Carnitine palmitoyltransferase 1A P479L and infant death: policy implications of emerging data

Fohner, Alison E.; Garrison, Nanibaa’ A.; Austin, Melissa A.; Burke, Wylie

doi:10.1038/gim.2016.202

Cited by 12 publications

(8 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Heterozygous female carriers may develop fatty liver of pregnancy when carrying a fetus with this disorder [ 83 ]. CPT1A deficiency is particularly prevalent in native populations of Alaska, Canada, Greenland and North-East Siberia [ 84 – 86 ]. The common c.1436C > T (p.P479L) variant in these populations causes a partially reduced CPT1A activity and is associated with infant mortality [ 87 – 90 ].…”

Section: Overview Of Different Long-chain Fatty Acid Oxidation Disordmentioning

confidence: 99%

Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle

Knottnerus

Bleeker

Wüst

et al. 2018

Rev Endocr Metab Disord

245

209

View full text Add to dashboard Cite

Mitochondrial fatty acid oxidation is an essential pathway for energy production, especially during prolonged fasting and sub-maximal exercise. Long-chain fatty acids are the most abundant fatty acids in the human diet and in body stores, and more than 15 enzymes are involved in long-chain fatty acid oxidation. Pathogenic mutations in genes encoding these enzymes result in a long-chain fatty acid oxidation disorder in which the energy homeostasis is compromised and long-chain acylcarnitines accumulate. Symptoms arise or exacerbate during catabolic situations, such as fasting, illness and (endurance) exercise. The clinical spectrum is very heterogeneous, ranging from hypoketotic hypoglycemia, liver dysfunction, rhabdomyolysis, cardiomyopathy and early demise. With the introduction of several of the long-chain fatty acid oxidation disorders (lcFAOD) in newborn screening panels, also asymptomatic individuals with a lcFAOD are identified. However, despite early diagnosis and dietary therapy, a significant number of patients still develop symptoms emphasizing the need for individualized treatment strategies. This review aims to function as a comprehensive reference for clinical and laboratory findings for clinicians who are confronted with pediatric and adult patients with a possible diagnosis of a lcFAOD.

show abstract

Section: Overview Of Different Long-chain Fatty Acid Oxidation Disordmentioning

confidence: 99%

Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle

Knottnerus

Bleeker

Wüst

et al. 2018

Rev Endocr Metab Disord

245

209

View full text Add to dashboard Cite

show abstract

“…77 78 As a result, given that the traditional arctic diet was rich in nutrients that activate CPT1A, the enzyme produced by the arctic variant might have been even more active than the wild-type one. 78 The traditional arctic diet was not only high in fat and low in carbohydrates but also four times higher in omega-3 polyunsaturated fatty acids (PUFAs) compared with a standard Western diet. 79 Omega-3 PUFAs are strong activators of CPT1A and have been shown to increase ketone levels twice as much as saturated fat in humans.…”

Section: Inborn Genetic Conditions With Effects On Kd Responsementioning

confidence: 99%

“…88 Public recommendations to increase feeding with nontraditional carbohydrate-rich diets are not based on evidence and may have unintended harmful consequences. 78 Box 2 The 'Arctic variant of CPT1A…”

Section: Box 2 Continuedmentioning

confidence: 99%

Genetic variants for personalised management of very low carbohydrate ketogenic diets

Aronica

Volek

Poff

et al. 2020

BMJNPH

View full text Add to dashboard Cite

The ketogenic diet (KD) is a low-carbohydrate, high-fat, adequate-protein diet proven to be effective for the reversal of obesity, metabolic syndrome and type 2 diabetes, and holding therapeutic potential for the prevention and treatment of other chronic diseases. Genetic and dynamic markers of KD response may help to identify individuals most likely to benefit from KD and point to individuals at higher risk for adverse health outcomes. Here, we provide a clinician-friendly review of state-of-the-art research on biomarkers of KD response for a variety of outcomes including weight loss, body composition and cognitive performance drawing data from both intervention trials and case reports of rare inborn errors of metabolism. We also present a selection of the most promising candidate genes to evaluate in future studies and discuss key aspects of study design and variant interpretation that may help accelerate the implementation of these biomarkers in clinical practice.

show abstract

“…Given the p.P479L variant's high frequency, there has been uncertainty regarding its clinical significance, which has created calls for larger and more comprehensive studies that include other risk factors important in these outcomes ( 26 ). We assessed early child health outcomes of 2,225 Inuit children residing in Nunavut to determine whether the CPT1A p.P479L variant is associated with infectious illness in the broader context of other relevant perinatal, postnatal and socioeconomic variables.…”

Section: Introductionmentioning

confidence: 99%

Association of the CPT1A p.P479L Metabolic Gene Variant With Childhood Respiratory and Other Infectious Illness in Nunavut

et al. 2021

View full text Add to dashboard Cite

Objective: Infectious illness, including lower respiratory tract infection (LRTI), is a leading cause of childhood morbidity and infant mortality in Inuit children in Nunavut Canada. The carnitine palmitoyltransferase 1A (CPT1A) p.P479L variant is common in arctic Indigenous populations of Alaska, Canada, and Greenland. CPT1A is a fatty acid oxidation enzyme expressed in the liver, immunocytes and other tissues, and is needed to use fats for energy during fasting. Previous association of the variant with early childhood infectious illness and infant death has been challenged because of sample size and limited adjustment for confounders. We evaluated whether the p.P479L variant is associated with infectious illness in Inuit children of Nunavut, Canada.Methods: We conducted a retrospective clinical chart review of 2,225 Inuit children (0–5 years) for infectious illness (including otitis media, gastroenteritis, and hospital admission for LRTI), prenatal, perinatal, and socioeconomic indicators, subsequently linking to CPT1A genotype. Multivariable logistic regression adjusted for birth characteristics, breastfeeding, maternal smoking, food insecurity, and socioeconomic indicators.Results: Overall, 27% of children were hospitalized for LRTI, 86% had otitis media and 50% had gastroenteritis. The p.P479L allele frequency was 0.82. In multivariable analysis, p.P479L homozygosity was associated with LRTI admission (aOR:2.88 95%CI:1.46–5.64), otitis media (aOR:1.83, 95%CI:1.05–3.21), and gastroenteritis (aOR:1.74, 95%CI:1.09–2.77), compared to non-carriers.Conclusion: Children homozygous for the p.P479L variant were more likely to experience infectious illness than non-carriers, including hospitalization for respiratory tract infections. Given the role of CPT1A in immunocytes, our findings indicate that more study is needed to determine if there is a role of the variant in immune response. Continued Inuit involvement is essential when considering next steps.

show abstract

Carnitine palmitoyltransferase 1A P479L and infant death: policy implications of emerging data

Cited by 12 publications

References 41 publications

Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle

Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle

Genetic variants for personalised management of very low carbohydrate ketogenic diets

Association of the CPT1A p.P479L Metabolic Gene Variant With Childhood Respiratory and Other Infectious Illness in Nunavut

Contact Info

Product

Resources

About