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Follow-up of fatty acid β-oxidation disorders in expanded newborn screening era

  • Patrícia JaneiroEmail author
  • Rita Jotta
  • Ruben Ramos
  • Cristina Florindo
  • Fátima V. Ventura
  • Laura Vilarinho
  • Isabel Tavares de Almeida
  • Ana Gaspar
Original Article

Abstract

Fatty acid β-oxidation (FAO) disorders have a wide variety of symptoms, not usually evident between episodes of acute decompensations. Cardiac involvement is frequent, and severe ventricular arrhythmias are suspected of causing sudden death. Expanded newborn screening (ENS) for these disorders, hopefully, contribute to prevent potentially acute life-threatening events. In order to characterize acute decompensations observed in FAO-deficient cases identified by ENS, a retrospective analysis was performed, covering a period of 9 years. Demographic data, number/type of acute decompensations, treatment, and follow-up were considered. Eighty-three clinical charts, including 66 medium-chain acyl-CoA dehydrogenase deficiency (MCADD), 5 carnitine-uptake deficiency (CUD), 3 carnitine palmitoyltransferase I and II (CPT I/II) deficiency, 5 very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), and 4 multiple acyl-CoA dehydrogenase deficiency (MADD) cases were reviewed. Nineteen patients had acute decompensations (1 CPT I, 1 CPT II, 3 MADD, 14 MCADD). Six patients developed symptoms previously to ENS diagnosis. Severe clinical manifestations included multiple organ failure, liver failure, heart failure, and sudden death. Long-chain FAO disorders had the highest number of decompensations per patient.

Conclusion: Despite earlier diagnosis by ENS, sudden deaths were not avoided and acute decompensations with severe clinical manifestations still occur as well.

What is Known:

Severe ventricular arrhythmias are suspected to cause unexpected death in FAO disorders.

Neonatal screening intends to reduce the incidence of severe metabolic crisis and death.

What is New:

Acute severe decompensations occurred in FAO disorders diagnosed through neonatal screening.

Sudden deaths were not avoided by starting treatment precociously.

Keywords

Fatty acid ß-oxidation disorders Acute decompensations Sudden death 

Abbreviations

CK

Creatine kinase

CK-MB

Creatine kinase muscle and brain subunits

CPT I

Carnitine palmitoyltransferase I

CPT II

Carnitine palmitoyltransferase II

CUD

Carnitine-uptake deficiency

DBS

Dry blood spot

DMD

Duchenne muscular dystrophy

ENS

Expanded newborn screening

FAO

Fatty acid β-oxidation

LC-FAO

Long-chain fatty acid oxidation disorders

MADD

Multiple acyl-CoA dehydrogenase deficiency

MCADD

Medium-chain acyl-CoA dehydrogenase deficiency

R.V.

Refference values

VLCADD

Very long-chain acyl-CoA dehydrogenase deficiency

Notes

Authors’ Contributions

The planning, carrying out, and reporting of the work was done by Patrícia Janeiro with guidance from Isabel Tavares de Almeida. Rita Jotta had a major contribution in data collection. Ruben Ramos and Fátima Ventura contributed with biochemical and molecular studies. Laura Vilarinho provided neonatal screening data. Ana Gaspar provided clinical outcome data and contributed in the article review process.

Compliance with ethical statements

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

This article does not contain any studies with human participants or animals performed by any of the authors. For this type of study, formal consent is not required.

References

  1. 1.
    Tucci S, Herebian D, Sturm M, Seibt A, Spiekerkoetter U (2012) Tissue-specific strategies of the very-long chain acyl-CoA dehydrogenase-deficient (VLCAD −/−) mouse to compensate a defective fatty acid β-oxidation. PLoS One 7(1–9):e45429.  https://doi.org/10.1371/journal.pone.0045429 CrossRefGoogle Scholar
  2. 2.
    Moczulski D, Majak I, Mamczur D (2009) An overview of β-oxidation disorders. Postepy Hig Med Dosw 63:266–277Google Scholar
  3. 3.
    Cox K, Liu J, Tian L, Barnes S, Yang Q, Wood P (2009) Cardiac hypertrophy in mice with long-chain acyl-CoA dehydrogenase (LCAD) or very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. NIH 89(12):1348–1354.  https://doi.org/10.1038/labinvest.2009.86 Google Scholar
  4. 4.
    Gélinas R, Thompson-Legault J, Bouchard B, Daneault C, Mansour A, Gillis MA, Charron G, Gavino V, Labarthe F, Des Rosiers C (2011) Prolonged QT interval and lipid alterations beyond b-oxidation in very long-chain acyl-CoA dehydrogenase null mouse hearts. Am J Physiol Heart Circ Physiol 301(3):H813–H823.  https://doi.org/10.1152/ajpheart.01275.2010 CrossRefGoogle Scholar
  5. 5.
    Fu L, Huang M, Chen S (2013) Primary carnitine deficiency and cardiomyopathy. Korean Circ J 43:785–792.  https://doi.org/10.4070/kcj.2013.43.12.785 CrossRefGoogle Scholar
  6. 6.
    Houten SM, Violante S, Ventura FV, Wanders RJA (2016) The biochemistry and physiology of mitochondrial fatty acid β-oxidation and its genetic disorders. Annu Rev Physiol 78:23–44CrossRefGoogle Scholar
  7. 7.
    Wiles J, Leslie N, Knilans T, Akinbi H (2014) Prolonged QTc interval in association with medium-chain acyl-coenzyme a dehydrogenase deficiency. Pediatrics 133(6):e1781–e1786.  https://doi.org/10.1542/peds.2013-1105 CrossRefGoogle Scholar
  8. 8.
    Bonnet D, Martin D, De Lonlay P, Villain E, Jouvet P, Rabier D, Brivet M, Saudubray JM (1999) Arrhytmias and conduction effects as presenting symptoms of fatty acid oxidation disorders in children. Circulation 100:2248–2253.  https://doi.org/10.1161/01.CIR.100.22.2248 CrossRefGoogle Scholar
  9. 9.
    Spiekerkoetter U (2010) Mithocondrial fatty acid oxidation disorders: clinical presentation of long-chain fatty ocid oxidation deffects before and after newborn screening. J Inherit Metab Dis 33:527–532.  https://doi.org/10.1007/s10545-010-9090-x CrossRefGoogle Scholar
  10. 10.
    Andresen B, Lund A, Hougaard D et al (2012) MCAD deficiency in Denmark. Mol Genet Metab 106:175–188.  https://doi.org/10.1016/j.ymgme.2012.03.018 CrossRefGoogle Scholar
  11. 11.
    Vilarinho L, Diogo L, Costa P (2017) Programa Nacional de Diagnóstico Precoce. 2016 Report. INSA, IP, Lisbon http://hdl.handle.net/10400.18/4932 Google Scholar
  12. 12.
    Yusupov R, Finegold D, Naylor E, Sahai I, Waisbren S, Lavy H (2010) Sudden death in medium chain acyl-coenzyme A dehydrogenase deficiency despite newborn screening. Mol Genet Metab 101:33–39.  https://doi.org/10.1016/j.ymgme.2010.05.007 CrossRefGoogle Scholar
  13. 13.
    Wilcken B (2010) Fatty acid oxidation disorders: outcome and long-term prognosis. J Inherit Metab Dis 33:501–506.  https://doi.org/10.1007/s10545-009-9001-1 CrossRefGoogle Scholar
  14. 14.
    Merritt J, Vedal S, Abdenur J et al (2014) Infants suspected to have very-long chain acyl-CoA dehydrogenase deficiency from newborn screening. Mol Genet Metab 4c:1–9.  https://doi.org/10.1016/j.ymgme.2014.01.009. Google Scholar
  15. 15.
    Vilarinho L, Rocha H, Sousa C, Marcão A, Fonseca H, Bogas M, Osório RV (2010) Four years of expanded newborn screening in Portugal with tandem mass spectrometry. J Inherit Metab Dis 33(3):S133–S138.  https://doi.org/10.1007/s10545-010-9048-z CrossRefGoogle Scholar
  16. 16.
    Ahrens-Nicklas R, Pyle L, Ficicioglu C (2016) Morbidity and mortality among exclusively breastfed neonates with medium-chain acyl-CoA dehydrogenase deficiency. Genet Med 18(12):1315–1319.  https://doi.org/10.1038/gim.2016.49 CrossRefGoogle Scholar
  17. 17.
    Schatz U, Ensenauer R (2010) The clinical manifestation of MCAD deficiency: challenges towards adulthood in the screened population. J Inherit Metab Dis 33:513–520.  https://doi.org/10.1007/s10545-010-9115-5 CrossRefGoogle Scholar
  18. 18.
    Ventura FV, Leandro P, al LA e (2014) Retrospective study of the medium chain acyl-CoA dehydrogenase deficiency in Portugal. Clin Genet 85:551–561.  https://doi.org/10.1111/cge.12227 CrossRefGoogle Scholar
  19. 19.
    Dessein A, Fontaine M, Andresen B et al (2010) A novel mutation of the ACADM gene (c.145C>G) associated with the common c.985A>G mutation on the other ACADM allele causes mild MCAD deficiency: a case report. Orphanet J Rare Dis 5(26):1–9.  https://doi.org/10.1186/1750-1172-5-26. Google Scholar
  20. 20.
    Jank JM, Maier EM, Reiβ DD, Haslbeck M, Kemter KF, Truger MS, Sommerhoff CP, Ferdinandusse S, Wanders RJ, Gersting SW, Muntau AC (2014) The domain-specific and temperature-dependent protein misfolding phenotype of variant medium-chain acyl-CoA dehydrogenase. PLoS One 9(4):e93852.  https://doi.org/10.1371/journal.pone.0093852 CrossRefGoogle Scholar
  21. 21.
    Bonito CA, Nunes J, Leandro J, Louro F, Leandro P, Ventura FV, Guedes RC (2016) Unvealing the pathogenic molecular mechanisms of the most common variant (pK329E) in medium-chain acyl-CoA dehydrogenase deficiency by in vitro and in silico approaches. Biochemistry 55(51):7086–7098.  https://doi.org/10.1021/acs.biochem.6b00759. CrossRefGoogle Scholar
  22. 22.
    Nennstiel-Ratzel U, Arenz S, Maier EM, Knerr I, Baumkötter J, Röschinger W, Liebl B, Hadorn HB, Roscher AA, von Kries R (2005) Reduced incidence of severe metabolic crises or death in children with medium chain acyl –CoA dehydrogenase deficiency homozygous for c.985A>G identified by neonatal sreening. Mol Genet Metab 85:157–151.  https://doi.org/10.1016/j.ymgme.2004.12.010 CrossRefGoogle Scholar
  23. 23.
    Bakermans AJ, Geraedts TR, van Weeghel M, Denis S, João Ferraz M, Aerts JM, Aten J, Nicolay K, Houten SM, Prompers JJ (2011) Fasting-induced myocardial lipid accumulation in long-chain acyl-CoA dehydrogenase knockout mice is accompanied by impaired left ventricular fuction. Circ Cardiovasc Imaging 4:558–565.  https://doi.org/10.1161/CIRCIMAGING.111.963751 CrossRefGoogle Scholar
  24. 24.
    Lovera C, Porta F, Caciotti A, Catarzi S, Cassanello M, Caruso U, Gallina MR, Morrone A, Spada M (2012) Sudden unexpected infant death (SUDI) in a newborn due to medium chain acyl CoA dehydrogenase (MACD) deficiency with an unusual severe genotype. Ital J Pediatr 38(59):1–3.  https://doi.org/10.1186/1824-7288-38-59 Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Patrícia Janeiro
    • 1
    Email author return OK on get
  • Rita Jotta
    • 2
  • Ruben Ramos
    • 3
  • Cristina Florindo
    • 3
  • Fátima V. Ventura
    • 3
  • Laura Vilarinho
    • 4
  • Isabel Tavares de Almeida
    • 3
  • Ana Gaspar
    • 1
  1. 1.Centro de Referência de Doenças Hereditárias do Metabolismo, Departamento de Pediatria MédicaHospital de Santa Maria – CHULNLisbonPortugal
  2. 2.Serviço de Pediatria Médica, Departamento de PediatriaHospital de Santa Maria – CHULNLisbonPortugal
  3. 3.Laboratório de Metabolismos e GenéticaFaculdade de Farmácia da Universidade de LisboaLisbonPortugal
  4. 4.Unidade de Rastreio Neonatal Metabolismo e Genética, Departamento de Genética HumanaInstituto Nacional de Saúde Dr. Ricardo JorgePortoPortugal

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