Dataset Information

Impairment of respiratory muscle strength in Berardinelli-Seip congenital lipodystrophy subjects.

ABSTRACT:

Background

Berardinelli-Seip Congenital Generalized Lipodystrophy (BSCL) is an ultra-rare metabolic disease characterized by hypertriglyceridemia, hyperinsulinemia, hyperglycemia, hypoleptinemia, and diabetes mellitus. Although cardiovascular disturbances have been observed in BSCL patients, there are no studies regarding the Respiratory Muscle Strength (RMS) in this type of lipodystrophy. This study aimed to evaluate RMS in BSCL subjects compared with healthy subjects.

Methods

Eleven individuals with BSCL and 11 healthy subjects matched for age and gender were included in this study. The Maximum Inspiratory Pressure (MIP), Maximum Expiratory Pressure (MEP), and Peripheral Muscle Strength (PMS) were measured for three consecutive years. BSCL subjects were compared to healthy individuals for MIP, MEP, and PMS. Correlations between PMS and MIP were also analyzed. The genetic diagnosis was performed, and sociodemographic and anthropometric data were also collected.

Results

BSCL subjects showed significantly lower values for MIP and MEP (p?ConclusionBSCL subjects showed lower respiratory muscle strength when compared with healthy subjects; however, PMS was not altered. These findings were maintained at similar levels during the two years of evaluation. Our data reveal the first association of BSCL with the development of respiratory muscle weakness.

SUBMITTER: Dantas de Medeiros JL

PROVIDER: S-EPMC6134719 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Publications

Impairment of respiratory muscle strength in Berardinelli-Seip congenital lipodystrophy subjects.

Dantas de Medeiros Jorge Luiz JL Carneiro Bezerra Bruno B Brito de Araújo Thiago Anderson TA Craveiro Sarmento Aquiles Sales AS de Azevedo Medeiros Lázaro Batista LB Peroni Gualdi Lucien L Luna Cruz Maria do Socorro MDS Xavier Nobre Thaiza Teixeira TT Gomes Lima Josivan J Araújo de Melo Campos Julliane Tamara JT

Respiratory research 20180912 1

<h4>Background</h4>Berardinelli-Seip Congenital Generalized Lipodystrophy (BSCL) is an ultra-rare metabolic disease characterized by hypertriglyceridemia, hyperinsulinemia, hyperglycemia, hypoleptinemia, and diabetes mellitus. Although cardiovascular disturbances have been observed in BSCL patients, there are no studies regarding the Respiratory Muscle Strength (RMS) in this type of lipodystrophy. This study aimed to evaluate RMS in BSCL subjects compared with healthy subjects.<h4>Methods</h4>El ...[more]

PMID: 30208912

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Project description:Berardinelli-Seip congenital lipodystrophy (BSCLD) (OMIM#269700) is a rare autosomal recessive disorder characterized by marked paucity of adipose tissue, a muscular habitus, insulin resistance, hypertriglyceridemia and hepatic steatosis. It is an anabolic syndrome due to the deficiency of leptin, a lipid modulator, leading to the inappropriate mobilization of fat. Four types of BSCLD have been described based on the site of genetic mutation. Type 2 accounts for an earlier onset, more severe complications and intellectual disability. This is due to the lower leptin levels and the loss of functional seipin in type 2 BSCLD. We report the evolving phenotype of type 2 BSCLD in a boy clinically diagnosed at age 5 months and confirmed by molecular genetic study which revealed a pathogenic mutation in the BSCL2 gene: c.782dupG, p.lle262Hisfs*12homozygous. He is the firstborn of non-consanguineous parents with no significant family history. He has a muscular habitus with a distinct facies, hypertrichosis, absence of subcutaneous fat and hepatomegaly. Investigations revealed hypertriglyceridemia and insulin resistance. A conventional approach to management with dietary fat restriction successfully controlled his biochemical parameters, thus preventing catastrophic complications such as systemic arterial hypertension, heart failure and pancreatitis. Genetic counseling was conferred and prenatal testing recommended for future pregnancies. On follow-up, he had a muscular habitus with hepatomegaly and global developmental delay. Despite early correction of his biochemical parameters, an abdominal ultrasound revealed early onset fatty liver disease and an echocardiogram showed a thickened interventricular septum suggestive of early hypertrophic obstructive cardiomyopathy (HOCM). A fasting serum leptin done was low at 0.8 ng/mL (normal range, 2.0-5.6 ng/mL) confirming leptin deficiency. A leptin analog is now available as an adjunct to mollify the metabolic complications of BSCLD. However, it is yet to be available in developing nations and whether it is able to assuage progressive hepatic cholestasis and HOCM remains a field to venture. This report highlights the importance of early recognition and confirmation by molecular diagnosis to direct appropriate surveillance of complications. This also enables early genetic counseling and prenatal testing for future pregnancies. We describe the evolving phenotype, pertinent investigations and the conventional approach to the management of BSCLD.

Project description:ObjectiveUnderstanding the mechanisms that control brown adipose tissue (BAT) mass and functionality is crucial for our understanding of how the disruption of energy homeostasis leads to obesity. Bernerdinali Seip Congenital Lipodystrophy (BSCL) type 2 (BSCL2, a.k.a. SEIPIN), a lipodystrophy-associated protein, has been shown to not be required for brown adipogenesis, but it has been shown to be essential for perinatal BAT development. However, its role in mature BAT maintenance and thermogenic programing remains poorly understood.MethodsWe subjected Bscl2f/f and Bscl2UCP1-BKO (BKO) mice with a brown adipose-specific loss of BSCL2 through UCP1 promoter-driven Cre to environmental, pharmacological and diet interventions to challenge BAT functionality and reprogramming. We carried out physiological, molecular and transcriptomic analyses of BAT.ResultsThe deletion of BSCL2 in mature brown adipocytes increased sympathetic nervous system-independent cAMP/protein kinase A (PKA) signaling in BAT. Such activation reduced BAT triglyceride content and mass and was sufficient to reduce plasma triglyceride, but not enough to combat thermoneutral and high fat diet-induced obesity. Surprisingly, BKO mice displayed an impaired response to acute and chronic cold challenges despite cAMP/PKA activation. When subjected to chronic cold exposure or the administration of a β3-adrenergic agonist, CL 316,243, BKO mice failed to induce BAT recruitment and underwent dramatic brown adipocyte loss. Transcriptomic analysis revealed pathological BAT remodeling with inflammation and fibrosis, which was further exacerbated by a chronic thermogenic challenge in BKO mice. Mechanistically, we found abnormal mitochondrial shapes and function in BAT of BKO mice housed at 21 °C; as well as mitochondrial DNA depletion and necroptotic-mediated brown adipocyte death after chronic thermogenic insult.ConclusionBSCL2-mediated lipid catabolism within BAT is crucial for mature brown adipocyte function and survival both during times of activation and quiescence. BSCL2 is an important regulator of mature brown adipocyte mitochondrial metabolism, necroptosis and thus adaptive thermogenesis.

Dataset Information

Impairment of respiratory muscle strength in Berardinelli-Seip congenital lipodystrophy subjects.

Background

Methods

Results

Publications

Impairment of respiratory muscle strength in Berardinelli-Seip congenital lipodystrophy subjects.

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