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

Project: Research project

Project Details


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.
Effective start/end date8/1/106/30/14


  • National Institutes of Health: $79,680.00
  • National Institutes of Health: $72,615.00


  • Medicine(all)


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