A Novel Generalized Lipodystrophy-Associated Progeroid Syndrome Due to Recurrent Heterozygous LMNA p.T10I Mutation
A Novel Generalized Lipodystrophy-Associated Progeroid Syndrome Due to Recurrent Heterozygous LMNA p.T10I Mutation
复制标题
DOI：
10.1210/jc.2017-02078
复制
发表时间：
2018-03-01
影响因子：
5.8
通讯作者：
Garg, Abhimanyu
中科院分区：
文献类型：
--
作者：
Hussain, Iram;Patni, Nivedita;Garg, Abhimanyu
背景资料：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Hutchinson-Gilford早老综合征、下颌骨肢端发育不良和非典型早老性综合征（APS）。先前报告的31例APS患者中，有5例携带复发性新发杂合子LMNA p.T10I突变。所有五个广泛的脂肪营养不良，以及类似的代谢和临床特征，表明一个独特的progeroid syndrome.Methods：我们报告了9个新的患者和后续的两个先前报告的患者与杂合子LMNA p.T10I突变，并比较他们的临床和代谢特征与其他患者与APS。与其他APS患者相比，携带杂合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、高脂血症和肝肿大的患病率增加，以及较高的空腹血清胰岛素和甘油三酯水平和较低的血清瘦素和高密度脂蛋白胆固醇水平。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名年龄分别为13岁、33岁和47岁的患者接受心脏移植。7例患者接受metreleptin治疗0.5至16年，所有，除了一个不符合患者，表现出显着的改善代谢complications.Conclusions：杂合子LMNA p.T10I突变的患者有不同的临床特征和显着恶化的代谢并发症相比，其他患者与APS以及Hutchinson-Gilford早衰综合征的患者。我们建议，他们被认为是具有全身性脂肪营养不良相关的早衰综合征。全身性脂肪营养不良相关的类早衰综合征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、高脂血症、肝脂肪变性和心肌病是发病率和死亡率的主要因素。
Background: 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.Methods: 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.Results: 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.Conclusions: 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.