Unusual Presentations of LMNA-Associated Lipodystrophy with Complex Phenotypes and Generalized Fat Loss: When the Genetic Diagnosis Uncovers Novel Features

Abstract

Objective: Lipodystrophy represents a group of rare diseases characterized by loss of body fat. While patients with generalized lipodystrophy exhibit near-total lack of fat, partial lipodystrophy is associated with selective fat loss affecting certain parts of the body. Although classical familial partial lipodystrophy (FPLD) is a well-described entity, recent reports indicate phenotypic heterogeneity among carriers of LMNA pathogenic variants. Methods: We have encountered 2 unique cases with complex phenotypes, generalized fat loss, and very low leptin levels that made the distinction between generalized versus partial lipodystrophy quite challenging. Results: We present a 61-year-old female with generalized fat loss, harboring the heterozygous pathogenic variant p.R541P (c.1622G>C) on the LMNA gene. The discovery of the pathogenic variant led to correct clinical diagnosis of her muscle disease, identification of significant heart disease, and a recommendation for the implantation of a defibrillator. She was able to start metreleptin based on her generalized fat loss pattern and demonstration of the genetic variant. Secondly, we report a 40-year-old Turkish female with generalized fat loss associated with a novel heterozygous LMNA pathogenic variant p.K486E (c.1456A>G), who developed systemic B cell follicular lymphoma. Conclusion: Clinicians need to recognize that the presence of an LMNA variant does not universally lead to FPLD type 2, but may lead to a phenotype that is more complex and may resemble more closely generalized lipo-dystrophy. Additionally, providers should recognize the multisystem features of laminopathies and should screen for these features in affected patients, especially if the variant is not at the known hotspot for FPLD type 2.

Clinical features of generalized lipodystrophy in Turkey: A cohort analysis

“…Classical forms of congenital generalized lipodystrophy (CGL) are caused by genetic mutations in the AGPAT2 (CGL1), BSCL2 (CGL2), CAV1 (CGL3) and CAVIN1/PTRF (CGL4) genes 2 . Additional genes have also been associated with generalized adipose tissue loss 3‐6 . These classical cases of CGL develop fat loss from birth.…”

“…2 Additional genes have also been associated with generalized adipose tissue loss. [3][4][5][6] These classical cases of CGL develop fat loss from birth. Consanguinity is a common finding.…”

A 20-year Clinical and Genetic Neuromuscular Cohort Analysis in Lebanon: An International Effort

“…A Lebanese family was reported with MDDGA12 (MIM# 615249), associated with homozygous mutations in the POMK gene [58]. Additionally, heterozygous LMNA variants were associated with cardiomyopathy and with Emery-Dreifuss Muscular Dystrophy 2 [59,60].…”

Obesity and Risk for Lymphoma: Possible Role of Leptin

“…Metreleptin is a human leptin analog for the treatment of metabolic pathologies, such as acquired generalized lipodystrophy (AGL) [ 231 ]. Although AGL is associated per se with a high risk of lymphoma [ 232 ], metreleptin may accelerate that risk since AGL patients have been reported to develop NHL during metreleptin treatment, including peripheral TCL and ALK-positive ALCL [ 233 ] and may also jeopardize the recurrence of lymphoma [ 234 ], although further research is needed in this sense to completely confirm this statement.…”