congenital generalized lipodystrophy
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2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Yen-Hua Huang ◽  
Tzu-Chien Su ◽  
Chung-Hsing Wang ◽  
Siew-Lee Wong ◽  
Yin-Hsiu Chien ◽  
...  

AbstractIllumina RNA-seq analysis was used to characterize the whole transcriptomes of peripheral blood mononuclear cells (PBMCs) from patients with congenital generalized lipodystrophy. RNA-seq information for seven patients with type 2 congenital generalized lipodystrophy (CGL2; Berardinelli-Seip congenital lipodystrophy, BSCL2) was obtained and compared with similar information for seven age- and sex-matched healthy control subjects. All seven CGL2 patients carried biallelic pathogenic mutations affecting the BSCL2 gene and had clinical symptoms of varying severity. The findings provide the whole-transcriptome signatures of PBMCs of CGL2 patients, allowing further exploration of gene expression patterns/signatures associated with the various clinical symptoms of patients with this disease.


2021 ◽  
Author(s):  
Asuman Nur Karhan ◽  
Jamila Zammouri ◽  
Martine Auclair ◽  
Emilie Capel ◽  
Feramuz Demir Apaydın ◽  
...  

Objective : CAV1 encodes caveolin-1, a major protein of plasma membrane microdomains called caveolae, involved in several signalling pathways. Caveolin-1 is also located at the adipocyte lipid droplet. Heterozygous pathogenic variants of CAV1 induce rare heterogeneous disorders including pulmonary arterial hypertension and neonatal progeroid syndrome. Only one patient was previously reported with a CAV1 homozygous pathogenic variant, associated with congenital generalized lipodystrophy (CGL3). We aimed to further delineate genetic transmission, clinical, metabolic and cellular characteristics of CGL3. Design/Methods: In a large consanguineous kindred referred for CGL, we performed next-generation sequencing, as well as clinical, imagery and metabolic investigations. We studied skin fibroblasts from the index case and the previously reported patient with CGL3. Results: Four patients, aged 8 months to 18 years, carried a new homozygous p.(His79Glnfs*3) CAV1 variant. They all displayed generalized lipodystrophy since infancy, insulin resistance, low HDL-cholesterol and/or high triglycerides, but no pulmonary hypertension. Two patients also presented at the age of 15 and 18 years with dysphagia due to achalasia, and one patient had retinitis pigmentosa. Heterozygous parents and relatives (n=9) were asymptomatic, without any metabolic abnormality. Patients’ fibroblasts showed a complete loss of caveolae and no protein expression of caveolin-1 and its caveolin-2 and cavin-1 partners. Patients’ fibroblasts also displayed insulin resistance, increased oxidative stress and premature senescence. Conclusions: The CAV1 null variant investigated herein leads to an autosomal recessive congenital lipodystrophy syndrome. Loss of caveolin-1 and/or caveolae induces specific manifestations including achalasia which requires specific management. Overlapping phenotypic traits between the different CAV1-related diseases require further studies.


2021 ◽  
Vol 22 (19) ◽  
pp. 10596
Author(s):  
Thiago Bruder-Nascimento ◽  
Taylor C. Kress ◽  
Matthew Pearson ◽  
Weiqin Chen ◽  
Simone Kennard ◽  
...  

The adipokine leptin, which is best-known for its role in the control of metabolic function, is also a master regulator of cardiovascular function. While leptin has been approved for the treatment of metabolic disorders in patients with congenital generalized lipodystrophy (CGL), the effects of chronic leptin deficiency and the treatment on vascular contractility remain unknown. Herein, we investigated the effects of leptin deficiency and treatment (0.3 mg/day/7 days) on aortic contractility in male Berardinelli-Seip 2 gene deficient mice (gBscl2-/-, model of CGL) and their wild-type control (gBscl2+/+), as well as in mice with selective deficiency in endothelial leptin receptor (LepREC-/-). Lipodystrophy selectively increased vascular adrenergic contractility via NO-independent mechanisms and induced hypertrophic vascular remodeling. Leptin treatment and Nox1 inhibition blunted adrenergic hypercontractility in gBscl2-/- mice, however, leptin failed to rescue vascular media thickness. Selective deficiency in endothelial leptin receptor did not alter baseline adrenergic contractility but abolished leptin-mediated reduction in adrenergic contractility, supporting the contribution of endothelium-dependent mechanisms. These data reveal a new direct role for endothelial leptin receptors in the control of vascular contractility and homeostasis, and present leptin as a safe therapy for the treatment of vascular disease in CGL.


Author(s):  
Erika Bastos Lima Freire ◽  
Catarina Brasil d’Alva ◽  
Mayara Ponte Madeira ◽  
Grayce Ellen da Cruz Paiva Lima ◽  
Ana Paula Dias Rangel Montenegro ◽  
...  

Congenital Generalized Lipodystrophy (CGL) is a rare syndrome characterized by the almost total absence of subcutaneous adipose tissue due to the inability of storing lipid in adipocytes. Patients present generalized lack of subcutaneous fat and normal to low weight. They evolve with severe metabolic disorders, non-alcoholic fatty liver disease, early cardiac abnormalities, and infectious complications. Although low body weight is a known risk factor for osteoporosis, it has been reported that type 1 and 2 CGL have a tendency of high bone mineral density (BMD). In this review, we discuss the role of bone marrow tissue, adipokines, and insulin resistance in the setting of the normal to high BMD of CGL patients. Data bases from Pubmed and LILACS were searched, and 113 articles published until 10 April 2021 were obtained. Of these, 76 were excluded for not covering the review topic. A manual search for additional literature was performed using the bibliographies of the studies located. The elucidation of the mechanisms responsible for the increase in BMD in this unique model of insulin resistance may contribute to the understanding of the interrelationships between bone, muscle, and adipose tissue in a pathophysiological and therapeutic perspective.


2021 ◽  
Vol 12 ◽  
Author(s):  
Erika Bastos Lima Freire ◽  
Mayara Ponte Madeira ◽  
Grayce Ellen da Cruz Paiva Lima ◽  
Virginia Oliveira Fernandes ◽  
Lindenberg Barbosa Aguiar ◽  
...  

Paget’s disease of bone (PDB) is a common skeleton disorder in which the diagnosis is suggested by radiological analyses. Congenital generalized lipodystrophy (CGL) is a rare, but a radiologic differential diagnosis of Paget’s disease. Patients present total or almost total lack of subcutaneous adipose tissue, leptin deficiency, and precocious ectopic lipid accumulation, which lead to intense insulin resistance, poorly controlled diabetes mellitus, and hypertriglyceridemia. CGL subtypes 1 and 2 present sclerosis and osteolytic lesions that can resemble “pagetic” lesions. The clinical correlation is, therefore, essential. We report a CGL patient with bone lesions in which the radiographic findings led to a misdiagnosis of PDB. This case report brings awareness to CGL, a life-threating condition. Its early recognition is essential to avoid clinical complications and premature death. Therefore, it is important to consider CGL as PDB’s differential diagnosis, especially in countries with high prevalence of this rare disease, such as Brazil.


2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Mayara Ponte Madeira ◽  
Erika Bastos Lima Freire ◽  
Virginia Oliveira Fernandes ◽  
Grayce Ellen da Cruz Paiva Lima ◽  
Ivana da Ponte Melo ◽  
...  

Abstract Background A new strain of human coronavirus (HCoV) spread rapidly around the world. Diabetes and obesity are associated with a worse prognosis in these patients. Congenital Generalized Lipodystrophy (CGL) patients generally have poorly controlled diabetes and require extremely high doses of insulin. There is no documentation in the literature of cases of COVID in CGL patients. Thus, we aimed to evaluate the prevalence of SARS-CoV-2 infection in CGL patients, and the association of their clinical and metabolic characteristics and outcomes. Methods This is a cross-sectional study carried out between July and October 2020. Clinical data collected were respiratory or other flu-like symptoms, need of hospitalization in the last three months, CGL comorbidities, and medications in use. Cholesterol, triglycerides, glycohemoglobin A1c levels, anti-SARS-CoV-2 antibodies and nasopharyngeal swab for RT-qPCR were also obtained in all CGL patients. Mann-Whitney U test was used to analyze the characteristics of the participants, verifying the non-adherence of the data to the Gaussian distribution. In investigating the association between categorical variables, we used Pearson's chi-square test and Fisher's exact test. A significance level of 5% was adopted. Results Twenty-two CGL patients were assessed. Eight subjects (36.4%) had reactive anti-SARS-CoV-2 antibodies. Only one of these, also presented detectable RT-qPCR. Five individuals (62.5%) were women, median age of 13.5 years (1 to 37). Symptoms like fever, malaise, nausea, diarrhea and chest pain were present, and all asymptomatic patients were children. All subjects had inadequate metabolic control, with no difference between groups. Among positive individuals there was no difference between those with AGPAT2 (75%) and BSCL2 gene mutations (25%) (p > 0.05). No patient needed hospitalization or died. Conclusions We described a high prevalence of SARS-CoV-2 infection in CGL patients with a good outcome in all of them. These findings suggest that at least young CGL patients infected by SARS-COV-2 are not at higher risk of poor outcome, despite known severe metabolic comorbidities.


2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A701-A702
Author(s):  
Cintya Schweisberger ◽  
Jill Diane Jacobson ◽  
Emily Paprocki

Abstract Background: Congenital generalized lipodystrophy (CGL) is a rare inherited disease characterized by widespread loss of subcutaneous fat and severe metabolic abnormalities. Metreleptin, a synthetic analog of leptin, is a treatment modality that has been shown to decrease fasting triglycerides, fasting glucose, and HbA1c. Metformin use in infants has only been described in a few case reports of CGL and Donohue syndrome (insulin receptor mutation), and there is no established dosing for this age group. We report metreleptin, insulin, and metformin use in an infant with type 1 CGL who presented with marked hypertriglyceridemia, hypoleptinemia, hyperglycemia, and transaminitis. Clinical Case: A 2-month-old African American female born SGA at term presented to her primary care physician for a well child check where she was noted to have poor weight gain, hyperphagia, and abdominal distension. She was subsequently admitted for failure to thrive with weight z-score of -2.17 and length z-score of -0.15. Initial labs were notable for triglycerides of 5,167 mg/dL, HDL 10 mg/dL, blood glucose 324 mg/dL, ALT 212 units/L, AST 215 units/L, and bicarbonate of 17 mmol/L. A random insulin level was elevated at 257 mcIU/mL. Adiponectin was undetectable and leptin was low at 0.3 ng/mL. Hemoglobin A1c was in diabetes mellitus range at 8.9%. She was started on detemir 1.0 units/kg/day on day 1 (titrated to a maximum dose of 4.4 units/kg/day) and metformin 50 mg/kg/day on day 3 of hospitalization. By day 4, triglycerides decreased to 758 mg/dL, AST to 119 units/L and ALT to 124 units/L. Pre-prandial glucoses improved ranging from 113 to 138 mg/dL. As her insurance denied coverage for detemir, she was discharged home on glargine 0.7 units/kg/day and metformin suspension. One month later, she was started on subcutaneous metreleptin, and glargine was discontinued. At 5 months of age, she had triglycerides 229 mg/dl, normal liver enzymes, and normal blood glucoses while on 0.056 mg/kg/day of subcutaneous metreleptin and metformin. Medications were well tolerated without side effects. She had improved growth and met all developmental milestones. Genetic evaluation revealed that she was homozygous for a pathogenic variant, c.589-2A>G; p.Gln196fs*228 (rs116807569), in the AGPAT2 gene. Conclusion: Leptin is important in regulation of lipid and glucose metabolism, and patients with CGL are deficient due to lack of adipose tissue. Metabolic abnormalities, including stabilization of glucoses and improved hypertriglyceridemia, in our patient markedly improved with initiation of metreleptin, metformin, and insulin. We present successful dosing of these treatment modalities without adverse reactions in an infant with CGL.


PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0244667
Author(s):  
Camilla O. D. Araújo ◽  
Renan M. Montenegro ◽  
Amanda P. Pedroso ◽  
Virgínia O. Fernandes ◽  
Ana Paula D. R. Montenegro ◽  
...  

Background Patients with congenital generalized lipodystrophy (CGL) have very low levels of leptin and are described as having a voracious appetite. However, a direct comparison between CGL and eutrophic individuals is lacking, regarding both appetite parameters and acylated ghrelin, the hormone form that is active in acute food intake stimulation. The objective of the present study was to address whether and in what extent the subjective appetite parameters and acylated ghrelin response to a meal are affected in CGL individuals, in comparison to eutrophic individuals. Additionally, an obese group was included in the study, to allow the comparison between a leptin-resistant and a leptin-deficient condition on these aspects. Methods Eutrophic controls (EUT, n = 10), obese subjects (OB, n = 10) and CGL (n = 11) were fasted overnight and then received an ad libitum meal. Blood was collected and the visual analogue scale was applied before and 90 minutes after the meal. An additional blood sample was collected at 60 minutes for ghrelin determination. Results The CGL patients showed low fasting levels of leptin and adiponectin, dyslipidemia, and insulin resistance. The caloric intake was similar among the 3 groups. However, both CGL (p = 0.02) and OB (p = 0.04) had shorter satiation times than EUT. The CGL patients also had lower satiety time (p = 0.01) and their sensation of hunger was less attenuated by the meal (p = 0.03). Fasting acylated ghrelin levels were lower in CGL than in EUT (p = 0.003). After the meal, the levels tended to decrease in EUT but not in CGL and OB individuals. Conclusion The data indicate that, although not hyperphagic, the CGL patients present appetite disturbances in relation to eutrophic individuals. Their low fasting levels of acylated ghrelin and the absence of the physiological drop after meal intake suggest a role of these disturbances in hunger attenuation and satiety but not in acute satiation.


Author(s):  
Nevena Chakarova ◽  
Lubomir Balabanski ◽  
Rumyana Dimova ◽  
Alexander Shinkov ◽  
Tsvetalina Tankova

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