dyslipidemia and lipodystrophy.
cell therapies
2024-06-14 | 1470-P: Modeling Familial Partial Lipodystropy Type 2 (LMNAp.R482W) Utilizing iPSC-Derived Adipocytes
Familial partial lipodystrophy type 2 (FPLD2) is a genetic syndrome characterized by loss of adipose tissue in the trunk and limbs and accumulation of supraclavicular fat. The most common genetic cause of FPLD2 is a pathogenic variant in the lamin A gene (LMNA; c.1444C>T; p.R482W). Our goal was to model FPLD2 in an induced pluripotent stem cell (iPSC) line. CRISPR/Cas9 gene editing was used to knock-in the heterozygous LMNA p.R482W variant into AN1.1 control iPSCs. Wild type and mutant iPSCs underwent a 2-stage differentiation process, first to mesenchymal cells then to adipocytes. Functional studies included 2-deoxyglucose (2-DG) uptake and mitochondrial stress testing. Adipocytes also underwent flow cytometry, RNA sequencing, and microscopy. We observed that both wild-type and mutant clones successfully differentiated to adipocytes after 26 days in adipogenic differentiation media. Adipogenic differentiation was diminished in mutant cells. Basal and insulin-stimulated uptake of 2-DG was impaired in mutant cells. Mitochondrial stress testing in mutant cells demonstrated decreased oxygen consumption rate (OCR), which was driven by a significant decrease in maximal respiration and coupling efficiency. RNA sequencing showed that the mutant cells had significant reduction in the expression of key adipogenic genes including ADIPOQ, CD36, ITIH5, CHCR7, LIPE, ITGA7, and OMD. Preliminary results from flow cytometry and high content microscopy both demonstrated decreased lipid droplet accumulation in the mutant cell lines. Our results show that an iPSC-based model system can recapitulate the adipose tissue dysfunction seen in FPLD2. We propose that this system is a useful model for studying pharmaceuticals aimed at restoring the metabolic function of adipose tissue in FPLD2. Additionally, our work suggests that iPSC-derived adipocytes may be used to study novel candidate disease genes in individuals with atypical lipodystrophy. Disclosure A. Borrego Alvarez: None. K. Liu: None. M.R.S. Gobble: None. M. Grupe: None. L. Mohammed Ali: None. W.J. Buchser: None. D. Baldridge: None. S.I. Stone: None. Funding UL1TR002345 Clinical and Translational Research Funding Program. This project is funded through the Pilot Translational and Clinical Studies function of the WU ICTS.
2023-08-28 | From scarcity to solutions: Therapeutic strategies to restore adipose tissue functionality in rare disorders of lipodystrophy
Abstract Aims Lipodystrophy is a rare disorder characterised by abnormal or deficient adipose tissue formation and distribution. It poses significant challenges to affected individuals, including the development of severe metabolic complications like diabetes and fatty liver disease. These conditions are often chronic, debilitating and life‐threatening, with limited treatment options and a lack of specialised expertise. This review aims to raise awareness of lipodystrophy disorders and highlights therapeutic strategies to restore adipose tissue functionality. Methods Extensive research has been conducted, including both historical and recent advances. We have examined and summarised the literature to provide an overview of potential strategies to restore adipose tissue functionality and treat/reverse metabolic complications in lipodystrophy disorders. Results A wealth of basic and clinical research has investigated various therapeutic approaches for lipodystrophy. These include ground‐breaking methods such as adipose tissue transplantation, innovative leptin replacement therapy, targeted inhibition of lipolysis and cutting‐edge gene and cell therapies. Each approach shows great potential in addressing the complex challenges posed by lipodystrophy. Conclusions Lipodystrophy disorders require urgent attention and innovative treatments. Through rigorous basic and clinical research, several promising therapeutic strategies have emerged that could restore adipose tissue functionality and reverse the severe metabolic complications associated with this condition. However, further research and collaboration between academics, clinicians, patient advocacy groups and pharmaceutical companies will be crucial in transforming these scientific breakthroughs into effective and viable treatment options for individuals and families affected by lipodystrophy. Fostering such interdisciplinary partnerships could pave the way for a brighter future for those battling this debilitating disorder.
2020-12-04 | Generation of an integration-free induced pluripotent stem cell line (PUMCHi001-A) from a patient with familial partial lipodystrophy type 2 (FPLD2) carrying a heterozygous p.R349W (c.1045C > T) mutation in the LMNA gene.
Familial partial lipodystrophy type 2 (FPLD2) is a rare autosomal dominant metabolic disorder caused by heterozygous mutations in the LMNA gene, which encodes for the lamin A/C. A human induced pluripotent stem cell (iPSC) line was generated from peripheral blood mononuclear cells (PBMCs) of a 30 year-old male patient with FPLD2 who had a heterozygous p.R349W (c.1045C > T) mutation in the LMNA gene using non-integrating episomal vector technique. This iPSC line offers a useful resource to investigate pathogenic mechanisms in FPLD2, as well as a cell-based model for drug development to treat FPLD2.
2020-03-19 | Relapsing and Progressive Complications of Severe Hypertriglyceridemia: Effective Long-Term Treatment with Double Filtration Plasmapheresis
Severe hypertriglyceridemia (HTG) is associated with major complications such as acute or relapsing pancreatitis (AP) and atherosclerotic cardiovascular disease (ASCVD). Rapid elimination of triglyceride (TG)-rich lipoproteins (LP) with double filtration plasmapheresis (DFPP) without need for substitution has been found to be effective for the acute, short-term treatment of HTG-induced AP. Data on the long-term use of DFPP to prevent HTG-associated complications are scarce.To evaluate the use and efficacy of regular DFPP treatment in clinical practice for preventing recurrence of HTG-associated complications in thera-py refractory patients.Retrospective multicenter study in patients with severe symptomatic drug and diet refractory HTG with regular DFPP treatment. Patients' incidence of HTG-associated pancreatic or cardiovascular complications was compared before treatment and with regular DFPP treatment.Ten patients (3 female) were identified with baseline maximal TG concentrations of 2,587-28,090 mg/dL (median 5,487 mg/dL; interquartile range [IQR] 4,340-12,636). The mean observation period was 3.9 ± 3.4 years before and 3.8 ± 3.0 years after commencement of DFPP. In 5 patients, severe HTG was related to chylomicronemia, 2 patients had familial partial lipodystrophy Dunnigan, and 1 patient had additional LP(a)-hyperlipoproteinemia. The main HTG-associated complication was recurrent AP in 8 patients, including 1 patient treated during pregnancy. Two patients presented severe progressive ASCVD. With long-term DFPP treatment, the annual rate of HTG-associa-ted pancreatic or cardiovascular complications declined from median 1.4 (IQR 0.7-2.6) to 0 (IQR 0.0-0.4; p < 0.005). The absolute number of events was reduced by 77%. In 6 patients (60%) episodes of AP did not occur, nor was progression of ASCVD detected clinically or by routine imaging techniques. DFPP was effective in the elimination of TG-rich LP from plasma, and was safe and well-tolerated.Long-term, regular DFPP treatment resulted in stabilization of patients with severe HTG and related recurrent AP or progression of ASCVD, who were refractory to conventional dietary and drug therapy.
2011-06-13 | Could Metabolic Syndrome, Lipodystrophy, and Aging Be Mesenchymal Stem Cell Exhaustion Syndromes?
One of the most important and complex diseases of modern society is metabolic syndrome. This syndrome has not been completely understood, and therefore an effective treatment is not available yet. We propose a possible stem cell mechanism involved in the development of metabolic syndrome. This way of thinking lets us consider also other significant pathologies that could have similar etiopathogenic pathways, like lipodystrophic syndromes, progeria, and aging. All these clinical situations could be the consequence of a progressive and persistent stem cell exhaustion syndrome (SCES). The main outcome of this SCES would be an irreversible loss of the effective regenerative mesenchymal stem cells (MSCs) pools. In this way, the normal repairing capacities of the organism could become inefficient. Our point of view could open the possibility for a new strategy of treatment in metabolic syndrome, lipodystrophic syndromes, progeria, and even aging: stem cell therapies.
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2026-06-22 | First diagnosis of familial partial lipodystrophy syndrome type 3 during pregnancy associated with a novel heterozygous PPARG variant and a concurrent ABCC8 variant: a case report
Familial partial lipodystrophy (FPLD) is a rare genetic syndrome characterised by persistent, selective loss of adipose tissue and is closely associated with severe metabolic disturbances. Pregnancy in women with FPLD is associated with a high risk for both mother and foetus, while clinical experience remains very limited. Evidence from case reports and small series is essential for risk stratification, multidisciplinary management, and optimization of maternal and foetal health. Here, we report the case of a woman at 18 weeks of gestation with very severe hypertriglyceridaemia complicated by acute pancreatitis. The patient had a history of young-onset diabetes mellitus, hypertension, polycystic ovary syndrome (PCOS) and previously known hypertriglyceridaemia, accompanied by characteristic loss of gluteofemoral and lower limb adipose tissue, raising the clinical suspicion of FPLD. Molecular genetic analysis was performed using next-generation sequencing-based gene panel diagnostics. Variants were described according to Human Genome Variation Society (HGVS) nomenclature and classified according to the American College of Medical Genetics and genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. We made the initial diagnosis of severe FPLD3 syndrome and detected a novel heterozygous c.380A>C, p.(Glu127Ala) variant in the peroxisome proliferator-activated receptor gamma gene ( PPARG ), classified as likely pathogenic and considered causative for the patient´s phenotype. In addition, a heterozygous variant of uncertain significance c.328G>A, p.(Ala110Thr) in the ATP-binding cassette transporter sub-family C member 8 gene ( ABCC8 ), was detected. High-dose intensive insulin therapy in combination with metformin and omega-3 fatty acids resulted in a marked reduction in triglyceride levels, normalised blood glucose levels until delivery and avoided further episodes of pancreatitis. Early recognition of FPLD is crucial, particularly in high-risk settings such as pregnancy. Intensive, multidisciplinary metabolic management can stabilize severe metabolic complications and may enable favourable maternal and foetal outcomes.
2026-06-05 | Molecular insight into the activator and deactivator mutations of peroxisome proliferator-activated receptor gamma.
The nuclear receptor known as peroxisome proliferator-activated receptor gamma (PPARγ) is essential for inflammation, lipid metabolism, glucose homeostasis, and adipogenesis. The function of PPARγ can be significantly impacted by mutations that either activate or deactivate the receptor. Deactivating variants can act as dominant-negative forms that sequester coactivators, impair ligand recognition, destabilize the activation function-2 (AF-2) surface, or favor corepressor binding. They are frequently found in the ligand-binding or DNA-binding domains. Metabolic disorders like severe insulin resistance and familial partial lipodystrophy type 3 are caused by these mutations. Activating mutations provide mechanistic insights into receptor overactivation by stabilizing helix 12 and the AF-2 surface, improving coactivator recruitment, and promoting ligand-independent transcription. These variations change the equilibrium between inactive and active states, modify coactivator binding, and reshape conformational ensembles, as demonstrated by molecular dynamics simulations. The design of selective modulators for precision therapy that target PPARγ is guided by an understanding of these molecular mechanisms, which also help classify mutations as dominant-negative or drug-rescuable.
2026-04-27 | Familial partial lipodystrophy type 2 associated with a novel LMNA variant (c.604G>C; p.Glu202Gln): a Colombian family case series.
Familial partial lipodystrophy type 2 (FPLD2) is a rare autosomal dominant laminopathy caused by LMNA gene variants. It is characterized by progressive gluteofemoral lipoatrophy and severe metabolic derangements, including insulin resistance and metabolic dysfunction-associated steatotic liver disease. Three Colombian women (two sisters and a daughter) underwent standardized clinical phenotyping, dual-energy X-ray absorptiometry (DXA), cardiometabolic laboratory testing, and next-generation sequencing-based testing for lipodystrophy-related genes with copy-number variant analysis. All patients carried the heterozygous LMNA variant c.604G>C (p.Glu202Gln). Patients 1 and 2 exhibited classic Dunnigan phenotypes with diabetes and severe hypertriglyceridemia (up to 1,471 mg/dL), as well as imaging evidence of metabolic dysfunction-associated steatotic liver disease. Patient 3 (age 27) presented an evolving phenotype with central adiposity, clinically reported lower-limb fat loss, and insulin resistance (homeostatic model assessment for insulin resistance [HOMA-IR], 4), without hepatic steatosis on abdominal ultrasound. Management optimization in Patients 1 and 2 using contemporary combination therapy, including glucagon-like peptide-1 receptor agonist-based treatment and sodium-glucose cotransporter-2 inhibitors, was followed by sustained improvement in glycemia (HbA1c 11.1% to 7.6% in Patient 1) and triglycerides. In Patient 3, liraglutide was discontinued due to poor tolerability and limited weight response, and she was transitioned to semaglutide in February 2026. This case series expands the phenotypic spectrum of LMNA-associated FPLD2 and supports a disease association for the p.Glu202Gln variant despite its current classification as a variant of uncertain significance. It demonstrates that modern cardiometabolic therapies can be implemented in middle-income settings; however, the absence of functional data, population frequency metrics, and genetic testing in unaffected relatives limits the strength of variant interpretation.
2026-03-19 | Lamin A/C in health, laminopathies, and familial partial lipodystrophy 2.
Familial partial lipodystrophy 2 (FPLD2) is a rare disease characterized by selective adipose tissue loss, expansion, and dysfunction, caused by pathogenic variants in LMNA encoding nuclear lamins A and C. Here, we synthesize current evidence on how nuclear shape abnormalities, impaired mechanosensing, blocked adipogenesis, chromatin remodeling, and altered lamin-binding partner interactions may contribute to FPLD2 pathology. Emerging data highlight chromatin and transcriptional dysregulation of lipogenic, mitochondrial, and inflammatory genes as central drivers, with other mechanisms acting in complementary ways. We also discuss depot-specific transcriptional remodeling that may explain differential adipose loss and expansion in FPLD2. Understanding how these mechanistic pathways converge across FPLD2 and other laminopathies may reveal new therapeutic targets to preserve adipose function.
2026-02-27 | A Novel PPARG R212W Variant Causes Familial Partial Lipodystrophy Type 3: Clinical Presentation and Functional Characterization.
Familial partial lipodystrophy type 3 (FPLD3) is a rare autosomal dominant disorder caused by mutations in peroxisome proliferator-activated receptor gamma(PPARG), which encodes the key adipogenic transcription factor peroxisome proliferator-activated receptor gamma(PPARγ). Clinical diagnosis is challenging due to phenotypic overlap with common metabolic syndromes. We identified a novel PPARG variant in a Chinese family and performed comprehensive functional characterization to elucidate its pathogenic mechanism. The proband, a 15-year-old boy presenting with atypical fat distribution, severe insulin resistance, hypertriglyceridemia, and pancreatitis, underwent clinical evaluation and whole-exome sequencing. The identified variant was confirmed by Sanger sequencing. Its functional impact was assessed through in silico modeling, luciferase reporter assays, protein stability analysis (cycloheximide chase), and evaluation of mitochondrial function (JC-1 staining) and adipocyte gene expression in cellular models. A heterozygous PPARG c.634C>T (p.Arg212Trp, R212W) variant was identified and segregated with the phenotype. Functional studies revealed that the R212W mutant exhibits a partial loss of transcriptional activity (~40% of wild-type) while retaining ligand sensitivity. Crucially, we demonstrated that the mutant protein has significantly reduced stability due to accelerated degradation. In adipocyte models, R212W expression led to impaired mitochondrial membrane potential, depleted cellular ATP levels, and downregulated expression of key metabolic genes (glucose transporter 4[GLUT4], adiponectin[ADIPOQ], fatty acid binding protein 4[FABP4], lipoprotein lipase[LPL], perilipin 1[PLIN1]). These functional deficits were partially rescued by treatment with the PPARγ agonist rosiglitazone. We report a novel pathogenic PPARG R212W variant associated with FPLD3. Our data extend beyond a simple loss-of-function model by establishing a multi-faceted pathogenic mechanism involving protein destabilization, mitochondrial dysfunction, and cellular bioenergetic failure. The partial rescue by rosiglitazone suggests a potential therapeutic avenue. This study underscores the importance of integrating clinical phenotyping with deep functional analysis to diagnose and understand rare monogenic lipodystrophies.
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2026-03-23 | Evaluating the therapeutic impact of tirzepatide in people with partial lipodystrophy.
Lipodystrophy syndromes (LD) are a group of rare conditions characterized by the generalized or partial absence and/or dysfunction of adipocytes. Due to the lack of fat storage capacity, excess lipid accumulates in other tissues, leading to severe insulin resistance. At present, effective therapeutic options remain limited, with metreleptin currently the only specific licensed treatment. To this end, we evaluated the therapeutic impact of tirzepatide in people with partial lipodystrophy (PLD). This was a single-center, retrospective, observational study, including all patients with PLD treated with tirzepatide between January 2022 and September 2025. Forty patients with PLD were included FPLD1 like = 26 (65%), FPLD2 = 4 (10%), FPLD3 = 7 (17.5%), FPLD7 = 1 (2.5%), APLD = 1 (2.5%), unclassified = 1 (2.5%). 87.5% (n = 35) were female with a median age of 47 years (IQR 39-59) and a median BMI of 31.5 kg/m2 (IQR 27.3 to 35.5). After a median 9.5 month follow-up (IQR 7 to 11), marked reductions were seen in body weight from 91.0 kg (IQR 75.0 to 106.0) to 82.8 kg (IQR 69.0 to 93.4; P < .0001), in HbA1c from 65 mmol/mol (IQR 54.5 to 85) to 52 mmol/mol (IQR 39 to 62; P < .0001) and in serum triglycerides from 2.80 mmol/L (IQR 1.6 to 3.7) to 1.83 mmol/L (IQR 1.0 to 2.9; P = .0005). Daily insulin requirements fell from 177.5 IU (IQR 101.3 to 213.8) to 58.0 IU (IQR 0 to 112.5; P = .0028). In patients with partial lipodystrophy, tirzepatide use resulted in substantial statistically significant reductions in weight, glycemic control, serum triglycerides, and daily insulin requirement. We recommend further prospective studies to support these findings and to evaluate its impact earlier in the course of the disorder.
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
2025-07-24 | A clinical case of pregnancy of a patient with a combination of two orphan diseases: familial partial lipodystrophy type 4 and HNF1A-MODY on the background of therapy with recombinant human methionyl leptin
Lipodystrophies are a group of orphan diseases (according to different sources, the prevalence of the disease varies from 1 to 5 cases per 1,000,000 population), which can be either hereditary or acquired. Diseases of this group represent a symptom complex characterized by varying degrees of loss of adipose tissue: complete (generalized lipodystrophy) or partial (partial lipodystrophy), as well as abnormal distribution of subcutaneous fat, provided that there is no influence of alimentary factors and catabolic conditions. Lipodystrophies are characterized by metabolic changes: dyslipidemia, carbohydrate metabolism disorders, insulin resistance, metabolically associated fatty liver disease. Separately, it is worth mentioning reproductive disorders, such as polycystic ovary syndrome, infertility, miscarriage, and others. A decrease in the body’s fat content leads to a decrease in the production of the hormone leptin, which affects the hypothalamic neurons that regulate hunger and satiety, and increases energy expenditure by stimulating thermogenesis. Hypoleptinemia is the main cause of metabolic disorders associated with lipodystrophy. Currently, a recombinant analogue of human leptin has been registered — metreleptin (methionyl leptin), which improves the quality of life of patients by achieving compensation for metabolic disorders, reducing hyperphagia, and also having a beneficial effect on fertility. HNF1A-MODY is diabetes mellitus with an autosomal dominant type of inheritance associated with heterozygous variants of the HNF1A gene, which is involved in the differentiation and functioning of the pancreas. The disease is characterized by onset at a young age, prevalence of postprandial hyperglycemia, presence of glucosuria, progressive course with a high risk of developing micro- and macrovascular complications, effectiveness of therapy with sulfonylurea drugs with the emergence of the need for insulin therapy over time. This article presents the first clinical case in Russia demonstrating the pregnancy of a patient with a combination of two orphan diseases: familial partial lipodystrophy type 4 and MODY 3 (list of rare (orphan) diseases of the Ministry of Health of Russia, dated February 6, 2023), who received pathogenetic treatment with metreleptin before confirmation of the fact of pregnancy.
2025-07-07 | Liraglutide use in pediatric type 2 familial partial lipodystrophy caused by LMNA mutation: a case report.
Type 2 familial partial lipodystrophy (FPLD2), or Dunnigan syndrome, is a rare genetic disorder characterized by selective subcutaneous fat loss, metabolic complications, and insulin resistance due to LMNA gene mutations. This case report describes the clinical presentation and treatment of a Chinese family with FPLD2, highlighting liraglutide's role in glycemic and lipid control. The index patient is a 14-year-old girl, presenting with fat accumulation in the neck, loss of subcutaneous fat on the face, arms, legs, and trunk, and metabolic complications including diabetes mellitus with insulin resistance, hepatomegaly, and dyslipidemia. The diagnosis of FPLD2 was confirmed by the identification of a heterozygous mutation c.1456 A > G (p. Lys486Glu) in exon 8 of the LMNA gene. The patient was initially treated with a diabetic diet, metformin, and insulin therapy, but glycemic control was only achieved after introducing liraglutide, resulting in satisfactory control within two months. The variable manifestations of FPLD2 within the family (the proband, her father, and elder sister), all carrying the same LMNA mutation are presented, highlighting the complexity of this genetic disorder. The fast clinical response to liraglutide in our patient suggests a potential therapeutic role for Glucagon-like peptide-1 receptor agonists in the management of metabolic complications in FPLD2. This case report underscores the importance of recognizing the variable expressivity of FPLD2 and the potential role of liraglutide in managing glycemic and lipid in pediatric patients. It also highlights the need for further research to explore novel therapeutic strategies for the metabolic complications associated with FPLD2.
2025-04-10 | Leptin acutely increases hepatic triglyceride secretion in patients with lipodystrophy.
Metreleptin ameliorates hepatic steatosis partially independent of its anorexic action. We previously showed that metreleptin increases hepatic very low-density lipoprotein triglycerides (VLDL1-TG) export in rodents and healthy humans requiring intact hepatic autonomic innervation. The primary aim of this study was to investigate whether metreleptin has anti-steatotic properties in patients with lipodystrophy by increasing VLDL1-TG export. In addition, we present a case of generalized lipodystrophy undergoing metreleptin treatment after liver transplantation, a model for hepatic autonomic denervation. In this randomized, placebo-controlled, crossover trial (EudraCT 2017-003014-22) we assessed the acute effects of a single metreleptin injection in 10 patients (8 females, 2 males; mean age ± SD: 49 ± 14 yrs; 9 familial partial and 1 generalized lipodystrophy) on hepatic VLDL1-TG secretion and hepatocellular lipid content (HCL) measured via an intravenous fat emulsion test and 1H-magnetic resonance spectroscopy, respectively. We found that a single injection of metreleptin increased hepatic VLDL1-TG secretion by 75 % (mean difference ± SD: +219 ± 149 mg/h metreleptin vs. placebo; p = 0.001), without significant changes in HCL within 3 h (mean difference ± SD: -8 ± 14 % metreleptin vs. placebo, p = 0.14). Metreleptin therapy in a patient with generalized lipodystrophy following liver transplantation failed to ameliorate hepatic steatosis despite improving glucose and lipid metabolism. Leptin acutely increases hepatic VLDL1-TG secretion in patients with lipodystrophy, likely contributing to metreleptin's body weight-independent anti-steatotic effects. The case report suggests that intact autonomic liver innervation may be required for this action, warranting further research.
gene therapies
2026-02-19 | Variable Expressivity in Type 2 Familial Partial Lipodystrophy Related to a Pathogenic LMNA Variant R482: Maternal Transmission to Non-Identical Twins.
Familial partial lipodystrophy type 2 (FPLD2), or Dunnigan syndrome, is a rare autosomal dominant disorder caused by mutations in the lamin A (LMNA) gene, most frequently involving the p.R482W variant. It is characterized by regional loss of subcutaneous fat and severe metabolic abnormalities, particularly dyslipidemia, insulin resistance, and hepatic steatosis. We report a family with three individuals -mother and two siblings- carrying the same pathogenic LMNA c.1444C>T (p.R482W) variant but exhibiting distinct clinical and biochemical profiles. The proband (patient 1) is a 29-year-old male, presented with moderate metabolic disturbances, including hypertriglyceridemia, low levels of high density lipoprotein-cholesterol (HDL-C), and hepatic steatosis, accompanied by physical features such as dorsocervical fat accumulation and winged neck. His dizygotic female twin (patient 2) exhibited a more severe phenotype with triglycerides levels approached 700 mg/dL, insulin resistance, and polycystic ovarian morphology (PCOM). Their 68-year-old mother, also a carrier, showed only mild dyslipidemia and unstable angina. The comparison of dizygotic twins and their mother carrying the same LMNA variant provides a unique opportunity to illustrate how sex, age, and hormonal status modulate metabolic severity in FPLD2. These findings reinforce the clinical relevance of family-based evaluation and early metabolic surveillance, even in mildly affected or asymptomatic carriers.
2026-01-01 | Unraveling the Natural History of Lipodystrophy Syndromes: Insights from the Prospective LD-LYNC Study:
Supplemental Table 1. Distribution of total number of probands and relatives across study sites.Supplemental Table 2. Overview of possible underlying etiologies or coexisting diseases in patients with acquired lipodystrophy syndromes.Supplemental Table 3. Metabolic and other uncommon complications of patients with lipodystrophy stratified by the centers.Supplemental Table 4. Features of glomerulonephritis in patients with lipodystrophy.Supplemental Table 5. Previous diagnosis of malignancy in patients with lipodystrophy.Supplemental Table 6. Comparison of the clinical characteristics and comorbidities of patients with acquired and congenital or familial lipodystrophy syndromes.Supplemental Table 7. Comparison of laboratory parameters based on metreleptin treatment status in females.Supplemental Table 8. Comparison of laboratory parameters based on metreleptin treatment status in males.Supplemental Table 9. Longitudinal laboratory results by lipodystrophy typeSupplemental Figure 1. Kaplan–Meier Estimates Incorporating Prospectively Observed Incident Events.Kaplan–Meier estimates of time to diagnosis for major comorbidities across lipodystrophy subgroups. Updated survival models incorporate both retrospectively reported age-of-onset data collected at enrollment and incident events observed prospectively after study entry. Participants were censored at their most recent follow-up visit. Panels show diabetes-free (A, B), hypertriglyceridemia (HighTG)-free (C, D), pancreatitis-free (E, F), metabolic dysfunction-associated steatotic liver disease (MASLD)-free (G, H), heart disease-free (I, J), and hospitalization-free (K, L) survival probabilities over time (years). The y-axis represents survival probability, and the x-axis represents age in years. GL, generalized lipodystrophy; PL, partial lipodystrophy; CGL, congenital generalized lipodystrophy; FPLD, familial partial lipodystrophy; MASLD, metabolic dysfunction-associated steatotic liver disease; HighTG, hypertriglyceridemia.Supplemental Figure 2. Longitudinal Trajectories of Laboratory Parameters in Generalized and Partial Lipodystrophy.Spaghetti plots illustrating individual longitudinal trajectories of key metabolic laboratory parameters in participants with generalized lipodystrophy (GL) and partial lipodystrophy (PL) during prospective follow-up. Each line represents a single participant with repeated measurements obtained from baseline through subsequent annual visits. Panels depict (A) HbA1c (%), (B) triglycerides (mg/dL), (C) HDL (mg/dL), (D) LDL (mg/dL), (E) total cholesterol (mg/dL), and (F) alanine aminotransferase (ALT, U/L). Time is shown in years since study enrollment.
2025-03-25 | A case of familial partial lipodystrophy type 2 masquerading as Cushing syndrome: Explaining an atypical phenotype by whole-exome sequencing.
Familial partial lipodystrophy type 2 is a rare disease, particularly when it is caused by nonclassical gene variants. A high index of suspicion is essential for a timely diagnosis. We present the case of a 32-year-old woman, referred to evaluation of a possible Cushing syndrome, which was clinically and biochemically ruled out. Yet, due to the finding of a rather abnormal fat distribution during physical examination, the diagnosis of lipodystrophy was cogitated. Whole-exome sequencing revealed a missense variant of exon 11 R582H of the gene encoding Laminin A (rs57830985,c.1745G>A, p.Arg582His). The patient presented some clinical and biochemical characteristics discordant with those previously reported in patients harboring other classical variants of this gene.
2025-03-21 | Hyperandrogenism as a clinical manifestation of familial partial lipodystrophy type 2 in an adolescent female patient
We present a case report of a girl with significant hyperandrogenism with accompanying metabolic disorders. In the physical examination, attention was drawn to tall stature, excessive body mass with a muscular build, broad shoulders and a narrow pelvis, low timbre of voice, acne lesions, enlarged mandible, hirsutism (19 points on the Ferriman-Gallwey scale), and elevated blood pressure. Substantial hyperandrogenemia was noted, with a significantly increased testosterone level and elevated levels of adrenal androgens. Based on steroid metabolome analysis from 24-hour urine collection, congenital adrenal hyperplasia was ruled out. Dyslipidemia and impaired glucose tolerance with hyperinsulinism in the oral glucose tolerance test were found. Magnetic resonance imaging of the abdomen and pelvis revealed a fatty liver and overgrowth of muscles and mesentery with adipose tissue. Whole exome sequencing was performed, revealing the presence of a known, pathogenic molecular variant, c.1394G > A, in the LMNA gene, associated with the occurrence of familial partial lipodystrophy.
2025-01-02 | I suffer from several serious diseases”. The Dunnigan-type of familial partial lipodystrophy: a multiple-symptom disorder caused by genetic mutation
DOI: 10.20452/pamw.16918, Published online: January 02, 2025, Authors: Magdalena Płonka-Stępień1,2, Jerzy Hohendorff1, Łukasz Pawliński1, Barbara Katra1, Maciej T. Małecki1
other
2024-09-03 | Circulating exosomal circRNA-miRNA-mRNA network in a familial partial lipodystrophy type 3 family with a novel PPARG frameshift mutation c.418dup.
Familial partial lipodystrophy 3 (FPLD3) is a rare genetic disorder caused by loss-of-function mutations in the PPARG gene, characterized by a selective absence of subcutaneous fat and associated metabolic complications. However, the molecular mechanisms of FPLD3 remain unclear. In this study, we recruited a 17-yr-old Chinese female with FPLD3 and her family, identifying a novel PPARG frameshift mutation (exon 4: c.418dup: p.R140Kfs*7) that truncates the PPARγ protein at the seventh amino acid, significantly expanding the genetic landscape of FPLD3. By performing next-generation sequencing of circular RNAs (circRNAs), microRNAs (miRNAs), and mRNAs in plasma exosomes, we discovered 59 circRNAs, 57 miRNAs, and 299 mRNAs were significantly altered in the mutation carriers compared with the healthy controls. Integration analysis highlighted that the circ_0001597-miR-671-5p pair and 18 mRNAs might be incorporated into the metabolic regulatory networks of the FPLD3 induced by the novel PPARG mutation. Functional annotation suggested that these genes were significantly enriched in glucose- and lipid metabolism-related pathways. Among the circRNA-miRNA-mRNA network, we identified two critical regulators, early growth response-1 (EGR1), a key transcription factor known for its role in insulin signaling pathways and lipid metabolism, and 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3), which gets involved in the biosynthesis of triglycerides and lipolysis. Circ_0001597 regulates the expression of these genes through miR-671-5p, potentially contributing to the pathophysiology of FPLD3. Overall, this study clarified a circulating exosomal circRNA-miRNA-mRNA network in a FPLD3 family with a novel PPARG mutation, providing evidence for exploring promising biomarkers and developing novel therapeutic strategies for this rare genetic disorder.NEW & NOTEWORTHY Through the establishment of a ceRNA regulatory networks in a novel PPARG frameshift mutation c.418dup-induced FPLD3 pedigree, this study reveals that circ_0001597 may contribute to the pathophysiology of FPLD3 by sequestering miR-671-5p to regulate the expression of EGR1 and AGPAT3, pivotal genes situated in the triglyceride (TG) synthesis and lipolysis pathways. Current findings expand our molecular understanding of adipose tissue dysfunction, providing potential blood biomarkers and therapeutic avenues for lipodystrophy and associated metabolic complications.
2023-01-23 | APOC-III: a Gatekeeper in Controlling Triglyceride Metabolism
Abstract Purpose of Review Apolipoprotein C-III (ApoC-III) is a widely known player in triglyceride metabolism, and it has been recently recognized as a polyhedric factor which may regulate several pathways beyond lipid metabolism by influencing cardiovascular, metabolic, and neurological disease risk. This review summarizes the different functions of ApoC-III and underlines the recent findings related to its multifaceted pathophysiological role. Recent Findings The role of ApoC-III has been implicated in HDL metabolism and in the development of atherosclerosis, inflammation, and ER stress in endothelial cells. ApoC-III has been recently considered an important player in insulin resistance mechanisms, lipodystrophy, diabetic dyslipidemia, and postprandial hypertriglyceridemia (PPT). The emerging evidence of the involvement of ApoC-III in the in the pathogenesis of Alzheimer’s disease open the way to further study if modification of ApoC-III level slows disease progression. Furthermore, ApoC-III is clearly linked to cardiovascular disease (CVD) risk, and progression of coronary artery disease (CAD) as well as the calcification of aortic valve and recent clinical trials has pointed out the inhibition of ApoC-III as a promising approach to manage hypertriglyceridemia and prevent CVD. Summary Several evidences highlight the role of ApoC-III not only in triglyceride metabolism but also in several cardio-metabolic pathways. Results from recent clinical trials underline that the inhibition of ApoC-III is a promising therapeutical strategy for the management of severe hypertriglyceridemia and in CVD prevention.
2022-09-09 | Severe loss of adipose tissue in a Vietnamese lipodystrophy patient caused by LMNA p.G465D mutation: a first clinical characterization and two-year follow-up.
Familial partial lipodystrophy type 2 is the most well-known subtype of lipodystrophy. We describe for the first time the phenotype of a case with lipodystrophy, who carried heterozygous mutation c.G1394A (p.G465D) in the LMNA gene. A 17-year-old girl was diagnosed with FPLD2 due to severe loss of subcutaneous fat in the extremities, buttocks and metabolic complications. However, there was no accumulation of fat over her face and neck, which is remarkably different from the FPLD2 clinical phenotypes. Two years of surveillance showed the challenge due to unable control of insulin resistance, glucose and lipid metabolism. Whole exome sequencing revealed the heterozygous mutation c.1394G>A at exon 11 of LMNA gene (p.G465D). Our case displayed an atypical phenotype of FPLD2 with metabolic anomalies, not cardiovascular diseases. The difficulties of medical management in this case pointed out the urgent need for more effective treatment for individuals suffering from this rare disease.
2021-08-03 | Selective Targeting of Angiopoietin-like 3 (ANGPTL3) with Vupanorsen for the Treatment of Patients with Familial Partial Lipodystrophy (FPLD): Results of a Proof-of-Concept Study
Abstract Background: Familial partial lipodystrophy (FPLD) is a rare disease characterized by selective loss of peripheral subcutaneous fat associated with dyslipidemia and diabetes mellitus. Reductions in circulating levels of ANGPTL3 are associated with lower triglyceride and other atherogenic lipids, making it an attractive target for treatment of FPLD patients. This proof-of-concept study was conducted to assess the efficacy and safety of targeting ANGPTL3 with vupanorsen in patients with FPLD. Methods: This was an open-label study. Four patients with FPLD (two with pathogenic variants in LMNA gene, and two with no causative genetic variant), diabetes (HbA1c≥7.0% and ≤12%), hypertriglyceridemia (≥500 mg/dL), and hepatic steatosis (hepatic fat fraction, HFF≥6.4%) were included. Patients received vupanorsen subcutaneously at a dose of 20 mg weekly for 26 weeks. The primary endpoint was the percent change from baseline in fasting triglycerides at Week 27. Other endpoints analyzed at the same time point included changes in ANGPTL3, fasting lipids and lipoproteins, insulin secretion/sensitivity, postprandial lipid and glycemic changes in response to a mixed meal test, HFF measured by MRI, and body composition measured by dual energy absorptiometry (DEXA). Results: Baseline mean ± SD fasting triglyceride level was 9.24 ± 4.9 mmol/L (817.8 ± 431.9 mg/dL). Treatment resulted in reduction in fasting levels of triglyceride by 59.9%, ANGPTL3 by 54.7%, and in several other lipoproteins/lipids including very low- density lipoprotein cholesterol by 53.5%, non-high-density lipoprotein cholesterol by 20.9%, and free fatty acids (FFA) by 41.7%. The area under the curve for postprandial triglycerides, FFA, and glucose were reduced by 60%, 32%, and 14%, respectively. Treatment with vupanorsen also resulted in 55% reduction in adipose tissue insulin resistance index, while other insulin sensitivity indices and HbA1c levels were not changed. Additional investigations in HFF and in DEXA parameters suggested dynamic changes in fat partitioning during treatment. Adverse events observed were related to common serious complications associated with diabetes and FPLD, vupanorsen was well tolerated, and there was no effect on platelet count. Conclusions: Although limited, these results suggest that targeting ANGPTL3 with vupanorsen could address several metabolic abnormalities in patients with FPLD. Clinical Trial: NCT03514420
2021-03-17 | Development of Antisense Oligonucleotide Gapmers for the Treatment of Dyslipidemia and Lipodystrophy.
Although technological advances in molecular genetics over the last few decades have greatly expedited the identification of mutations in many genetic diseases, the translation of the genetic mechanisms into a clinical setting has been quite challenging, with a minimum number of effective treatments available. The advancements in antisense therapy have revolutionized the field of neuromuscular disorders as well as lipid-mediated diseases. With the approval of splice-switching antisense oligonucleotide (AO) therapy for nusinersen and eteplirsen for the treatment of spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD), several modified AOs are now being evaluated in clinical trials for the treatment of a number of disorders. In order to activate RNase H-mediated cleavage of the target mRNA, as well as to increase the binding affinity and specificity, gapmer AOs are designed that have a PS backbone flanked with the modified AOs on both sides. Mipomersen (trade name Kynamro), a 2'-O-methoxyethyl (MOE) gapmer, was approved by the Food and Drug Administration (FDA) for the treatment of homozygous familial hypercholesterolemia (HoFH) in 2013. Volanesorsen, another 20-mer MOE gapmer has shown to be successful in lowering the levels of triglycerides (TGs) in several lipid disorders and has received conditional approval in the European Union for the treatment of Familial chylomicronemia syndrome (FCS) in May 2019 following successful results from phase II/III clinical trials. This chapter focuses on the clinical applications of gapmer AOs for genetic dyslipidemia and lipodystrophy.
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Drug Discovery Landscape
2 orphan drug designations for Familial partial lipodystrophy, including 1 approved therapy.
2 orphan drug designations for Familial partial lipodystrophy, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Volanesorsen sodium | oligonucleotides | EMA | 2016-07-14 | — | Akcea Therapeutics Ireland Limited |
Metreleptin [Myalepta] | proteins | EMA | 2012-07-17 | 2018-08-01 | Chiesi Farmaceutici S.p.A. |
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