Abstract
Background: Primary carnitine deficiency (PCD) is a disorder of fatty acid oxidation with a high prevalence in the Faroe Islands. Only patients homozygous for the c.95A>G (p.N32S) mutation have displayed severe symptoms in the Faroese patient cohort. In this study, we investigated carnitine levels in skeletal muscle, plasma, and urine as well as renal elimination kinetics before and after intermission with l-carnitine in patients homozygous for c.95A>G.
Methods: Five male patients homozygous for c.95A>G were included. Regular l-carnitine supplementation was stopped and the patients were observed during five days. Blood and urine were collected throughout the study. Skeletal muscle biopsies were obtained at 0, 48, and 96 h.
Results: Mean skeletal muscle free carnitine before discontinuation of l-carnitine was low, 158 nmol/g (SD 47.4) or 5.4% of normal. Mean free carnitine in plasma (fC0) dropped from 38.7 (SD 20.4) to 6.3 (SD 1.7) μmol/L within 96 h (p < 0.05). Mean T 1/2 following oral supplementation was approximately 9 h. Renal reabsorption of filtered carnitine following oral supplementation was 23%. The level of mean free carnitine excreted in urine correlated (R 2 = 0.78, p < 0.01) with fC0 in plasma.
Conclusion: Patients homozygous for the c.95A>G mutation demonstrated limited skeletal muscle carnitine stores despite long-term high-dosage l-carnitine supplementation. Exacerbated renal excretion resulted in a short T 1/2 in plasma carnitine following the last oral dose of l-carnitine. Thus a treatment strategy of minimum three daily separate doses of l-carnitine is recommended, while intermission with l-carnitine treatment might prove detrimental.
Competing interests: None declared
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Bergstrom J (1975) Percutaneous needle biopsy of skeletal muscle in physiological and clinical research. Scand J Clin Lab Invest 35(7):609–616
Cano A, Ovaert C, Vianey-Saban C et al (2008) Carnitine membrane transporter deficiency: a rare treatable cause of cardiomyopathy and anemia. Pediatr Cardiol 29(1):163–165
Engel AG, Rebouche CJ, Wilson DM et al (1981) Primary systemic carnitine deficiency. II. Renal handling of carnitine. Neurology 31(7):819–825
Evans AM, Faull R, Fornasini G et al (2000) Pharmacokinetics of L-carnitine in patients with end-stage renal disease undergoing long-term hemodialysis. Clin Pharm Ther 68(3):238–249
Flanagan JL, Simmons PA, Vehige J et al (2010) Role of carnitine in disease. Nutr Metab 7:30
Lang RM, Bierig M, Devereux RB et al (2005) Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 18(12):1440–1463
Longo N, di San A, Filippo C, Pasquali M (2006) Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet 142C(2):77–85
Lund AM, Joensen F, Hougaard DM et al (2007) Carnitine transporter and holocarboxylase synthetase deficiencies in The Faroe Islands. J Inherit Metab Dis 30(3):341–349
Madsen KL, Preisler N, Orngreen MC et al (2013) Patients with medium-chain acyl-coenzyme a dehydrogenase deficiency have impaired oxidation of fat during exercise but no effect of L-carnitine supplementation. J Clin Endocrinol Metab 98(4):1667–1675
Magoulas PL, El-Hattab AW (2012) Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management. Orphanet J Rare Dis 7:68
Nezu J, Tamai I, Oku A et al (1999) Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nat Genet 21(1):91–94
Rasmussen J, Nielsen OW, Lund AM et al (2013) Primary carnitine deficiency and pivalic acid exposure causing encephalopathy and fatal cardiac events. J Inherit Metab Dis 36(1):35–41
Rasmussen J, Kober L, Lund AM et al (2014a) Primary Carnitine deficiency in the Faroe Islands: health and cardiac status in 76 adult patients diagnosed by screening. J Inherit Metab Dis 37(2):223–230
Rasmussen J, Nielsen OW, Janzen N et al (2014b) Carnitine levels in 26,462 individuals from the nationwide screening program for primary carnitine deficiency in the Faroe Islands. J Inherit Metab Dis 37(2):215–222
Rasmussen J, Lund AM, Risom L et al (2014c) Residual OCTN2 transporter activity, carnitine levels and symptoms correlate in patients with primary carnitine deficiency. Mol Genet Metab Reports 1:241–248
Rebouche CJ (2004) Kinetics, pharmacokinetics, and regulation of L-carnitine and acetyl-L-carnitine metabolism. Ann N Y Acad Sci 1033:30–41
Rebouche CJ, Lombard KA, Chenard CA (1993) Renal adaptation to dietary carnitine in humans. Am J Clin Nutr 58(5):660–665
Reuter SE, Evans AM (2012) Carnitine and acylcarnitines: pharmacokinetic, pharmacological and clinical aspects. Clin Pharmacokinet 51(9):553–572
Reuter SE, Evans AM, Chace DH et al (2008) Determination of the reference range of endogenous plasma carnitines in healthy adults. Ann Clin Biochem 45(Pt 6):585–592
Scaglia F, Wang Y, Singh RH et al (1998) Defective urinary carnitine transport in heterozygotes for primary carnitine deficiency. Genet Med 1(1):34–39
Shoji Y, Koizumi A, Kayo T et al (1998) Evidence for linkage of human primary systemic carnitine deficiency with D5S436: a novel gene locus on chromosome 5q. Am J Hum Genet 63(1):101–108
Stanley CA (2004) Carnitine deficiency disorders in children. Ann N Y Acad Sci 1033:42–51
Stanley CA, DeLeeuw S, Coates PM et al (1991) Chronic cardiomyopathy and weakness or acute coma in children with a defect in carnitine uptake. Ann Neurol 30(5):709–716
Steiber A, Kerner J, Hoppel CL (2004) Carnitine: a nutritional, biosynthetic, and functional perspective. Mol Aspects Med 25(5–6):455–473
Tein I (2003) Carnitine transport: pathophysiology and metabolism of known molecular defects. J Inherit Metab Dis 26(2–3):147–169
Acknowledgments
The authors would like to thank the participants for their committed effort, the Faroese Biobank for its support, and the technical staff in the National Hospital of the Faroe Islands for their skillful assistance.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Daniela Karall
Appendices
Compliance with Ethics Guidelines
Conflict of Interest
Jan Rasmussen, Jákup A. Thomsen, Jess H. Olesen, Trine M. Lund, Magni Mohr, Jón Clementsen, Olav W. Nielsen, and Allan M. Lund have no conflicts of interest to report.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study. Proof that informed consent was obtained is available upon request.
Contributions of Individual Authors
Jan Rasmussen: First author and involved in all aspects of the work including conception, design, recruiting patients, analysis, and drafting of the manuscript. Guarantor of the article.
Jákup A. Thomsen: Involved in recruiting patients, collecting data, and critical revision of the manuscript.
Jess H. Olesen: Analyzed blood, skeletal muscle, and urine for carnitine and was also involved in critically revising the manuscript.
Trine M. Lund: Involved in design, pharmacokinetic analyses, and critical revision of the manuscript.
Magni Mohr: Involved in collecting data, performed the muscle biopsies, and revised the manuscript critically.
Jón Clementsen: Involved in collecting data and biomaterial and critically revising the manuscript.
Olav W. Nielsen: Involved in design, analysis, and critical revision of the manuscript.
Allan M. Lund: Involved in conception, design, analysis of data, and critically revising the manuscript.
Rights and permissions
Copyright information
© 2014 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Rasmussen, J. et al. (2014). Carnitine Levels in Skeletal Muscle, Blood, and Urine in Patients with Primary Carnitine Deficiency During Intermission of l-Carnitine Supplementation. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 20. JIMD Reports, vol 20. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_398
Download citation
DOI: https://doi.org/10.1007/8904_2014_398
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-46699-5
Online ISBN: 978-3-662-46700-8
eBook Packages: MedicineMedicine (R0)