Metreleptin improves glucose metabolism and hepatic steatosis in a patient with Werner syndrome and partial lipodystrophy: a case report with review of literature

Werner syndrome (WS) is a rare autosomal recessive progeroid disorder caused by mutations in the WRN gene and is characterized by distinctive physical features and metabolic complications, including insulin resistance, diabetes, hypertriglyceridemia, and hepatic steatosis. Although lipodystrophy is a recognized component of WS, clinical reports of metreleptin use in this setting remain very limited. We report the case of a 38-year-old woman with WS complicated by partial lipodystrophy, diabetes with suboptimal glycemic levels, hypertriglyceridemia and severe hepatic steatosis. She presented with distal limb lipoatrophy, a bird-like facial appearance, premature hair graying, and cataracts. Genetic testing identified two pathogenic WRN variants (c.1105C>T and c.3446del) resulting in premature protein termination, confirming the diagnosis. At baseline, hemoglobin A1c (HbA1c) was 8.6% despite insulin and oral hypoglycemic agents, and imaging demonstrated hepatomegaly with marked steatosis. Metreleptin therapy was initiated and titrated. Over 26 weeks, HbA1c improved to 7.4% and the visceral-to-subcutaneous fat ratio decreased, accompanied by reduction in liver transaminases, cholestatic enzymes, and imaging-based indices of hepatic steatosis, liver stiffness, and liver volume. To date, only three cases of WS treated with metreleptin, including ours, have been reported. While glycemic improvement is consistent with prior reports, our case additionally demonstrated improvements in hepatic steatosis across biochemical, and imaging parameters. These findings suggest that metreleptin may improve both glucose metabolism and hepatic steatosis in WS-associated lipodystrophy. Further accumulation of cases is essential to clarify its role in the management of WS.