Generalized Lipodystrophy Research Articles

A Rare case in Indians -- Berardinelli–Seip Congenital Lipodystrophy

Berardinelli-Seip Congenital Lipodystrophy( BSCL) also called Congenital Generalised Lipodystrophy (CGL) is a very rare autosomal recessive metabolic syndrome with a prevalence of less than1 case in 12 million 1 . About 200 cases have been reported so far world-wide 2 . BSCL2 ,the more severe form of the disease with onset in the neonatal period or early infancy is present in Lebanon, Portugal, Norway and the Middle East with the world's highest prevalence in the Brazilian population of Portuguese descent 3,4,5 . However , reports from India are few and far between. We are therefore reporting a case of a 3 year old boy who presented wih features typical of the disease, characterised by generalised lipodystrophy, acromegaloid features, hepatosplenomegaly, involvement of the face with empty cheeks and hypertriglyceridemia along with mild mental retardation, penile enlargement and hirsutism. The boy had developed an obstructed Richter's hernia at 3 months of age for which he was operated and subsequently developed cirrhosis at 1 year of age. Other than only one report of a case of BSCL2 having developed cirrhosis as early as 4 months of age, ours is the second report of BSCL with early onset of cirrhotic changes in the liver by one year of age. Moreover, though there have been some reports of umbilical hernia associated with BSCL, ours is the first report of Richter's hernia developing at 3 months of age in a case of BSCL.

A case of Berardinelli-Seip syndrome presenting clinical with cirrhosis

Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare autosomal recessive disorder of generalised lipoatrophy, characterised by the absence of functioning adipocytes, with lipid being stored in muscles, the liver and the pancreas. The usual presentation is in adulthood, with manifestations of insulin resistance, hypertriglyceridaemia and liver steatosis. Cirrhosis as the first presentation of BSCL in a young adult is rare. We describe a patient with BSCL presenting with cirrhosis. To the best of our knowledge this is the first case of BSCL reported in a Sri Lankan patient.

Syndromes lipodystrophiques

Human lipodystrophies represent a group of diseases characterized by altered body fat amount and/or repartition. Most forms of lipodystrophies are associated with metabolic alterations such as insulin resistance, diabetes and dyslipemia, leading to diabetic complications, increased cardiovascular risk or liver steatosis. Lipodystrophies can be classified as genetic or acquired, generalized or partial. Genetic forms such as Berardinelli-Seip syndrome or partial familial lipodystrophies are uncommon and acquired forms are much more frequent. Beside the rare Lawrence or Barraquer-Simons syndromes, the main forms of acquired lipodystrophies are those observed in HIV-infected people treated with antiretroviral therapies or in people exposed to an endogenous or an exogenous hypercortisolism. The treatment of lipodystrophies is difficult. Lifestyle modifications (e.g., specific diet, physical training) may be helpful but are usually insufficient. Associated metabolic disorders should be treated as soon as possible with insulin sensitizers, insulin and lipid lowering drugs. New therapies such as leptin have been proven to be helpful in some genetic or acquired forms of lipodystrophy.

Clinical and histopathological study of Charcot-Marie-Tooth neuropathy with a novel S90W mutation in BSCL2

The objective of the study was to investigate the disease-causing mutation in an autosomal dominant Charcot-Marie-Tooth disease type 2 family and examine the clinical and histopathological evaluation. We enrolled a family of Korean origin with axonal Charcot-Marie-Tooth disease neuropathy (FC305; 13 males, six females) and applied genome-wide linkage analysis. Whole exome sequencing was performed for two patients. In addition, sural nerve biopsies were obtained from two patients. Through whole exome sequencing, we identified an average of 20,336 coding variants from two patients. We also found evidence of linkage mapped to chromosome 11p11-11q13.3 (LOD score of 3.6). Among these variants in the linkage region, we detected a novel p.S90W mutation in the Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene, after filtering 31 Korean control exomes. Our p.S90W patients had frequent sensory disturbances, pyramidal tract signs, and predominant right thenar muscle atrophy in comparison with reported p.S90L patients. The phenotypic spectra were wide and demonstrated intrafamilial variability. Two patients with different clinical features underwent sural nerve biopsies; the myelinated fiber densities were increased slightly in both patients, which differed from two previous case reports of BSCL2 mutations (p.S90L and p.N88S). This report expands the variability of the clinical spectrum associated with the BSCL2 gene and describes the first family with the p.S90W mutation.

Alterations in Lipid Signaling Underlie Lipodystrophy Secondary to AGPAT2 Mutations

Congenital generalized lipodystrophy (CGL), secondary to AGPAT2 mutation is characterized by the absence of adipocytes and development of severe insulin resistance. In the current study, we investigated the adipogenic defect associated with AGPAT2 mutations. Adipogenesis was studied in muscle-derived multipotent cells (MDMCs) isolated from vastus lateralis biopsies obtained from controls and subjects harboring AGPAT2 mutations and in 3T3-L1 preadipocytes after knockdown or overexpression of AGPAT2. We demonstrate an adipogenic defect using MDMCs from control and CGL human subjects with mutated AGPAT2. This defect was rescued in CGL MDMCs with a retrovirus expressing AGPAT2. Both CGL-derived MDMCs and 3T3-L1 cells with knockdown of AGPAT2 demonstrated an increase in cell death after induction of adipogenesis. Lack of AGPAT2 activity reduces Akt activation, and overexpression of constitutively active Akt can partially restore lipogenesis. AGPAT2 modulated the levels of phosphatidic acid, lysophosphatidic acid, phosphatidylinositol species, as well as the peroxisome proliferator–activated receptor γ (PPARγ) inhibitor cyclic phosphatidic acid. The PPARγ agonist pioglitazone partially rescued the adipogenic defect in CGL cells. We conclude that AGPAT2 regulates adipogenesis through the modulation of the lipome, altering normal activation of phosphatidylinositol 3-kinase (PI3K)/Akt and PPARγ pathways in the early stages of adipogenesis.

Neuroanatomical characterisation of the expression of the lipodystrophy and motor-neuropathy gene Bscl2 in adult mouse brain.

The endoplasmic reticulum localised protein seipin, encoded by the gene Berardinelli–Seip congenital lipodystrophy type 2 (BSCL2), serves a critical but poorly defined function in the physiology of both adipose and neural tissue. In humans, BSCL2 loss-of-function mutations cause a severe form of lipodystrophy, whilst a distinct set of gain-of-toxic-function mutations are associated with a heterogeneous group of neuropathies. However, despite the importance of seipin dysfunction to the pathophysiology of these conditions, little is known about its physiological role in adipocytes or neurons. BSCL2 mRNA has previously been identified in human and mouse brain, yet no definitive assessment of its expression has been undertaken. Here we comprehensively characterised the neuroanatomical distribution of mouse Bscl2 using complementary in situ hybridisation histochemistry and immunohistochemistry techniques. Whilst Bscl2 was broadly expressed throughout the rostral-caudal extent of the mouse brain, it exhibited a discrete neuroanatomical profile. Bscl2 was most abundantly expressed in the hypothalamus and in particular regions associated with the regulation of energy balance including, the paraventricular, ventromedial, arcuate and dorsomedial nuclei. Bscl2 expression was also identified within the brainstem dorsal vagal complex, which together with the paraventricular nucleus of the hypothalamus represented the site of highest expression. Further neurochemical profiling of these two nuclei revealed Bscl2/seipin expression within energy balance related neuronal populations. Specifically, seipin was detected in oxytocin neurons of the paraventricular nucleus of the hypothalamus and in catecholamine neurons of the dorsal vagal complex. These data raise the possibility that in addition to its role in adipose tissue development, seipin may also be involved in the central regulation of energy balance.

Identification of a novel nonsense mutation and a missense substitution in the AGPAT2 gene causing congenital generalized lipodystrophy type 1

Congenital generalized lipodystrophy (CGL) is an autosomal recessive disease characterized by the generalized scant of adipose tissue. CGL type 1 is caused by mutations in gene encoding 1-acylglycerol-3-phosphate O-acyltransferase-2 (AGPAT2). A clinical and molecular genetic investigation was performed in affected and unaffected members of two families with CGL type 1. The AGPAT2 coding region was sequenced in index cases of the two families. The presence of the identified mutations in relevant parents was tested. We identified a novel nonsense mutation (c.685G>T, p.Glu229*) and a missense substitution (c.514G>A, p.Glu172Lys). The unaffected parents in both families were heterozygous carrier of the relevant mutation. The results expand genotype–phenotype spectrum in CGL1 and will have applications in prenatal and early diagnosis of the disease. This is the first report of Persian families identified with AGPAT2 mutations.

Diabetes lipoatrófica. Un reto terapéutico

Congenital generalised lipodystrophy is a rare autosomal recessive disorder characterised by a marked deficiency of adipose tissue and usually recognised at birth. This disorder is associated with early development of metabolic complications such as hypertriglyceridemia, hepatic steatosis, and insulin resistance. These complications ultimately lead to fatal events as a consequence of early atherosclerosis, lipoatrophic diabetes and hepatic cirrhosis. The authors report the case of a patient diagnosed, based on clinical and laboratory findings, in the first year of life. The established diagnosis was then confirmed by identifying a mutation in the BSCL2 gene. Because the hypertriglyceridemia and diabetes were refractory to treatment, the authors present this case in order to reflect on the best therapeutic management of this pathology.

Seipin: from human disease to molecular mechanism

The most-severe form of congenital generalized lipodystrophy (CGL) is caused by mutations in BSCL2/seipin. Seipin is a homo-oligomeric integral membrane protein in the endoplasmic reticulum that concentrates at junctions with cytoplasmic lipid droplets (LDs). While null mutations in seipin are responsible for lipodystrophy, dominant mutations cause peripheral neuropathy and other nervous system pathologies. We first review the clinical aspects of CGL and the discovery of the responsible genetic loci. The structure of seipin, its normal isoforms, and mutations found in patients are then presented. While the function of seipin is not clear, seipin gene manipulation in yeast, flies, mice, and human cells has recently yielded a trove of information that suggests roles in lipid metabolism and LD assembly and maintenance. A model is presented that attempts to bridge these new data to understand the role of this fascinating protein.

Diabetes Mellitus in Children and Adolescents with Genetic Syndromes

Several genetic syndromes are associated with diabetes mellitus (DM). This study aimed to analyse data from the DPV database with regard to frequency, treatment strategies and long-term complications in paediatric DM patients with genetic syndromes, including Turner syndrome (TS), Prader-Willi syndrome (PWS), Friedreich ataxia (FA), Alström syndrome (AS), Klinefelter syndrome (KS), Bardet-Biedl syndrome (BBS), Berardinelli-Seip syndrome (BSS) and Down syndrome (DS). Longitudinal data for 43 521 patients with DM onset at age < 20 years were collected from 309 treatment centres in Germany and Austria using the DPV software. Data included anthropometric parameters, type of diabetes, mean age, age at diabetes onset, daily insulin dose, HbA 1c , micro- and macroalbuminuria, retinopathy and dyslipidaemia. Descriptive statistics and standard statistical tests were used for data analysis. In total, 205 DM patients had one of the following syndromes: DS (141 patients), TS (24), PWS (23), FA (5), AS (5), KS (4), BBS (2) and BSS (1). Diabetes-specific antibodies were positive in the majority of patients with DS, TS and FA. Despite the well-known association between DM and certain syndromic disorders, the number of affected patients in the German and Austrian paediatric diabetic population is very low. Nevertheless, physicians should be aware of syndromic forms of diabetes. Joint multicentre analyses are needed to draw relevant conclusions.

Phenotypic heterogeneity in hereditary motor neuropathy type V: a new case report series

Previous studies have revealed a wide phenotypic heterogeneity in hereditary motor neuropathy type V in which upper and lower motor neurons and peripheral motor axons are variously affected, even within the same family. In this case series, we describe the genetic, clinical and electrophysiological features of patients belonging to a four-generation Italian family. Because of a possible anticipation phenomenon, the disorder became apparent at an earlier age as it passed to the next generation, with a median age of onset of 65years for the first 2 generations, 32 for the third, and 13.5 for the fourth. The symptoms at onset varied considerably among the sufferers, with a predominant impairment of the hands in seven cases, the impairment of the four limbs in one patient and only of the lower limbs in another. Also muscle atrophy was variable, from very mild to severe (wasting of the distal muscles of the limbs). Moreover, electrophysiological results were heterogeneous, including cases with isolated and with diffuse axonal motor neuropathy, and one case of motor sensory polyneuropathy. A novel polymorphism G→T was also found in the Berardinelli-Seip congenital lipodystrophy 2 gene on intron 4. This broad phenotypic and genotypic spectrum calls the clinician attention to this rare and still insufficiently known disease.

Delayed emergence from anesthesia in a child with congenital generalized lipodystrophy (Berardinelli–Seip syndrome)

Delayed emergence from anesthesia in a child with congenital generalized lipodystrophy (Berardinelli–Seip syndrome)

Overexpression of a short human seipin/BSCL2 isoform in mouse adipose tissue results in mild lipodystrophy

Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is a recessive disorder characterized by an almost complete loss of adipose tissue, insulin resistance, and fatty liver. BSCL2 is caused by loss-of-function mutations in the BSCL2/seipin gene, which encodes seipin. The essential role for seipin in adipogenesis has recently been established both in vitro and in vivo. However, seipin is highly upregulated at later stages of adipocyte development, and its role in mature adipocytes remains to be elucidated. We therefore generated transgenic mice overexpressing a short isoform of human BSCL2 gene (encoding 398 amino acids) using the adipocyte-specific aP2 promoter. The transgenic mice produced ∼150% more seipin than littermate controls in white adipose tissue. Surprisingly, the increased expression of seipin markedly reduced the mass of white adipose tissue and the size of adipocytes and lipid droplets. This may be due in part to elevated lipolysis rates in the transgenic mice. Moreover, there was a nearly 50% increase in the triacylglycerol content of transgenic liver. These results suggest that seipin promotes the differentiation of preadipocytes but may inhibit lipid storage in mature adipocytes.

Molecular characterization of seipin and its mutants: implications for seipin in triacylglycerol synthesis

The human lipodystrophy gene product Berardinelli-Seip congenital lipodystrophy 2/seipin has been implicated in adipocyte differentiation, lipid droplet (LD) formation, and motor neuron development. However, the molecular function of seipin and its disease-causing mutants remains to be elucidated. Here, we characterize seipin and its mis-sense mutants: N88S/S90L (both linked to motoneuron disorders) and A212P (linked to lipodystrophy) in cultured mammalian cells. Knocking down seipin significantly increases oleate incorporation into triacylglycerol (TAG) and the steady state level of TAG, and induces the proliferation and clustering of small LDs. By contrast, overexpression of seipin reduces TAG synthesis, leading to decreased formation of LDs. Expression of the A212P mutant, however, had little effect on LD biogenesis. Surprisingly, expression of N88S or S90L causes the formation of many small LDs reminiscent of seipin deficient cells. This dominant-negative effect may be due to the N88S/S90L-induced formation of inclusions where wild-type seipin can be trapped. Importantly, coexpression of wild-type seipin and the N88S or S90L mutant can significantly reduce the formation of inclusions. Finally, we demonstrate that seipin can interact with itself and its mutant forms. Our results provide important insights into the biochemical characteristics of seipin and its mis-sense mutants, and suggest that seipin may function to inhibit lipogenesis.

Progressive right lower extremity enlargement

The patient and clinicians were concerned about the right lower extremity when in fact MRI showed the diseased extremity to be the left. The MR images (Figs. 1 and 2) show loss of subcutaneous fat throughout the left lower extremity with relative sparing of the muscle mass and medial thigh subcutaneous fat, accounting for the asymmetric size of the lower extremities and the misleading clinical appearance of an abnormally enlarged right lower extremity. The MRI distribution of subcutaneous fat loss of the left extremity was felt to be consistent with the diagnosis of lipodystrophy and in this patient attributed to adult onset dermatomyositis, which has been previously associated with lipodystrophy [1–3]. In addition, increased T2 signal on the STIR sequence within the subcutaneous tissues, particularly overlying the lateral left leg are indicative of active disease. Lipodystrophies are a group of disorders characterized by the loss of adipose tissue from various parts of the body, and have been categorized as being congenital or acquired and further subcategorized as generalized, partial, or localized [4]. The generalized varieties include congenital generalized lipodystrophy (Berardinelli–Seip syndrome) and acquired generalized lipodystrophy. Berardinelli–Seip syndrome is a rare autosomal recessive disorder in which there is a complete absence of adipose tissue at birth, while acquired generalized lipodystrophy manifests in late childhood and adolescence. Partial lipodystrophies include familial partial lipodystrophy (Dunnigan variety), which presents at onset of puberty, and acquired forms, which have been linked to HIV, drug use, and various autoimmune diseases. Localized forms of lipodystrophy are most often related to trauma, drug use, and autoimmune causes [4]. Patients affected by lipodystrophy are predisposed to insulin resistance. The central cause of morbidity and mortality in patients with lipodystrophy are diabetes mellitus and its long-term complications, including recurrent pancreatitis related to hypertriglyceridemia, chronic liver disease related to hepatic steatosis, and atherosclerotic disease [5]. Acquired lipodystrophies are the most common subtype, with HIV lipodystrophy accounting for over 100,000 cases of lipodystrophy in the United States alone [5]. The typical pattern of HIV lipodystrophy is loss of subcutaneous fat in the face and extremities, with compensatory circumferential adipose deposition in the submental (double chin), dorsocervical spine (buffalo hump), chest, and intra-abdominal regions [6]. This is in contradistinction to acquired partial lipodystrophy (Barraquer–Simons syndrome) and acquired generalized partial lipodystrophy. Acquired partial lipodystrophy is very rare (250 cases in the English literature), and characterized by subcutaneous adipose loss involving the face, neck, arms, chest, and abdomen, with compensatory circumferential adipose deposition in the thighs and lower legs [5]. Acquired generalized lipodystrophy (80 reported cases in the English literature) is characterized by circumThe case question and presentation can be found at doi:10.1007/ s00256-011-1271-7.

Description of an AGPAT2 pathologic allelic variant in a 54-year-old Caucasian woman with Berardinelli-Seip syndrome

A 54-year-old Italian female patient was admitted to our Department with the diagnosis of type 2 diabetes poorly controlled with insulin therapy. The patient was born by consanguineous parents (first degree cousins); she had acromegaloid features, diffuse lipoatrophy and muscular pseudo-hypertrophy since childhood. To confirm the clinical hypothesis of congenital generalized lipodystrophy (CGL) or Berardinelli-Seip syndrome, the sequences of AGPAT2 (encoding for 1-acyl-sn-glycerol-3-phosphate acyltransferase beta) and BSCL2 (encoding for seipin) candidate genes were analyzed. DNA analysis showed the presence of a homozygous mutation in exon 3 of the AGPAT2 gene (P112L). This is the first description of a Caucasian subject with CGL who carries the pathologic allelic variant P112L of the AGPAT2 gene.

Serum retinol binding protein 4 is not decreased in congenital generalized lipodystrophy: a case series

Previous studies have suggested that Retinol Binding Protein 4 (RPB4), a protein produced by the adipose tissue, is associated with insulin resistance (IR). Congenital Generalized Lipodystrophy (CGL) is a rare disease characterized by IR and paucity of adipose tissue. Our objective was to determine RBP4 levels in patients with CGL. Six (6) patients with CGL and a healthy control group were selected to participate in the study. Anthropometric and biochemical variables were compared between groups. No difference was observed in RBP4 levels between the two groups (CGL 42.5 [12.5 - 127] vs. control 57.4 [15.9 - 165]; p = 0.78). On the other hand, leptin levels were significantly lower in CGL patients (CGL 0.65 [0.2 - 0.7] vs. control 10.9 [0.9 - 38.6]; p = 0.015). No correlation was found between RBP-4 and waist circunference (r = 0.18, p = 0.57), or BMI (r = 0.24, p = 0.45). RBP4 is not decreased in CGL. These results suggest that adipose tissue may not be the main source of RBP4.

Seipin ablation in mice results in severe generalized lipodystrophy

Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is an autosomal recessive disorder characterized by an almost complete loss of adipose tissue, insulin resistance and fatty liver. Here, we create the first murine model of BSCL2 by targeted disruption of seipin, the causative gene for BSCL2. Compared with their wild-type littermates, the seipin(-/-) mice are viable and of normal weight but display significantly reduced adipose tissue mass, hepatic steatosis, glucose intolerance and hyperinsulinemia. The levels of leptin and adiponectin were both significantly decreased in seipin(-/-) mice, so were non-esterified fatty acids upon fasting. Surprisingly, however, hypertriglyceridemia which is common in human BSCL, was not observed in seipin(-/-) mice. Our findings suggest a possible tissue-autonomous role of seipin in liver lipid storage. The availability of the seipin(-/-) mice should help elucidate the molecular function of seipin and lead to a better understanding of the many metabolic consequences of human BSCL2.

Tissue-Autonomous Function of Drosophila Seipin in Preventing Ectopic Lipid Droplet Formation

Obesity is characterized by accumulation of excess body fat, while lipodystrophy is characterized by loss or absence of body fat. Despite their opposite phenotypes, these two conditions both cause ectopic lipid storage in non-adipose tissues, leading to lipotoxicity, which has health-threatening consequences. The exact mechanisms underlying ectopic lipid storage remain elusive. Here we report the analysis of a Drosophila model of the most severe form of human lipodystrophy, Berardinelli-Seip Congenital Lipodystrophy 2, which is caused by mutations in the BSCL2/Seipin gene. In addition to reduced lipid storage in the fat body, dSeipin mutant flies accumulate ectopic lipid droplets in the salivary gland, a non-adipose tissue. This phenotype was suppressed by expressing dSeipin specifically within the salivary gland. dSeipin mutants display synergistic genetic interactions with lipogenic genes in the formation of ectopic lipid droplets. Our data suggest that dSeipin may participate in phosphatidic acid metabolism and subsequently down-regulate lipogenesis to prevent ectopic lipid droplet formation. In summary, we have demonstrated a tissue-autonomous role of dSeipin in ectopic lipid storage in lipodystrophy.

Further evidence for a marfanoid syndrome with neonatal progeroid features and severe generalized lipodystrophy due to frameshift mutations near the 3′ end of the FBN1 gene

We report on a 20-year-old man who presented in infancy with severe generalized lipodystrophy with a progeroid appearance and some Marfanoid features. He subsequently was diagnosed with bilateral lens subluxations at the age of 16 years which prompted analysis of the FBN1 gene. This analysis showed him to have a novel heterozygous, de novo, c.8156_8175del, p.Lys2719ThrfsX12, frameshift mutation in exon 64 of his FBN1 gene. His phenotype is similar to a patient described by Graul-Neumann et al. [2010] who was found to have a de novo, heterozygous, c.8155_8156del deletion in exon 64 of FBN1. Both mutations result in a truncated protein with an extremely charged C-terminus, containing two positive and four negative charges in the last eight amino acids. This most likely has a profound impact on protein–protein interactions, which are very important in the extracellular matrix. The similarities in the phenotypes, and overlapping molecular defects, provides further evidence that the phenotype with features of Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy is a distinct clinical entity due to frameshift mutations in exon 64 of the FBN1 gene.