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

描述（由申请人提供）：2003年10月，阿拉斯加州通过串联质谱法（MS/MS）启动了扩大新生儿筛查，这导致了肉毒碱棕榈酰转移酶1A（CPT 1A）缺乏症（一种罕见的脂肪酸氧化障碍）的意外高发病率的鉴定。 受影响的婴儿都是阿拉斯加原住民的遗产，在CPT 1A基因（c.1436C？T），这导致氨基酸479处的脯氨酸被亮氨酸取代（p.P479L）。 CPT 1催化线粒体脂肪酸氧化的第一步和限速步骤。 它还起着关键的调节作用，响应生理信号，对能量生产中碳水化合物和脂肪的相对使用进行控制。 由CPT 1失调引起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的与脂肪酸代谢相关的其他关键功能。 CPT 1A是CPT 1的肝脏同种型，是禁食期间生酮所必需的。 患有严重形式的CPT 1A缺乏症的患者可能会出现各种各样的症状，包括低血糖症、癫痫发作和雷耶斯综合征，其特征在于肝功能障碍、低酮性低血糖症和昏迷。 在患有CPT 1A缺乏症的患者中，由于需要脂肪酸氧化来产生酮和能量，因此禁食会引发症状。 婴儿和幼儿特别容易受到禁食的影响，这会因发烧和病毒感染而明显加剧，这在这个年龄段很常见。 与其他脂肪酸氧化障碍一样，CPT 1A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纯合子的c.1436C？T序列变异，另外34%是杂合子。 这种序列变异的高流行率导致了推测它可能是一种良性多态性。 然而，存在的代谢障碍的标志物，可以通过扩大新生儿筛查确定反对这种观点。 在目前的时间有没有数据的频率的症状或长期的结果阿拉斯加土著婴儿纯合子的c.1436C？T序列变异。 然而，流行病学数据显示，地理区域的c.1436C？T序列变异也是阿拉斯加婴儿死亡率最高的。 根据这些观察，研究人员假设，纯合性为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，以确定是否流行的c.1436C？在12个月前死亡的阿拉斯加婴儿中，T序列变异高于一般人群。 项目叙述：有效的新生儿遗传性代谢紊乱筛查不仅需要准确和完整的筛查系统，而且还需要提供有效和适当治疗的机制。 关于对患有c.1436C的婴儿进行适当治疗的不确定性？CPT 1A中的T序列变异，以及缺乏关于其对儿童和成人健康的潜在影响的信息，构成了阿拉斯加州面临的重大公共卫生挑战。 在这项研究中，研究人员将评估是否c.1436C？T序列变异是婴儿死亡的危险因素。 这项研究的结果将有助于制定循证指南，用于治疗通过新生儿筛查诊断为CPT 1A缺乏症的阿拉斯加土著婴儿。

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.