Endocrine Abstracts

Introduction: Mutations of the LMNA gene cause a wide range of diseases including lipodystrophy, myopathy [including dilated cardiomyopathy (DCM)], neuropathy and progeroid syndrome, and are collectively known as A-type laminopathies.

Case report: A 51-year-old Caucasian male with history of heart, liver and kidney transplants was referred for evaluation and treatment of post-transplant diabetes. He was diagnosed with hypertriglyceridemia at age 38. At 43, he was diagnosed with idiopathic cardiomyopathy. Subsequently, he developed liver failure that was presumed to be secondary to passive congestion from heart failure. He underwent simultaneous heart and liver transplants at 44. By age 51, he developed end stage renal disease, treated with hemodialysis prior to recent renal transplant. He developed post-transplant diabetes and endocrine consult was requested. He was noted to be extremely thin with BMI 17.4 kg/m² (weight=130 lbs, height=6′1″), with generalized lipodystrophy including face, trunk and extremities. Diabetes was managed with a basal/bolus insulin regimen requiring approximately 1.8 units of insulin/kg to control hyperglycemia suggesting severe insulin resistance. Laboratory evaluation was notable for leptin of 2.5 ng/ml (0.3–13.4). Genetic testing revealed a heterozygous LMNA gene missense mutation (c.1045 C>T; p. Arg349Trp). Since identification of the mutation, metformin was added to the insulin with the goal of improving insulin resistance.

Discussion: To date, 19 additional patients have been reported with the c.1045C>T LMNA mutation identified in our patient, including a family with 16 affected members, of whom 4 had renal disease. Patients with c.1045C>T mutations have partial lipodystrophy of the non-Dunnigan type (affecting face and extremities), with the exception of one with Dunnigan-type. In the 19 patients, DCM was noted in less than half and elevated creatine kinase, with or without clinical signs of myopathy, was also noted. Less than half had overt diabetes and at least one had euglycemic insulin resistance. The c.1045 C>T variant was not observed in the NHLBI Exome sequencing project, 1000 Genomes Project or Exome Aggregation Consortium database; however the p.Arg349Trp substitution has been identified in patients with skeletal, cardiac and metabolic phenotypes. Collective evidence supports c.1045 C>T as a likely pathogenic variant for an A-type laminopathy and the multiorgan failure seen in our patient. Multiorgan failure should alert endocrinologists of the possibility of LMNA mutation.