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

CPT1A 中的 P479L 变异对阿拉斯加婴儿死亡率的影响

• 批准号: 7788016
• 负责人: David M Koeller
• 金额: $ 7.97万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7788016
• 关键词: Adult; Affect; Age; Alaska; Alaska Native; Amino Acids; Appetite Regulation; Benign; Biochemical Markers; Carbohydrates; Carnitine O-Palmitoyltransferase; Case-Control Studies; Censuses; Cessation of life; Child; Child health care; Clinical; Coma; Control Groups; County; DNA Sequence; DNA analysis; Data; Data Sources; Defect; Development; Diagnosis; Disease; Energy Metabolism; Fasting; Fatty Acids; Fatty acid glycerol esters; Fever; Frequencies; General Population; Genes; Genetic Polymorphism; Geographic Locations; High Prevalence; Hypoglycemia; Impairment; Inborn Genetic Diseases; Incidence; Individual; Infant; Infant Mortality; Instruction; Ketones; Lead; Leucine; Liver; Liver Dysfunction; Matched Case-Control Study; Metabolic; Metabolic Marker; Metabolism; Mitochondria; Neonatal Screening; Outcome; Patients; Physiological; Play; Prevalence; Production; Proline; Protein Isoforms; Public Health; Published Comment; Rare Diseases; Relative (related person); Reporting; Research Personnel; Reye Syndrome; Risk; Risk Factors; Role; Screening procedure; Seizures; Signal Transduction; Sudden infant death syndrome; Symptoms; System; Testing; Text; Time; Uncertainty; Variant; Virus Diseases; Vital Statistics; age group; base; epidemiologic data; evidence based guidelines; fatty acid metabolism; fatty acid oxidation; health record; infant death; insulin sensitivity; ketogenesis; oxidation; tandem mass spectrometry

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.

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）启动了新生儿筛查，这导致鉴定出意外的肉碱棕榈转移酶1A（CPT1A）缺乏症，这是脂肪酸氧化的罕见无序。受影响的婴儿都是阿拉斯加本地遗产，并且在CPT1A基因（c.1436c？t）中相同的DNA序列变体纯合子，这导致在氨基酸479（p.p479l）的亮氨酸取代的脯氨酸。 CPT1催化线粒体脂肪酸的第一个且限制的步骤 - 氧化。它还起着关键的调节作用，响应生理信号，以控制对碳液和脂肪的相对使用中的能量生产。 CPT1失调引起的能量代谢的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其他关键功能越来越多的列表。 CPT1A是CPT1的肝同工型，在禁食期间是生酮发生所必需的。严重形式的CPT1A缺乏症患者可以出现多种症状，包括低血糖，癫痫发作和Reyes综合征，其特征是肝功能障碍，低血性低血糖和昏迷。在CPT1A缺乏症状的患者中，由于禁食症状是促脂肪酸氧化和能量产生的，因此触发了禁食。婴儿和幼儿特别容易受到禁食的影响，这在该年龄组中很常见的发烧和病毒感染严重加剧了。像其他脂肪酸氧化疾病一样，CPT1A缺乏会导致婴儿猝死。初步证据表明，所有阿拉斯加本地婴儿中有26％对于C.1436c？t序列变体都是纯合的，另外34％是杂合的。该序列变体的高流行率导致人们猜测它可能是良性多态性。但是，可以通过以这种观点来识别的代谢障碍标记物的存在。目前，尚无有关均质均质的症状频率或长期结局的数据。但是，流行病学数据表明，C.1436C？T序列变体患病率最高的地理区域在阿拉斯加的婴儿死亡率也最高。基于这些观察结果，研究者假设C.1436C？T序列变体的纯合性导致婴儿死亡的风险增加。为了检验这一假设，他们将进行一项病例对照研究，以确定C.1436c？T序列变体的患病率是否比一般人群中死亡的阿拉斯加婴儿更高。 项目叙述：对代谢的遗传疾病的有效新生儿筛查不仅需要准确，完整的筛查系统，而且还需要提供有效且适当的治疗的机制。不确定性涉及对CPT1A中C.1436c？T序列变体的适当治疗，以及缺乏有关其对儿童和成人健康影响的潜在影响的信息，构成了对阿拉斯加州的重大公共卫生挑战。在这项研究中，研究人员将评估C.1436c？t序列变体是否是婴儿死亡的危险因素。这项研究的结果将有助于制定基于证据的指南，以通过新生儿筛查诊断为CPT1A缺乏症的阿拉斯加本地婴儿。