Abstract
Phenotypic heterogeneity is a well-known feature of Familial Partial Lipodystrophy Type 2 (FPLD2) which is caused by pathogenic variants in the LMNA gene. Clinical diagnosis can be challenging in some cases. Likewise, trained physicians can report differences in body composition and clinical manifestation of FPLD2, highlighting the importance of accurate phenotyping. In this study, we aimed to identify phenotype-genotype correlations in a cohort of systematically evaluated patients with FPLD2. We retrospectively evaluated 43 patients diagnosed with FPLD2 (age 50.3±16.1 years, 79.1% women). Per pathogenic variants, patients were divided into two groups; 24 with R482Q (RQ: 55 ± 3.2 years, 70.8% women) and 19 with non-R482Q (Non-RQ: 46 ± 3.2 years, 84.2% women). Non-RQ group consisted of several pathogenic LMNA variants in exons 1, and 5 through 11. Also, DEXA parameters were studied in a subgroup of 19 patients with available assessments (in 11 RQ and 8 non-RQ patients) that were matched for age, sex and BMI. Patients in the RQ group were older when they were first diagnosed with lipodystrophy (48.6 ± 3.2 years and 37.4 ± 3.1 years, p = 0.03). Although the prevalence of diabetes, hepatic steatosis and other co-morbidities associated with metabolic control were similar in both groups at the time of the study, patients with RQ pathogenic variants were diagnosed later in life with diabetes (46.0 ± 4.2 years vs. 35 ± 3.5 years, p = 0.03) and hepatic steatosis (45.3 ± 6.9 years vs. 30.1 ± 3.7 years, p < 0.01. Although more pancreatitis episodes were reported in the RQ group (13 ± 3 vs. 2 ± 1, p = 0.02), the number of patients with a history of pancreatitis was similar across the groups suggesting the occurrence of recurrent pancreatitis episodes in selected patients with RQ pathogenic variant. Pain was a common complaint among the patients, but it was less severe in the RQ group (4.2±2.1 vs 2.3±2.0, p=0.05). In terms of body composition, patients with RQ pathogenic variants had greater bone mass (legs: 879 ± 59.3 g vs. 703.5 ± 33.7 g, p= 0.01; trunk 914.2 ± 65.5 g vs. 674.1 ± 28.0 g, p = 0.005, total body: 2643.7 ± 158.9 g vs. 2140.6 ± 78.4 g, p = 0.005) and higher fat mass in the legs (19 vs. 14%, p = 0.02). Similarly, patients with RQ pathogenic variants had less lean percentage (76 vs. 81%, p = 0.009), and accordingly, less fat-free mass percentage (80 vs. 85%, p = 0.02) in the legs. Total fat-free mass of the RQ group was also lower (66 vs. 76%, p = 0.0009). Genotype-phenotype characterization is important not only for understanding the natural history and clinical manifestation of the disease but also for establishing more accurate and precise diagnostic criteria or therapeutic approaches. Our data suggest more fat preservation in LMNA R482Q carriers, presumably leading to a later diagnosis of lipodystrophy and metabolic abnormalities. More studies are needed to confirm the differences observed in body composition.
Variable Expressivity in Type 2 Familial Partial Lipodystrophy Related to R482 and N466 Variants in the LMNA Gene
