Phenotype and course of Hutchinson-Gilford progeria syndrome
Phenotype and course of Hutchinson-Gilford progeria syndrome
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DOI：
10.1056/nejmoa0706898
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发表时间：
2008-02-07
影响因子：
158.5
通讯作者：
Introne, Wendy J.
中科院分区：
文献类型：
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作者：
Merideth, Melissa A.;Gordon, Leslie B.;Introne, Wendy J.
背景资料：Hutchinson-Gilford早衰综合征是一种罕见的散发性常染色体显性遗传综合征，涉及过早衰老，通常导致约13岁时因心肌梗死或中风死亡。这种综合征的大多数病例的遗传基础是核纤层蛋白A（LMNA）基因的密码子608从甘氨酸GGC变为甘氨酸GGT，这激活了隐蔽剪接供体位点以产生异常核纤层蛋白A;这破坏了核膜并改变了转录。我们招募了15名1至17岁的儿童，代表了世界上已知的Hutchinson-Gilford早衰综合征患者的近一半，结果：15例患者均出现皮肤瘢痕、关节挛缩、骨骼畸形、脱发、生长发育障碍，并伴有心血管和中枢神经系统后遗症。以前未被认识到的结果包括凝血酶原时间延长，血小板计数和血清磷水平升高，关节活动度降低，低频传导性听力损失和功能性口腔缺陷。生长障碍与营养不足、胰岛素无反应性或生长激素缺乏无关。少数患者的生长激素治疗使身高增长增加10%，体重增长增加50%。心血管研究显示，随着年龄的增长，包括血压升高，血管顺应性降低，踝肱指数下降，血管外膜thicken.Conclusions：建立详细的表型Hutchinson-Gilford早衰综合征是重要的，因为在了解这种综合征的进展可能会提供洞察到正常老化。异常核纤层蛋白A（早老蛋白）似乎随着正常细胞的老化而积累。（ClinicalTrials.gov编号，NCT 00365092.）。
Background: Hutchinson-Gilford progeria syndrome is a rare, sporadic, autosomal dominant syndrome that involves premature aging, generally leading to death at approximately 13 years of age due to myocardial infarction or stroke. The genetic basis of most cases of this syndrome is a change from glycine GGC to glycine GGT in codon 608 of the lamin A (LMNA) gene, which activates a cryptic splice donor site to produce abnormal lamin A; this disrupts the nuclear membrane and alters transcription.Methods: We enrolled 15 children between 1 and 17 years of age, representing nearly half of the world's known patients with Hutchinson-Gilford progeria syndrome, in a comprehensive clinical protocol between February 2005 and May 2006.Results: Clinical investigations confirmed sclerotic skin, joint contractures, bone abnormalities, alopecia, and growth impairment in all 15 patients; cardiovascular and central nervous system sequelae were also documented. Previously unrecognized findings included prolonged prothrombin times, elevated platelet counts and serum phosphorus levels, measured reductions in joint range of motion, low-frequency conductive hearing loss, and functional oral deficits. Growth impairment was not related to inadequate nutrition, insulin unresponsiveness, or growth hormone deficiency. Growth hormone treatment in a few patients increased height growth by 10% and weight growth by 50%. Cardiovascular studies revealed diminishing vascular function with age, including elevated blood pressure, reduced vascular compliance, decreased ankle-brachial indexes, and adventitial thickening.Conclusions: Establishing the detailed phenotype of Hutchinson-Gilford progeria syndrome is important because advances in understanding this syndrome may offer insight into normal aging. Abnormal lamin A (progerin) appears to accumulate with aging in normal cells. (ClinicalTrials.gov number, NCT00365092.).