Fetal Fatty Acid Oxidation Disorders, Their Effect on Maternal Health and Neonatal Outcome: Impact of Expanded Newborn Screening on Their Diagnosis and Management

Abstract

Mitochondrial fatty acid oxidation disorders (FAOD) are recessively inherited errors of metabolism. Newborns with FAOD typically present with hypoketotic hypoglycemia, metabolic acidosis, hepatic failure, and cardiomyopathy. Late presentations include episodic myopathy, neuropathy, retinopathy, and arrhythmias. Sudden unexpected death can occur at any age and can be confused with sudden infant death syndrome. Some FAOD are associated with intrauterine growth restriction, prematurity, and pregnancy complications in the heterozygous mother, such as severe preeclampsia, acute fatty liver of pregnancy (AFLP), or hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Maternal pregnancy complications occur primarily in mothers carrying a fetus with long-chain L-3-hydroxyacyl CoA dehydrogenase deficiency or general trifunctional protein deficiencies. FAOD as a group represent the most common inborn errors of metabolism, and presymptomatic diagnosis of FAOD is the key to reduce morbidity and avoid mortality. The application of tandem mass spectrometry to newborn screening provides an effective means to identify most FAOD patients presymptomatically. At the beginning of 2005, 36 state newborn screening programs have mandated or adopted this technology resulting in a marked increase in the number of asymptomatic neonates with FAOD diagnosed. To ensure the long-term benefits of such screening programs, pediatricians and other health care providers must be educated about these disorders and their treatment. Fatty acids constitute the largest energy reserve in the body and play a crucial role in supplying energy-yielding substrates during periods of fasting and stress through the ␤-oxidation pathway (1). FAO provides nearly 80% of energy to organs like heart, liver, and skeletal muscles, especially during fasting when tissue glycogen stores become depleted. The ␤-oxidation pathway also generates ketone bodies, which are used by peripheral tissues and brain (2). This metabolic pathway is critical for the neonate who has limited glycogen reserve and a high metabolic rate leading to rapid metabolic decompensation if there is any perturbation of individual enzymes (3). FAOD are potentially fatal autosomal recessive disorders and are now diagnosed frequently in the perinatal and infantile periods. Mothers heterozygous for a FAOD and pregnant with an affected fetus may develop severe preeclampsia, AFLP, and the HELLP syndrome, and may deliver a premature, intrauterine growth-restricted (IUGR) infant (4).

Analysis of plasma ghrelin in patients with medium-chain acyl-CoA dehydrogenase deficiency and glutaric aciduria type II

“…FAO deficiency contributes to such clinical problems as sudden infant death syndrome, cyclic vomiting syndrome, fulminant liver disease, and maternal complications (8,9). Early diagnosis and appropriate management are required to reduce mortality and morbidity associated with this class of disorders.…”

“…Mitochondrial fatty acid oxidation (FAO) disorders result from genetic defects in transport proteins or enzymes involved in fatty acid b-oxidation (8,9). The clinical phenotypes have recently been associated with a growing number of disorders, such as Reye syndrome, sudden infant death syndrome, cyclic vomiting syndrome, fulminant liver disease, and maternal complications during pregnancy (10).…”

“…Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, the most common inherited defect in FAO, causes elevated serum octanoylcarnitine levels (11), reflecting elevated octanoyl-CoA levels. Glutaric aciduria type II (GA2), which is caused by defects in electron transfer flavoprotein (ETF), ETFubiquinone oxidoreductase, or other unknown abnormalities in flavin metabolism or transport, is characterized by elevated serum acylcarnitine levels, including octanoylcarnitine (8,9). In carnitine palmitoyltransferase II (CPT II) deficiency and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, serum octanoyl-CoA levels do not increase, but at times actually decrease (8,9).…”

Pregnancy-Related Liver Disorders

“…36 The screening is usually by acylcarnitine assay of dried blood sample. Confirmation of diagnosis and picking up a specific fatty acid oxidation defect remains cumbersome and depends on pattern of organic acidurias, plasma fatty acid profile and acylcarnitine profile, enzyme activity analysis and genetic mutation analysis.…”

Retardo de Crecimiento Intrauterino (Rciu) y Sus Alteraciones Bioquímicas.

“…Estudios recientes sobre el rol de la oxidación de los ácidos grasos en la unidad fetoplacentaria han demostrado que la placenta expresa enzimas importantes para el proceso de ß-oxidación de ácidos grasos de cadena larga, comparables a las presentes en el músculo esquelético (17). Cuando no se produce la ß-oxidación, hay una transferencia de metabolitos intermediarios a la circulación materna, quienes han sido postulados ser causantes de preclampsia, lo que a su vez puede causar RCIU (18).…”