The decision to discontinue screening for carnitine uptake disorder in New Zealand

  • Callum Wilson
  • Detlef Knoll
  • Mark de Hora
  • Campbell Kyle
  • Emma Glamuzina
  • Dianne Webster
Original Article


When screening for carnitine uptake disorder (CUD), the New Zealand (NZ) newborn screening (NBS) service identified infants as screen-positive if they had initial and repeat free carnitine (C0) levels of less than 5.0 μmol/L. Since 2006, the NBS service has identified two infants with biochemical and genetic features consistent with neonatal CUD and nine mothers with features consistent with maternal CUD. A review of the literature suggests that these nine women reflect less than half the true prevalence and that CUD is relatively common. However, the NZ results (two infants) suggest a very low sensitivity and positive predictive value of NBS. While patients presenting with significant disease due to CUD are well described, the majority of adults with CUD are asymptomatic. Nonetheless, treatment with high-dose oral L-carnitine is recommended. Compliance with oral L-carnitine is likely to be poor long term. This may represent a specific risk as treatment could repress the usual compensatory mechanisms seen in CUD, such that a sudden discontinuation of treatment may be dangerous. L-carnitine is metabolized to trimethylamine-N-oxide (TMAO) and treated patients have extremely high plasma TMAO levels. TMAO is an independent risk factor for atherosclerosis and, thus, caution should be exercised regarding long-term treatment with high-dose carnitine of asymptomatic patients who may have a biochemical profile without disease. Due to these concerns, the NZ Newborn Metabolic Screening Programme (NMSP) initiated a review via a series of advisory and governance committees and decided to discontinue screening for CUD.


Compliance with ethical standards

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.

Conflict of interest

Dr. Callum Wilson, Mr. Detlef Knoll, Mr. Mark de Hora, Dr. Campbell Kyle, Dr. Emma Glamuzina, and Dr. Dianne Webster declare that they have no conflict of interest.


  1. Abegaz TM, Shehab A, Gebreyohannes EA, Bhagavathula AS, Elnour AA (2017) Nonadherence to antihypertensive drugs: a systematic review and meta-analysis. Medicine (Baltimore) 96:e5641CrossRefGoogle Scholar
  2. Amat di San Filippo C, Pasquali M, Longo N (2006) Pharmacological rescue of carnitine transport in primary carnitine deficiency. Hum Mutat 27:513–523CrossRefPubMedGoogle Scholar
  3. Aron-Wisnewsky J, Clément K (2016) The gut microbiome, diet, and links to cardiometabolic and chronic disorders. Nat Rev Nephrol 12:169–181CrossRefPubMedGoogle Scholar
  4. Bae S, Ulrich CM, Neuhouser ML et al (2014) Plasma choline metabolites and colorectal cancer risk in the Women’s Health Initiative Observational Study. Cancer Res 74:7442–7452CrossRefPubMedPubMedCentralGoogle Scholar
  5. Christodoulou J, Teo SH, Hammond J et al (1996) First prenatal diagnosis of the carnitine transporter defect. Am J Med Genet 66:21–24CrossRefPubMedGoogle Scholar
  6. Couce ML, Castiñeiras DE, Bóveda MD et al (2011) Evaluation and long-term follow-up of infants with inborn errors of metabolism identified in an expanded screening programme. Mol Genet Metab 104:470–475Google Scholar
  7. Dixon MA, Leonard JV (1992) Intercurrent illness in inborn errors of intermediary metabolism. Arch Dis Child 67:1387–1391CrossRefPubMedPubMedCentralGoogle Scholar
  8. Hoffmann GF, von Kries R, Klose D et al (2004) Frequencies of inherited organic acidurias and disorders of mitochondrial fatty acid transport and oxidation in Germany. Eur J Pediatr 163:76–80CrossRefPubMedGoogle Scholar
  9. Knapp AC, Todesco L, Torok M, Beier K, Krähenbühl S (2008) Effect of carnitine deprivation on carnitine homeostasis and energy metabolism in mice with systemic carnitine deficiency. Ann Nutr Metab 52:136–144CrossRefPubMedGoogle Scholar
  10. Koeth RA, Wang Z, Levison BS et al (2013) Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19:576–585CrossRefPubMedPubMedCentralGoogle Scholar
  11. Lahrouchi N, Lodder EM, Mansouri M et al (2017) Exome sequencing identifies primary carnitine deficiency in a family with cardiomyopathy and sudden death. Eur J Hum Genet 25:783–787CrossRefPubMedGoogle Scholar
  12. Lamhonwah AM, Olpin SE, Pollitt RJ et al (2002) Novel OCTN2 mutations: no genotype–phenotype correlations: early carnitine therapy prevents cardiomyopathy. Am J Med Genet 111:271–284CrossRefPubMedGoogle Scholar
  13. Lee NC, Tang NLS, Chien YH et al (2010) Diagnoses of newborns and mothers with carnitine uptake defects through newborn screening. Mol Genet Metab 100:46–50CrossRefPubMedGoogle Scholar
  14. Lindner M, Gramer G, Haege G et al (2011) Efficacy and outcome of expanded newborn screening for metabolic diseases—report of 10 years from South-West Germany. Orphanet J Rare Dis 6:44CrossRefPubMedPubMedCentralGoogle Scholar
  15. Melegh B, Bene J, Mogyorósy G et al (2004) Phenotypic manifestations of the OCTN2 V295X mutation: sudden infant death and carnitine-responsive cardiomyopathy in Roma families. Am J Med Genet A 131:121–126CrossRefPubMedGoogle Scholar
  16. Miller MJ, Bostwick BL, Kennedy AD et al (2016) Chronic oral L-carnitine supplementation drives marked plasma TMAO elevations in patients with organic acidemias despite dietary meat restrictions. JIMD Rep 30:39–44CrossRefPubMedPubMedCentralGoogle Scholar
  17. Mutlu-Albayrak H, Bene J, Oflaz MB, Tanyalçın T, Çaksen H, Melegh B (2015) Identification of SLC22A5 gene mutation in a family with carnitine uptake defect. Case Rep Genet 2015:259627PubMedPubMedCentralGoogle Scholar
  18. 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 21:91–94CrossRefPubMedGoogle Scholar
  19. Phan K, Gomez YH, Elbaz L, Daskalopoulou SS (2014) Statin treatment non-adherence and discontinuation: clinical implications and potential solutions. Curr Pharm Des 20:6314–6324CrossRefPubMedGoogle Scholar
  20. Rasmussen J, Køber L, Lund AM, Nielsen OW (2014) Primary carnitine deficiency in the Faroe Islands: health and cardiac status in 76 adult patients diagnosed by screening. J Inherit Metab Dis 37:223–230CrossRefPubMedGoogle Scholar
  21. Rasmussen J, Thomsen JA, Olesen JH et al (2015) Carnitine levels in skeletal muscle, blood, and urine in patients with primary carnitine deficiency during intermission of L-carnitine supplementation. JIMD Rep 20:103–111CrossRefPubMedPubMedCentralGoogle Scholar
  22. Rasmussen J, Hougaard DM, Sandhu N et al (2017) Primary carnitine deficiency: is foetal development affected and can newborn screening be improved? JIMD Rep 36:35–40CrossRefPubMedPubMedCentralGoogle Scholar
  23. Sabater-Molina M, Pérez-Sánchez I, Hernández Del Rincón JP, Gimeno JR (2018) Genetics of hypertrophic cardiomyopathy: a review of current state. Clin Genet 93:3–14CrossRefPubMedGoogle Scholar
  24. Schimmenti LA, Crombez EA, Schwahn BC et al (2007) Expanded newborn screening identifies maternal primary carnitine deficiency. Mol Genet Metab 90:441–445CrossRefPubMedGoogle Scholar
  25. Schmidt JL, Castellanos-Brown K, Childress S et al (2012) The impact of false-positive newborn screening results on families: a qualitative study. Genet Med 14:76–80CrossRefPubMedGoogle Scholar
  26. 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 30:709–716CrossRefPubMedGoogle Scholar
  27. Steuerwald U, Lund AM, Rasmussen J, Janzen N, Hougaard DM, Longo N (2017) Neonatal screening for primary carnitine deficiency: lessons learned from the Faroe Islands. Int J Neonatal Screen 3:1CrossRefGoogle Scholar
  28. Suenaga M, Kuwajima M, Himeda T et al (2004) Identification of the up- and down-regulated genes in the heart of juvenile visceral steatosis mice. Biol Pharm Bull 27:496–503CrossRefPubMedGoogle Scholar
  29. Suzuki T, Heaney LM, Bhandari SS, Jones DJ, Ng LL (2016) Trimethylamine N-oxide and prognosis in acute heart failure. Heart 102:841–848CrossRefPubMedGoogle Scholar
  30. Tang WH, Hazen SL (2014) The contributory role of gut microbiota in cardiovascular disease. J Clin Investig 124:4204–4211Google Scholar
  31. Tang WHW, Wang Z, Levison BS et al (2013) Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 368:1575–1584CrossRefPubMedPubMedCentralGoogle Scholar
  32. Treem WR, Stanley CA, Finegold DN, Hale DE, Coates PM (1988) Primary carnitine deficiency due to a failure of carnitine transport in kidney, muscle, and fibroblasts. N Engl J Med 319:1331–1336CrossRefPubMedGoogle Scholar
  33. Uenaka R, Kuwajima M, Ono A et al (1996) Increased expression of carnitine palmitoyltransferase I gene is repressed by administering L-carnitine in the hearts of carnitine-deficient juvenile visceral steatosis mice. J Biochem 119:533–540CrossRefPubMedGoogle Scholar
  34. Waisbren SE, Landau Y, Wilson J, Vockley J (2013) Neuropsychological outcomes in fatty acid oxidation disorders: 85 cases detected by newborn screening. Dev Disabil Res Rev 17:260–268CrossRefPubMedPubMedCentralGoogle Scholar
  35. Wang Y, Korman SH, Ye J et al (2001) Phenotype and genotype variation in primary carnitine deficiency. Genet Med 3:387–392CrossRefPubMedGoogle Scholar
  36. Wilcken B, Wiley V, Sim KG, Carpenter K (2001) Carnitine transporter defect diagnosed by newborn screening with electrospray tandem mass spectrometry. J Pediatr 138:581–584CrossRefPubMedGoogle Scholar
  37. Wilcken B, Haas M, Joy P et al (2009) Expanded newborn screening: outcome in screened and unscreened patients at age 6 years. Pediatrics 124:e241–e248CrossRefPubMedGoogle Scholar
  38. Wilson JMG, Jungner G (1968) Principles and practice of screening for disease. World Health Organization, Geneva. Available from: Google Scholar
  39. Yamak A, Bitar F, Karam P, Nemer G (2007) Exclusive cardiac dysfunction in familial primary carnitine deficiency cases: a genotype-phenotype correlation. Clin Genet 72:59–62Google Scholar

Copyright information

© SSIEM 2018

Authors and Affiliations

  1. 1.National Metabolic ServiceStarship Children’s HospitalAucklandNew Zealand
  2. 2.Newborn Metabolic Screening UnitAuckland City HospitalAucklandNew Zealand
  3. 3.Newborn Metabolic Screening ProgrammeLabPlus Auckland City HospitalAucklandNew Zealand
  4. 4.LabPlus Auckland City HospitalAucklandNew Zealand

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