Long-term effects of recombinant human insulin-like growth factor I treatment on glucose and lipid metabolism and the growth of a patient with congenital generalized lipodystrophy.
Congenital generalized lipodystrophy (CGL) is a disease characterized by generalized lack of body fat, insulin resistance, hypertriglyceridemia, and fatty liver. We studied the long-term effects of recombinant human insulin-like growth factor I (rhIGF-I) treatment on glucose and lipid metabolism and the growth in a patient with CGL. During rhIGF-I treatment, the serum triglyceride level was maintained almost within the normal range, and the plasma glycosylated hemoglobin A1c (HbA1c) levels were maintained under 8.0% (5.8%-7.9%). Thus, rhIGF-I treatment was effective in lowering glucose and triglyceride levels over the long-term in a CGL patient. However, it was difficult to suppress the patient's voracious appetite. Although serum total IGF-I levels were extremely high (1000-1700 ng/ml), growth was not accelerated after the start of rhIGF-I treatment, likely because of normal IGF binding protein 3 (IGFBP-3) levels. During rhIGF-I treatment, the patient developed a recurrence of mild hypertrophic cardiomyopathy and a mild elevation of intraocular pressure. (+info
Thematic review series: Adipocyte Biology. Lipodystrophies: windows on adipose biology and metabolism.
The lipodystrophies are characterized by loss of adipose tissue in some anatomical sites, frequently with fat accumulation in nonatrophic depots and ectopic sites such as liver and muscle. Molecularly characterized forms include Dunnigan-type familial partial lipodystrophy (FPLD), partial lipodystrophy with mandibuloacral dysplasia (MAD), Berardinelli-Seip congenital generalized lipodystrophy (CGL), and some cases with Barraquer-Simons acquired partial lipodystrophy (APL). The associated mutant gene products include 1) nuclear lamin A in FPLD type 2 and MAD type A; 2) nuclear lamin B2 in APL; 3) nuclear hormone receptor peroxisome proliferator-activated receptor gamma in FPLD type 3; 4) lipid biosynthetic enzyme 1-acylglycerol-3-phosphate O-acyltransferase 2 in CGL type 1; 5) integral endoplasmic reticulum membrane protein seipin in CGL type 2; and 6) metalloproteinase ZMPSTE24 in MAD type B. An unresolved question is whether metabolic disturbances are secondary to adipose repartitioning or result from a direct effect of the mutant gene product. Careful analysis of clinical, biochemical, and imaging phenotypes, using an approach called "phenomics," reveals differences between genetically stratified subtypes that can be used to guide basic experiments and to improve our understanding of common clinical entities, such as metabolic syndrome or the partial lipodystrophy syndrome associated with human immunodeficiency virus infection. (+info
Metabolic correction induced by leptin replacement treatment in young children with Berardinelli-Seip congenital lipoatrophy.
OBJECTIVE: Berardinelli-Seip syndrome is a rare congenital lipoatrophy with a severe prognosis and no efficient therapy. Children present with low leptin levels and severe metabolic complications (insulin resistance, elevated triglyceride levels, and hepatic steatosis). The objective of this study was to test safety and efficacy of recombinant-methionyl-human leptin replacement in children with Berardinelli-Seip syndrome before development of severe metabolic disease METHODS: As part of an open trial, recombinant-methionyl-human leptin was given daily for 4 months to children who did not have diabetes and had Berardinelli-Seip congenital lipoatrophy and metabolic complications at a dosage that was meant to achieve physiologic levels. Six boys and 1 girl (age: 2.4-13.6 years), with a mean fasting insulin level of >15 mIU/L and hypertriglyceridemia, were included. RESULTS: At the end of the recombinant-methionyl-human leptin treatment, a 63% reduction of fasting triglycerides level was achieved. A simultaneous 30% increase in insulin sensitivity was seen, and liver volume was reduced by 20.3%. More remarkable, values of insulin sensitivity and triglyceride level were in the reference range in 4 patients. CONCLUSIONS: Leptin replacement is able to reverse metabolic complications in the majority of children with Berardinelli-Seip congenital lipoatrophy and with insulin resistance or dyslipidemia before the development of overt diabetes. (+info
Novel BSCL2 gene mutation E189X in Chinese congenital generalized lipodystrophy child with early onset diabetes mellitus.
CONTEXT: Congenital generalized lipodystrophy (CGL) is a rare and heterogeneous disease of autosomal recessive inheritance. Until now, no genetic findings had been reported in Chinese patients with CGL. OBJECTIVE: To analyze Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) and 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) gene variation in a Chinese boy with CGL and his family. DESIGN, SETTING, AND PARTICIPANTS: All exons of BSCL2 and AGPAT2 with adjacent intron-exon junctions were analyzed using direct sequencing. MAIN OUTCOME MEASURES: Sequences of each exon and nearby intron of the BSCL2 and AGPAT2 genes of the family members were compared with the gene bank genomic sequences. RESULTS: DNA sequence analysis of the entire coding regions and surrounding uncoding regions disclosed a novel homozygous G-->T mutation at nucleotide 909 in exon 5 of the BSCL2 gene in the affected child. A heterozygous state of the G-->T mutation of the BSCL2 gene was also found in other family members. This mutation predicts the substitution of glutamic acid at codon 189 by the stop codon (Glu189X or E189X). No variation was found in the AGPAT2 gene. Conclusion E189X is a novel BSCL2 gene mutation that contributes to CGL formation in a family of Chinese origin. (+info
Dilated cardiomyopathy and myocardial infarction secondary to congenital generalized lipodystrophy.
Congenital generalized lipodystrophy, also known as Berardinelli-Seip syndrome, is a very rare hereditary syndrome that is characterized by an almost complete absence of adipose tissue from birth. Cardiac involvement seems to have substantial influence in the long-term prognosis. Herein, we report an apparently unique case of congenital generalized lipodystrophy with cardiac sequelae. A 17-year-old woman, diagnosed in childhood with Berardinelli-Seip syndrome, presented with severe epigastric pain that was secondary to previous myocardial infarction. The patient had ischemia, dilated cardiomyopathy, and congestive heart failure, but no coronary artery disease. She was discharged from the hospital in stable condition after 3 days of medical treatment. To our knowledge, this is the 1st reported case of congenital generalized lipodystrophy with dilated cardiomyopathy, congestive heart failure, severe mitral regurgitation, and inferior myocardial infarction as cardiac sequelae of this syndrome--but without evidence of coronary artery disease or cardiac hypertrophy. In addition to discussing this patient's case, we present diagnostic and therapeutic approaches to Berardinelli-Seip syndrome. (+info
Energy balance in congenital generalized lipodystrophy type I.
Effect of depot medroxyprogesterone acetate on glucose tolerance in generalized lipodystrophy.
Novel subtype of congenital generalized lipodystrophy associated with muscular weakness and cervical spine instability.