Impact of the P479L Variant in CPT1A on Infant Mortality in Alaska

描述（由申请人提供）：2003年10月，阿拉斯加州开始采用串联质谱法（MS/MS）扩大新生儿筛查，结果发现肉碱棕榈酰转移酶1A （CPT1A）缺乏症的发病率出乎意料地高，这是一种罕见的脂肪酸氧化疾病。受影响的婴儿都是阿拉斯加土著血统，并且在CPT1A基因中具有相同的DNA序列变异纯合子(c.1436C？T)，在第479号氨基酸上产生脯氨酸到亮氨酸的取代（p.P479L）。CPT1催化线粒体脂肪酸氧化的第一步和限速步骤。它还发挥着关键的调节作用，对生理信号作出反应，控制碳水化合物和脂肪的相对使用，以产生能量。由CPT1失调引起的能量代谢改变会影响胰岛素敏感性、食欲调节以及与脂肪酸代谢相关的越来越多的其他关键功能。CPT1A是CPT1的肝脏异构体，是禁食期间生酮所必需的。严重CPT1A缺乏症的患者可出现多种症状，包括低血糖、癫痫发作和雷耶斯综合征（以肝功能障碍、低酮性低血糖和昏迷为特征）。在患有CPT1A缺乏症的患者中，由于需要脂肪酸氧化以产生酮和能量，空腹会引发CPT1A缺乏症。婴幼儿特别容易受到禁食的影响，而在这一年龄组中常见的发烧和病毒感染会大大加剧这种情况。与其他脂肪酸氧化障碍一样，CPT1A缺乏可导致婴儿猝死。初步证据表明，26%的阿拉斯加土著婴儿是c.1436C？T序列变异，另有34%是杂合的。这种序列变异的高流行率导致人们猜测它可能是一种良性多态性。然而，通过扩大新生儿筛查可以识别的代谢障碍标志物的存在反驳了这一观点。目前尚无关于阿拉斯加本地纯合子c.1436C?的婴儿的症状频率或长期结果的数据。T序列变异。然而，流行病学数据显示，c.1436C . ？在阿拉斯加，T序列变异的婴儿死亡率也最高。基于这些观察，研究人员假设c.1436C？T序列变异导致婴儿死亡风险增加。为了验证这一假设，他们将进行一项病例对照研究，以确定c.1436C？T序列变异在12个月前死亡的阿拉斯加婴儿中比在一般人群中更高。

DESCRIPTION (Provided by Applicant): In October of 2003, the State of Alaska initiated expanded newborn screening by tandem mass spectrometry (MS/MS), which led to the identification of an unexpectedly high incidence of carnitine palmitoyltransferase 1A (CPT1A) deficiency, a rare disorder of fatty acid oxidation. The affected infants are all of Alaska Native heritage, and homozygous for the same DNA sequence variant in the CPT1A gene (c.1436C?T), which results in a proline to leucine substitution at amino acid 479 (p.P479L). CPT1 catalyzes the first and rate- limiting step in mitochondrial fatty acid ¿-oxidation. It also plays a critical regulatory role, responding to physiologic signals to exert control over the relative usage of carbohydrates and fats for energy production. Alterations of energy metabolism resulting from dysregulation of CPT1 affects insulin sensitivity, appetite regulation, and a growing list of other critical functions that are tied to fatty acid metabolism. CPT1A is the liver isoform of CPT1 and is required for ketogenesis during periods of fasting. Patients with severe forms of CPT1A deficiency can present with a wide variety of symptoms, including hypoglycemia, seizures, and Reyes syndrome, which is characterized by liver dysfunction, hypoketotic hypoglycemia, and coma. In patients with CPT1A deficiency symptoms are triggered by fasting, as a result of the requirement for fatty acid oxidation for ketone and energy production. Infants and young children are particularly vulnerable to fasting, and this is significantly exacerbated by fever and viral infections, which are common in this age group. Like other disorders of fatty acid oxidation, CPT1A deficiency can lead to sudden infant death. Preliminary evidence indicates that 26% of all Alaska Native infants are homozygous for the c.1436C?T sequence variant, and an additional 34% are heterozygous. The high prevalence of this sequence variant has led to the speculation that it may be a benign polymorphism. However, the presence of markers of metabolic impairment that can be identified via expanded newborn screening argues against this viewpoint. At the current time there is no data on the frequency of symptoms or long-term outcome of Alaska Native infants homozygous for the c.1436C?T sequence variant. However, epidemiologic data show that the geographic regions with the highest prevalence of the c.1436C?T sequence variant also have the highest rates of infant mortality in Alaska. Based on these observations the investigators hypothesize that homozygosity for the c.1436C?T sequence variant results in an increased risk of infant death. To test this hypothesis they will conduct a case-control study to determine whether the prevalence of the c.1436C?T sequence variant is higher among Alaskan infants who died before the age of 12 months than in the general population. PROJECT NARRATIVE: Effective newborn screening for inherited disorders of metabolism requires not only accurate and complete screening systems, but also a mechanism for the delivery of effective and appropriate treatment. The uncertainty regarding the appropriate treatment for infants with the c.1436C?T sequence variant in CPT1A, as well as the lack of information on its potential effect on the health of children and adults, constitute a significant public health challenge for the State of Alaska. In this study the investigators will evaluate whether the c.1436C?T sequence variant is a risk factor for infant death. The results of this study will aid in the development of evidence-based guidelines for the treatment of Alaska Native infants diagnosed with CPT1A deficiency by newborn screening.