MON-203 - Metreleptin Use in Identical Twins with Generalized Congenital Lipodystrophy with POLD1 Mutation

Background: Metreleptin is commonly used to treat complications of leptin deficiency in generalized lipodystrophy (GL). However, its use in individuals with GL caused by POLD1 mutation remains undocumented and we describe the first cases of Metreleptin use in GL from POLD1 mutation.

Clinical

Case: Identical 15-year-old twin brothers were identified with POLD1 mutation following their mother's diagnosis of the same genetic alteration in adulthood. The mother experienced severe complications of GL from diabetes mellitus and hypertriglyceridemia. Both twins exhibited mandibular hypoplasia, progeroid facial features, bilateral deafness, and marked loss of subcutaneous fat, particularly in the limbs and submaxillary region. Additionally, both exhibited hyperglycemia symptoms, including polyuria, polydipsia, and nocturia, as well as clinical findings of hypogonadism with pre-pubertal testes ( < 1cc). Initial laboratory evaluation revealed elevated LH (Twin A: 12.69 mIU/mL; Twin B: 14.50 mIU/mL), elevated FSH (Twin A: 38.04 mIU/mL; Twin B: 39.96 mIU/mL), below normal total testosterone for age (Twin A: 79 ng/dL; Twin B: 65 ng/dL), elevated HbA1c (Twin A: 5.8%; Twin B: 5.8%), and low leptin (Twin A: 0.9 ng/mL; Twin B: 2.4 ng/mL). Twin A had a normal lipid profile and hepatic function, whereas Twin B demonstrated dyslipidemia with elevated total cholesterol (209 mg/dL), triglycerides (276 mg/dL), LDL cholesterol (118 mg/dL), and elevated ALT (35 U/L) and AST (40 U/L). Both patients received counseling on lifestyle modifications to prevent further deterioration of metabolic parameters.

At the 3-month follow-up, both twins initiated testosterone supplementation 50 mg monthly for hypergonadotropic hypogonadism and Metreleptin (synthetic leptin analog) at 43 units (2.1mg) daily (Twin A) and 42 units (2.1mg) daily (Twin B) to promote subcutaneous fat accumulation and prevent further metabolic complications. After five months of Metreleptin therapy, Twin A showed no significant increase in subcutaneous fat but achieved normalization of HbA1c (5.6%) and maintained normal lipid and hepatic profiles. In contrast, Twin B gained about 12 pounds, maintained a normal HbA1c (5.6%), and demonstrated improvements in total cholesterol (163 mg/dL), triglycerides (176 mg/dL), LDL cholesterol (88 mg/dL), and normalization of liver enzymes (ALT: 13 U/L; AST: 16 U/L). Both twins developed facial hair and deepened voices following testosterone supplementation. Despite these changes, physical examination continued to reveal pre-pubertal testes ( < 3cc) and persistently low testosterone levels, necessitating an increase in testosterone administration frequency to 50 mg every two weeks.

Conclusion: Metreleptin may be effective in restoring subcutaneous fat and preventing or reversing metabolic complications in individuals with generalized congenital lipodystrophy due to POLD1 mutation.

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