Oral, Elif A

Abstract Context Lipodystrophy syndromes are rare disorders characterized by deficient adipose tissue, leading to insulin resistance, dyslipidemia, and organ system abnormalities. Objective Our goal was to develop a lipodystrophy severity score (LDS) to holistically capture the diverse manifestations of lipodystrophy into a numerical score to aid in prediction of clinical outcomes and/or treatment impact. Design An 8-domain LDS was developed by 8 disease experts in consultation with patient organizations. The LDS was rated for feasibility and content validity by 28 additional clinicians and 9 patient representatives. LDS was compared to the Clinical Global Impression (CGI) of severity for 20 putative patient profiles, each at 2 different time points, and by comparing change in LDS to global impression of change. For external validation, LDS was calculated in 2 cohorts of patients with lipodystrophy treated with metreleptin. Results LDS domains include Diabetes/Insulin Resistance, Microvascular Complications of Diabetes, Lipids, Cardiovascular, Liver, Kidney, Reproductive, and Other. Each domain is assessed by 1 or more questions assessing both lifetime and recent complications of lipodystrophy. The LDS had high content validity and feasibility and high reliability by intraclass correlation coefficients (>0.95). Global and domain-specific LDS were strongly correlated with CGI, as were changes in scores across visits (R = 0.79-0.99, P < .001 for all). In generalized lipodystrophy, metreleptin significantly reduced LDS (from 46 to 26 at 12 months, P < .001). The reductions were smaller in partial lipodystrophy (from 65 to 61 at 12 months, P = .04). Conclusion The LDS can reflect the severity of diverse manifestations of lipodystrophy and monitor changes following interventions.

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.