Sudden Death of a Four-Day-Old Newborn Due to Mitochondrial Trifunctional Protein/Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiencies and a Systematic Literature Review of Early Deaths of Neonates with Fatty Acid Oxidation Disorders

Abstract

Mitochondrial trifunctional protein (MTP) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiencies have been a part of the Slovenian newborn screening (NBS) program since 2018. We describe a case of early lethal presentation of MTPD/LCHADD in a term newborn. The girl was born after an uneventful pregnancy and delivery, and she was discharged home at the age of 3 days, appearing well. At the age of 4 days, she was found without signs of life. Resuscitation was not successful. The NBS test performed using tandem mass spectrometry (MS/MS) showed a positive screen for MTPD/LCHADD. Genetic analysis performed on a dried blood spot (DBS) sample identified two heterozygous variants in the HADHA gene: a nucleotide duplication introducing a premature termination codon (p.Arg205Ter) and a nucleotide substitution (p.Glu510Gln). Post-mortem studies showed massive macro-vesicular fat accumulation in the liver and, to a smaller extent, in the heart, consistent with MTPD/LCHADD. A neonatal acute cardiac presentation resulting in demise was suspected. We conducted a systematic literature review of early neonatal deaths within 14 days postpartum attributed to confirmed fatty acid oxidation disorders (FAODs), which are estimated to account for 5% of sudden infant deaths. We discuss the pitfalls of the NBS for MTPD/LCHADD.

Keywords: FAOD; LCHAD deficiency; LCHADD; MTP deficiency; MTPD; NBS; fatty acid oxidation disorder; newborn; newborn screening; sudden infant death.

Figure 1

Post-mortem histology tests: diffuse accumulation of fat droplets within the hepatocyte (A–D) and cardiomyocyte (E–H) sections. Arrows show fat accumulation detected on EM (C–F). (A) Liver, HE stain 4× magnification, the orthotopic liver structure is preserved. There is diffuse steatosis, and optically clear vacuoles are present in nearly all hepatocytes. (B) Liver, HE stain 20× magnification, diffuse steatosis. Sinusoids are congested. (C) Liver on EM. (D) Single hepatocyte on EM. (E) Cardiac tissue on EM. (F) Cardiocyte on EM. (G) Myocard, HE stain 4× magnification, the orthotopic structure is preserved. Intracytoplasmatic clear vacuoles (fat droplets) are present within cardiomyocytes. (H) Myocard, HE stain, 20× magnification. Legend: HE stain hematoxylin and eosin stain, M magnification, EM electron microscopy.