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.

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.

Impaired signaling pathways on Berardinelli-Seip congenital lipodystrophy macrophages during Leishmania infantum infection.

Berardinelli-Seip congenital lipodystrophy (CGL), a rare autosomal recessive disorder, is characterized by a lack of adipose tissue. Infections are one of the major causes of CGL individuals' premature death. The mechanisms that predispose to infections are poorly understood. We used Leishmania infantum as an in vitro model of intracellular infection to explore mechanisms underlying the CGL infection processes, and to understand the impact of host mutations on Leishmania survival, since this pathogen enters macrophages through specialized membrane lipid domains. The transcriptomic profiles of both uninfected and infected monocyte-derived macrophages (MDMs) from CGL (types 1 and 2) and controls were studied. MDMs infected with L. infantum showed significantly downregulated expression of genes associated with infection-response pathways (MHC-I, TCR-CD3, and granzymes). There was a transcriptomic signature in CGL cells associated with impaired membrane trafficking and signaling in response to infection, with concomitant changes in the expression of membrane-associated genes in parasites (e.g. δ-amastins). We identified pathways suggesting the lipid storage dysfunction led to changes in phospholipids expression and impaired responses to infection, including immune synapse (antigen presentation, IFN-γ signaling, JAK/STAT); endocytosis; NF-kappaB signaling; and phosphatidylinositol biosynthesis. In summary, lipid metabolism of the host plays an important role in determining antigen presentation pathways.

Associations between Components of Metabolic Syndrome and Demographic, Nutritional, and Lifestyle Factors.

Objectives: To evaluate the associations between individuals with and without changes in components of metabolic syndrome (MetS) and demographic, nutritional, and lifestyle factors. Methods: A cross-sectional study was conducted with 224 individuals followed-up at a public hospital in Northeast Brazil. We used National Cholesterol Education Program-Adult Treatment Panel III (NCEP) criteria to diagnose MetS. We assessed components of MetS as dependent variables, while sex, age, food consumption, smoking, alcohol intake, physical activity, anthropometric parameters, and sleep hours were independent variables. Results: Comparing individuals with and without changes in components of MetS, the logistic regression models revealed that female sex was predictive of increased waist circumference and low HDL-c levels while advanced age was predictive of increased blood pressure and blood glucose levels. BMI emerged as a predictor for waist circumference and a protective factor for triglyceride levels. In addition, potassium intake, physical activity, and sleep duration were protective against decreased HDL-c, elevated triglyceride, and elevated blood pressure levels, respectively. Conclusion: This study demonstrated that sex, age, BMI, dietary potassium intake, physical activity, and hours of sleep are factors to be targeted in public health actions for prevention and treatment of MetS.

Status de vitamina D e risco cardiovascular em indivíduos com síndrome metabólica / Vitamin D status and cardiovascular risk in individuals with metabolic syndrome

Introdução: A síndrome metabólica é um conjunto de desordens metabólicas, consideradas fatores de risco cardiovascular. Estima-se que indivíduos com síndrome metabólica apresentam probabilidade três vezes maior de desenvolver doenças cardiovasculares. O status inadequado de vitamina D tem apresentado múltiplos mecanismos fisiopatológicos que sugerem um envolvimento no desenvolvimento de doenças cardiovasculares. Objetivo: avaliar a associação entre o status de vitamina D e o risco de doenças cardiovasculares em indivíduos com síndrome metabólica. Métodos: Estudo do tipo transversal realizado com 161 indivíduos adultos, diagnosticados com síndrome metabólica. Foram realizadas as medidas antropométricas, pressão arterial, e as análises bioquímicas, incluindo a dosagem de 25(OH)D no soro. O critério estabelecido para classificação do status de 25(OH)D foi deficiente < 20 ng/mL; insuficiente≤ 29 ng/mL e suficiente ≥ 30 ng/mL. Ademais, avaliou-se o risco absoluto de desenvolver doenças cardiovasculares usando o Escore de Risco de Framingham. Resultados: A mediana da concentração de 25(OH)D foi 29,7 (21-34) ng/mL, indicando status de 25(OH)D insuficiente na população. Não houve associação entre status de vitamina D e o risco cardiovascular em indivíduos com síndrome metabólica (p > 0,05). Conclusão: Não se observou associação entre status 25(OH)D inadequado e maior risco cardiovascular nos indivíduos com síndrome metabólica. Entretanto,esses resultados reforçam a importância do monitoramento clínico para prevenir os impactos da hipovitaminose D nos indivíduos com síndrome metabólica e o desenvolvimento de novos estudos para avaliar a relação entre status de 25(OH)D e risco cardiovascular.

Introduction: Metabolic syndrome is a set of metabolic disorders that are considered cardiovascular risk factors. It is estimated that individuals with metabolic syndrome are three times more likely to develop cardiovascular disease. Inadequate vitamin D status has shown multiple pathophysiological mechanisms that suggest an involvement in the development of cardiovascular disease. Objective: To evaluate the association between vitamin D status and the risk of cardiovascular disease in individuals with metabolic syndrome. Methods: This is a cross-sectional study carried out with 161 adult individuals diagnosed with metabolic syndrome. Anthropometric measurements, blood pressure, and biochemical analyzes were performed, including serum 25(OH)D status. The established criterion for classifying 25(OH)D status was deficient < 20 ng/mL; insufficient ≤ 29 ng/mL and sufficient ≥ 30 ng/mL. Furthermore, the absolute risk of developing cardiovascular disease was assessed using the Framingham Risk Score. Results: The mean 25(OH)D concentration was 29.7 (21-34) ng/mL, indicating insufficient 25(OH)D status in the population. There was no association between vitamin D status and cardiovascular risk in subjects with metabolic syndrome (p > 0.05). Conclusion: There was no association between inadequate 25(OH)D status and increased cardiovascular risk in individuals with metabolic syndrome. However, these results reinforce the importance of clinical monitoring to prevent the impacts of hypovitaminosis D in individuals with metabolic syndrome and the development of new studies to assess the relationship between 25(OH)D status and cardiovascular risk.

DNA repair-related genes and adipogenesis: Lessons from congenital lipodystrophies.

Classical and progeroid congenital lipodystrophies are a collection of rare diseases displaying a large genetic heterogeneity. They occur due to pathogenic variants in genes associated with adipogenesis, DNA repair pathways, and genome stability. Subjects with lipodystrophy exhibit an impairment in the homeostasis of subcutaneous white adipose tissue (sWAT), resulting in low leptin and adiponectin levels, insulin resistance (IR), diabetes, dyslipidemia, ectopic fat deposition, inflammation, mitochondrial and endoplasmic reticulum commitments, among others. However, how pathogenic variants in adipogenesis-related genes modulate DNA repair in some classical congenital lipodystrophies has not been elucidated. In the same way, no data is clarifying how pathogenic variants in DNA repair genes result in sWAT loss in different types of progeroid lipodystrophies. This review will concentrate on the main molecular findings to understand the link between DNA damage/repair and adipogenesis in human and animal models of congenital lipodystrophies. We will focus on classical and progeroid congenital lipodystrophies directly or indirectly related to DNA repair pathways, highlighting the role of DNA repair-related proteins in maintaining sWAT homeostasis.

A method based on non-ionizing microwave radiation for ancillary diagnosis of osteoporosis: a pilot study.

BACKGROUND: Osteoporosis is a condition characterized by low bone mineral density, which typically leads to fractures and reduced quality of life. Currently, diagnostic devices used to assess this condition (e.g., dual-energy X-ray absorptiometry) are very costly, making it infeasible to meet the demand for testing in most countries. Therefore, we proposed a preclinical validation of a prototype called Osseus in an attempt to enhance osteoporosis screening tests and alleviate their costs. Osseus is a device developed to assist bone mineral density classification. It integrates a microcontroller into other peripheral devices to measure the attenuation at the middle phalanx of the middle finger, with two antennas operating at the 2.45 GHz frequency. RESULTS: We conducted tests with plaster, poultry, and porcine bones. A comparison of the measurements of the original and mechanically altered samples demonstrated that the device can handle the complexity of the tissues within the bone structure and characterize its microarchitecture. CONCLUSIONS: Osseus is a device that has been preliminarily validated. Ionising radiation needed for DXA tests is replaced by non-ionising microwave electromagnetic radiation. Osseus enables early detection of osteoporosis, reduces costs, and optimizes high-complexity testing referrals. There is a lack of validation studies with the reference/gold standard that are currently under development.