Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas.
Division of Pediatric Endocrinology, Department of Pediatrics, Center for Human Nutrition, UT Southwestern Medical Center, Dallas, Texas.
J Clin Endocrinol Metab. 2018 Mar 1;103(3):1005-1014. doi: 10.1210/jc.2017-02078.
Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNA p.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome.
We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNA p.T10I mutation and compare their clinical and metabolic features with other patients with APS.
Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-density lipoprotein cholesterol levels. Prominent clinical features included mottled skin pigmentation, joint contractures, and cardiomyopathy resulting in cardiac transplants in three patients at ages 13, 33, and 47 years. Seven patients received metreleptin therapy for 0.5 to 16 years with all, except one noncompliant patient, showing marked improvement in metabolic complications.
Patients with the heterozygous LMNA p.T10I mutation have distinct clinical features and significantly worse metabolic complications compared with other patients with APS as well as patients with Hutchinson-Gilford progeria syndrome. We propose that they be recognized as having generalized lipodystrophy-associated progeroid syndrome. Patients with generalized lipodystrophy-associated progeroid syndrome should undergo careful multisystem assessment at onset and yearly metabolic and cardiac evaluation, as hyperglycemia, hypertriglyceridemia, hepatic steatosis, and cardiomyopathy are the major contributors to morbidity and mortality.
核纤层蛋白 A/C（LMNA）基因突变导致一组异质性的早老性疾病，包括亨廷顿病样 2 型、颌骨面骨发育不全症和非典型早老性综合征（APS）。在之前报道的 31 例 APS 患者中，有 5 例存在反复发生的新异质 LMNA p.T10I 突变。这 5 例患者均存在全身性脂肪营养不良，以及相似的代谢和临床特征，提示存在一种独特的早老性综合征。
我们报告了 9 例新患者，并对之前报道的 2 例具有杂合性 LMNA p.T10I 突变的患者进行了随访，并将其临床和代谢特征与其他 APS 患者进行了比较。
与其他 APS 患者相比，具有杂合性 LMNA p.T10I 突变的患者年龄更小，但全身性脂肪营养不良、糖尿病、黑棘皮病、高三酰甘油血症和肝肿大的患病率更高，同时空腹血清胰岛素和三酰甘油水平更高，血清瘦素和高密度脂蛋白胆固醇水平更低。突出的临床特征包括斑驳的皮肤色素沉着、关节挛缩和心肌病，导致 3 例患者在 13、33 和 47 岁时进行心脏移植。7 例患者接受 metreleptin 治疗 0.5 至 16 年，除 1 例不依从的患者外，所有患者的代谢并发症均显著改善。
与其他 APS 患者以及亨廷顿病样 2 型患者相比，具有杂合性 LMNA p.T10I 突变的患者具有独特的临床特征和明显更严重的代谢并发症。我们建议将其识别为具有全身性脂肪营养不良相关早老性综合征。具有全身性脂肪营养不良相关早老性综合征的患者应在发病时进行仔细的多系统评估，并每年进行代谢和心脏评估，因为高血糖、高三酰甘油血症、肝脂肪变性和心肌病是导致发病率和死亡率的主要原因。
