Download PDF
Am J Perinatol 2021; 38(08): 828-833
DOI: 10.1055/s-0039-3402723
Original Article

Perinatal Reduced Blood Concentrations of Free Carnitine and Acylcarnitines in Infants with Cystic Fibrosis

Kleopatra H. Schulpis
1   Institute of Child Health, Aghia Sophia Children's Hospital, Athens, Greece
,
Elina Molou
2   Laboratory of Prenatal and Neonatal Screening, Neoscreen Ltd., Athens, Greece
,
Penelope Manta-Vogli
3   Department of Clinical Nutrition and Dietetics, Aghia Sofia Children's Hospital, Athens, Greece
,
Yannis Dotsikas
4   Laboratory of Pharmaceutical Analysis, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
,
Georgia Thodi
2   Laboratory of Prenatal and Neonatal Screening, Neoscreen Ltd., Athens, Greece
,
Maria Chatzidaki
2   Laboratory of Prenatal and Neonatal Screening, Neoscreen Ltd., Athens, Greece
,
Yannis L. Loukas
4   Laboratory of Pharmaceutical Analysis, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
› Author Affiliations Funding None.
› Further Information
    Permissions and Reprints

Abstract

Objective Cystic fibrosis (CF) is a multisystemic inherited disease. The aim of this study was to determine free carnitine (FC) and acylcarnitine concentrations in CF newborns with various mutations of the CFTR gene perinatally.

Study Design FC/acylcarnitines were determined in dried blood spots via liquid chromatography-tandem mass spectrometry (LC-MS/MS) on the third day of life of full-term normal (n = 50) and CF (n = 28) newborns. For infants with elevated immunoreactive trypsinogen values, FC/acylcarnitines were quantified again 48 hours later, followed by mutational analysis of CFTR gene via Sanger sequencing.

Results Initial FC and sums of acylcarnitine concentrations were statistically significantly lower in CF patients than in controls and even lower 48 hours later. The mutations F508del and 621 + 1G > T were predominantly identified among CF patients.

Conclusion Low FC and acylcarnitine concentrations were measured perinatally in CF patients, for all CFTR mutations detected. Carnitine supplementation of breastfeeding mothers could be beneficial.

Keywords

cystic fibrosis - CFTR gene - acylcarnitines - newborn screening - fatty acids


Publication History

Received: 23 August 2019

Accepted: 25 November 2019

Article published online:
31 December 2019

© 2019. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Riordan JR, Rommens JM, Kerem B. et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989; 245 (4922): 1066-1073
    CrossrefPubMedGoogle Scholar
  • 2 Southern KW, Munck A, Pollitt R. et al; ECFS CF Neonatal Screening Working Group. A survey of newborn screening for cystic fibrosis in Europe. J Cyst Fibros 2007; 6 (01) 57-65
    CrossrefPubMedGoogle Scholar
  • 3 Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration 2000; 67 (02) 117-133
    CrossrefPubMedGoogle Scholar
  • 4 Cystic Fibrosis Mutation Database. Accessed August 2, 2019 at: http://www.gent.sickkids.on.ca/cftr
    Google Scholar
  • 5 Kanavakis E, Efthymiadou A, Strofalis S, Doudounakis S, Traeger-Synodinos J, Tzetis M. Cystic fibrosis in Greece: molecular diagnosis, haplotypes, prenatal diagnosis and carrier identification amongst high-risk individuals. Clin Genet 2003; 63 (05) 400-409
    CrossrefPubMedGoogle Scholar
  • 6 Loukas YL, Thodi G, Molou E, Georgiou V, Dotsikas Y, Schulpis KH. Clinical diagnostic Next-Generation sequencing: the case of CFTR carrier screening. Scand J Clin Lab Invest 2015; 75 (05) 374-381
    CrossrefPubMedGoogle Scholar
  • 7 Brass EP. Pivalate-generating prodrugs and carnitine homeostasis in man. Pharmacol Rev 2002; 54 (04) 589-598
    CrossrefPubMedGoogle Scholar
  • 8 Reuter SE, Evans AM. Carnitine and acylcarnitines: pharmacokinetic, pharmacological and clinical aspects. Clin Pharmacokinet 2012; 51 (09) 553-572
    CrossrefPubMedGoogle Scholar
  • 9 Jeukendrup AE, Saris WH, Wagenmakers AJ. Fat metabolism during exercise: a review. Part I: fatty acid mobilization and muscle metabolism. Int J Sports Med 1998; 19 (04) 231-244
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Shortland GJ, Walter JH, Stroud C, Fleming PJ, Speidel BD, Marlow N. Randomised controlled trial of L-carnitine as a nutritional supplement in preterm infants. Arch Dis Child Fetal Neonatal Ed 1998; 78 (03) F185-F188
    CrossrefPubMedGoogle Scholar
  • 11 Campoy C, Liemlahi S, Rivero M, López C, Bayés R. Capacity for fatty acid oxidation in the neonatal period. Prenat Neonatal Med 1996; 1: 366
    PubMedGoogle Scholar
  • 12 Rebouche CJ. Carnitine function and requirements during the life cycle. FASEB J 1992; 6 (15) 3379-3386
    CrossrefPubMedGoogle Scholar
  • 13 Lloyd-Still JD, Bohan T, Hughes S, Wessel HU. Acylcarnitine is low in cord blood in cystic fibrosis. Acta Paediatr Scand 1990; 79 (04) 427-430
    CrossrefPubMedGoogle Scholar
  • 14 Lloyd-Still JD, Powers CA, Wessel HU. Carnitine metabolites in infants with cystic fibrosis: a prospective study. Acta Paediatr 1993; 82 (02) 145-149
    CrossrefPubMedGoogle Scholar
  • 15 Loukas YL, Soumelas GS, Dotsikas Y. et al. Expanded newborn screening in Greece: 30 months of experience. J Inherit Metab Dis 2010; 33 (Suppl. 03) S341-S348
    CrossrefPubMedGoogle Scholar
  • 16 Shekhawat PS, Sonne S, Carter AL, Matern D, Ganapathy V. Enzymes involved in L-carnitine biosynthesis are expressed by small intestinal enterocytes in mice: implications for gut health. J Crohn's Colitis 2013; 7 (06) e197-e205
    CrossrefPubMedGoogle Scholar
  • 17 Stanley CA. Carnitine deficiency disorders in children. Ann N Y Acad Sci 2004; 1033: 42-51
    CrossrefPubMedGoogle Scholar
  • 18 Mamedov I, Zolkina I, Nikolaeva E, Glagovsky P, Sukhorukov V. Carnitine insufficiency in children with inborn errors of metabolism: prevalence and treatment efficacy. J Pediatr Endocrinol Metab 2015; 28 (11-12): 1299-1304
    CrossrefPubMedGoogle Scholar
  • 19 Crill CM, Helms RA. The use of carnitine in pediatric nutrition. Nutr Clin Pract 2007; 22 (02) 204-213
    CrossrefPubMedGoogle Scholar
  • 20 Li L, Somerset S. Digestive system dysfunction in cystic fibrosis: challenges for nutrition therapy. Dig Liver Dis 2014; 46 (10) 865-874
    CrossrefPubMedGoogle Scholar
  • 21 Durieu I, Josserand RN. [Cystic fibrosis in 2008]. Rev Med Interne 2008; 29 (11) 901-907
    CrossrefPubMedGoogle Scholar
  • 22 De Lisle RC, Borowitz D. The cystic fibrosis intestine. Cold Spring Harb Perspect Med 2013; 3 (09) a009753
    CrossrefPubMedGoogle Scholar
  • 23 Cipolli M, Castellani C, Wilcken B. et al. Pancreatic phenotype in infants with cystic fibrosis identified by mutation screening. Arch Dis Child 2007; 92 (10) 842-846
    CrossrefPubMedGoogle Scholar
  • 24 Borowitz D, Robinson KA, Rosenfeld M. et al; Cystic Fibrosis Foundation. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatr 2009; 155 (6, Suppl) S73-S93
    CrossrefPubMedGoogle Scholar
  • 25 Njoroge SW, Laposata M, Katrangi W, Seegmiller AC. DHA and EPA reverse cystic fibrosis-related FA abnormalities by suppressing FA desaturase expression and activity. J Lipid Res 2012; 53 (02) 257-265
    CrossrefPubMedGoogle Scholar
  • 26 Van Biervliet S, Van Biervliet JP, Robberecht E, Christophe A. Fatty acid composition of serum phospholipids in cystic fibrosis (CF) patients with or without CF related liver disease. Clin Chem Lab Med 2010; 48 (12) 1751-1755
    CrossrefPubMedGoogle Scholar
  • 27 Meyburg J, Schulze A, Kohlmueller D. et al. Acylcarnitine profiles of preterm infants over the first four weeks of life. Pediatr Res 2002; 52 (05) 720-723
    CrossrefPubMedGoogle Scholar
  • 28 Clark RH, Kelleher AS, Chace DH, Spitzer AR. Gestational age and age at sampling influence metabolic profiles in premature infants. Pediatrics 2014; 134 (01) e37-e46
    CrossrefPubMedGoogle Scholar
  • 29 Storni V, Clausters M, Chinet T, Ravilly S. Diagnostic de la mucoviscidose. Arch Pediatr 2001; 8: 818-832
    CrossrefPubMedGoogle Scholar
  • 30 Kalivianakis M, Minich DM, Bijleveld CM. et al. Fat malabsorption in cystic fibrosis patients receiving enzyme replacement therapy is due to impaired intestinal uptake of long-chain fatty acids. Am J Clin Nutr 1999; 69 (01) 127-134
    CrossrefPubMedGoogle Scholar
  • 31 Peretti N, Roy CC, Drouin E. et al. Abnormal intracellular lipid processing contributes to fat malabsorption in cystic fibrosis patients. Am J Physiol Gastrointest Liver Physiol 2006; 290 (04) G609-G615
    CrossrefPubMedGoogle Scholar
  • 32 Novak M, Monkus EF, Chung D, Buch M. Carnitine in the perinatal metabolism of lipids. I. Relationship between maternal and fetal plasma levels of carnitine and acylcarnitines. Pediatrics 1981; 67 (01) 95-100
    CrossrefPubMedGoogle Scholar
  • 33 Penn D, Dolderer M, Schmidt-Sommerfeld E. Carnitine concentrations in the milk of different species and infant formulas. Biol Neonate 1987; 52 (02) 70-79
    CrossrefPubMedGoogle Scholar
  • 34 Scaglia F, Longo N. Primary and secondary alterations of neonatal carnitine metabolism. Semin Perinatol 1999; 23 (02) 152-161
    CrossrefPubMedGoogle Scholar
  • 35 Kepka A, Minarowska A, Minarowski L. et al. Serum and urinary carnitine in children with cystic fibrosis. Prog Health Sci 2013; 3: 13-18
    PubMedGoogle Scholar
  • 36 Giovannini M, Agostoni C, Salari PC. Is carnitine essential in children?. J Int Med Res 1991; 19 (02) 88-102
    CrossrefPubMedGoogle Scholar
  • 37 Engelen MP, Com G, Deutz NE. Protein is an important but undervalued macronutrient in the nutritional care of patients with cystic fibrosis. Curr Opin Clin Nutr Metab Care 2014; 17 (06) 515-520
    CrossrefPubMedGoogle Scholar
  • 38 Colombo C, Costantini D, Zazzeron L. et al. Benefits of breastfeeding in cystic fibrosis: a single-centre follow-up survey. Acta Paediatr 2007; 96 (08) 1228-1232
    CrossrefPubMedGoogle Scholar
  • 39 Jadin SA, Wu GS, Zhang Z. et al. Growth and pulmonary outcomes during the first 2 y of life of breastfed and formula-fed infants diagnosed with cystic fibrosis through the Wisconsin Routine Newborn Screening Program. Am J Clin Nutr 2011; 93 (05) 1038-1047
    CrossrefPubMedGoogle Scholar