Author

Sarah Lowe

Date

6-2010

Document Type

Thesis

Degree Name

M.S.

Institution

Oregon Health & Science University

Abstract

Background: Carnitine Palmitoyltransferase 1A (CPT1A) catalyzes the rate limiting step for hepatic fatty acid oxidation and is critical for normal ketogenesis during fasting. Through advances in newborn screening by tandem mass spectrometry(MS/MS), a sequence variant in the CPT1A gene that decreases the enzymes activity in the liver has been identified in the Native Alaskan population as well as other Arctic populations. Over the past four years, over 300 Native Alaska infants have been identified with this specific sequence variant of CPT1A by newborn screening. All are homozygous for the same c.1436C[right pointing arrow]T variant in CPT1A, resulting in approximately an 80% reduction in CPT1A activity. The clinical implications of the c.1436C[right pointing arrow]T variant of CPT1A are unknown. The goal of this study was to determine the metabolic response to fasting in Native Alaskan children homozygous for the c.1436C[right pointing arrow]T sequence variant in CPT1A. Method: Recruitment of children between 3-5 years of age that had been identified with the specific c.1436C[right pointing arrow]T variant of CPT1A via newborn screening was done in collaboration with the Alaska Department of Health and Social Services. Subjects were admitted to the inpatient research unit in Doernbecher Children's Hospital for evaluations which included an 18 hour medically supervised fast. Fasting began at approximately 6:00pm, after the participants were given an ad lib diner at 5:00pm. Glucose, ketone bodies (KB), free fatty acid (FFA) and the ratio of FFA to KB (FFA/KB) were measured over the course of the fast, and levels were compared to published fasting data from age-matched controls. Results: Two of the subjects became hypoglycemic during the fast (blood glucose less than 55 mg/dL), and developed symptoms of hypoglycemia including lethargy. Hypoglycemic symptoms were quickly resolved when the subjects were administered an intravenous solution of 25% Dextrose (D25) along with initiation of oral carbohydrate consumption. Among the other 3 subjects, there was no difference in mean glucose or free fatty acid concentrations between the control children and the children with the c.1436C[right pointing arrow]T variant of CPT1A. The maximum ketone (KB) production in children with the c.1436C[right pointing arrow]T variant of CPT1A was approximately 10% of that in control children (0.233 mmol/L vs. 2.4mmol/L) .The average FFA/KB ratio was significantly elevated in children with the c.1436C[right pointing arrow]T variant of CPT1A (4.9 at 12 hrs; 7.6 at 18 hrs), compared to controls (hours), suggesting an inability of these children to utilize fats for energy during the fast. Discussion: Children with the c.1436C[right pointing arrow]T variant of CPT1A had reduced ketone production and an elevated FFA/KB ratio in response to fasting, indicating that homozygosity for the c.1436C[right pointing arrow]T sequence variant impairs the normal ketone production in the liver in response to fasting. Two of the participants developed hypoketotic hypoglycemia before the 18 hour completion of the fast. These two subjects had final FFA/KB ratios of 4.1 and 16. The ratio in the participants who did not develop hypoketotic hypoglycemia was 6.3, 8.7, and 7.07. One of the two participants who developed hypoketotic hypoglycemia was the youngest participant in the study, 3.5 years old compared to and average age 4.6, this participant also had the lowest FFA/KB ratio. The cause of hypoketotic hypoglycemia can not be attributed to altered fatty acid mobilization, due to a normal rise in free fatty acid levels in children with the specific c.1436C[right pointing arrow]T variant of CPT1A. Conclusion: Children with c.1436C[right pointing arrow]T variant of CPT1A have an altered response to fasting, presenting with hypoketosis as well as an increased risk for developing hypoketotic hypoglycemia. Thus, sequence variant c.1436C[right pointing arrow]T in the CPT1A gene impacts fasting tolerance, can present with clinical symptoms of hypoglycemia under conditions of environmental stress, and therefore should not be considered a benign variant.

Identifier

doi:10.6083/M46Q1V6B

Division

Graduate Programs in Human Nutrition

School

School of Medicine

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