Assessment of aortomesenteric distance and mesenteric and retroperitoneal adipose tissue thickness in genetic forms of lipodystrophy.

INTRODUCTION: Lipodystrophy is a rare disease characterized by the loss of adipose tissue. Visceral adipose tissue loss in certain forms of lipodystrophy may affect the amount of mesenteric fat. METHOD: We studied visceral adipose tissue by measuring the thickness of mesenteric and retroperitoneal adipose tissue and the aortomesenteric (AOM) distance in patients with genetic forms of lipodystrophy (n = 48; 7 males; 41 females; mean age 39.1 ± 11.9 years; 19 with congenital generalized lipodystrophy [CGL], and 29 with familial partial lipodystrophy [FPLD]). An age- and gender-matched control group with a ratio of 1:2 was generated. RESULTS: Patients with CGL had severely depleted mesenteric adipose tissue (2.0 [IQR: 1.5-3.5] mm vs. 18.8 [IQR: 4.4-42.2] mm in FPLD, P < .001; 30.3 [IQR: 13.9-46.6] mm in controls, P < .001) and retroperitoneal adipose tissue (1.3 [IQR: 0.0-5.3] mm vs. 33.7 [IQR: 21.6-42.1] mm in FPLD, P < .001; 29.7 [IQR: 23.1-36.7] mm in controls, P < .001). The AOM distance was shorter in patients with CGL (8.1 [IQR: 6.0-10.8] mm) compared to patients with FPLD (vs. 13.0 [IQR: 8.8-18.1] mm; P = .023) and controls (vs. 11.3 [IQR: 8.4-15.5] mm, P = .016). Leptin levels were positively correlated with AOM distance in lipodystrophy (r = .513, P < .001). Multivariate linear regression analysis identified body mass index as a significant predictor of AOM distance (data controlled for age and sex; beta = 0.537, 95% CI: 0.277-0.798, P < .001). Twelve of 19 patients (63%) with CGL had an AOM distance of < 10 mm, a risk factor that may predispose patients to developing superior mesenteric artery syndrome. CONCLUSION: CGL is associated with a severe loss of mesenteric adipose tissue, which leads to a narrowing of the space between the superior mesenteric artery and the aorta.

Familial partial lipodystrophy resulting from loss-of-function PPARγ pathogenic variants: phenotypic, clinical, and genetic features.

The PPARG gene encodes a member of a nuclear receptor superfamily known as peroxisome proliferator-activated gamma (PPARγ). PPARγ plays an essential role in adipogenesis, stimulating the differentiation of preadipocytes into adipocytes. Loss-of-function pathogenic variants in PPARG reduce the activity of the PPARγ receptor and can lead to severe metabolic consequences associated with familial partial lipodystrophy type 3 (FPLD3). This review focuses on recent scientific data related to FPLD3, including the role of PPARγ in adipose tissue metabolism and the phenotypic and clinical consequences of loss-of-function variants in the PPARG gene. The clinical features of 41 PPARG pathogenic variants associated with FPLD3 patients were reviewed, highlighting the genetic and clinical heterogeneity observed among 91 patients. Most of them were female, and the average age at the onset and diagnosis of lipoatrophy was 21 years and 33 years, respectively. Considering the metabolic profile, hypertriglyceridemia (91.9% of cases), diabetes (77%), hypertension (59.5%), polycystic ovary syndrome (58.2% of women), and metabolic-dysfunction-associated fatty liver disease (87,5%). We also discuss the current treatment for FPLD3. This review provides new data concerning the genetic and clinical heterogeneity in FPLD3 and highlights the importance of further understanding the genetics of this rare disease.

Anesthetic management of a patient with mandibular hypoplasia, deafness, progeroid features, lipodystrophy syndrome: a case report.

BACKGROUND: Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome is a rare autosomal dominant disorder that presents unique challenges for anesthetic management due to its multisystemic manifestations. This report outlines the anesthetic considerations for MDPL patients based on our case experience. CASE PRESENTATION: A 15-year-old male with MDPL syndrome underwent testicular extraction under general anesthesia. Insertion of a peripheral venous catheter was challenging due to scleroderma-like skin. Although the facial features of MDPL syndrome suggested a difficult airway, intubation with a McGrath™ Mac video laryngoscope was successful. Despite MDPL syndrome's association with hypertriglyceridemia due to lipodystrophy, this patient's triglyceride levels were normal. Thiamylal and sevoflurane were used without issues such as delayed emergence from anesthesia. CONCLUSIONS: MDPL syndrome requires careful preoperative assessment and tailored anesthetic management due to potential airway challenges arising from its distinctive facial features and the possibility of altered anesthetic pharmacokinetics associated with lipodystrophy.

Partial Lipodystrophy Affecting the Extremities in a Young Woman With Autoimmune Polyglandular Syndrome 1.

Autoimmune polyglandular syndrome 1 (APS1) is an autosomal recessive disorder due to biallelic pathogenic variants in the autoimmune regulator (AIRE) gene that manifests with chronic mucocutaneous candidiasis, primary hypoparathyroidism, and adrenal insufficiency. We report a 39-year-old woman with APS1 who developed partial lipodystrophy during adulthood. She presented with diaper rashes, oral thrush, and tetany during infancy due to candidiasis and hypoparathyroidism. During childhood, she developed hypothyroidism, primary adrenal insufficiency, and ovarian insufficiency. At age 14, she received a sibling-matched allogenic bone marrow transplant due to multiple antibiotic-refractory fungal infections. At age 35, her serum triglycerides were 914 mg/dL (10.32 mmol/L) and she had loss of subcutaneous fat from the upper and lower extremities and hips. A whole-body dual-energy x-ray absorptiometry revealed lower-extremity fat at less than the first percentile. Whole-exome sequencing on DNA extracted from saliva revealed pathogenic variants, p.Leu28Pro and p.Arg257* in AIRE but none in the known lipodystrophy genes. Phage-immunoprecipitation-sequencing revealed the presence of autoantibodies to MAGEB1, MAGEB4, and RFX6, which have been previously reported in APS1. Our case suggests that patients with APS1 may develop partial lipodystrophy due to autoantibodies against novel adipocyte-expressed proteins. A causal relationship of high levels of autoantibodies in our patient to adipose tissue-expressed ODC1, NUCKS1, or FNBP1L and lipodystrophy remains uncertain.

Correlation of APOE polymorphism, expression, and plasma levels with cardiac comorbidities among lipodystrophy in HIV-infected patients.

Lipodystrophy in HIV-infected patients (LDHIV) includes morphological and metabolic abnormalities, including lipid and glucose metabolism. ApoE plays a role in the transport and clearance of lipoprotein. In the general population, ApoE 112 (rs429358) and 158 (rs7412) polymorphisms were linked to severe dyslipidemia. Therefore, we investigated ApoE polymorphism using PCR-RFLP in 200 HIV patients (100 with HIV-associated lipodystrophy (HIVLD), 100 without HIVLD), as well as 100 healthy controls. We also assessed ApoE expression using qRT-PCR and measured its level using ELISA. The APOE 4/4, 3/4, and 2/4 genotypes have been associated with a decreased risk of HIV-1 infection. (P = 0.0001, OR = 0.18; P = 0.006, OR = 0.87; P = 0.006, OR = 0.09) when compared between HIV-positive individuals and healthy controls. Conversely, APOE allele 2 was linked to a higher risk of acquiring HIV-1 (P = 0.03, OR = 3.02). APOE allele 2 was linked to a higher likelihood of HIVLD severity when compared between patients with and without HIVLD (P = 0.05, OR = 2.82). When comparing patients with HIVLD to healthy controls, the APOE 4/4 and 2/4 genotypes as well as allele 4 were linked with the reduced risk of LDHIV (P = 0.0006, OR = 0.21; P = 0.01, OR = 0.18; P = 0.0002, OR = 0.40). When compared to patients without HIVLD from healthy controls, the ApoE 4/4 genotype, 2 and 4 alleles, were linked to a reduced risk of developing HIVLD (P = 0.0009, OR = 0.14; P = 0.0001, OR = 0.17; P = 0.00001, OR = 0.39). When comparing impaired to normal cholesterol levels in patients without HIVLD, the ApoE 3/4 genotype was linked with the increased risk of impaired cholesterol levels (P = 0.02, OR = 3.37). When comparing impaired and normal glucose levels in patients without HIVLD, the ApoE 4/4 genotype was associated to an elevated risk of impaired glucose levels (P = 0.03, OR = 8.27). In multivariate analysis, independent impaired cholesterol, LDL, and glucose levels were associated with a higher risk of lipodystrophy severity (P = 0.04, OR = 2.33; P = 0.001, OR = 4.05; P = 0.05, OR = 2.63). ApoE expression was up-regulated in LDHIV with a fold change value of 4.02 compared to those without HIVLD. ApoE protein level was found to be higher in patients of the HIVLD group (3.01 mg/dL) compared to those without HIVLD group (2.83 mg/dL). In conclusion, individuals with ApoE allele 2 were at higher risk for HIV-1 acquisition and severity of HIVLD, whereas those with ApoE allele 4 were at reduced HIVLD severity and development risk. It's possible that ApoE's increased level and its overexpression are related to the ApoE allele 2 in HIVLD patients. The development of LDHIV may be facilitated by the APOE 3/4 and 4/4 genotypes as well as abnormal glucose and cholesterol levels.

Involvement of a battery of investigated genes in lipid droplet pathophysiology and associated comorbidities.

Lipid droplets (LDs) are highly specialized energy storage organelles involved in the maintenance of lipid homoeostasis by regulating lipid flux within white adipose tissue (WAT). The physiological function of adipocytes and LDs can be compromised by mutations in several genes, leading to NEFA-induced lipotoxicity, which ultimately manifests as metabolic complications, predominantly in the form of dyslipidemia, ectopic fat accumulation, and insulin resistance. In this review, we delineate the effects of mutations and deficiencies in genes - CIDEC, PPARG, BSCL2, AGPAT2, PLIN1, LIPE, LMNA, CAV1, CEACAM1, and INSR - involved in lipid droplet metabolism and their associated pathophysiological impairments, highlighting their roles in the development of lipodystrophies and metabolic dysfunction.

Anthropometric measurements as a key diagnostic tool for familial partial lipodystrophy in women.

BACKGROUND: Familial Partial Lipodystrophy (FPLD) is a disease with wide clinical and genetic variation, with seven different subtypes described. Until genetic testing becomes feasible in clinical practice, non-invasive tools are used to evaluate body composition in lipodystrophic patients. This study aimed to analyze the different anthropometric parameters used for screening and diagnosis of FPLD, such as thigh skinfold thickness (TS), Köb index (Köbi), leg fat percentage (LFP), fat mass ratio (FMR) and leg-to-total fat mass ratio in grams (LTR), by dual-energy X-ray absorptiometry, focusing on determining cutoff points for TS and LFP within a Brazilian population. METHODS: Thirty-seven patients with FPLD and seventy-four healthy controls matched for body mass index, sex and age were studied. Data were collected through medical record review after signing informed consent. All participants had body fat distribution evaluated by skinfolds and DXA measures. Fasting blood samples were collected to evaluate glycemic and lipid profiles. Genetic studies were carried out on all patients. Two groups were categorized based on genetic testing and/or anthropometric characteristics: FPLD+ (positive genetic test) and FPLD1 (negative genetic testing, but positive clinical/anthropometric criteria for FPLD). RESULTS: Eighteen (48.6%) patients were classified as FPLD+, and 19 (51.4%) as FPLD1. Unlike what is described in the literature, the LMNA variant in codon 582 was the most common. Among the main diagnostic parameters of FPLD, a statistical difference was observed between the groups for, Köbi, TS, LFP, FMR, and LTR. A cutoff point of 20 mm for TS in FPLD women was found, which is lower than the value classically described in the literature for the diagnosis of FPLD. Additionally, an LFP < 29.6% appears to be a useful tool to aid in the diagnosis of these women. CONCLUSION: Combining anthropometric measurements to assess body fat distribution can lead to a more accurate diagnosis of FPLD. This study suggests new cutoff points for thigh skinfold and leg fat percentage in women with suspected FPLD in Brazil. Further studies are needed to confirm these findings.

Novel PIK3R1 gene mutation associated with SHORT syndrome: a case report of a 15-year-old female.

OBJECTIVES: To present the clinical journey and management of a 15-year-old female with SHORT syndrome, highlighting the diagnostic challenges and the novel genetic mutation identified. CASE PRESENTATION: A 15-year-old Filipino female was initially seen in a dermatology clinic at 9 years old for axillary skin darkening, indicative of acanthosis nigricans. Early evaluations revealed elevated blood glucose levels, resulting in a pediatric diabetes diagnosis without the usual hyperglycemic symptoms. Her medical history was notable for premature birth, intrauterine growth restriction, a cardiac murmur from patent ductus arteriosus and a bicuspid aortic valve, delayed teething, and distinct dysmorphic features. Genetic testing identified a novel PIK3R1 gene mutation. Treatment with Metformin significantly improved her glycemic control and lipid profiles. The patient also displayed delayed puberty and polycystic ovary syndrome-like symptoms, but growth hormone deficiency was excluded. Endocrine evaluation for her short stature and lipodystrophy confirmed the presence of the PIK3R1 mutation. CONCLUSIONS: This case highlights the importance of thorough endocrine and genetic evaluations in patients with complex clinical presentations like SHORT syndrome. The identification of a novel PIK3R1 gene mutation expands the understanding of the genetic basis of this syndrome and underscores the need for individualized treatment approaches.

Lipodystrophic Laminopathies: From Dunnigan Disease to Progeroid Syndromes.

Lipodystrophic laminopathies are a group of ultra-rare disorders characterised by the presence of pathogenic variants in the same gene (LMNA) and other related genes, along with an impaired adipose tissue pattern and other features that are specific of each of these disorders. The most fascinating traits include their complex genotype-phenotype associations and clinical heterogeneity, ranging from Dunnigan disease, in which the most relevant feature is precisely adipose tissue dysfunction and lipodystrophy, to the other laminopathies affecting adipose tissue, which are also characterised by the presence of signs of premature ageing (Hutchinson Gilford-progeria syndrome, LMNA-atypical progeroid syndrome, mandibuloacral dysplasia types A and B, Nestor-Guillermo progeria syndrome, LMNA-associated cardiocutaneous progeria). This raises several questions when it comes to understanding how variants in the same gene can lead to similar adipose tissue disturbances and, at the same time, to such heterogeneous phenotypes and variable degrees of metabolic abnormalities. The present review aims to gather the molecular basis of adipose tissue impairment in lipodystrophic laminopathies, their main clinical aspects and recent therapeutic strategies. In addition, it also summarises the key aspects for their differential diagnosis.

A cohort analysis of familial partial lipodystrophy from two Mediterranean countries.

AIM: To assess the disease burden of familial partial lipodystrophy (FPLD) caused by LMNA (FPLD2) and PPARG (FPLD3) variants to augment the knowledge of these rare disorders characterized by selective fat loss and metabolic complications. MATERIALS AND METHODS: An observational longitudinal study, including 157 patients (FPLD2: 139 patients, mean age 46 ± 17 years, 70% women; FPLD3: 18 patients, mean age: 44 ± 17 years, 78% women) from 66 independent families in two countries (83 from Turkey and 74 from Spain), was conducted. RESULTS: Patients were diagnosed at a mean age of 39 ± 19 years, 20 ± 16 years after the first clinical signs appeared. Men reported symptoms later than women. Symptom onset was earlier in FPLD2. Fat loss was less prominent in FPLD3. In total, 92 subjects (59%) had diabetes (age at diagnosis: 34 ± 1 years). Retinopathy was more commonly detected in FPLD3 (P < .05). Severe hypertriglyceridaemia was more frequent among patients with FPLD3 (44% vs. 17%, P = .01). Hepatic steatosis was detected in 100 subjects (66%) (age at diagnosis: 36 ± 2 years). Coronary artery disease developed in 26 patients (17%) and 17 (11%) suffered from a myocardial infarction. Turkish patients had a lower body mass index, a higher prevalence of hepatic steatosis, greater triglyceride levels and a tendency towards a higher prevalence of coronary artery disease. A total of 17 patients died, with a mean time to death of 75 ± 3 years, which was shorter in the Turkish cohort (68 ± 2 vs. 83 ± 4 years, P = .01). Cardiovascular events were a major cause of death. CONCLUSIONS: Our analysis highlights severe organ complications in patients with FPLD, showing differences between genotypes and Mediterranean countries. FPLD3 presents a milder phenotype than FPLD2, but with comparable or even greater severity of metabolic disturbances.

Adipose tissue in health and disease.

This Virtual Special Issue on Adipose tissue in health and disease features 26 original articles from different international contexts. It expands our understanding of the adipose tissue as an essential organ involved in relevant physiological functions such as reproduction, metabolism, energy balance, endocrinology, circadian rhythm, and inflammation. The focus is on the adipose tissue as a common key mediator of different severe metabolic pathologies including insulin resistance, liver diseases, cardiometabolic diseases, diabetes, lipodystrophy, Cushing's syndrome, obesity, and polycystic ovary syndrome. This adipose tissue-associated diseases are linked with a high mortality and increased health care costs worldwide. Thus, the 26 contributions of this Special Issue aim at identifying molecular mechanisms by which the adipose tissue is involved in the progression of its associated pathologies. Deeper understanding of these mechanisms in health and disease and the context-dependent parameters shaping them, is likely key to decipher the full potential of the adipose tissue for novel therapeutic approaches and strategies for managing complications associated with obesity and the metabolic syndrome.

Case report: First Chinese patient with family partial lipodystrophy type 6 due to novel compound heterozygous mutations in the LIPE gene.

Background: Family partial lipodystrophy (FPLD) is a rare autosomal dominant disease characterized by disorders of variable body fat loss associated with metabolic complications. FPLD6 has only been reported in a limited number of cases. Here, we reported a Chinese FPLD6 patient with compound heterozygous mutations in the lipase E, hormone-sensitive type (LIPE) gene. Case presentation: A 20-year-old female patient presented with hypertriglyceridemia, diabetes mellitus, hepatomegaly, and hepatic steatosis. Subcutaneous fat was significantly diminished in her face, abdomen, and limbs. The patient was assessed by detailed clinical and biochemical examinations. A liver biopsy showed severe lipodystrophy. In addition, there were retinal changes, peripheral nerve damage, and renal tubular injury. Sequencing was performed on extracted DNA. Genetic analysis revealed that the patient had compound heterozygous mutations in the LIPE gene: c.2497_250ldel (p.Glu833LysfsTer22) and c.2705del (p.Ser902ThrfsTer27) heterozygous mutations. Verification revealed that this mutation was inherited from her father and mother, respectively, and that they formed newly discovered compound heterozygous mutations occurring in the LIPE gene, causing FPLD6. Conclusion: We reported the first case of FPLD6 in China. Gene analysis demonstrated compound heterozygous mutations in LIPE in this patient. Our case emphasizes the importance of genetic testing in young patients with severe metabolic syndromes.

Navigating Lipodystrophy: Insights from Laminopathies and Beyond.

Recent research into laminopathic lipodystrophies-rare genetic disorders caused by mutations in the LMNA gene-has greatly expanded our knowledge of their complex pathology and metabolic implications. These disorders, including Hutchinson-Gilford progeria syndrome (HGPS), Mandibuloacral Dysplasia (MAD), and Familial Partial Lipodystrophy (FPLD), serve as crucial models for studying accelerated aging and metabolic dysfunction, enhancing our understanding of the cellular and molecular mechanisms involved. Research on laminopathies has highlighted how LMNA mutations disrupt adipose tissue function and metabolic regulation, leading to altered fat distribution and metabolic pathway dysfunctions. Such insights improve our understanding of the pathophysiological interactions between genetic anomalies and metabolic processes. This review merges current knowledge on the phenotypic classifications of these diseases and their associated metabolic complications, such as insulin resistance, hypertriglyceridemia, hepatic steatosis, and metabolic syndrome, all of which elevate the risk of cardiovascular disease, stroke, and diabetes. Additionally, a range of published therapeutic strategies, including gene editing, antisense oligonucleotides, and novel pharmacological interventions aimed at addressing defective adipocyte differentiation and lipid metabolism, will be explored. These therapies target the core dysfunctional lamin A protein, aiming to mitigate symptoms and provide a foundation for addressing similar metabolic and genetic disorders.

Prevalence and associated factors of lipodystrophy in type 1 diabetic children and adolescents at Ayder Comprehensive Specialized Hospital, Tigray, Ethiopia.

INTRODUCTION: Lipodystrophy can cause poor glycemic control in addition to cosmetic problems in children and adolescents with type 1 diabetes mellitus. However, data on its prevalence and associated factors is scarce among children and adolescents who live in developing countries like Ethiopia. OBJECTIVE: To determine the prevalence and identify associated factors of lipodystrophy in children and adolescents with type 1 diabetes mellitus who visited the endocrinology clinic of Ayder Comprehensive Specialized Hospital between May 1 and July 31, 2020. METHOD: This was an institution-based cross-sectional study conducted on 57 children and 65 adolescents with type 1 diabetes mellitus who had been taking insulin injections for a year or more. The dependent variable was lipodystrophy. A pretested, structured questionnaire was used to collect data related to lipodystrophy and other characteristics. The principal investigator oversaw the data collection, which was done by pediatric and child health specialty residents with training. Data was subjected to descriptive statistics, and predictors of lipodystrophy were identified by fitting a multivariable logistic regression model. Statistical significance was declared at p < 0.05. RESULTS: More than half (53.3%) of patients were in the age range of 13 to 17. The male-to-female ratio was almost 1:1. Educational status for 63.1% of patients was primary school. Four-fifths of patients were residing in urban areas. Of the 122 participants, 60 (49.2%) had lipodystrophy (48.3% lipohypertrophy and 0.8% lipoatrophy), with grade II lipohypertrophy being the most common type at 81.7%. The thigh was the most common site of lipodystrophy. In multivariable regression analysis, the long duration of insulin injection (AOR = 3.6, 95% CI, 1.5 to 9.0, p = 0.005) and inappropriate rotation of the injection site (AOR = 9.0, 95% CI, 2.2 to 37.0, p = 0.002) were significantly associated with lipodystrophy. HbA1c testing was conducted for 70 patients, and poor glycemic control (HbA1c ≥ 7%) was found in 43 (61.4%) of them. Patients with lipodystrophy were more likely to have poor glycemic control (75%) than those without lipodystrophy (47.1%) (p = 0.016). CONCLUSION: The prevalence of lipodystrophy was comparable with other studies. Long duration of insulin injection and improper rotation of the injection site are associated with an increased risk of lipodystrophy. Patients with lipodystrophy were more likely to have poor glycemic control, defined by higher HgA1c, than those without lipodystrophy. Proper education of patients and their parents must include correct injection techniques, rotating injection sites, and changing injection sites intermittently to lessen the risk of developing lipodystrophy.

Disentangling the detrimental effects of local from systemic adipose tissue dysfunction on articular cartilage in the knee.

OBJECTIVE: Obesity increases osteoarthritis (OA) risk due to adipose tissue dysfunction with associated metabolic syndrome and excess weight. Lipodystrophy syndromes exhibit systemic metabolic and inflammatory abnormalities similar to obesity without biomechanical overloading. Here, we used lipodystrophy mouse models to investigate the effects of systemic versus intra-articular adipose tissue dysfunction on the knee. METHODS: Intra-articular adipose tissue development was studied using reporter mice. Mice with selective lipodystrophy of intra-articular adipose tissue were generated by conditional knockout (cKO) of Bscl2 in Gdf5-lineage cells, and compared with whole-body Bscl2 knockout (KO) mice with generalised lipodystrophy and associated systemic metabolic dysfunction. OA was induced by surgically destabilising the medial meniscus (DMM) and obesity by high-fat diet (HFD). Gene expression was analysed by quantitative RT-PCR and tissues were analysed histologically. RESULTS: The infrapatellar fat pad (IFP), in contrast to overlying subcutaneous adipose tissue, developed from a template established from the Gdf5-expressing joint interzone during late embryogenesis, and was populated shortly after birth by adipocytes stochastically arising from Pdgfrα-expressing Gdf5-lineage progenitors. While female Bscl2 KO mice with generalised lipodystrophy developed spontaneous knee cartilage damage, Bscl2 cKO mice with intra-articular lipodystrophy did not, despite the presence of synovial hyperplasia and inflammation of the residual IFP. Furthermore, male Bscl2 cKO mice showed no worse cartilage damage after DMM. However, female Bscl2 cKO mice showed increased susceptibility to the cartilage-damaging effects of HFD-induced obesity. CONCLUSION: Our findings emphasise the prevalent role of systemic metabolic and inflammatory effects in impairing cartilage homeostasis, with a modulatory role for intra-articular adipose tissue.

A rapid action plan to improve diagnosis and management of lipodystrophy syndromes.

Introduction: Lipodystrophy syndromes are rare diseases that can present with a broad range of symptoms. Delays in diagnosis are common, which in turn, may predispose to the development of severe metabolic complications and end-organ damage. Many patients with lipodystrophy syndromes are only diagnosed after significant metabolic abnormalities arise. Prompt action by clinical teams may improve disease outcomes in lipodystrophy syndromes. The aim of the Rapid Action Plan is to serve as a set of recommendations from experts that can support clinicians with limited experience in lipodystrophy syndromes. Methods: The Rapid Action Plan was developed using insights gathered through a series of advisory meetings with clinical experts in lipodystrophy syndromes. A skeleton template was used to facilitate interviews. A consensus document was developed, reviewed, and approved by all experts. Results: Lipodystrophy is a clinical diagnosis. The Rapid Action Plan discusses tools that can help diagnose lipodystrophy syndromes. The roles of clinical and family history, physical exam, patient and family member photos, routine blood tests, leptin levels, skinfold measurements, imaging studies, and genetic testing are explored. Additional topics such as communicating the diagnosis to the patients/families and patient referrals are covered. A set of recommendations regarding screening and monitoring for metabolic diseases and end-organ abnormalities is presented. Finally, the treatment of lipodystrophy syndromes is reviewed. Discussion: The Rapid Action Plan may assist clinical teams with the prompt diagnosis and holistic work-up and management of patients with lipodystrophy syndromes, which may improve outcomes for patients with this rare disease.

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.

Diagnosis, treatment and management of lipodystrophy: the physician perspective on the patient journey.

BACKGROUND: Lipodystrophy syndromes are a heterogeneous group of rare, life-limiting diseases characterized by a selective loss of adipose tissue and severe metabolic complications. There is a paucity of information describing the experiences and challenges faced by physicians who have seen and treated patients with lipodystrophy. This study aimed to provide a better understanding of the physician's perspective regarding the patient journey in lipodystrophy, including diagnosis, the burden of disease, and treatment approaches. METHODS: Thirty-three physicians from six countries who had seen or treated patients with lipodystrophy were interviewed using a semi-structured questionnaire. Interviews were transcribed, anonymized, and analyzed for themes and trends. Four main themes were developed: (1) the diagnostic journey in lipodystrophy including the disease features or 'triggers' that result in the onward referral of patients to specialist medical centers with experience in managing lipodystrophy; (2) the impact of lipodystrophy on patient quality of life (QoL); (3) the use of standard therapies and leptin replacement therapy (metreleptin) in lipodystrophy, and (4) barriers to metreleptin use. RESULTS: Participants reported that, due to their rarity and phenotypic heterogeneity, lipodystrophy cases are frequently unrecognized, leading to delays in diagnosis and medical intervention. Early consultation with multidisciplinary specialist medical teams was recommended for suspected lipodystrophy cases. The development and progression of metabolic complications were identified as key triggers for the referral of patients to specialist centers for follow-up care. Participants emphasized the impact of lipodystrophy on patient QoL, including effects on mental health and self-image. Although participants routinely used standard medical therapies to treat specific metabolic complications associated with lipodystrophy, it was acknowledged that metreleptin was typically required in patients with congenital generalized lipodystrophy and in some acquired generalized and partial lipodystrophy cases. A lack of experience among some participants and restrictions to access remained as barriers to metreleptin use. CONCLUSIONS: To our knowledge, this is one of the first studies describing the qualitative experiences of physicians regarding the diagnosis and management of lipodystrophy. Other physician-centered studies may help increase the awareness of lipodystrophy among the wider medical community and support clinical approaches to this rare disease.

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

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