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Congenital lipodystrophy induces severe osteosclerosis.

ABSTRACT: Berardinelli-Seip congenital generalized lipodystrophy is associated with increased bone mass suggesting that fat tissue regulates the skeleton. Because there is little mechanistic information regarding this issue, we generated "fat-free" (FF) mice completely lacking visible visceral, subcutaneous and brown fat. Due to robust osteoblastic activity, trabecular and cortical bone volume is markedly enhanced in these animals. FF mice, like Berardinelli-Seip patients, are diabetic but normalization of glucose tolerance and significant reduction in circulating insulin fails to alter their skeletal phenotype. Importantly, the skeletal phenotype of FF mice is completely rescued by transplantation of adipocyte precursors or white or brown fat depots, indicating that adipocyte derived products regulate bone mass. Confirming such is the case, transplantation of fat derived from adiponectin and leptin double knockout mice, unlike that obtained from their WT counterparts, fails to normalize FF bone. These observations suggest a paucity of leptin and adiponectin may contribute to the increased bone mass of Berardinelli-Seip patients.

SUBMITTER: Zou W

PROVIDER: S-EPMC6611650 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Congenital lipodystrophy induces severe osteosclerosis.

Zou Wei W Rohatgi Nidhi N Brestoff Jonathan R JR Zhang Yan Y Scheller Erica L EL Craft Clarissa S CS Brodt Michael D MD Migotsky Nicole N Silva Matthew J MJ Harris Charles A CA Teitelbaum Steven L SL

PLoS genetics 20190624 6

Berardinelli-Seip congenital generalized lipodystrophy is associated with increased bone mass suggesting that fat tissue regulates the skeleton. Because there is little mechanistic information regarding this issue, we generated "fat-free" (FF) mice completely lacking visible visceral, subcutaneous and brown fat. Due to robust osteoblastic activity, trabecular and cortical bone volume is markedly enhanced in these animals. FF mice, like Berardinelli-Seip patients, are diabetic but normalization o ...[more]

PMID: 31233501

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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.

Dataset Information

Congenital lipodystrophy induces severe osteosclerosis.

Publications

Congenital lipodystrophy induces severe osteosclerosis.

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