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

描述(申请人提供)：2003年10月，阿拉斯加州启动了串联质谱仪(MS/MS)扩大新生儿筛查，导致发现肉碱棕榈酰转移酶1A(CPT1A)缺乏症的发病率出人意料地高，这是一种罕见的脂肪酸氧化障碍。受影响的婴儿都是阿拉斯加土生土长的，CPT1A基因(c.1436C？T)中相同DNA序列变异的纯合子，导致第479位氨基酸的脯氨酸到亮氨酸的替换(p.P479L)。CPT1催化线粒体脂肪酸氧化的第一步，也是限速步骤。它还发挥着关键的调节作用，对生理信号做出反应，对碳水化合物和脂肪的相对使用进行控制，以产生能量。CPT1调节失调导致的能量代谢改变影响胰岛素敏感性、食欲调节，以及越来越多与脂肪酸代谢有关的其他关键功能。CPT1a是CPT1的肝脏异构体，在禁食期间是酮体生成所必需的。严重形式的CPT1A缺乏症患者会出现各种各样的症状，包括低血糖、癫痫和雷耶斯综合征，其特征是肝功能障碍、低酮症和昏迷。在CPT1a缺乏的患者中，症状是由禁食引发的，这是酮和能量产生所需的脂肪酸氧化的结果。婴幼儿特别容易禁食，发烧和病毒感染在这个年龄段很常见，大大加剧了这种情况。与其他脂肪酸氧化障碍一样，CPT1a缺乏症也会导致婴儿猝死。初步证据表明，所有阿拉斯加土生土长的婴儿中有26%是c.1436C？T序列变体的纯合子，另外34%是杂合子。这种序列变异体的高流行率导致人们猜测它可能是一种良性的多态。然而，代谢损伤标记物的存在可以通过扩大新生儿筛查来识别，这与这一观点相反。目前还没有关于阿拉斯加土生土长的婴儿出现症状的频率或长期结局的数据，这些婴儿是C.1436C？T序列变异的纯合子。然而，流行病学数据显示，在阿拉斯加，C.1436C？T序列变异最常见的地理区域的婴儿死亡率也最高。基于这些观察，研究人员假设C.1436C？T序列变异的纯合性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，以确定在12个月前死亡的阿拉斯加婴儿中，c.1436C？T序列变异的患病率是否高于普通人群。 项目简介：对遗传性新陈代谢疾病进行有效的新生儿筛查不仅需要准确和完整的筛查系统，还需要一种提供有效和适当治疗的机制。对于CPT1a中带有C.1436C？T序列变异的婴儿的适当治疗的不确定性，以及缺乏关于其对儿童和成人健康的潜在影响的信息，对阿拉斯加州构成了重大的公共卫生挑战。在这项研究中，研究人员将评估C.1436C？T序列变异是否是婴儿死亡的风险因素。这项研究的结果将有助于制定循证指南，通过新生儿筛查诊断为CPT1A缺乏症的阿拉斯加本土婴儿的治疗。

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.