Genetic lipodystrophies are a heterogeneous group of autosomal dominant and recessive disorders characterized by generalized or partial loss of body fat. Most patients with familial partial lipodystrophy (FPLD) have dominant inheritance with heterozygous pathogenic missense variants in LMNA. Here, we report two females with rare biallelic variants in LMNA presenting with divergent lipodystrophic phenotypes. Proband 1, a 32-year-old female, has near-generalized lipodystrophy (body fat 12.7%) due to compound heterozygous c.1745G>T (p.R582L) and c.1750C>T (p.R584C) LMNA variants. She was diagnosed with diabetes at age 17, hypertriglyceridemia at age 18, and metabolic dysfunction-associated steatotic liver disease (MASLD) at age 20. She was treated with metreleptin with only partial improvement in metabolic parameters. Her parents, heterozygous carriers of these variants, did not have lipodystrophy. Proband 2, a 35-year-old female, has partial lipodystrophy (body fat 21.2%) due to a homozygous c.1750C>T (p.R584C) LMNA variant. She was diagnosed with diabetes at age 19 and had a history of hypertriglyceridemia and mild hepatic steatosis. Her parents reportedly did not have lipodystrophy. These cases highlight the expression of LMNA variants in the homozygous or compound heterozygous state, manifesting in near-generalized and partial loss of body fat with distinct phenotypic heterogeneity.
Hwang et al. (Wed,) studied this question.