Treffer: Pitfalls in the diagnosis of carnitine palmitoyltransferase 1 deficiency.
Title:
Pitfalls in the diagnosis of carnitine palmitoyltransferase 1 deficiency.
Authors:
Grünert SC; Faculty of Medicine, Department of Pediatrics, 9174 Children's Hospital, Adolescent Medicine and Neonatology, Freiburg University Hospital , Freiburg, Germany., Berger U; Faculty of Medicine, Department of Pediatrics, 9174 Children's Hospital, Adolescent Medicine and Neonatology, Freiburg University Hospital , Freiburg, Germany., Hörster F; Medical Faculty, Division of Pediatric Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, Heidelberg University, Heidelberg, Germany., Schwarz K; Medical Faculty, Division of Pediatric Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, Heidelberg University, Heidelberg, Germany., Thimm E; Medical Faculty, Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany., Spiekerkoetter U; Faculty of Medicine, Department of Pediatrics, 9174 Children's Hospital, Adolescent Medicine and Neonatology, Freiburg University Hospital , Freiburg, Germany., Haas D; Medical Faculty, Division of Pediatric Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, Heidelberg University, Heidelberg, Germany., Schumann A; Faculty of Medicine, Department of Pediatrics, 9174 Children's Hospital, Adolescent Medicine and Neonatology, Freiburg University Hospital , Freiburg, Germany.
Source:
Journal of pediatric endocrinology & metabolism : JPEM [J Pediatr Endocrinol Metab] 2025 Sep 29; Vol. 38 (12), pp. 1324-1331. Date of Electronic Publication: 2025 Sep 29 (Print Publication: 2025).
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: Walter de Gruyter Country of Publication: Germany NLM ID: 9508900 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 2191-0251 (Electronic) Linking ISSN: 0334018X NLM ISO Abbreviation: J Pediatr Endocrinol Metab Subsets: MEDLINE
Imprint Name(s):
Publication: Mar. 2011- : Berlin : Walter de Gruyter
Original Publication: London : Freund Pub. House, [1995-
Original Publication: London : Freund Pub. House, [1995-
MeSH Terms:
Cardiomyopathies*/diagnosis , Cardiomyopathies*/blood , Carnitine O-Palmitoyltransferase*/deficiency , Carnitine O-Palmitoyltransferase*/blood , Metabolism, Inborn Errors*/diagnosis , Metabolism, Inborn Errors*/blood , Muscular Diseases*/diagnosis , Muscular Diseases*/blood, Carnitine/blood ; Carnitine/analogs & derivatives ; Neonatal Screening/methods ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Dried Blood Spot Testing ; Follow-Up Studies ; Prognosis ; Hypoglycemia ; Lipid Metabolism, Inborn Errors
References:
Bonnefont, J-P, Djouadi, F, Prip-Buus, C, Gobin, S, Munnich, A, Bastin, J. Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects. Mol Aspect Med 2004;25:495–520. https://doi.org/10.1016/j.mam.2004.06.004 . (PMID: 10.1016/j.mam.2004.06.004)
Olpin, SE, Allen, J, Bonham, JR, Clark, S, Clayton, PT, Calvin, J, et al.. Features of carnitine palmitoyltransferase type I deficiency. J Inherit Metab Dis 2001;24:35–42. https://doi.org/10.1023/a:1005694320063 .
Bennett, MJ, Santani, AB. Carnitine palmitoyltransferase 1A deficiency. In: Adam, MP, Feldman, J, Mirzaa, GM, Pagon, RA, Wallace, SE, Bean, LJ, et al., editors. GeneReviews® . Seattle (WA): University of Washington, Seattle; 1993.
Balci, MC, Karaca, M, Selamioglu, A, Korbeyli, HK, Durmus, A, Ak, B, et al.. A different perspective into clinical symptoms in CPT I deficiency. Mol Genet Metab Rep 2024;38:101032. https://doi.org/10.1016/j.ymgmr.2023.101032 . (PMID: 10.1016/j.ymgmr.2023.101032)
Prasad, C, Johnson, JP, Bonnefont, JP, Dilling, LA, Innes, AM, Haworth, JC, et al.. Hepatic carnitine palmitoyl transferase 1 (CPT1 A) deficiency in North American Hutterites (Canadian and American): evidence for a founder effect and results of a pilot study on a DNA-based newborn screening program. Mol Genet Metabol 2001;73:55–63. https://doi.org/10.1006/mgme.2001.3149 . (PMID: 10.1006/mgme.2001.3149)
Clemente, FJ, Cardona, A, Inchley, CE, Peter, BM, Jacobs, G, Pagani, L, et al.. A selective sweep on a deleterious mutation in CPT1A in arctic populations. Am J Hum Genet 2014;95:584–9. https://doi.org/10.1016/j.ajhg.2014.09.016 . (PMID: 10.1016/j.ajhg.2014.09.016)
Greenberg, CR, Dilling, LA, Thompson, GR, Seargeant, LE, Haworth, JC, Phillips, S, et al.. The paradox of the carnitine palmitoyltransferase type Ia P479L variant in Canadian Aboriginal populations. Mol Genet Metabol 2009;96:201–7. https://doi.org/10.1016/j.ymgme.2008.12.018 . (PMID: 10.1016/j.ymgme.2008.12.018)
Stanley, CA, Sunaryo, F, Hale, DE, Bonnefont, JP, Demaugre, F, Saudubray, JM. Elevated plasma carnitine in the hepatic form of carnitine palmitoyltransferase-1 deficiency. J Inherit Metab Dis 1992;15:785–9. https://doi.org/10.1007/bf01800021 . (PMID: 10.1007/bf01800021)
Fingerhut, R, Röschinger, W, Muntau, AC, Dame, T, Kreischer, J, Arnecke, R, et al.. Hepatic carnitine palmitoyltransferase I deficiency: acylcarnitine profiles in blood spots are highly specific. Clin Chem 2001;47:1763–8.
de Sain-van der Velden, MGM, Diekman, EF, Jans, JJ, van der Ham, M, Prinsen, BHCMT, Visser, G, et al.. Differences between acylcarnitine profiles in plasma and bloodspots. Mol Genet Metabol 2013;110:116–21. https://doi.org/10.1016/j.ymgme.2013.04.008 . (PMID: 10.1016/j.ymgme.2013.04.008)
Dowsett, L, Lulis, L, Ficicioglu, C, Cuddapah, S. Utility of genetic testing for confirmation of abnormal newborn screening in disorders of long-chain fatty acids: a missed case of carnitine palmitoyltransferase 1A (CPT1A) deficiency. Int J Neonatal Screen. 2017;3:10. https://doi.org/10.3390/ijns3020010 . (PMID: 10.3390/ijns3020010)
American College of medical genetics and Genomics. https://www.acmg.net/PDFLibrary/C0-C16-C18-Elevated-Algorithm.pdf (Accessed 2024-03-15).
Borch, L, Lund, AM, Wibrand, F, Christensen, E, Søndergaard, C, Gahrn, B, et al.. Normal levels of plasma free carnitine and acylcarnitines in follow-up samples from a presymptomatic case of carnitine palmitoyl transferase 1 (CPT1) deficiency detected through newborn screening in Denmark. JIMD Rep 2012;3:11–5. https://doi.org/10.1007/8904_2011_35 . (PMID: 10.1007/8904_2011_35)
Primassin, S, Spiekerkoetter, U. ESI-MS/MS measurement of free carnitine and its precursor γ-butyrobetaine in plasma and dried blood spots from patients with organic acidurias and fatty acid oxidation disorders. Mol Genet Metabol 2010;101:141–5. https://doi.org/10.1016/j.ymgme.2010.06.012 . (PMID: 10.1016/j.ymgme.2010.06.012)
Reuter, SE, Evans, AM. Carnitine and acylcarnitines: pharmacokinetic, pharmacological and clinical aspects. Clin Pharmacokinet 2012;51:553–72. https://doi.org/10.1007/bf03261931 . (PMID: 10.1007/bf03261931)
Van Hove, JL, Kahler, SG, Feezor, MD, Ramakrishna, JP, Hart, P, Treem, WR, et al.. Acylcarnitines in plasma and blood spots of patients with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase defiency. J Inherit Metab Dis 2000;23:571–82. https://doi.org/10.1023/a:1005673828469 .
Spiekerkoetter, U, Mueller, M, Sturm, M, Hofmann, M, Schneider, DT. Lethal undiagnosed very long-chain acyl-CoA dehydrogenase deficiency with mild C14-acylcarnitine abnormalities on newborn screening. JIMD Rep 2012;6:113–5. https://doi.org/10.1007/8904_2012_129 . (PMID: 10.1007/8904_2012_129)
Evers, C, Seitz, A, Assmann, B, Opladen, T, Karch, S, Hinderhofer, K, et al.. Diagnosis of CoPAN by whole exome sequencing: waking up a sleeping tiger’s eye. Am J Med Genet 2017;173:1878–86. https://doi.org/10.1002/ajmg.a.38252 . (PMID: 10.1002/ajmg.a.38252)
Olpin, SE, Allen, J, Bonham, JR, Clark, S, Clayton, PT, Calvin, J, et al.. Features of carnitine palmitoyltransferase type I deficiency. J Inherit Metab Dis 2001;24:35–42. https://doi.org/10.1023/a:1005694320063 .
Bennett, MJ, Santani, AB. Carnitine palmitoyltransferase 1A deficiency. In: Adam, MP, Feldman, J, Mirzaa, GM, Pagon, RA, Wallace, SE, Bean, LJ, et al., editors. GeneReviews® . Seattle (WA): University of Washington, Seattle; 1993.
Balci, MC, Karaca, M, Selamioglu, A, Korbeyli, HK, Durmus, A, Ak, B, et al.. A different perspective into clinical symptoms in CPT I deficiency. Mol Genet Metab Rep 2024;38:101032. https://doi.org/10.1016/j.ymgmr.2023.101032 . (PMID: 10.1016/j.ymgmr.2023.101032)
Prasad, C, Johnson, JP, Bonnefont, JP, Dilling, LA, Innes, AM, Haworth, JC, et al.. Hepatic carnitine palmitoyl transferase 1 (CPT1 A) deficiency in North American Hutterites (Canadian and American): evidence for a founder effect and results of a pilot study on a DNA-based newborn screening program. Mol Genet Metabol 2001;73:55–63. https://doi.org/10.1006/mgme.2001.3149 . (PMID: 10.1006/mgme.2001.3149)
Clemente, FJ, Cardona, A, Inchley, CE, Peter, BM, Jacobs, G, Pagani, L, et al.. A selective sweep on a deleterious mutation in CPT1A in arctic populations. Am J Hum Genet 2014;95:584–9. https://doi.org/10.1016/j.ajhg.2014.09.016 . (PMID: 10.1016/j.ajhg.2014.09.016)
Greenberg, CR, Dilling, LA, Thompson, GR, Seargeant, LE, Haworth, JC, Phillips, S, et al.. The paradox of the carnitine palmitoyltransferase type Ia P479L variant in Canadian Aboriginal populations. Mol Genet Metabol 2009;96:201–7. https://doi.org/10.1016/j.ymgme.2008.12.018 . (PMID: 10.1016/j.ymgme.2008.12.018)
Stanley, CA, Sunaryo, F, Hale, DE, Bonnefont, JP, Demaugre, F, Saudubray, JM. Elevated plasma carnitine in the hepatic form of carnitine palmitoyltransferase-1 deficiency. J Inherit Metab Dis 1992;15:785–9. https://doi.org/10.1007/bf01800021 . (PMID: 10.1007/bf01800021)
Fingerhut, R, Röschinger, W, Muntau, AC, Dame, T, Kreischer, J, Arnecke, R, et al.. Hepatic carnitine palmitoyltransferase I deficiency: acylcarnitine profiles in blood spots are highly specific. Clin Chem 2001;47:1763–8.
de Sain-van der Velden, MGM, Diekman, EF, Jans, JJ, van der Ham, M, Prinsen, BHCMT, Visser, G, et al.. Differences between acylcarnitine profiles in plasma and bloodspots. Mol Genet Metabol 2013;110:116–21. https://doi.org/10.1016/j.ymgme.2013.04.008 . (PMID: 10.1016/j.ymgme.2013.04.008)
Dowsett, L, Lulis, L, Ficicioglu, C, Cuddapah, S. Utility of genetic testing for confirmation of abnormal newborn screening in disorders of long-chain fatty acids: a missed case of carnitine palmitoyltransferase 1A (CPT1A) deficiency. Int J Neonatal Screen. 2017;3:10. https://doi.org/10.3390/ijns3020010 . (PMID: 10.3390/ijns3020010)
American College of medical genetics and Genomics. https://www.acmg.net/PDFLibrary/C0-C16-C18-Elevated-Algorithm.pdf (Accessed 2024-03-15).
Borch, L, Lund, AM, Wibrand, F, Christensen, E, Søndergaard, C, Gahrn, B, et al.. Normal levels of plasma free carnitine and acylcarnitines in follow-up samples from a presymptomatic case of carnitine palmitoyl transferase 1 (CPT1) deficiency detected through newborn screening in Denmark. JIMD Rep 2012;3:11–5. https://doi.org/10.1007/8904_2011_35 . (PMID: 10.1007/8904_2011_35)
Primassin, S, Spiekerkoetter, U. ESI-MS/MS measurement of free carnitine and its precursor γ-butyrobetaine in plasma and dried blood spots from patients with organic acidurias and fatty acid oxidation disorders. Mol Genet Metabol 2010;101:141–5. https://doi.org/10.1016/j.ymgme.2010.06.012 . (PMID: 10.1016/j.ymgme.2010.06.012)
Reuter, SE, Evans, AM. Carnitine and acylcarnitines: pharmacokinetic, pharmacological and clinical aspects. Clin Pharmacokinet 2012;51:553–72. https://doi.org/10.1007/bf03261931 . (PMID: 10.1007/bf03261931)
Van Hove, JL, Kahler, SG, Feezor, MD, Ramakrishna, JP, Hart, P, Treem, WR, et al.. Acylcarnitines in plasma and blood spots of patients with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase defiency. J Inherit Metab Dis 2000;23:571–82. https://doi.org/10.1023/a:1005673828469 .
Spiekerkoetter, U, Mueller, M, Sturm, M, Hofmann, M, Schneider, DT. Lethal undiagnosed very long-chain acyl-CoA dehydrogenase deficiency with mild C14-acylcarnitine abnormalities on newborn screening. JIMD Rep 2012;6:113–5. https://doi.org/10.1007/8904_2012_129 . (PMID: 10.1007/8904_2012_129)
Evers, C, Seitz, A, Assmann, B, Opladen, T, Karch, S, Hinderhofer, K, et al.. Diagnosis of CoPAN by whole exome sequencing: waking up a sleeping tiger’s eye. Am J Med Genet 2017;173:1878–86. https://doi.org/10.1002/ajmg.a.38252 . (PMID: 10.1002/ajmg.a.38252)
Contributed Indexing:
Keywords: CPT1A; acylcarnitines; carnitine palmitoyltransferase 1A deficiency; dried blood spots; free carnitine; newborn screening
Substance Nomenclature:
S7UI8SM58A (Carnitine)
EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
EC 2.3.1.21 (CPT1A protein, human)
EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
EC 2.3.1.21 (CPT1A protein, human)
SCR Disease Name:
Carnitine palmitoyl transferase 1A deficiency
Entry Date(s):
Date Created: 20250929 Date Completed: 20251202 Latest Revision: 20260127
Update Code:
20260130
DOI:
10.1515/jpem-2025-0382
PMID:
41017303
Database:
MEDLINE
Weitere Informationen
Objectives: Carnitine palmitoyltransferase 1 A (CPT1A) deficiency is an ultra-rare autosomal recessive disorder of the carnitine cycle caused by biallelic pathogenic variants in the CPT1A gene. It mainly presents with a hepatic phenotype and is a target disease of newborn screening programs worldwide. Disease-specific and diagnostic abnormalities of CPT1A deficiency comprise elevated concentrations of free carnitine as well as an elevated metabolite ratio [C0/(C16 + C18)] in blood, but the ideal sample material has been a matter of debate.
Methods: We present biochemical data of five CPT1A deficient patients, of whom four were diagnosed by newborn screening from dried blood spots.
Results: Our cases demonstrate that acylcarnitine profiles and especially concentrations of free carnitine can be normal in plasma in infants with CPT1AD at confirmation diagnosis after screening and during follow-up. Even the [C0/(C16 + C18)] ratio yielded normal results in some cases.
Conclusions: Our data show, that dried blood is the preferred sample material for the diagnosis of CPT1A deficiency as it is superior to serum/plasma with respect to diagnostic sensitivity and reliability in quantification of the ratio [C0/(C16 + C18)]. CPT1A deficiency can be missed, if the analysis is only performed in serum or plasma, and confirmatory diagnostics in serum or plasma after screening can be false negative.
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