RARE DISEASE
Congenital generalized lipodystrophy
Congenital generalized lipodystrophy
Congenital generalized lipodystrophy
Synonyms: BSCL, Berardinelli-Seip congenital lipodystrophy, Berardinelli-Seip syndrome, CGL, Lipoatrophic diabetes
Synonyms: BSCL, Berardinelli-Seip congenital lipodystrophy, Berardinelli-Seip syndrome, CGL, Lipoatrophic diabetes
Synonyms: BSCL, Berardinelli-Seip congenital lipodystrophy, Berardinelli-Seip syndrome, CGL, Lipoatrophic diabetes
Drug discovery
4
drugs
With orphan designations
Overview
Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near-total absence of adipose tissue from birth, leading to severe metabolic complications including insulin resistance, diabetes mellitus, hypertriglyceridemia, and hepatic steatosis. Four subtypes (CGL1-4) are defined by mutations in AGPAT2, BSCL2, CAV1, or CAVIN1 genes. Clinical features include acromegaloid facies, muscular hypertrophy, and hepatomegaly. Complications involve cardiomyopathy, pancreatitis, and hepatic cirrhosis, with reduced life expectancy if untreated [1][2][4].
Burden
Early-onset metabolic derangements (e.g., diabetes by adolescence) drive end-organ damage (liver cirrhosis, pancreatitis, cardiac hypertrophy) [4][10][16].
High morbidity from diabetes complications, recurrent infections, and hypertrophic cardiomyopathy [4][8].
Reduced life expectancy without treatment; significant psychosocial impact due to physical stigma and chronic disease burden [10][16].
Therapies
Leptin replacement therapy (metreleptin) approved for generalized forms to improve metabolic control [8][13].
Aggressive management of comorbidities: insulin sensitizers (e.g., metformin), lipid-lowering agents, and dietary restriction of fats/carbohydrates [3][8][10].
Investigational approaches include adipose tissue transplantation and gene/cell therapies targeting adipocyte dysfunction [3][13].
Categories: rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases, rare neurological diseases, rare skin diseases
Research Papers
351 drug discovery papers about Congenital generalized lipodystrophy, with 4 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
351 drug discovery papers about Congenital generalized lipodystrophy, with 4 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-19 | Efficacy and Safety of SGLT2 Inhibitors in Patients With Genetic Lipodystrophy: A Real-Life Experience From a National Reference Network.
Lipodystrophy syndromes are rare diseases with metabolic and cardiovascular consequences. This study explores the metabolic and renal effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with genetic lipodystrophy. Patients with familial partial lipodystrophy (n = 57) or congenital generalised lipodystrophy (n = 2) (86% women) were initiated with SGLT2i in the French reference network PRISIS. We retrospectively collected clinical and biological data before initiation, after 6-18 months (short-term, mean ± SD 12.5 ± 6.4 months) and at the latest follow-up on SGLT2i (long-term, 29.0 ± 10.7 months). Body mass index decreased from 25 [22.9-28] (median [IQR]) to 24.4 [22.1-26.5] then 23.9 [22.1-26.4] kg/m2 (p < 0.001) and HbA1c from 7.8 [7.1-8.8] to 7.3 [6.7-7.7] and 7.3% [6.9-8] (p < 0.01 and p = 0.05, respectively). Systolic blood pressure (130 [120-143.25] to 126 [120-137] mmHg), ALT (33 [23.5-44] to 30 [26-40] IU/L), GGT (44 [28.5-62.5] to 37 [27.85-45.5] IU/L) and liver stiffness (6.8 [5.9-11.8] to 5.8 [5-6.9] kPa) declined significantly at short-term (p < 0.05, 0.02, 0.02 and < 0.01, respectively). The dual-energy X-ray absorptiometry-based fat mass percentage (23.6 [18-29.3] to 20.8 [17.8-25.3], p = 0.07) and truncal-to-lower limb fat ratio (1.36 [1.18-1.50] to 1.17 [0.98-1.41], p = 0.08) tended to decrease at short-term. Urinary albumin-to-creatinine ratio, when elevated at baseline (> 3 mg/mmol, n = 18 patients), decreased from 10.8 [6.3-24.9] to 8.0 mg/mmol [2.8-14.4] (p = 0.02). Treatment discontinuation (7%) was mainly due to vaginal mycoses. No serious adverse events were reported. In a real-life setting, SGLT2i therapy is associated with improvement in HbA1c, body weight, blood pressure, hepatic parameters and albuminuria in patients with genetic lipodystrophy.
2026-07-23 | A Lean Metabolic Catastrophe - A Case Report on Congenital Generalized Lipodystrophy Presenting as Severe Insulin Resistance and Hypertriglyceridemia.
We report a 20-year-old female who presented with acute abdominal pain and vomiting, with a background of diabetes mellitus and severe hypertriglyceridemia since the age of 16 years. Clinical examination revealed a marked paucity of subcutaneous adipose tissue throughout the body. Laboratory investigations confirmed severe insulin resistance with HbA1c (glycated hemoglobin) of 8.5%, massive hypertriglyceridemia (1257 mg/dL), and preserved C-peptide levels (3.75 ng/mL). The clinical phenotype and biochemical profile suggested a diagnosis of congenital lipodystrophy, though genetic confirmation was not feasible due to financial constraints. Congenital lipodystrophy is characterized by ectopic fat accumulation in the liver, muscles, and pancreas, with resultant severe insulin resistance and metabolic complications. Management with dual PPAR agonist therapy (saroglitazar), omega-3 fatty acids (icosapent ethyl), thiazolidinediones (pioglitazone-metformin combination), and basal insulin resulted in significant improvement in lipid and glycemic parameters on subsequent follow-ups.
2026-03-26 | Gpat3 Knockout Attenuates Adipose Loss and Steatohepatitis in Agpat2-Deficient Mice.
Congenital generalized lipodystrophy (CGL) type 1, caused by mutations in 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2), is characterized by near-total absence of adipose tissue and severe metabolic disturbances, including hepatic steatosis, insulin resistance, and hypertriglyceridemia. Although AGPAT2's enzymatic function in lysophosphatidic acid acylation during glycerolipid biosynthesis is well characterized, the molecular mechanisms driving disease pathogenesis remain incompletely understood. In this study, significant up-regulation of glycerol-3-phosphate acyltransferase 3 (GPAT3), in both embryonic fibroblasts and liver tissue from AGPAT2-deficient mice, was identified. Through generation of Agpat2/Gpat3 double-knockout mice, it was demonstrated that GPAT3 ablation leads to multiple metabolic improvements: enhanced survival rates, partial preservation of adipose tissue (with more pronounced effects in brown than white adipose depots), marked attenuation of hepatic steatosis accompanied by reduced inflammation and fibrosis, and amelioration of hyperglycemia and hyperinsulinemia. Neonatal analyses demonstrated that GPAT3 deletion delayed adipose tissue degeneration while markedly decreasing macrophage infiltration (F4/80+ cells) and apoptotic signaling (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells). Ultrastructural examination revealed improved adipocyte morphology with normalized organelle architecture. These results identify GPAT3 as a key metabolic regulator in AGPAT2 deficiency, demonstrating that its inhibition partially restores adipose tissue and liver function. The conserved benefits of GPAT3 deficiency in both CGL1/AGPAT2 and CGL2/Seipin models highlight GPAT3 as a promising therapeutic target for congenital lipodystrophies.
2024-11-17 | A series of genetically confirmed congenital lipodystrophy and diabetes in adult southern Indian patients.
In this study, we analysed the mutation spectrum in subjects with suspected lipodystrophy using a targeted Next-generation sequencing (NGS) approach. Subjects with suspected lipodystrophy were for screened six genes (AGPAT2, BSCL2, LMNA, PPARG, ZMPSTE24, INSR) and the variants identified were confirmed through Sanger sequencing. The clinical and biochemical parameters were compared among the mutation positive and negative subjects. We identified eight individuals with pathogenic or likely pathogenic mutations, including both homozygous and heterozygous variants. Homozygous variants included AGPAT2(NM_006412.4):c.493-2A>G, AGPAT2(NM_006412.4):c.254_258dup, and BSCL2(NM_001122955.4):c.570del, while heterozygous variants encompassed LMNA(NM_170707.4):c.1444C>T, LMNA(NM_170707.4):c.1456A>G, LMNA(NM_170707.4):c.1445G>A, and PPARG(NM_015869.5):c.949T>C mutations. In this cohort, three subjects were diagnosed with congenital generalized lipodystrophy, while the remaining five had familial partial lipodystrophy. Majority (7/8) of the patients with lipodystrophy had hepatic involvement. Notably, more than half of the subjects (5/8) achieved optimal glycemic control through insulin sensitizers (PPARγ agonist and Metformin). Interestingly, even with a limited gene panel test, mutation-positive individuals exhibited a higher prevalence of typical clinical features and biochemical characteristics associated with lipodystrophy compared to their mutation-negative counterparts. In subjects with lipodystrophy, targeted NGS based screening may establish a genetic diagnosis and aid in family screening and genetic counselling. Knowing the clinical and biochemical features typical to lipodystrophy may help in diagnosis especially in resource limited setting.
2024-10-01 | 6941 Congenital Generalized Lipodystrophy - An Undiagnosed Case in an Underserved Border Community
Abstract Disclosure: D. Evans: None. A. Gutierrez: None. S. Echetebu: None. M. Zerah: None. Introduction: Congenital Generalized Lipodystrophy (Berardinelli-Seip Syndrome) is estimated to occur 1-10/10 million people1. Patients may present with specific clinical features and/or hormonal imbalances such as hyperinsulinemia and hypertriglyceridemia. Complications of CGL result in a decreased average life expectancy of 51.2 years2. Here we present a case of a female from a medically underserved city in Mexico who was not diagnosed until the age of 16, three years after immigration to the United States. Case Presentation: The patient lived in Mexico and had little medical care. After she immigrated, she was referred to Pediatric Endocrinology due to an elevated hemoglobin A1c, hypertriglyceridemia, and elevated liver enzymes. At birth and in adolescence, the patient did not resemble any of her five fully biological siblings, had little adipose tissue, and had well-defined musculature. Physical exam findings included generalized absence of adipose tissue and prominent musculature, large hands and feet, acromegaloid features, acanthosis nigricans, hirsutism, and phlebomegaly. Breast development was Tanner Stage IV, and genitalia was Tanner Stage V, without clitoromegaly. Patient is currently being treated by psychiatry for Major Depressive Disorder and suicidal ideation. Results: She was diagnosed with diabetes mellitus due to elevated glucose on OGGT and hypertriglyceridemia. She was then started on a low carbohydrate diet, Metformin, and Atorvastatin. After treatment a significant improvement in labs were observed. Triglyceride levels decreased from 1112 mg/dL to 392 mg/dL(35-150 mg/dL), A1c from 8.5% to 5.8%(<5.8%), AST from 36 U/L to 16 U/L(12-32U/L), and ALT from 51 U/L to 20 U/L(5-32U/L). OGGT levels measured after treatment began were as follows: fasting: 95 mg/dL (70-100mg/dL), 1 hour: 242 mg/dL (130-140 mg/dL), and 2 hours: 229 mg/dL(<155 mg/dL). A liver ultrasound was normal. Genetic testing, Echocardiogram, EKG, and Leptin levels are all pending. Discussion/Conclusion: This case of an adolescent with CGL, who was not diagnosed until 16 years of age, demonstrates not only the health disparities and challenges faced by patients in border communities, but it also demonstrates the lack of knowledge of CGL in healthcare. By presenting this case, we hope to increase awareness of CGL within the medical community at large, and to improve the quality of life of our patients. References: 1. Garg, A. N Engl J Med 2004;350:1220-34 2.Akinci, B. et al., J Clin Endocrinol Metab 88:5433-5437, 2003 Presentation: 6/2/2024
proteins
2026-09-22 | Liraglutide use in congenital generalized lipodystrophy: glycemic and metabolic outcomes
Objective Evidence on glucagon-like peptide 1 receptor agonists (GLP-1RAs) in lipodystrophies is limited. We evaluated the effects of liraglutide on metabolic control and satiety in patients with congenital generalized lipodystrophy (CGL). Methods In this case series, patients with CGL received liraglutide 1.8 mg/day for 12 weeks. Metabolic parameters, satiety, and body composition were assessed at baseline, week 12, and after a 12-week post-treatment follow-up (week 24). Liver imaging was performed at baseline and week 12. Results Eight patients were enrolled (aged 24–45 years; 75% female), and three discontinued treatment due to gastrointestinal adverse events during the dose-escalation phase. Among the five participants who completed the 12-week intervention, liraglutide significantly reduced HbA1c (median change, −2.5%; p=0.012) and total daily insulin dose (−20%; p=0.042), whereas the reduction in triglyceride levels was not statistically significant. Twelve weeks after liraglutide discontinuation, median HbA1c and body weight increased by 2.2% (p=0.026) and 3.7% (p=0.001), respectively. Triglyceride levels increased in 80% of participants, with a median increase of 421.5 mg/dL (p=0.334). Insulin requirements also increased overall: one participant resumed insulin therapy, while the remaining participants increased their insulin dose by a median of 22% (p=0.024). Conclusions This first study of liraglutide in CGL provides an exploratory signal of improved glycemic control and reduced insulin requirements, but treatment tolerability remains a limitation. Larger, controlled, and longer-term studies are needed to confirm these effects and assess potential benefits on satiety, body composition, and liver disease.
2026-09-13 | Clinical heterogeneity and disease progression during adolescence in AGPAT2-associated congenital generalized lipodystrophy: a case series of four patients.
This case series describes the clinical presentation and longitudinal course of four adolescents with genetically confirmed AGPAT2-associated congenital generalized lipodystrophy (CGL) followed at a pediatric lipodystrophy center. Despite shared phenotypic features - including generalized lipoatrophy, muscular hypertrophy, acromegaloid features, and hyperphagia - metabolic severity varied markedly, even between siblings carrying the same homozygous AGPAT2 variant. All three female patients experienced rapid metabolic deterioration during puberty, developing insulin resistance, diabetes, and severe hypertriglyceridemia, while the male patient remained relatively metabolically stable. Three patients developed progressive albuminuria during adolescence, and two required ACE inhibitor therapy for hypertension, highlighting early renal involvement independent of diabetes. Metreleptin therapy led to substantial metabolic improvement in all treated patients, with normalization of glycemic control, triglyceride levels, and liver enzymes, as well as reduced hyperphagia and, in one case, spontaneous menarche. However, metabolic decompensation occurred during acute illness in one patient, necessitating treatment escalation, indicating that metreleptin does not fully protect against metabolic stress. Notably, pronounced daytime fatigue persisted in three patients despite metabolic stabilization, suggesting an underrecognized, potentially central component of the disease. These findings underscore the phenotypic variability of AGPAT2-associated CGL, the critical impact of puberty - especially in females - the frequent early onset of nephropathy, and the partial but incomplete response to leptin replacement. Close monitoring during adolescence and individualized management are essential.
2026-07-27 | Effect of metreleptin treatment in congenital generalized lipodystrophy: a retrospective analysis from the MENA region.
Congenital generalized lipodystrophy (CGL) is characterized by near-total loss of body fat, leptin deficiency, and severe metabolic complications. Clinical data show that metreleptin improves metabolic control in CGL; however, data from the Middle East and North Africa (MENA) is limited. We assessed the real-world effectiveness and safety of metreleptin in patients with CGL from this region. We conducted a multicenter, retrospective chart review of patients with CGL. Baseline, 6 ± 2months (short-term), 2 ± 1years (long-term), and >3 years follow-up data were analyzed. Median changes from baseline were calculated for short- and long-term assessments; >3 years data were reviewed individually. Safety was evaluated up to 90 days after last dose. Thirty-eight patients were included (82% female; median age at baseline, 6.3 years). Median treatment duration with metreleptin was 25 months (max dose, 10 mg/day). Significant short-term median reductions from baseline were observed for HbA1c (- 1.4%; n = 26), fasting plasma glucose (- 0.5 mmol/L; n = 21); fasting triglycerides (TG; -1.5 mmol/L; n = 26), alanine aminotransferase (- 18 IU/L, n = 27) and aspartate aminotransferase (- 7 IU/L, n = 27) (all p ≤ 0.02). These reductions were significant at long-term follow-up (p < 0.01) except for aspartate aminotransferase. At short-term follow-up, 50.0% of patients achieved ≥1% reduction in HbA1c and 65.4% had a ≥30% reduction in TG; corresponding long-term patient proportions were 46.7% and 61.5%. Most patients with >3 years follow-up showed improvement/maintenance of metabolic parameters. Overall, metreleptin was well tolerated with no new safety signals detected. Our findings support early intervention with metreleptin for sustained diabetes and hypertriglyceridemia control in CGL.
2026-07-16 | Congenital generalized lipodystrophy Type 2 (BSCL2; OMIM #269700) presenting with muscular hypertrophy and chronic steatorrhea in a Pakistani child: a pediatric case report confirmed by real-time PCR gene analysis
Abstract Background Congenital generalized lipodystrophy (CGL), or Berardinelli-Seip syndrome, is a rare autosomal recessive condition with near-complete lack of metabolically functional adipocytes since birth or in early infancy, leading to severe metabolic complications. The prevalence of CGL is less than 1 case per million births, and it occurs in four genetic types (CGL1-CGL4). CGL type 2 (mutations in the BSCL2 gene; OMIM #269700) is the most common subtype (70–80% of cases), and has the most severe metabolic complications. Timely diagnosis is essential to avoid potentially fatal complications by early metabolic surveillance and treatment. Case presentation A 5.5-year-old Pakistani male child was referred for a muscular bodybuilder-like look since 24 months of age, chronic steatorrhea (4–5 times a day, aggravated by fat intake), hyperphagia, and poor growth. His birth was normal at term through a normal vaginal delivery and with normal weight and milestones. His family history was negative for lipodystrophy and metabolic disease. His weight (16 kg) and height (105 cm) were below 10th percentile with a BMI of 14.5 kg/m² (< 5th percentile). He had diffuse muscular hypertrophy with a complete loss of subcutaneous fat, visible veins, coarse face with facial lipoatrophy, abdominal distension with hepatomegaly (4 cm below the right costal margin, span 12 cm) and an everted umbilicus. There were no signs of acanthosis nigricans, xanthomas, hirsutism or splenomegaly. Real-Time PCR (RT-PCR) gene analysis confirmed CGL Type 2: BSCL2 exons 4 and 7 were detected; AGPAT2, CAV1, and PTRF were not detected. Both parents confirmed as carriers; all four siblings are unaffected (three heterozygous carriers, one non-carrier). Routine investigations showed macrocytic anaemia (Hb 10 g/dL, MCV 110.8 fL), raised transaminases (ALT 71 U/L, AST 97 U/L), grossly raised IgG (2727.98 mg/dL) and low IgA (4.39 mg/dL). Ultrasonography showed hepatic steatosis. Creatine phosphokinase (103 U/L) was normal, ruling out primary muscular dystrophy. IgA anti-tissue transglutaminase was negative, so coeliac disease was excluded. Hepatitis B, C and HIV were negative. Rickets and skeletal dysplasia were ruled out by a skeletal survey. Fasting triglycerides 862 mg/dL, serum leptin 0.4 ng/mL, and HOMA-IR 10.4 confirmed severe metabolic dysfunction characteristic of CGL2. Based on clinical and biochemical findings, RT-PCR confirmed the diagnosis of CGL type 2 (BSCL2; OMIM #269700) was made. A low-fat diet (20–30% of total energy) with medium-chain triglyceride supplementation, metabolic control and genetic counselling was started. Conclusions This RT-PCR confirmed case of CGL2 demonstrates the triad of CGL: diffuse lipoatrophy with muscular hypertrophy, hepatomegaly secondary to steatosis, and steatorrhoea, with poor growth. To our knowledge, this is the first RT-PCR confirmed CGL2 case reported from Pakistan. Early diagnosis of this rare condition is important to start life-changing metabolic interventions that include dietary restriction, metreleptin replacement and treatment of dyslipidaemia, which may dramatically impact the disease progression and outcome in childhood.
2026-06-01 | Case Report: Twenty years of metreleptin therapy in congenital generalized lipodystrophy type 1: the longest reported follow-up to date.
Congenital generalized lipodystrophy (CGL) is a rare disorder marked by near-total loss of adipose tissue and severe metabolic disturbances due to leptin deficiency and the inability to store nutrients in adipose tissue effectively. Metreleptin is the only approved leptin replacement therapy for this condition. Here we present the >20-year follow-up of two sisters with CGL type 1 (AGPAT2 deficiency, OMIM# 608594), enrolled in early metreleptin trials. Clinical outcomes, adherence, immunogenicity, and pregnancies were assessed. Both cases showed rapid and sustained metabolic improvement after metreleptin initiation, allowing insulin discontinuation and triglyceride normalization. Menstrual cycles resumed within six months; allowing both to carry successful pregnancies while continuing metreleptin. Both cases experienced reduced treatment adherence over time, linked to psychological distress. One case developed both anti-drug antibodies and neutralizing activity through immune based assay after 14 years, but without significant clinical impact. In conclusion, these cases highlight both the sustained metabolic benefits of therapy and the complex challenges that may arise over time, such as antibody formation and difficulties in maintaining long-term adherence. Documentation of unmet medical needs can provide guidance and impetus for improved therapeutic approaches to achieve optimum quality of life.
cell therapies
2025-07-02 | Preliminary high-dose irradiation of the recipient and associated damage of bone marrow stromal compartment enables bone marrow stroma transplantation.
Transplantability of allogeneic mesenchymal stem cells (MSCs) as a stable engraftment and participation in physiological renewal of bone marrow (BM) stroma remains an open question. We hypothesized that a necessary condition for successful MSCs transplantation is the prior significant damage to the recipient's BM stroma. To test this, BM derived from male B10 mice was injected intravenously into syngeneic female mice irradiated with 6.5 Gy and 13 Gy, and unirradiated individuals. We measured donor chimerism 30 days after irradiation in recipients' bones by RQ-PCR and in BM CFU-Fs by ddPCR. The ratio of PCR signals from single-copy Y chromosome-linked Prssly gene and autosomal Gapdh gene was used to determine donor chimerism. None of the non-irradiated recipients had donor cells in the BM subpopulation under study. In the group of recipients irradiated at a dose of 6.5 Gy, donor cells were detected at 0.16% in BM of only one animal. Increasing the radiation dose resulted in a significant increase in donor chimerism among BM stromal cells: it was 11% and 14% in two survived animals of this group. Donor chimerism in the bones of unirradiated recipients was not observed in any of the 15 samples. It was detected in only 2/18 bones of recipients irradiated with 6.5 Gy (0.8% and 1%). The median donor chimerism in bones of recipients irradiated with 13 Gy was 15%. We conclude that the condition for successful engraftment of donor stromal progenitor cells is prior damage to the recipient's BM stroma. Development of protocols of MSCs and HSCs co-transplantation, when full donor chimerism of hematopoietic and stromal tissue will be observed in recipient BM, is feasible. It will allow to increase the efficiency of therapy of malignant and other diseases of blood system, for which allogeneic BM transplantation is indicated, as well as patients with impaired stroma function such as osteogenesis imperfecta and congenital generalized lipodystrophy.
2024-04-08 | Effects of Seipin on Mouse Mesenchymal Stem Cell Osteo-Adipogenic Balance.
Seipin deficiency is an important cause of type 2 Berardinelli-Seip congenital dyslipidemia (BSCL2). BSCL2 is a severe lipodystrophy syndrome with lack of adipose tissue, hepatic steatosis, insulin resistance, and normal or higher bone mineral density. Bone marrow mesenchymal stem cells (BMSCs) are believed to maintain bone and fat homeostasis by differentiating into osteoblasts and adipocytes. We aimed to explore the role of seipin in the osteogenic/adipogenic differentiation balance of BMSCs. Seipin loxP/loxP mice are used to explore metabolic disorders caused by seipin gene mutations. Compared with wild-type mice, subcutaneous fat deficiency and ectopic fat accumulation were higher in seipin knockout mice. Microcomputed tomography of the tibia revealed the increased bone content in seipin knockout mice. We generated seipin-deficient BMSCs in vitro and revealed that lipogenic genes are downregulated and osteogenic genes are upregulated in seipin-deficient BMSCs. In addition, peroxisome proliferator-activated receptor gamma (PPARγ) signaling is reduced in seipin-deficient BMSCs, while using the PPARγ activator increased the lipogenic differentiation and decreased osteogenic differentiation of seipin-deficient BMSCs. Our findings indicated that bone and lipid metabolism can be regulated by seipin through modulating the differentiation of mesenchymal stem cells. Thus, a new insight of seipin mutations in lipid metabolism disorders was revealed, providing a prospective strategy for MSC transplantation-based treatment of BSCL2.
2024-02-07 | Liver transplantation in patient with Berardinelli-Seip syndrome: A literature review and case report.
Berardinelli-Seip syndrome is an infrequently seen and potentially fatal genetic disorder characterized by the absence of adipose tissue. Herein, we report a first-in-literature liver transplant done on a 7-year-old girl because of liver cirrhosis caused by the Berardinelli-Seip syndrome. Physical examination showed prominent subdermal fat tissue loss and mild muscle hypertrophy, giving her a slim appearance, hirsutism, thick hair, a large head in contrast to the body, low anterior hairline, icterus, prominent facial contours, prominent mandibula, loss of buccal fat, low set ears, and large limbs. After the diagnosis, she admitted to our clinic because of variceal esophageal bleeding and increasing liver enzymes. Transplantation decision was made and orthothopic liver transplantation done by the surgery team. Common causes of death in Berardinelli-Seip syndrome patients are infections and liver cirrhosis. The mean age of the patients was 27.1 at the time of death. There is no any established cure for congenital lipodystrophies so far. However, some symptomatic treatment methods are found to be helpful. The main point of the case report to be discussed is the liver transplantation done by our surgical team. There are no examples of any transplantation in Berardinelli-Seip syndrome patients, but several reports can be found of patients with kidney or liver failure. Berardinelli-Seip syndrome is a rare disorder with no cure but a chance of improving lifestyle and life expectancy. The transplantation option should be considered in young patients after a multidisciplinary review.
2024-01-24 | Across-species benefits of adrenalectomy on congenital generalized lipoatrophic diabetes: a review.
Two adrenalectomies py -45erformed fourteen years apart notoriously alleviated insulin resistance in a female teenager with Congenital Generalized Lipoatrophy (CGL, 1988) and in a murine model of CGL (2002). Following a successful therapeutic trial with anti-glucocorticoids, we performed the first surgical procedure on an 18-year-old girl. Before surgery, the anti-glucocorticoid therapy produced a rapid and striking drop in fasting serum insulin levels (from over 400 to 7.0 mU/L) and a slower -but impressive- fall in fasting serum triglycerides from 7,400 to 220-230 mg/dL. In contrast, fasting serum glucose levels dropped more slowly, from 225-290 to 121-138 mg/dL. Two weeks following total adrenalectomy, the fasting serum glucose level was 98 mg/dL, with a corresponding serum insulin level of 10 mU/L. During an Oral Glucose Tolerance Test, the 2-hour serum glucose was 210 mg/dL, and serum insulin values during the test did not exceed 53 mU/L. In 2002, the A-ZIP/F1 hypoleptinemic mouse had its adrenal glands removed. Even though this CGL model does not respond well to leptin replacement, an infusion of recombinant leptin reduced the characteristic hypercorticosteronemia of this murine model of CGL. Adrenalectomy in this transgenic mouse improved insulin sensitivity in the liver and muscle. In summary, adrenalectomy -in both a human and a mouse case of CGL- limited adipose tissue exposure to corticosteroid action and led to a notorious metabolic improvement. On a broader scenario, given that leptin restrains the adrenal axis, the reduced leptin activity of the leptin resistance displayed by obese subjects should lead to adrenal axis overactivity. This overactivity should result in elevated serum levels of free cortisol, free fatty acids, and glycerol. In this manner, leptin resistance should lead to peripheral (adipose tissue, liver, and muscle) insulin resistance and islet beta-cell apoptosis, paving the way to Type 2 diabetes.
2023-09-03 | 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.
gene therapies
2026-04-07 | AAV-mediated delivery of leptin but not adiponectin improves metabolic health in a mouse model of congenital generalised lipodystrophy
Lipodystrophies are a group of disorders featuring reduced adipose tissue mass or function, which often leads to significant metabolic disease, reduced lifespan and impaired quality of life. Individuals with congenital generalised lipodystrophy (CGL) have severely reduced adipose tissue mass. The loss of healthy systemic lipid storage typically causes hepatic steatosis and lipoatrophic diabetes. In addition, adipocyte-secreted hormones including leptin and adiponectin are dramatically reduced. Leptin has critical roles regulating appetite and broader effects on lipid and glucose metabolism. Daily injection with recombinant leptin is currently the only specific, approved treatment for CGL. The consequences of adiponectin loss in these patients are not fully understood. Likewise, the potential therapeutic benefit of adiponectin delivery is unclear. Here we examine the effect of delivering leptin or adiponectin by adeno-associated virus (AAV) as potential gene therapy treatment for metabolic disease in CGL using a well-characterised murine model of the condition. AAV mediated leptin delivery significantly improved hepatic steatosis and hyperinsulinemia. However, adiponectin delivery did not lead to any observed beneficial effects. This demonstrates the potential of gene therapy approaches for long-term delivery of leptin in individuals with lipodystrophy, without the need for continuous supply of perishable therapeutics and painful daily injections.
2024-06-27 | Preclinical evaluation of tissue-selective gene therapies for congenital generalised lipodystrophy
ABSTRACT Lipodystrophy is a rare disorder which can be life-threatening. Here individuals fail to develop or maintain appropriate adipose tissue stores. This typically causes severe metabolic complications, including hepatic steatosis and lipoatrophic diabetes. There is no cure for lipodystrophy, and treatment options remain very limited. Here we evaluate whether tissue-selective adeno-associated virus (AAV) vectors can provide a targeted form of gene therapy for lipodystrophy, using a preclinical lipodystrophic mouse model of Bscl2 deficiency. We designed AAV vectors containing the mini/aP2 or thyroxine-binding globulin promoter to selectively target adipose or liver respectively. The AAV-aP2 vectors also contained the liver-specific microRNA-122 target sequence, restricting hepatic transgene expression. Systemic delivery of AAV-aP2 vectors overexpressing human BSCL2 restored adipose tissue development and metabolic health in lipodystrophic mice without detectable expression in the liver. High doses (1×10 12 GCs) of liver-selective vectors led to off target expression and adipose tissue development, whilst low doses (1×10 10 GCs) expressed selectively and robustly in the liver but did not improve metabolic health. This reveals that adipose tissue-selective, but not liver directed, AAV-mediated gene therapy is sufficient to substantially recover metabolic health in generalised lipodystrophy. This provides an exciting potential new avenue for an effective, targeted, and thereby safer therapeutic intervention.
2024-03-08 | Identification of genetic suppressors for a BSCL2 lipodystrophy pathogenic variant in Caenorhabditis elegans.
Seipin (BSCL2), a conserved endoplasmic reticulum protein, plays a critical role in lipid droplet (LD) biogenesis and in regulating LD morphology, pathogenic variants of which are associated with Berardinelli-Seip congenital generalized lipodystrophy type 2 (BSCL2). To model BSCL2 disease, we generated an orthologous BSCL2 variant, seip-1(A185P), in Caenorhabditis elegans. In this study, we conducted an unbiased chemical mutagenesis screen to identify genetic suppressors that restore embryonic viability in the seip-1(A185P) mutant background. A total of five suppressor lines were isolated and recovered from the screen. The defective phenotypes of seip-1(A185P), including embryonic lethality and impaired eggshell formation, were significantly suppressed in each suppressor line. Two of the five suppressor lines also alleviated the enlarged LDs in the oocytes. We then mapped a suppressor candidate gene, lmbr-1, which is an ortholog of human limb development membrane protein 1 (LMBR1). The CRISPR/Cas9 edited lmbr-1 suppressor alleles, lmbr-1(S647F) and lmbr-1(P314L), both significantly suppressed embryonic lethality and defective eggshell formation in the seip-1(A185P) background. The newly identified suppressor lines offer valuable insights into potential genetic interactors and pathways that may regulate seipin in the lipodystrophy model.
2023-09-24 | Identification of Genetic Suppressors for a Berardinelli-Seip Congenital Generalized Lipodystrophy Type 2 (BSCL2) Pathogenic Variant in C. elegans.
Maintaining the metabolic homeostasis of fatty acids is crucial for human health. Excess fatty acids are stored in lipid droplets (LDs), the primary energy reservoir that helps regulate fat and lipid homeostasis in nearly all cell types. Seipin (BSCL2), a conserved endoplasmic reticulum protein, plays a critical role in LD biogenesis and regulating LD morphology. Pathogenic variants of seipin are associated with multiple human genetic diseases, including Berardinelli-Seip Congenital Generalized Lipodystrophy Type 2 (BSCL2). However, the cellular and molecular mechanisms by which dysfunctional seipin leads to these diseases remain unclear. To model BSCL2 disease, we generated an orthologous BSCL2 pathogenic variant seip-1(A185P) using CRISPR/Cas9 genome editing in Caenorhabditis elegans . This variant led to severe developmental and cellular defects, including embryonic lethality, impaired eggshell formation, and abnormally enlarged LDs. We set out to identify genetic determinants that could suppress these defective phenotypes in the seip-1(A185P) mutant background. To this end, we conducted an unbiased chemical mutagenesis screen to identify genetic suppressors that restore embryonic viability in the seip-1(A185P) mutant background. A total of five suppressor lines were isolated and recovered from the screen. The defective phenotypes of seip-1(A185P) , including embryonic lethality and impaired eggshell formation, were significantly suppressed in each suppressor line. Two of the five suppressor lines also alleviated the enlarged LDs in the oocytes. We then mapped a suppressor candidate gene, R05D3.2 (renamed as lmbr-1 ), which is an ortholog of human LMBR1 (limb development membrane protein 1). The CRISPR/Cas9 edited lmbr-1 suppressor alleles, lmbr-1(Ser647Phe) and lmbr-1(Pro314Leu) , both significantly suppressed embryonic lethality and defective eggshell formation in the seip-1(A185P) background. The newly identified suppressor lines offer valuable insights into potential genetic interactors and pathways that may regulate seipin in the lipodystrophy model.
2022-12-01 | Gene therapy restores adipose tissue and metabolic health in a pre-clinical mouse model of lipodystrophy
Congenital generalized lipodystrophy type 2 is a serious multisystem disorder with limited treatment options. It is caused by mutations affecting the BSCL2 gene, which encodes the protein seipin. Patients with congenital generalized lipodystrophy type 2 lack both metabolic and mechanical adipose tissue and develop severe metabolic complications including hepatic steatosis, lipoatrophic diabetes, and cardiovascular disease. Gene therapies are becoming viable treatments, helping to alleviate inherited and acquired human disorders. We aimed to determine whether gene therapy could offer an effective form of medical intervention for lipodystrophy. We examined whether systemic adeno-associated virus delivery of human BSCL2 could reverse metabolic disease in seipin knockout mice, where white adipose tissue is absent. We reveal that adeno-associated virus gene therapy targets adipose progenitor cells in vivo and substantially restores white adipose tissue development in adult seipin knockout mice. This resulted in both rapid and prolonged beneficial effects to metabolic health in this pre-clinical mouse model of congenital generalized lipodystrophy type 2. Hyperglycemia was normalized within 2 weeks post-treatment together with normalization of severe insulin resistance. We propose that gene therapy offers great potential as a therapeutic strategy to correct multiple metabolic complications in patients with congenital lipodystrophy. Congenital generalized lipodystrophy type 2 is a serious multisystem disorder with limited treatment options. It is caused by mutations affecting the BSCL2 gene, which encodes the protein seipin. Patients with congenital generalized lipodystrophy type 2 lack both metabolic and mechanical adipose tissue and develop severe metabolic complications including hepatic steatosis, lipoatrophic diabetes, and cardiovascular disease. Gene therapies are becoming viable treatments, helping to alleviate inherited and acquired human disorders. We aimed to determine whether gene therapy could offer an effective form of medical intervention for lipodystrophy. We examined whether systemic adeno-associated virus delivery of human BSCL2 could reverse metabolic disease in seipin knockout mice, where white adipose tissue is absent. We reveal that adeno-associated virus gene therapy targets adipose progenitor cells in vivo and substantially restores white adipose tissue development in adult seipin knockout mice. This resulted in both rapid and prolonged beneficial effects to metabolic health in this pre-clinical mouse model of congenital generalized lipodystrophy type 2. Hyperglycemia was normalized within 2 weeks post-treatment together with normalization of severe insulin resistance. We propose that gene therapy offers great potential as a therapeutic strategy to correct multiple metabolic complications in patients with congenital lipodystrophy.
other
2022-04-06 | Case Report: Precision COVID-19 Immunization Strategy to Overcome Individual Fragility: A Case of Generalized Lipodystrophy Type 4
A 48-year-old patient affected with congenital generalized lipodystrophy type 4 failed to respond to two doses of the BNT162b2 vaccine, consisting of lipid nanoparticle encapsulated mRNA. As the disease is caused by biallelic variants of CAVIN1 , a molecule indispensable for lipid endocytosis and regulation, we complemented the vaccination cycle with a single dose of the Ad26.COV2 vaccine. Adenovirus-based vaccine entry is mediated by the interaction with adenovirus receptors and transport occurs in clathrin-coated pits. Ten days after Ad26.COV2 administration, S- and RBD-specific antibodies and high-affinity memory B cells increased significantly to values close to those observed in Health Care Worker controls.
small molecules
2026-08-19 | Efficacy and Safety of SGLT2 Inhibitors in Patients With Genetic Lipodystrophy: A Real-Life Experience From a National Reference Network.
Lipodystrophy syndromes are rare diseases with metabolic and cardiovascular consequences. This study explores the metabolic and renal effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with genetic lipodystrophy. Patients with familial partial lipodystrophy (n = 57) or congenital generalised lipodystrophy (n = 2) (86% women) were initiated with SGLT2i in the French reference network PRISIS. We retrospectively collected clinical and biological data before initiation, after 6-18 months (short-term, mean ± SD 12.5 ± 6.4 months) and at the latest follow-up on SGLT2i (long-term, 29.0 ± 10.7 months). Body mass index decreased from 25 [22.9-28] (median [IQR]) to 24.4 [22.1-26.5] then 23.9 [22.1-26.4] kg/m2 (p < 0.001) and HbA1c from 7.8 [7.1-8.8] to 7.3 [6.7-7.7] and 7.3% [6.9-8] (p < 0.01 and p = 0.05, respectively). Systolic blood pressure (130 [120-143.25] to 126 [120-137] mmHg), ALT (33 [23.5-44] to 30 [26-40] IU/L), GGT (44 [28.5-62.5] to 37 [27.85-45.5] IU/L) and liver stiffness (6.8 [5.9-11.8] to 5.8 [5-6.9] kPa) declined significantly at short-term (p < 0.05, 0.02, 0.02 and < 0.01, respectively). The dual-energy X-ray absorptiometry-based fat mass percentage (23.6 [18-29.3] to 20.8 [17.8-25.3], p = 0.07) and truncal-to-lower limb fat ratio (1.36 [1.18-1.50] to 1.17 [0.98-1.41], p = 0.08) tended to decrease at short-term. Urinary albumin-to-creatinine ratio, when elevated at baseline (> 3 mg/mmol, n = 18 patients), decreased from 10.8 [6.3-24.9] to 8.0 mg/mmol [2.8-14.4] (p = 0.02). Treatment discontinuation (7%) was mainly due to vaginal mycoses. No serious adverse events were reported. In a real-life setting, SGLT2i therapy is associated with improvement in HbA1c, body weight, blood pressure, hepatic parameters and albuminuria in patients with genetic lipodystrophy.
2026-07-23 | A Lean Metabolic Catastrophe - A Case Report on Congenital Generalized Lipodystrophy Presenting as Severe Insulin Resistance and Hypertriglyceridemia.
We report a 20-year-old female who presented with acute abdominal pain and vomiting, with a background of diabetes mellitus and severe hypertriglyceridemia since the age of 16 years. Clinical examination revealed a marked paucity of subcutaneous adipose tissue throughout the body. Laboratory investigations confirmed severe insulin resistance with HbA1c (glycated hemoglobin) of 8.5%, massive hypertriglyceridemia (1257 mg/dL), and preserved C-peptide levels (3.75 ng/mL). The clinical phenotype and biochemical profile suggested a diagnosis of congenital lipodystrophy, though genetic confirmation was not feasible due to financial constraints. Congenital lipodystrophy is characterized by ectopic fat accumulation in the liver, muscles, and pancreas, with resultant severe insulin resistance and metabolic complications. Management with dual PPAR agonist therapy (saroglitazar), omega-3 fatty acids (icosapent ethyl), thiazolidinediones (pioglitazone-metformin combination), and basal insulin resulted in significant improvement in lipid and glycemic parameters on subsequent follow-ups.
2026-03-26 | Gpat3 Knockout Attenuates Adipose Loss and Steatohepatitis in Agpat2-Deficient Mice.
Congenital generalized lipodystrophy (CGL) type 1, caused by mutations in 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2), is characterized by near-total absence of adipose tissue and severe metabolic disturbances, including hepatic steatosis, insulin resistance, and hypertriglyceridemia. Although AGPAT2's enzymatic function in lysophosphatidic acid acylation during glycerolipid biosynthesis is well characterized, the molecular mechanisms driving disease pathogenesis remain incompletely understood. In this study, significant up-regulation of glycerol-3-phosphate acyltransferase 3 (GPAT3), in both embryonic fibroblasts and liver tissue from AGPAT2-deficient mice, was identified. Through generation of Agpat2/Gpat3 double-knockout mice, it was demonstrated that GPAT3 ablation leads to multiple metabolic improvements: enhanced survival rates, partial preservation of adipose tissue (with more pronounced effects in brown than white adipose depots), marked attenuation of hepatic steatosis accompanied by reduced inflammation and fibrosis, and amelioration of hyperglycemia and hyperinsulinemia. Neonatal analyses demonstrated that GPAT3 deletion delayed adipose tissue degeneration while markedly decreasing macrophage infiltration (F4/80+ cells) and apoptotic signaling (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells). Ultrastructural examination revealed improved adipocyte morphology with normalized organelle architecture. These results identify GPAT3 as a key metabolic regulator in AGPAT2 deficiency, demonstrating that its inhibition partially restores adipose tissue and liver function. The conserved benefits of GPAT3 deficiency in both CGL1/AGPAT2 and CGL2/Seipin models highlight GPAT3 as a promising therapeutic target for congenital lipodystrophies.
2024-11-17 | A series of genetically confirmed congenital lipodystrophy and diabetes in adult southern Indian patients.
In this study, we analysed the mutation spectrum in subjects with suspected lipodystrophy using a targeted Next-generation sequencing (NGS) approach. Subjects with suspected lipodystrophy were for screened six genes (AGPAT2, BSCL2, LMNA, PPARG, ZMPSTE24, INSR) and the variants identified were confirmed through Sanger sequencing. The clinical and biochemical parameters were compared among the mutation positive and negative subjects. We identified eight individuals with pathogenic or likely pathogenic mutations, including both homozygous and heterozygous variants. Homozygous variants included AGPAT2(NM_006412.4):c.493-2A>G, AGPAT2(NM_006412.4):c.254_258dup, and BSCL2(NM_001122955.4):c.570del, while heterozygous variants encompassed LMNA(NM_170707.4):c.1444C>T, LMNA(NM_170707.4):c.1456A>G, LMNA(NM_170707.4):c.1445G>A, and PPARG(NM_015869.5):c.949T>C mutations. In this cohort, three subjects were diagnosed with congenital generalized lipodystrophy, while the remaining five had familial partial lipodystrophy. Majority (7/8) of the patients with lipodystrophy had hepatic involvement. Notably, more than half of the subjects (5/8) achieved optimal glycemic control through insulin sensitizers (PPARγ agonist and Metformin). Interestingly, even with a limited gene panel test, mutation-positive individuals exhibited a higher prevalence of typical clinical features and biochemical characteristics associated with lipodystrophy compared to their mutation-negative counterparts. In subjects with lipodystrophy, targeted NGS based screening may establish a genetic diagnosis and aid in family screening and genetic counselling. Knowing the clinical and biochemical features typical to lipodystrophy may help in diagnosis especially in resource limited setting.
2024-10-01 | 6941 Congenital Generalized Lipodystrophy - An Undiagnosed Case in an Underserved Border Community
Abstract Disclosure: D. Evans: None. A. Gutierrez: None. S. Echetebu: None. M. Zerah: None. Introduction: Congenital Generalized Lipodystrophy (Berardinelli-Seip Syndrome) is estimated to occur 1-10/10 million people1. Patients may present with specific clinical features and/or hormonal imbalances such as hyperinsulinemia and hypertriglyceridemia. Complications of CGL result in a decreased average life expectancy of 51.2 years2. Here we present a case of a female from a medically underserved city in Mexico who was not diagnosed until the age of 16, three years after immigration to the United States. Case Presentation: The patient lived in Mexico and had little medical care. After she immigrated, she was referred to Pediatric Endocrinology due to an elevated hemoglobin A1c, hypertriglyceridemia, and elevated liver enzymes. At birth and in adolescence, the patient did not resemble any of her five fully biological siblings, had little adipose tissue, and had well-defined musculature. Physical exam findings included generalized absence of adipose tissue and prominent musculature, large hands and feet, acromegaloid features, acanthosis nigricans, hirsutism, and phlebomegaly. Breast development was Tanner Stage IV, and genitalia was Tanner Stage V, without clitoromegaly. Patient is currently being treated by psychiatry for Major Depressive Disorder and suicidal ideation. Results: She was diagnosed with diabetes mellitus due to elevated glucose on OGGT and hypertriglyceridemia. She was then started on a low carbohydrate diet, Metformin, and Atorvastatin. After treatment a significant improvement in labs were observed. Triglyceride levels decreased from 1112 mg/dL to 392 mg/dL(35-150 mg/dL), A1c from 8.5% to 5.8%(<5.8%), AST from 36 U/L to 16 U/L(12-32U/L), and ALT from 51 U/L to 20 U/L(5-32U/L). OGGT levels measured after treatment began were as follows: fasting: 95 mg/dL (70-100mg/dL), 1 hour: 242 mg/dL (130-140 mg/dL), and 2 hours: 229 mg/dL(<155 mg/dL). A liver ultrasound was normal. Genetic testing, Echocardiogram, EKG, and Leptin levels are all pending. Discussion/Conclusion: This case of an adolescent with CGL, who was not diagnosed until 16 years of age, demonstrates not only the health disparities and challenges faced by patients in border communities, but it also demonstrates the lack of knowledge of CGL in healthcare. By presenting this case, we hope to increase awareness of CGL within the medical community at large, and to improve the quality of life of our patients. References: 1. Garg, A. N Engl J Med 2004;350:1220-34 2.Akinci, B. et al., J Clin Endocrinol Metab 88:5433-5437, 2003 Presentation: 6/2/2024
proteins
2026-09-22 | Liraglutide use in congenital generalized lipodystrophy: glycemic and metabolic outcomes
Objective Evidence on glucagon-like peptide 1 receptor agonists (GLP-1RAs) in lipodystrophies is limited. We evaluated the effects of liraglutide on metabolic control and satiety in patients with congenital generalized lipodystrophy (CGL). Methods In this case series, patients with CGL received liraglutide 1.8 mg/day for 12 weeks. Metabolic parameters, satiety, and body composition were assessed at baseline, week 12, and after a 12-week post-treatment follow-up (week 24). Liver imaging was performed at baseline and week 12. Results Eight patients were enrolled (aged 24–45 years; 75% female), and three discontinued treatment due to gastrointestinal adverse events during the dose-escalation phase. Among the five participants who completed the 12-week intervention, liraglutide significantly reduced HbA1c (median change, −2.5%; p=0.012) and total daily insulin dose (−20%; p=0.042), whereas the reduction in triglyceride levels was not statistically significant. Twelve weeks after liraglutide discontinuation, median HbA1c and body weight increased by 2.2% (p=0.026) and 3.7% (p=0.001), respectively. Triglyceride levels increased in 80% of participants, with a median increase of 421.5 mg/dL (p=0.334). Insulin requirements also increased overall: one participant resumed insulin therapy, while the remaining participants increased their insulin dose by a median of 22% (p=0.024). Conclusions This first study of liraglutide in CGL provides an exploratory signal of improved glycemic control and reduced insulin requirements, but treatment tolerability remains a limitation. Larger, controlled, and longer-term studies are needed to confirm these effects and assess potential benefits on satiety, body composition, and liver disease.
2026-09-13 | Clinical heterogeneity and disease progression during adolescence in AGPAT2-associated congenital generalized lipodystrophy: a case series of four patients.
This case series describes the clinical presentation and longitudinal course of four adolescents with genetically confirmed AGPAT2-associated congenital generalized lipodystrophy (CGL) followed at a pediatric lipodystrophy center. Despite shared phenotypic features - including generalized lipoatrophy, muscular hypertrophy, acromegaloid features, and hyperphagia - metabolic severity varied markedly, even between siblings carrying the same homozygous AGPAT2 variant. All three female patients experienced rapid metabolic deterioration during puberty, developing insulin resistance, diabetes, and severe hypertriglyceridemia, while the male patient remained relatively metabolically stable. Three patients developed progressive albuminuria during adolescence, and two required ACE inhibitor therapy for hypertension, highlighting early renal involvement independent of diabetes. Metreleptin therapy led to substantial metabolic improvement in all treated patients, with normalization of glycemic control, triglyceride levels, and liver enzymes, as well as reduced hyperphagia and, in one case, spontaneous menarche. However, metabolic decompensation occurred during acute illness in one patient, necessitating treatment escalation, indicating that metreleptin does not fully protect against metabolic stress. Notably, pronounced daytime fatigue persisted in three patients despite metabolic stabilization, suggesting an underrecognized, potentially central component of the disease. These findings underscore the phenotypic variability of AGPAT2-associated CGL, the critical impact of puberty - especially in females - the frequent early onset of nephropathy, and the partial but incomplete response to leptin replacement. Close monitoring during adolescence and individualized management are essential.
2026-07-27 | Effect of metreleptin treatment in congenital generalized lipodystrophy: a retrospective analysis from the MENA region.
Congenital generalized lipodystrophy (CGL) is characterized by near-total loss of body fat, leptin deficiency, and severe metabolic complications. Clinical data show that metreleptin improves metabolic control in CGL; however, data from the Middle East and North Africa (MENA) is limited. We assessed the real-world effectiveness and safety of metreleptin in patients with CGL from this region. We conducted a multicenter, retrospective chart review of patients with CGL. Baseline, 6 ± 2months (short-term), 2 ± 1years (long-term), and >3 years follow-up data were analyzed. Median changes from baseline were calculated for short- and long-term assessments; >3 years data were reviewed individually. Safety was evaluated up to 90 days after last dose. Thirty-eight patients were included (82% female; median age at baseline, 6.3 years). Median treatment duration with metreleptin was 25 months (max dose, 10 mg/day). Significant short-term median reductions from baseline were observed for HbA1c (- 1.4%; n = 26), fasting plasma glucose (- 0.5 mmol/L; n = 21); fasting triglycerides (TG; -1.5 mmol/L; n = 26), alanine aminotransferase (- 18 IU/L, n = 27) and aspartate aminotransferase (- 7 IU/L, n = 27) (all p ≤ 0.02). These reductions were significant at long-term follow-up (p < 0.01) except for aspartate aminotransferase. At short-term follow-up, 50.0% of patients achieved ≥1% reduction in HbA1c and 65.4% had a ≥30% reduction in TG; corresponding long-term patient proportions were 46.7% and 61.5%. Most patients with >3 years follow-up showed improvement/maintenance of metabolic parameters. Overall, metreleptin was well tolerated with no new safety signals detected. Our findings support early intervention with metreleptin for sustained diabetes and hypertriglyceridemia control in CGL.
2026-07-16 | Congenital generalized lipodystrophy Type 2 (BSCL2; OMIM #269700) presenting with muscular hypertrophy and chronic steatorrhea in a Pakistani child: a pediatric case report confirmed by real-time PCR gene analysis
Abstract Background Congenital generalized lipodystrophy (CGL), or Berardinelli-Seip syndrome, is a rare autosomal recessive condition with near-complete lack of metabolically functional adipocytes since birth or in early infancy, leading to severe metabolic complications. The prevalence of CGL is less than 1 case per million births, and it occurs in four genetic types (CGL1-CGL4). CGL type 2 (mutations in the BSCL2 gene; OMIM #269700) is the most common subtype (70–80% of cases), and has the most severe metabolic complications. Timely diagnosis is essential to avoid potentially fatal complications by early metabolic surveillance and treatment. Case presentation A 5.5-year-old Pakistani male child was referred for a muscular bodybuilder-like look since 24 months of age, chronic steatorrhea (4–5 times a day, aggravated by fat intake), hyperphagia, and poor growth. His birth was normal at term through a normal vaginal delivery and with normal weight and milestones. His family history was negative for lipodystrophy and metabolic disease. His weight (16 kg) and height (105 cm) were below 10th percentile with a BMI of 14.5 kg/m² (< 5th percentile). He had diffuse muscular hypertrophy with a complete loss of subcutaneous fat, visible veins, coarse face with facial lipoatrophy, abdominal distension with hepatomegaly (4 cm below the right costal margin, span 12 cm) and an everted umbilicus. There were no signs of acanthosis nigricans, xanthomas, hirsutism or splenomegaly. Real-Time PCR (RT-PCR) gene analysis confirmed CGL Type 2: BSCL2 exons 4 and 7 were detected; AGPAT2, CAV1, and PTRF were not detected. Both parents confirmed as carriers; all four siblings are unaffected (three heterozygous carriers, one non-carrier). Routine investigations showed macrocytic anaemia (Hb 10 g/dL, MCV 110.8 fL), raised transaminases (ALT 71 U/L, AST 97 U/L), grossly raised IgG (2727.98 mg/dL) and low IgA (4.39 mg/dL). Ultrasonography showed hepatic steatosis. Creatine phosphokinase (103 U/L) was normal, ruling out primary muscular dystrophy. IgA anti-tissue transglutaminase was negative, so coeliac disease was excluded. Hepatitis B, C and HIV were negative. Rickets and skeletal dysplasia were ruled out by a skeletal survey. Fasting triglycerides 862 mg/dL, serum leptin 0.4 ng/mL, and HOMA-IR 10.4 confirmed severe metabolic dysfunction characteristic of CGL2. Based on clinical and biochemical findings, RT-PCR confirmed the diagnosis of CGL type 2 (BSCL2; OMIM #269700) was made. A low-fat diet (20–30% of total energy) with medium-chain triglyceride supplementation, metabolic control and genetic counselling was started. Conclusions This RT-PCR confirmed case of CGL2 demonstrates the triad of CGL: diffuse lipoatrophy with muscular hypertrophy, hepatomegaly secondary to steatosis, and steatorrhoea, with poor growth. To our knowledge, this is the first RT-PCR confirmed CGL2 case reported from Pakistan. Early diagnosis of this rare condition is important to start life-changing metabolic interventions that include dietary restriction, metreleptin replacement and treatment of dyslipidaemia, which may dramatically impact the disease progression and outcome in childhood.
2026-06-01 | Case Report: Twenty years of metreleptin therapy in congenital generalized lipodystrophy type 1: the longest reported follow-up to date.
Congenital generalized lipodystrophy (CGL) is a rare disorder marked by near-total loss of adipose tissue and severe metabolic disturbances due to leptin deficiency and the inability to store nutrients in adipose tissue effectively. Metreleptin is the only approved leptin replacement therapy for this condition. Here we present the >20-year follow-up of two sisters with CGL type 1 (AGPAT2 deficiency, OMIM# 608594), enrolled in early metreleptin trials. Clinical outcomes, adherence, immunogenicity, and pregnancies were assessed. Both cases showed rapid and sustained metabolic improvement after metreleptin initiation, allowing insulin discontinuation and triglyceride normalization. Menstrual cycles resumed within six months; allowing both to carry successful pregnancies while continuing metreleptin. Both cases experienced reduced treatment adherence over time, linked to psychological distress. One case developed both anti-drug antibodies and neutralizing activity through immune based assay after 14 years, but without significant clinical impact. In conclusion, these cases highlight both the sustained metabolic benefits of therapy and the complex challenges that may arise over time, such as antibody formation and difficulties in maintaining long-term adherence. Documentation of unmet medical needs can provide guidance and impetus for improved therapeutic approaches to achieve optimum quality of life.
cell therapies
2025-07-02 | Preliminary high-dose irradiation of the recipient and associated damage of bone marrow stromal compartment enables bone marrow stroma transplantation.
Transplantability of allogeneic mesenchymal stem cells (MSCs) as a stable engraftment and participation in physiological renewal of bone marrow (BM) stroma remains an open question. We hypothesized that a necessary condition for successful MSCs transplantation is the prior significant damage to the recipient's BM stroma. To test this, BM derived from male B10 mice was injected intravenously into syngeneic female mice irradiated with 6.5 Gy and 13 Gy, and unirradiated individuals. We measured donor chimerism 30 days after irradiation in recipients' bones by RQ-PCR and in BM CFU-Fs by ddPCR. The ratio of PCR signals from single-copy Y chromosome-linked Prssly gene and autosomal Gapdh gene was used to determine donor chimerism. None of the non-irradiated recipients had donor cells in the BM subpopulation under study. In the group of recipients irradiated at a dose of 6.5 Gy, donor cells were detected at 0.16% in BM of only one animal. Increasing the radiation dose resulted in a significant increase in donor chimerism among BM stromal cells: it was 11% and 14% in two survived animals of this group. Donor chimerism in the bones of unirradiated recipients was not observed in any of the 15 samples. It was detected in only 2/18 bones of recipients irradiated with 6.5 Gy (0.8% and 1%). The median donor chimerism in bones of recipients irradiated with 13 Gy was 15%. We conclude that the condition for successful engraftment of donor stromal progenitor cells is prior damage to the recipient's BM stroma. Development of protocols of MSCs and HSCs co-transplantation, when full donor chimerism of hematopoietic and stromal tissue will be observed in recipient BM, is feasible. It will allow to increase the efficiency of therapy of malignant and other diseases of blood system, for which allogeneic BM transplantation is indicated, as well as patients with impaired stroma function such as osteogenesis imperfecta and congenital generalized lipodystrophy.
2024-04-08 | Effects of Seipin on Mouse Mesenchymal Stem Cell Osteo-Adipogenic Balance.
Seipin deficiency is an important cause of type 2 Berardinelli-Seip congenital dyslipidemia (BSCL2). BSCL2 is a severe lipodystrophy syndrome with lack of adipose tissue, hepatic steatosis, insulin resistance, and normal or higher bone mineral density. Bone marrow mesenchymal stem cells (BMSCs) are believed to maintain bone and fat homeostasis by differentiating into osteoblasts and adipocytes. We aimed to explore the role of seipin in the osteogenic/adipogenic differentiation balance of BMSCs. Seipin loxP/loxP mice are used to explore metabolic disorders caused by seipin gene mutations. Compared with wild-type mice, subcutaneous fat deficiency and ectopic fat accumulation were higher in seipin knockout mice. Microcomputed tomography of the tibia revealed the increased bone content in seipin knockout mice. We generated seipin-deficient BMSCs in vitro and revealed that lipogenic genes are downregulated and osteogenic genes are upregulated in seipin-deficient BMSCs. In addition, peroxisome proliferator-activated receptor gamma (PPARγ) signaling is reduced in seipin-deficient BMSCs, while using the PPARγ activator increased the lipogenic differentiation and decreased osteogenic differentiation of seipin-deficient BMSCs. Our findings indicated that bone and lipid metabolism can be regulated by seipin through modulating the differentiation of mesenchymal stem cells. Thus, a new insight of seipin mutations in lipid metabolism disorders was revealed, providing a prospective strategy for MSC transplantation-based treatment of BSCL2.
2024-02-07 | Liver transplantation in patient with Berardinelli-Seip syndrome: A literature review and case report.
Berardinelli-Seip syndrome is an infrequently seen and potentially fatal genetic disorder characterized by the absence of adipose tissue. Herein, we report a first-in-literature liver transplant done on a 7-year-old girl because of liver cirrhosis caused by the Berardinelli-Seip syndrome. Physical examination showed prominent subdermal fat tissue loss and mild muscle hypertrophy, giving her a slim appearance, hirsutism, thick hair, a large head in contrast to the body, low anterior hairline, icterus, prominent facial contours, prominent mandibula, loss of buccal fat, low set ears, and large limbs. After the diagnosis, she admitted to our clinic because of variceal esophageal bleeding and increasing liver enzymes. Transplantation decision was made and orthothopic liver transplantation done by the surgery team. Common causes of death in Berardinelli-Seip syndrome patients are infections and liver cirrhosis. The mean age of the patients was 27.1 at the time of death. There is no any established cure for congenital lipodystrophies so far. However, some symptomatic treatment methods are found to be helpful. The main point of the case report to be discussed is the liver transplantation done by our surgical team. There are no examples of any transplantation in Berardinelli-Seip syndrome patients, but several reports can be found of patients with kidney or liver failure. Berardinelli-Seip syndrome is a rare disorder with no cure but a chance of improving lifestyle and life expectancy. The transplantation option should be considered in young patients after a multidisciplinary review.
2024-01-24 | Across-species benefits of adrenalectomy on congenital generalized lipoatrophic diabetes: a review.
Two adrenalectomies py -45erformed fourteen years apart notoriously alleviated insulin resistance in a female teenager with Congenital Generalized Lipoatrophy (CGL, 1988) and in a murine model of CGL (2002). Following a successful therapeutic trial with anti-glucocorticoids, we performed the first surgical procedure on an 18-year-old girl. Before surgery, the anti-glucocorticoid therapy produced a rapid and striking drop in fasting serum insulin levels (from over 400 to 7.0 mU/L) and a slower -but impressive- fall in fasting serum triglycerides from 7,400 to 220-230 mg/dL. In contrast, fasting serum glucose levels dropped more slowly, from 225-290 to 121-138 mg/dL. Two weeks following total adrenalectomy, the fasting serum glucose level was 98 mg/dL, with a corresponding serum insulin level of 10 mU/L. During an Oral Glucose Tolerance Test, the 2-hour serum glucose was 210 mg/dL, and serum insulin values during the test did not exceed 53 mU/L. In 2002, the A-ZIP/F1 hypoleptinemic mouse had its adrenal glands removed. Even though this CGL model does not respond well to leptin replacement, an infusion of recombinant leptin reduced the characteristic hypercorticosteronemia of this murine model of CGL. Adrenalectomy in this transgenic mouse improved insulin sensitivity in the liver and muscle. In summary, adrenalectomy -in both a human and a mouse case of CGL- limited adipose tissue exposure to corticosteroid action and led to a notorious metabolic improvement. On a broader scenario, given that leptin restrains the adrenal axis, the reduced leptin activity of the leptin resistance displayed by obese subjects should lead to adrenal axis overactivity. This overactivity should result in elevated serum levels of free cortisol, free fatty acids, and glycerol. In this manner, leptin resistance should lead to peripheral (adipose tissue, liver, and muscle) insulin resistance and islet beta-cell apoptosis, paving the way to Type 2 diabetes.
2023-09-03 | 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.
gene therapies
2026-04-07 | AAV-mediated delivery of leptin but not adiponectin improves metabolic health in a mouse model of congenital generalised lipodystrophy
Lipodystrophies are a group of disorders featuring reduced adipose tissue mass or function, which often leads to significant metabolic disease, reduced lifespan and impaired quality of life. Individuals with congenital generalised lipodystrophy (CGL) have severely reduced adipose tissue mass. The loss of healthy systemic lipid storage typically causes hepatic steatosis and lipoatrophic diabetes. In addition, adipocyte-secreted hormones including leptin and adiponectin are dramatically reduced. Leptin has critical roles regulating appetite and broader effects on lipid and glucose metabolism. Daily injection with recombinant leptin is currently the only specific, approved treatment for CGL. The consequences of adiponectin loss in these patients are not fully understood. Likewise, the potential therapeutic benefit of adiponectin delivery is unclear. Here we examine the effect of delivering leptin or adiponectin by adeno-associated virus (AAV) as potential gene therapy treatment for metabolic disease in CGL using a well-characterised murine model of the condition. AAV mediated leptin delivery significantly improved hepatic steatosis and hyperinsulinemia. However, adiponectin delivery did not lead to any observed beneficial effects. This demonstrates the potential of gene therapy approaches for long-term delivery of leptin in individuals with lipodystrophy, without the need for continuous supply of perishable therapeutics and painful daily injections.
2024-06-27 | Preclinical evaluation of tissue-selective gene therapies for congenital generalised lipodystrophy
ABSTRACT Lipodystrophy is a rare disorder which can be life-threatening. Here individuals fail to develop or maintain appropriate adipose tissue stores. This typically causes severe metabolic complications, including hepatic steatosis and lipoatrophic diabetes. There is no cure for lipodystrophy, and treatment options remain very limited. Here we evaluate whether tissue-selective adeno-associated virus (AAV) vectors can provide a targeted form of gene therapy for lipodystrophy, using a preclinical lipodystrophic mouse model of Bscl2 deficiency. We designed AAV vectors containing the mini/aP2 or thyroxine-binding globulin promoter to selectively target adipose or liver respectively. The AAV-aP2 vectors also contained the liver-specific microRNA-122 target sequence, restricting hepatic transgene expression. Systemic delivery of AAV-aP2 vectors overexpressing human BSCL2 restored adipose tissue development and metabolic health in lipodystrophic mice without detectable expression in the liver. High doses (1×10 12 GCs) of liver-selective vectors led to off target expression and adipose tissue development, whilst low doses (1×10 10 GCs) expressed selectively and robustly in the liver but did not improve metabolic health. This reveals that adipose tissue-selective, but not liver directed, AAV-mediated gene therapy is sufficient to substantially recover metabolic health in generalised lipodystrophy. This provides an exciting potential new avenue for an effective, targeted, and thereby safer therapeutic intervention.
2024-03-08 | Identification of genetic suppressors for a BSCL2 lipodystrophy pathogenic variant in Caenorhabditis elegans.
Seipin (BSCL2), a conserved endoplasmic reticulum protein, plays a critical role in lipid droplet (LD) biogenesis and in regulating LD morphology, pathogenic variants of which are associated with Berardinelli-Seip congenital generalized lipodystrophy type 2 (BSCL2). To model BSCL2 disease, we generated an orthologous BSCL2 variant, seip-1(A185P), in Caenorhabditis elegans. In this study, we conducted an unbiased chemical mutagenesis screen to identify genetic suppressors that restore embryonic viability in the seip-1(A185P) mutant background. A total of five suppressor lines were isolated and recovered from the screen. The defective phenotypes of seip-1(A185P), including embryonic lethality and impaired eggshell formation, were significantly suppressed in each suppressor line. Two of the five suppressor lines also alleviated the enlarged LDs in the oocytes. We then mapped a suppressor candidate gene, lmbr-1, which is an ortholog of human limb development membrane protein 1 (LMBR1). The CRISPR/Cas9 edited lmbr-1 suppressor alleles, lmbr-1(S647F) and lmbr-1(P314L), both significantly suppressed embryonic lethality and defective eggshell formation in the seip-1(A185P) background. The newly identified suppressor lines offer valuable insights into potential genetic interactors and pathways that may regulate seipin in the lipodystrophy model.
2023-09-24 | Identification of Genetic Suppressors for a Berardinelli-Seip Congenital Generalized Lipodystrophy Type 2 (BSCL2) Pathogenic Variant in C. elegans.
Maintaining the metabolic homeostasis of fatty acids is crucial for human health. Excess fatty acids are stored in lipid droplets (LDs), the primary energy reservoir that helps regulate fat and lipid homeostasis in nearly all cell types. Seipin (BSCL2), a conserved endoplasmic reticulum protein, plays a critical role in LD biogenesis and regulating LD morphology. Pathogenic variants of seipin are associated with multiple human genetic diseases, including Berardinelli-Seip Congenital Generalized Lipodystrophy Type 2 (BSCL2). However, the cellular and molecular mechanisms by which dysfunctional seipin leads to these diseases remain unclear. To model BSCL2 disease, we generated an orthologous BSCL2 pathogenic variant seip-1(A185P) using CRISPR/Cas9 genome editing in Caenorhabditis elegans . This variant led to severe developmental and cellular defects, including embryonic lethality, impaired eggshell formation, and abnormally enlarged LDs. We set out to identify genetic determinants that could suppress these defective phenotypes in the seip-1(A185P) mutant background. To this end, we conducted an unbiased chemical mutagenesis screen to identify genetic suppressors that restore embryonic viability in the seip-1(A185P) mutant background. A total of five suppressor lines were isolated and recovered from the screen. The defective phenotypes of seip-1(A185P) , including embryonic lethality and impaired eggshell formation, were significantly suppressed in each suppressor line. Two of the five suppressor lines also alleviated the enlarged LDs in the oocytes. We then mapped a suppressor candidate gene, R05D3.2 (renamed as lmbr-1 ), which is an ortholog of human LMBR1 (limb development membrane protein 1). The CRISPR/Cas9 edited lmbr-1 suppressor alleles, lmbr-1(Ser647Phe) and lmbr-1(Pro314Leu) , both significantly suppressed embryonic lethality and defective eggshell formation in the seip-1(A185P) background. The newly identified suppressor lines offer valuable insights into potential genetic interactors and pathways that may regulate seipin in the lipodystrophy model.
2022-12-01 | Gene therapy restores adipose tissue and metabolic health in a pre-clinical mouse model of lipodystrophy
Congenital generalized lipodystrophy type 2 is a serious multisystem disorder with limited treatment options. It is caused by mutations affecting the BSCL2 gene, which encodes the protein seipin. Patients with congenital generalized lipodystrophy type 2 lack both metabolic and mechanical adipose tissue and develop severe metabolic complications including hepatic steatosis, lipoatrophic diabetes, and cardiovascular disease. Gene therapies are becoming viable treatments, helping to alleviate inherited and acquired human disorders. We aimed to determine whether gene therapy could offer an effective form of medical intervention for lipodystrophy. We examined whether systemic adeno-associated virus delivery of human BSCL2 could reverse metabolic disease in seipin knockout mice, where white adipose tissue is absent. We reveal that adeno-associated virus gene therapy targets adipose progenitor cells in vivo and substantially restores white adipose tissue development in adult seipin knockout mice. This resulted in both rapid and prolonged beneficial effects to metabolic health in this pre-clinical mouse model of congenital generalized lipodystrophy type 2. Hyperglycemia was normalized within 2 weeks post-treatment together with normalization of severe insulin resistance. We propose that gene therapy offers great potential as a therapeutic strategy to correct multiple metabolic complications in patients with congenital lipodystrophy. Congenital generalized lipodystrophy type 2 is a serious multisystem disorder with limited treatment options. It is caused by mutations affecting the BSCL2 gene, which encodes the protein seipin. Patients with congenital generalized lipodystrophy type 2 lack both metabolic and mechanical adipose tissue and develop severe metabolic complications including hepatic steatosis, lipoatrophic diabetes, and cardiovascular disease. Gene therapies are becoming viable treatments, helping to alleviate inherited and acquired human disorders. We aimed to determine whether gene therapy could offer an effective form of medical intervention for lipodystrophy. We examined whether systemic adeno-associated virus delivery of human BSCL2 could reverse metabolic disease in seipin knockout mice, where white adipose tissue is absent. We reveal that adeno-associated virus gene therapy targets adipose progenitor cells in vivo and substantially restores white adipose tissue development in adult seipin knockout mice. This resulted in both rapid and prolonged beneficial effects to metabolic health in this pre-clinical mouse model of congenital generalized lipodystrophy type 2. Hyperglycemia was normalized within 2 weeks post-treatment together with normalization of severe insulin resistance. We propose that gene therapy offers great potential as a therapeutic strategy to correct multiple metabolic complications in patients with congenital lipodystrophy.
other
2022-04-06 | Case Report: Precision COVID-19 Immunization Strategy to Overcome Individual Fragility: A Case of Generalized Lipodystrophy Type 4
A 48-year-old patient affected with congenital generalized lipodystrophy type 4 failed to respond to two doses of the BNT162b2 vaccine, consisting of lipid nanoparticle encapsulated mRNA. As the disease is caused by biallelic variants of CAVIN1 , a molecule indispensable for lipid endocytosis and regulation, we complemented the vaccination cycle with a single dose of the Ad26.COV2 vaccine. Adenovirus-based vaccine entry is mediated by the interaction with adenovirus receptors and transport occurs in clathrin-coated pits. Ten days after Ad26.COV2 administration, S- and RBD-specific antibodies and high-affinity memory B cells increased significantly to values close to those observed in Health Care Worker controls.
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Drug Discovery Landscape
4 orphan drug designations for Congenital generalized lipodystrophy, including 2 approved therapies.
4 orphan drug designations for Congenital generalized lipodystrophy, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Mibavademab | antibodies | EMA | Regeneron Ireland Designated Activity Company | |
Metreleptin [Myalepta] | proteins | EMA | Approved | Chiesi Farmaceutici S.p.A. |
metreleptin | proteins | FDA | Chiesi Farmaceutici S.p.A. | |
metreleptin [MYALEPT] | proteins | FDA | Approved | Chiesi Farmaceutici S.p.A. |
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