ESPE Abstracts

Lipodystrophy syndromes are a heterogeneous cluster of complex, life-threatening, rare diseases associated with reduced levels of leptin and include Congenital Generalized Lipodystrophy (CGL). Patients are at significant risk of developing metabolic problems that include elevated triglycerides, severe insulin resistance, and impaired glycemic control, and abnormalities in multiple organs. We report a case of 16-year-old Emirati female with CGL with special focus on reversal of metabolic abnormalities by metreleptin (a synthetic analog of the hormone leptin). She was diagnosed with CGL in early childhood based on clinical signs (scant subcutaneous fat, prominent muscles, large jaw, hands and feet, acanthosis and hirsutism) and genetic testing revealed pathological homozygous mutation AGPAT2, c.158del p.(Gly53Alafs*8). She had normal growth throughout childhood (weight and BMI ranged between 50^th and 75^th centile). Laboratory studies before the age of 13 revealed normal glucose profile, HbA1C, insulin levels, liver enzymes, HDL and LDL cholesterol. Triglycerides were mildly elevated (1.65-3.02 mmlol/l). At age 14 years, she developed severe acanthosis, diabetes, further rise in triglycerides, elevated liver enzymes and fatty liver disease. Diabetes was initially controlled with low dose insulin, but she developed severe insulin resistance within few months with worsening glycemic control resulting insulin requirement reaching 180 units daily (3.6U/kg/day). Despite receiving Fenofibrate 145 mg daily, triglycerides remained high. Within a few days of initiating metreleptin 5 mg subcutaneous injection (q.d.), a significant reduction in glucose levels and insulin requirement was observed. Insulin Lispro was stopped within 3 days and insulin Lantus dose was tapered rapidly to 5 units daily and then stopped 3 months later. After stopping insulin, her blood glucose remained normal with fasting glucose ranging between 3.9-5.6 mmol /L and post-prandial below 7.5 mmol/l. Eight months after stopping insulin, HbA1C was 5.2% pre-metreleptin. Triglyceride level ranged 4.09-7.48 mmol/l in the 6 months pre-metreleptin and dropped to 1.41 three-months post-metreleptin. Triglyceride level was 3.02, 1.84 and 1.42 after 1, 4 and 9 months, respectively, after stopping Fenofibrate. AST ranged 41-59 IU/L and ALT 57-81 IU/L pre-metreleptin treatment. AST and ALT normalized within 3 months after treatment and remained normal 1 year later (AST 12-16 IU/L and ALT 5-14 IU/L). The patient had complete reversal of hyperglycemia and hypertriglyceridemia and normalization of hypertransaminasemia with metreleptin monotherapy. The normalization of liver enzymes is promising for possible long-term prevention of liver cirrhosis, a serious and potentially fatal complication of severe fatty liver disease.