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PubMedDate not supplied

Uncommon allele in apo AI-CIII-AIV gene cluster in a family with congenital generalized lipodystrophy.

Congenital generalized lipodystrophy is a rare inherited disease. One of its features is a disturbance in lipid metabolism characterized by hypercholesterolemia and hypertriglyceridemia. A brother and a sister with congenital generalized lipodystrophy, an 8-year old male and a 12-year old female were studied. The mother and a 6-year old brother were healthy. The genetic analysis of Sstl RFLP of the apo AI-CIII-AIV gene cluster showed the presence of the rare Sstl allele (S2) in the patients but not in the healthy mother and brother. As this uncommon allele has been reported to be related to high plasma triglyceride levels, this association could be relevant in explaining in part the hypertriglyceridemia observed in these patients.

Alleles↗
PubMed2006

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.

Adolescent↗
PubMed2003

Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Recently, mutations in 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) genes were reported in pedigrees linked to chromosomes 9q34 and 11q13, respectively. There are limited data regarding phenotypic differences between the various subtypes of CGL. Furthermore, whether there are additional loci for CGL remains unknown. Therefore, we genotyped 45 pedigrees with CGL for AGPAT2 and BSCL2 loci and compared the phenotypes in the various subtypes. Twenty-six pedigrees harbored mutations, including seven novel variants, in the AGPAT2 gene, and 11 pedigrees harbored mutations in the BSCL2 gene, including five novel variants. Eight pedigrees had no substantial alterations in either gene. Of these, three informative pedigrees showed no linkage to markers spanning the AGPAT2 and BSCL2 loci, and in six of the affected subjects, the transcripts of AGPAT2 and BSCL2 were normal. All subtypes of CGL showed high prevalence of diabetes, hypertriglyceridemia, and acanthosis nigricans. However, patients with BSCL2 mutations had lower serum leptin levels, an earlier onset of diabetes, and higher prevalence of mild mental retardation compared with other subtypes. We conclude that besides AGPAT2 and BSCL2, there may be additional loci for CGL. The genetic heterogeneity in CGL patients is accompanied by phenotypic heterogeneity.

1-Acylglycerol-3-Phosphate O-Acyltransferase↗
PubMed2004

Genetic basis of congenital generalized lipodystrophy.

Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder characterized by extreme lack of body fat and severe insulin resistance since birth. Recently, mutations have been reported in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2 or Seipin) genes in affected subjects from pedigrees linked to chromosomes 9q34 and 11q13, respectively. The AGPAT2 catalyses the acylation of the lysophosphatidic acid at the sn-2 position to form phosphatidic acid, a key intermediate in the biosynthesis of triacylglycerol and glycerophospholipids. High expression of AGPAT2 mRNA in adipose tissue compared to other isoforms suggests that the mutations might affect the adipose tissue the most. The function of BSCL2 remains unknown. Several CGL pedigrees reveal no mutation in either of the above genes and are not linked to these loci, suggesting additional genetic loci for CGL. Thus, several distinct mechanisms can lead to extreme lack of adipose tissue in humans and cause CGL.

1-Acylglycerol-3-Phosphate O-Acyltransferase↗
PubMed1992

Peculiar distribution of adipose tissue in patients with congenital generalized lipodystrophy.

Congenital generalized lipodystrophy (CGL) is a rare genetic disease with extreme paucity of fat from birth which is believed to be generalized, involving the whole body. Affected patients are characterized by severe insulin resistance. Sites of adipose tissue distribution in patients with CGL have not been studied systematically. Therefore, the fat distribution in three women (17-20 yr old) with CGL was investigated. Determination of body composition by underwater volume displacement suggested the complete absence of body fat (range, -3 to -7%; normal, 15-25%). Whole body magnetic resonance imaging, however, detected fat in particular anatomical sites, namely in orbits, palms and soles, and periarticular and epidural regions. Some fat was also localized in the tongue, breasts, vulva, and buccal area. Fat in other subcutaneous areas, intraabdominal and intrathoracic regions, and bone marrow was essentially absent. Thus, patients with CGL do not have a complete absence of body fat; of interest, fat is present in those sites where adipose tissue may be serving mainly a mechanical function. Patients with CGL, therefore, provided a unique opportunity to identify the various sites of localization of "mechanical" adipose tissue in the human body. Our study suggests that the genetic defect in CGL results in poor growth and development of metabolically active adipose tissue, whereas mechanical adipose tissue is well preserved.

Adipose Tissue↗
PubMed2002

Induction of adipocyte differentiation by a thiazolidinedione in cultured, subepidermal, fibroblast-like cells of an infant with congenital generalized lipodystrophy.

Congenital generalized lipodystrophy (CGL) is characterized by the absence of adipose tissue from birth due to a hypothetical differentiation block. The genetic causes of CGL are still not completely understood. Subepidermal, fibroblast-like cells were prepared from the sc tissue of an infant with CGL. Preadipocytes from sc adipose tissue and foreskin fibroblasts from three healthy patients, respectively, were used as controls. Adipose differentiation was induced in cultured cells by exposure to 10 nM insulin, 200 pM T(3), 1 microM cortisol, and 2 microM rosiglitazone. Under these conditions 42% of the subepidermal, fibroblast-like CGL cells developed into mature adipocytes. Adipogenic differentiation was dependent on rosiglitazone. The differentiation rate was comparable in cultures of preadipocytes from control patients maintained under the same conditions (53%, 38%, and 20%). In contrast, foreskin fibroblasts did not differentiate into adipocytes. Morphological changes in CGL cells during differentiation were associated with the expression of fat cell-specific mRNAs (PPARgamma, leptin, and glut-4). In addition, these cells revealed characteristic features of mature adipocytes, such as lipogenesis or leptin secretion. Taken together, we show that adipocyte precursor cells were present in subepidermal tissue of a patient with CGL and were able to differentiate into adipocytes in the presence of a thiazolidinedione. These findings strongly support clinical trials with thiazolidinediones in patients with CGL.

Adipocytes↗
PubMed2000

Skeletal muscle morphology and exercise response in congenital generalized lipodystrophy.

OBJECTIVE: Congenital generalized lipodystrophy (CGL) is an autosomal recessive genetic disorder characterized by almost complete absence of adipose tissue, muscular appearance, and severe insulin resistance since birth. We investigated whether insulin resistance in CGL patients is associated with abnormal muscle morphology and whether increased muscularity imparts increased muscle strength and exercise capacity RESEARCH DESIGN AND METHODS: We obtained quadriceps muscle biopsies to study muscle fiber types and capillary density in three African-American women (aged 17-20 years) with CGL. We also assessed quadriceps muscle strength, muscle metabolism, and maximal O2 consumption in the patients. RESULTS: Quadriceps muscle biopsies revealed a markedly higher percentage of type II (fast-twitch glycolytic) muscle fibers in patients with CGL versus sedentary young women (75-78 vs. 47-57%, respectively). The capillary-to-fiber ratio (2.7-3.0), however, was normal. Cross-sectional areas of type I (slow-twitch oxidative) (1,262-2,685 microm2) and type II (2,304-3,594 microm2) fibers were far below the normal values (3,811-4,310 and 3,115-4,193 microm2, respectively), suggesting muscle hyperplasia but not hypertrophy The quadriceps muscle strength, as measured by Cybex, was below average; the maximal O2 consumption (23-32 ml x kg(-1) x min(-1)) was also below average. 31P nuclear magnetic resonance spectroscopy of the forearm muscles revealed normal pH and metabolic responses to static and dynamic exercises. CONCLUSIONS: We conclude that insulin resistance in patients with CGL is associated with an increased proportion of type II muscle fibers but not reduced capillary density. Increased muscularity in CGL is due to muscle hyperplasia and is not associated with increased muscle strength.

Adipose Tissue↗
PubMed1977

Decreased binding of insulin to its receptor in patients with congenital generalized lipodystrophy.

Patients with congenital generalized lipodystrophy are extremely insulin resistant. To ascertain whether this resistance is due to an insulin receptor defect, we tested four young patients with congenital generalized lipodystrophy and seven healthy persons of comparable age for the binding of 125I insulin to mononuclear leukocytes isolated from peripheral blood. Mononuclear leukocytes from patients with congenital generalized lipodystrophy bound significantly less insulin than cells from normal subjects (P less than 0.01). When patients with lipodystrophy fasted for 60 hours, the insulin binding increased. Altered insulin receptors may be responsible for the pronounced insulin resistance and the decreased synthesis of triglycerides in congenital generalized lipodystrophy.

Adolescent↗
PubMed1996

Generalized lipodystrophy, congenital and acquired (lipoatrophy).

This review is based on longitudinal studies on our seven patients with congenital generalized lipodystrophy, our patient with acquired generalized lipodystrophy, and published papers on these subjects. An inability to store energy in adipose tissue is of pathogenetic importance. In congenital lipodystrophy, insulin resistance is present from birth, resulting in hyperinsulinaemia, dyslipidaemia. and insulin-resistant diabetes with an anabolic syndrome worsened by a voracious appetite. Clinically, we observed increased height velocity in pre-school age children, and organomegaly with hypertrophic cardiomyopathy, which seems to be lethal in early adulthood: three of our patients died at the ages of 24, 32 and 37 years. The oldest alive, 39 years, suffers from stenocardia. Regarding treatment, it is most important to reduce energy consumption. The congenital form is recessively inherited. The aetiology may be related to insulin receptor or postreceptor mechanisms. Acquired generalized lipodystrophy seems to be an autoimmune disorder with secondary destruction of the adipose organ: the anabolic syndrome with insulin-resistant diabetes is secondary. Our patient died when 24 years old from pneumonia.

Carbohydrate Metabolism↗
PubMed1996

Detection of an aberrant fragment in growth hormone gene cluster in a girl with congenital generalized lipodystrophy.

The etiology of congenital generalized lipodystrophy (CGL) is unknown, but one of the clinical features is an accelerated rate of growth. In order to determine whether this abnormality is related to an abnormality of the GH or the IGF-I gene, we studied the DNA of lymphocytes of a girl with CGL. The IGF-I gene autoradiographic patterns of this patient were found not to differ from those of normal subjects, but after BamHI digestion, this patient's GH gene cluster had an aberrant 5.7 kb fragment in addition to the constant 8.3, 6.7, 5.3, 3.8, 2.9 kg fragments. The new 5.7 kb fragment was not detected in any of 60 unrelated Japanese individuals. In conclusion, the CGL patient carries an abnormal GH gene cluster, but further studies are needed to clarify whether this abnormal fragment is specific to CGL or just a rare polymorphic fragment.

Autoradiography↗
PubMed1975

Congenital generalized lipodystrophy.

Six patients with congenital generalized lipodystrophy are described. They had generalized paucity of fat tissue, acanthosis nigricans, prominent superficial veins and muscle hypertrophy. They were mentally retarded. Three had corneal opacities. They had normal external genitalia and none was tall for age. Their bone age was advanced and some had minor skeletal anomalies and nephromegaly. The muscle histology on light microscopy was normal. The majority had elevated serum aldolase and to a lesser degree serum lactic dehydrogenase and creatinine phosphokinase. Four of five examined had a myopathic electromyogram. They had normal or deranged liver function tests. The fatty liver infiltration in one seems to be progressive. Four had a normal and two an abnormal metyrapone test. They had an age-dependent abnormality of growth hormone, insulin and carbohydrate homeostasis.

Acanthosis Nigricans↗
PubMed2002

AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34.

Congenital generalized lipodystrophy is an autosomal recessive disorder characterized by marked paucity of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis and early onset of diabetes. We report several different mutations of the gene (AGPAT2) encoding 1-acylglycerol-3-phosphate O-acyltransferase 2 in 20 affected individuals from 11 pedigrees of diverse ethnicities showing linkage to chromosome 9q34. The AGPAT2 enzyme catalyzes the acylation of lysophosphatidic acid to form phosphatidic acid, a key intermediate in the biosynthesis of triacylglycerol and glycerophospholipids. AGPAT2 mRNA is highly expressed in adipose tissue. We conclude that mutations in AGPAT2 may cause congenital generalized lipodystrophy by inhibiting triacylglycerol synthesis and storage in adipocytes.

1-Acylglycerol-3-Phosphate O-Acyltransferase↗
PubMedDate not supplied

[Congenital generalized lipodystrophy].

OBJECTIVE: To present the major clinical and biochemical characteristics of congenital generalized lipodystrophy. DESCRIPTION: Eight infants with congenital generalized lipodystrophy were identified at the Endocrine and Nutritional Pediatric Disease Outpatient Clinics at Hospital de Clínicas, Universidade Federal de Minas Gerais (UFMG). Clinical manifestations common to all patients included muscle hypertrophy, generalized lipoatrophy, and acromegalic physical appearance. Acanthosis nigricans was identified in five patients, hepatosplenomegaly in six, hypertriglyceridemia and low levels of HDL cholesterol in seven, cardiac hypertrophy in one and diabetes mellitus in two patients. All patients are under dietetic and clinical control. COMMENTS: The phenotypic characteristics of congenital generalized lipodystrophy are well identified, which, in most cases, favors the clinical diagnosis. The congenital generalized lipodystrophy is a very unusual syndrome that illustrates the importance of the adipose tissue for the majority of metabolic processes. A better understanding of this syndrome may open new horizons in the research of more prevalent diseases such as diabetes mellitus and obesity.

Acromegaly↗
PubMed1996

Studies of insulin resistance in congenital generalized lipodystrophy.

Two well-characterized patients with congenital, generalized lipodystrophy have been studied by the euglycaemic hyperinsulinaemic clamp technique in combination with indirect calorimetry. Furthermore, glycogen synthase in muscle biopsies was studied in one patient with regard to enzyme activity, immunoreactive protein and mRNA levels. The patients had fasting hyperinsulinaemia, and the rate of total glucose disposal was severely impaired, primarily due to a decreased non-oxidative glucose metabolism. In the patient studied with muscle biopsy, the expected activation of glycogen synthase by insulin did not occur. In both patients there was severely increased hepatic glucose output in the basal state, suggesting a failure of insulin to suppress hepatic gluconeogenesis. During insulin infusion a substantially elevated rate of lipid oxidation remained in the patients, in contrast to the almost completely suppressed lipid oxidation in the controls. It is concluded that patients with congenital generalized lipodystrophy may present severe insulin resistance with regard to hepatic glucose production as well as muscle glycogen synthesis and lipid oxidation. The results suggest a postreceptor defect in the action of insulin in congenital generalized lipodystrophy. The further localization of such a defect is hampered by the still incomplete understanding of the pathways that link insulin-stimulated tyrosine phosphorylation to the ultimate action of insulin upon target cells.

Calorimetry, Indirect↗
PubMed2003

Congenital generalized lipodystrophy: significance of triglyceride biosynthetic pathways.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by marked lack of body fat since birth, which results in striking muscular appearance. Patients develop extreme insulin resistance and its complications, such as diabetes, hyperlipidemia and fatty liver. Mutations in the BSCL2 (which encodes seipin, a protein of unknown function) and AGPAT2 (which encodes 1-acylglycerol-3-phosphate O-acyltransferase 2) genes have been reported in patients with CGL. AGPAT2 is a key enzyme involved in triglyceride and phospholipid biosynthesis and, thus, the discovery of AGPAT2 mutations has heightened interest in the biochemical pathways of triglyceride synthesis and their implications in human physiology and in the pathophysiology of obesity, lipodystrophies and other adipose tissue disorders. All enzymes involved in triglyceride synthesis, including AGPAT, have several known isoforms encoded by different genes. Assuming different substrate specificities of these enzymes, the human body might have many forms of triglycerides and phospholipids. Here, we discuss the significance of these in energy storage, in addition to the normal functioning of cell membranes.

Animals↗
PubMed1999

A gene for congenital generalized lipodystrophy maps to human chromosome 9q34.

Congenital generalized lipodystrophy (CGL, Berardinelli-Seip Syndrome, OMIM # 269700) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Affected individuals have marked insulin resistance, hypertriglyceridemia and acanthosis nigricans, and develop diabetes mellitus during teenage years. The genetic defect for CGL is unknown. A semi-automated genome-wide scan with a set of highly polymorphic short tandem repeats (STR) was carried out in 17 well-characterized pedigrees and identified a locus for CGL to chromosome 9q34. The maximum two-point lod score obtained was 3.6 at D9S1818 (theta(max) = 0.05). There was evidence for genetic heterogeneity (alpha = 0.73) and 2 of the pedigrees were unlinked. Multipoint linkage analysis excluding the 2 unlinked families yielded a peak lod score of 5.4 between loci D9S1818 and D9S1826. The CGL1 critical region harbors a plausible candidate gene encoding the retinoid X receptor alpha (RXRA) that plays a central role in adipocyte differentiation. Identification of the CGL gene(s) will contribute to our understanding of the adipocyte differentiation and elucidation of the mechanisms of insulin resistance in disorders of adipose tissue.

Acanthosis Nigricans↗
PubMed1975

Lipoatrophy produced in mice and rabbits by a fraction prepared from the urine from patients with congenital generalized lipodystrophy.

Urine from 5 patients with congenital generalized lipodystrophy has been fractionated by protein precipitation and Sephadex gel filtration. A fraction with a molecular weight in the range of 1000 was observed to be metabolically active in mice, rats, and rabbits. Hypophysectomized rats got hypoglycaemia following an injection, and the lipolytic-hyperglycaemic effect of ACTH was reduced after injection into intact mice. This effect was probably due to insulin release, because no insulin-like activity was observed on isolated fat cells in vitro. Persistant changes were observed in the animals after 3 weeks of daily injections of the urinary fraction. Adult mice and rabbits developed lipoatrophy with decrease of body weight in spite of a doubling of the food consumption. The metabolic rate and the body temperature were raised. Infantile animals developed a lipodystrophic state with increased growth velocity, and 50 per cent increase of the body weight, although no fat depots were observed. The treated animals got hyperglycaemia, hypertriglyceridaemia, hyperinsulinaemia, and insulin resistance. The rabbits developed manifest diabetes. The corresponding fraction prepared from the urine from the lipoatrophic rabbits produced lipoatrophy after injection into the mice. It is suggested that the lipodystrophic urinary fraction is of hypothalamic origin, and that it acts through the pituitary gland. The fraction is still heterogenous, and was observed to contain thyrotrophin releasing activity.

Adolescent↗