Pediatric Endocrinology and Diabetes Unit, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, 6 Weizmann St, 64239-06, Tel Aviv, Israel.
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Acta Diabetol. 2023 Aug;60(8):1099-1108. doi: 10.1007/s00592-023-02109-9. Epub 2023 May 9.
Implementing genetic analyses have unraveled rare alterations causing early-onset obesity and complications, in whom treatment is challenging. We aimed to report on the effects of adjuvant off-label therapy with liraglutide, glucagon-like peptide-1 analogue (GLP-1a), in rare genetic diagnoses.
Case scenarios and review of the literature.
Case 1: Nine-year-old boy with early-onset severe obesity and nonalcoholic fatty liver disease (NAFLD) due to a homozygous mutation in the MC4R gene deteriorated under lifestyle change and metformin therapy [at 10.5 years: body mass index (BMI) 51.2kg/m, 226% of the 95th percentile, fat percentage (FP) 65% and muscle-to-fat ratio (MFR) z-score of -2.41]. One year of liraglutide treatment halted progressive weight gain [BMI 50.3kg/m, 212% of the 95th percentile, 63.7% FP and MFR z-score of -2.34], with biochemical improvement. Case 2: Twelve-year-old boy with obesity presented with diabetes and progressive NAFLD. Exome analysis revealed two heterozygous mutations compatible with monogenic diabetes (HNF1A) and familial hypercholesterolemia (LDLR). Lifestyle modifications resulted in clinical and laboratory improvement (BMI 87th percentile, 32.8% FP, MFR z-score of -1.63, HbA1c 5.5%) without the expected recovery in liver transaminases. Liraglutide treatment augmented the improvement in weight status (BMI 68th percentile, 22.6% FP, MFR z-score of -1.13) with normalization of liver transaminases. Case 3: Nineteen-year-old male with spinal muscular atrophy type 3 presented with sarcopenic obesity and comorbidities. Treatment strategy included dietary counseling and multiple drug therapies (metformin, anti-hypertensive and statins). Liraglutide therapy led to a gradual recovery of metabolic complications allowing tapering-down other medications.
Considering the pleiotropic effects of GLP1-a beyond BMI reduction, this treatment modality may serve as a game changer in challenging cases.
实施基因分析揭示了导致早发性肥胖和并发症的罕见改变，这些疾病的治疗具有挑战性。我们旨在报告罕见遗传诊断中辅助标签外治疗用利拉鲁肽、胰高血糖素样肽-1 类似物 (GLP-1a) 的效果。
病例情况和文献复习。
病例 1：一名 9 岁男孩因 MC4R 基因纯合突变导致早发性严重肥胖和非酒精性脂肪性肝病 (NAFLD)，生活方式改变和二甲双胍治疗后病情恶化[10.5 岁时：体重指数 (BMI) 51.2kg/m，第 95 百分位的 226%，脂肪百分比 (FP) 65%和肌肉与脂肪比 (MFR) z 评分为-2.41]。利拉鲁肽治疗 1 年停止了体重的持续增加[BMI 50.3kg/m，第 95 百分位的 212%，FP 为 63.7%，MFR z 评分-2.34]，生化指标得到改善。病例 2：一名 12 岁肥胖男孩出现糖尿病和进行性 NAFLD。外显子分析显示两个杂合突变与单基因糖尿病 (HNF1A) 和家族性高胆固醇血症 (LDLR) 相容。生活方式改变导致临床和实验室改善 (BMI 第 87 百分位，FP 为 32.8%，MFR z 评分-1.63，HbA1c 5.5%)，但预期的肝转氨酶恢复没有发生。利拉鲁肽治疗增强了体重状况的改善 (BMI 第 68 百分位，FP 为 22.6%，MFR z 评分-1.13)，同时肝转氨酶恢复正常。病例 3：一名 19 岁男性患有 3 型脊髓性肌萎缩症，表现为肌少症性肥胖和合并症。治疗策略包括饮食咨询和多种药物治疗 (二甲双胍、抗高血压药和他汀类药物)。利拉鲁肽治疗导致代谢并发症逐渐改善，从而减少了其他药物的使用。
鉴于 GLP1-a 的多效作用超出了 BMI 降低的范围，这种治疗方式可能成为挑战性病例的改变游戏规则者。
