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Clinical and biological features at diagnosis in mitochondrial fatty acid beta-oxidation defects: a French pediatric study of 187 patients

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Introduction

Mitochondrial fatty acid β-oxidation defects (FAODs) are a group of severe inherited metabolic diseases, most of which can be treated with favorable prognosis following diagnosis. A description of the broad range of phenotypes resulting from these defects remains incomplete, and for this study, we sought to investigate the semiology at diagnosis in a country without a newborn screening program for FAODs.

Methods

Using a retrospective French multicentre study, we analyzed 187 children aged <6 years at diagnosis with FAOD confirmed by enzymatic and/or molecular analyses. Clinical and biological parameters at diagnosis were assessed to screen liver, heart, neurological, and muscle symptoms. Information concerning the long-term prognosis was also collected.

Results

Predominant hepatic symptoms were observed in 89 % of patients regardless of the underlying defect. The most frequent symptoms observed were hepatomegaly (92 %), increased blood alanine aminotransferase (ALAT) level (82 %), and steatosis (88 %). Other frequent features included Reye syndrome (49 %), increased gamma-glutamyltranspeptidase (GGT) (37 %), and liver failure (27 %). Extrahepatic features were often associated in the foreground. Hypoglycemia (75 %), neurological (64 %), muscle (61 %), or cardiac features (55 %) [as either cardiomyopathy (47 %) or arrhythmias (31 %)] were frequently documented. Hemodynamic events (41 %) were represented by shock (31 %) or sudden death (35 %). Hyperammonemia (73 %) and hyperlactacidemia (57 %) were the two main biochemical features. Total, very-long-chain acyl-CoA dehydrogenase (VLCADD), long-chain 3-hydroxyacylCoA dehydrogenase (LCHADD), and medium-chain acyl-CoA dehydrogenase (MCADD) deficiency mortality rates were 48 %, 60 %, 63 %, and 20 % respectively.

Conclusion

This study presents clinical features of a large cohort of patients with FAODs in a country without neonatal screening for FAODs. Our results highlight liver as the main organ involved at diagnosis regardless of age at diagnosis, classical phenotype (i.e., cardiac, hepatic, or muscular), or enzyme deficiency. Although steatosis may be observed in various inherited metabolic defects, it is a reliable indicator of FAOD and should prompt systematic screening when the diagnosis is suspected. The poor long-term prognoses reported are a strong argument for inclusion of FAODs in newborn screening programs.

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Abbreviations

AFLP:

Acute fatty liver of pregnancy

ALAT:

Alanine aminotransferase

CACT:

Carnitine acylcarnitine translocase

CMP:

Cardiomyopathy

CPTI:

Carnitine palmitoyl transferase I

CPTII:

Carnitine palmitoyl transferase II

CTD:

Carnitine transporter defect

FAO:

Fatty acid β-oxidation

FAODs:

FAO defects

GGT:

Gamma-glutamyl transpeptidase

HELLP syndrome:

Hemolysis–liver–low platelets

KB:

Ketone bodies

LCHAD:

Long-chain 3-hydroxyacyl-CoA dehydrogenase

LCHADD:

LCHAD deficiency

MADD:

Multiple acyl-CoA dehydrogenase deficiency

MCAD:

Medium-chain acyl-CoA dehydrogenase deficiency

MCADD:

MCAD deficiency

MTP:

Mitochondrial trifunctional protein

NSP:

Newborn screening program

PPAR-α:

Peroxisome proliferator activated receptor alpha

PT:

Prothrombin time

ROS:

Reactive oxygen species

VLCAD:

Very-long-chain acyl-CoA dehydrogenase

VLCADD:

VLCAD deficiency

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Acknowledgements

Mr. Laouamri for statistical assistance, Robert Debré Hospital, Paris, France; Dr. Emma Footitt for English review, Great Ormond Street Hospital, London, United Kingdom; Dr. Benoist, Robert Debré Hospital, Paris, France; Pr. Billette de Villemeur, Trousseau Hospital, Paris, France; Pr. Chabrol, University Hospital, Marseille, France; Dr. Cano, University Hospital, Marseille, France; Dr. Coupe, Local Hospital, Vesoul, France; Dr. Garcia, University Hospital, Marseille, France; Dr. Gay, University Hospital, St Etienne, France; Pr. Gouyon, University Hospital, Dijon, France; Dr. Küster, University Hospital, Nantes, France; Pr. Labarthe, University Hospital, Tours, France; Dr. Lamireau, University Hospital, Bordeaux, France; Pr. de Lonlay, Necker Hospital, Paris, France; Dr. Masurel, University Hospital, Dijon, France; Dr. Patural, University Hospital, St Etienne, France; Dr. Peralta, Local Hospital, Mulhouse, France; Dr. Poujol, Local Hospital, Aix en Provence, France; Pr. Tardieu, Bicêtre Hospital, Paris, France; Dr. Rigal, Robert Debré Hospital, Paris, France; Dr. Terral, University Hospital, Clermont Ferrand, France; Dr. Touati, Necker Hospital, Paris, France; Dr. Valayannopoulos, Necker Hospital, Paris, France for support with the data collection.

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Correspondence to Julien Baruteau.

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Communicated by: Ronald J.A. Wanders

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Baruteau, J., Sachs, P., Broué, P. et al. Clinical and biological features at diagnosis in mitochondrial fatty acid beta-oxidation defects: a French pediatric study of 187 patients. J Inherit Metab Dis 36, 795–803 (2013). https://doi.org/10.1007/s10545-012-9542-6

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  • DOI: https://doi.org/10.1007/s10545-012-9542-6

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