Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia. A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity. Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway). We identified a new disease locus, designated BSCL2, within the 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13. Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34. Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), gamma3-linked gene (Gng3lg) in all BSCL2-linked families. BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function. Most of the variants are null mutations and probably result in a severe disruption of the protein. These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.
Generalised lipodystrophy of the Berardinelli-Seip type (BSCL) is a rare autosomal recessive human disorder with severe adverse metabolic consequences. A gene on chromosome 9 (BSCL1) has recently been identified, predominantly in African-American families. More recently, mutations in a previously undescribed gene of unknown function (BSCL2) on chromosome 11, termed seipin, have been found to be responsible for this disorder in a number of European and Middle Eastern families. We have studied the genotype/phenotype relationships in 70 affected subjects from 44 apparently unrelated pedigrees of diverse ethnic origin. In all subjects, hepatic dysfunction, hyperlipidaemia, diabetes mellitus, and hypertrophic cardiomyopathy were significant contributors to morbidity with no clear differences in their prevalence between subjects with BSCL1 or BSCL2 and those with evidence against cosegregation with either chromosome 9 or 11 (designated BSCLX). BSCL2 appears to be a more severe disorder than BSCL1 with a higher incidence of premature death and a lower prevalence of partial and/or delayed onset of lipodystrophy. Notably, subjects with BSCL2 had a significantly higher prevalence of intellectual impairment than those with BSCL1 or BSCLX (p<0.0001, OR 17.0, CI 3.6 to 79.0). The higher prevalence of intellectual impairment and the increased risk of premature death in BSCL2 compared to BSCL1 emphasise the importance of molecular diagnosis of this syndrome and have clear implications for genetic counselling.
Seip M, Trygstad 0. Generalized lipodystrophy, congenital and acquired (lipoatrophy) Acta Pediatr 1996; Suppl413:2-28. Stockholm. ISSN 0803-5326 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. 0 Acanthosis nigricans. anabolic syndrome, generalized lipodvstrophy, h~vpermetaholism, hypertrophic cardiomyopathy , lipoatrophic diabetes 0 Trygstad, Department of Paediatrics, Rikshospitalet. N-0027 Oslo, Norway cr) Scandinavian University Press 1996. ISSN 0803-5253 Generu1i:ed lipodwtrophy 3 ACTA PEDIATR SUPPL 413 (1W6) Tuhle 1. Main clinical features in generalized lipodystrophy. Congenital type ( Berurdinelli-Seip syndrome) 1. 2. 3. 4. 5. 6. 7. Extreme paucity of fat in subcutaneous and other adipose tissues, with insulin resistance, hyperinsulinaemia, hypertriglyceridaemia, and non-ketotic diabetes Voracious appetite and hypermetabolism, hyperhidrosis An anabolic syndrome with increased height velocity, advanced bone age. muscular hypertrophy, masculine body build, acromegaloid stigmata, organomegaly, enlarged genitalia in infancy, abundant hair of the scalp, hypertrichosis Hypertrophic cardiomyopathy (serious) Acanthosis nigricans Often mild mental retardation Hypothalamic-pituitary dysfunction Acquired type (Seip-Lowrence svndronte)
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