| Summary: | The p.P479L (c.1436C>T) variant of hepatic CPT1A is frequent in Inuit and British Columbia First Nations populations of Canada. CPT1A is a major regulatory point in long chain fatty acid oxidation in the liver. CPT1A deficiency is an autosomal recessive disorder that causes metabolic decompensation triggered by fasting, which can progress to seizures and sudden death, if not treated. This study assesses prevalence and clinical impact of the P479L variant in the Canadian territories and reviews modifiable risk factors associated with infant mortality (IM) in Nunavut. Methods: Ethics approval was obtained from university REBs and local research institutes, with consultation with territorial Aboriginal groups. Newborn screening blood spots from all infants born in 2006 (n=1584) and sudden death in infancy cases (n=31; 1999-2008) in the territories were genotyped for the P479L variant. Results: P479L homozygosity in each territory was 64%, 3%, and 1% for Nunavut, NWT, and Yukon, respectively. Within NWT, homozygosity was highest in Inuvialuit (21%) and very low in First Nations (1%). Homozygosity in sudden death cases was highest in Nunavut (18/20) and associated with an increased risk (OR: 5.15; 95% CI: 1.19-22.38). Homozygosity was 29% for NWT cases (2/7), 67% in NWT Inuvialuit (2/3), and was not present in Yukon cases (0/4). Review of Nunavut IM cases (n=78; 1999-2008) identified Sudden Infant Death Syndrome (SIDS) and Sudden Unexpected Death in Infancy (SUDI) as the leading causes of infant death (47%), followed by death due to infectious disease (28%). At least 23% of IM cases were premature. Discussion: The P479L variant is very frequent in the Inuit/Inuvialuit of Canada. Although the sample size was small, there was an associated risk for sudden death in infants homozygous for the variant in Nunavut. SIDS and SUDI are the leading causes of infant death in Nunavut, followed by death due to infectious disease. Since deaths in these two categories are largely preventable, prevention strategies and further exploration into the P479L variant and other determinants are indicated. Management strategies, including newborn screening for the P479L variant, need to be developed in consultation with health authorities, local medical professionals, and local communities.
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