Phenotypic and Genetic Heterogeneity in Congenital Generalized Lipodystrophy

Abstract

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.

Metreleptin for metabolic disorders associated with generalized or partial lipodystrophy

“…Affected subjects have extreme paucity of adipose tissue from birth leading to a muscular appearance, with prominent veins and an acromegaloid appearance. Subtle differences in pattern of fat loss have been recognized among the different subtypes of CGL [7], but common features include severe acanthosis nigricans, hepatosplenomegaly and early onset of diabetes, hypertriglyceridemia and steatohepatitis [8]. Marked hypoleptinemia is a universal feature of this disease [9].…”

Genetic basis of congenital generalized lipodystrophy

“…As shown in Figure 1a, various AGPAT2 mutations, including null, splice-site, frame-shift, insertion and deletion, have been found in several affected subjects. [5][6][7][8] The IVS4-2A4G mutation was found to recur in pedigrees of African origin and the chromosomes carrying it had the same haplotype for seven SNPs within and around AGPAT2, indicating that this mutation is of ancestral origin. 5 AGPAT2, a 278 amino-acid protein, catalyses an essential acylation reaction in the biosynthesis of all glycerophospholipids and TG in eukaryotes (Figure 1b).…”

Clinical Utility Gene Card for: Congenital Generalized Lipodystrophy

“…2 The following molecular defects have been reported: nonsense, missense, splice-site variants, deletions and insertions. 3 Most of them result in frameshift and/or truncated proteins, which are likely to lead to the complete loss of AGPAT2 function. This can be demonstrated in vitro by measurement of AGPAT2 enzymatic activity.…”

“…The following molecular defects have been reported: nonsense, missense, splice-site variants, deletions and insertions. 3,5 Most of them result in frameshift and/or truncated proteins, which are likely to lead to complete loss of BSCL2 function (for more details, see http://databases.lovd.nl/shared/variants/ BSCL2/unique). Notably, disease-causing variants in this gene have also been identified in patients with distal hereditary motor neuropathies or neurodegenerative syndromes.…”

“…Molecular testing of AGPAT2 and BSCL2 explain more than 95% of cases, 3 whereas CAV1 and PTRF explain very few of them. When genetic testing is negative in a patient with symptoms evocative of CGL, differential diagnoses can be considered (please see section 3.1).…”