Prenatal diagnosis of disorders of fatty acid transport and mitochondrial oxidation.

Abstract

Fatty acid transport and mitochondrial oxidation (FATMO) is a complex pathway that plays a major role in energy production during fasting or when illness and stressful situations require higher energy consumption. After long-chain fatty acids are mobilized from adipose tissue, taken up by liver and muscle cells, and activated to coenzyme A esters, they are transported into mitochondria by the sequential action of carnitine palmitoyltransferase (CPT) I, carnitineacylcarnitine translocase, and CPT II (Bonnefont et al., 1999). Fatty acids are then oxidized in a cyclic fashion by four sequential reactions, each catalyzed by one of multiple enzymes with overlapping substrate chainlength specificity: FAD-dependent acyl-CoA dehydrogenase, enoyl-CoA hydratase, NAD-dependent L-3hydroxyacyl-CoA dehydrogenase, and ketoacyl-CoA thiolase. Each cycle of the pathway produces a molecule of acetyl-CoA and a shortened fatty acid that re-enters the cycle until it is completely metabolized. In the liver, acetyl-CoA constitutes the building block for the synthesis of ketone bodies, which serve as fuels for production of energy in other tissues. Inherited FATMO disorders represent a rapidly expanding class of metabolic diseases (Bennett et al., 2000). Signs and symptoms may vary greatly in severity and typically include hypoketotic hypoglycemia, transient to fulminant liver disease, skeletal myopathy, cardiomyopathy, and sudden and unexpected death in early life. Symptoms may appear at any age, from birth to adult life, and in variable combinations, frequently leading to life-threatening episodes of metabolic decompensation. To date, all known FATMO disorders are inherited as autosomal recessive traits, with a recurrence risk of 25%. Although prenatal ‘screening’ could occasionally be informative (Nada et al., 1996; Chalmers et al., 1997), the pursuit of a prenatal diagnosis after an index case with an unspecified diagnosis should be limited to special circumstances, recommending instead aggressive preventive treatment and a thorough evaluation of the newborn immediately after birth. The prenatal diagnosis of FATMO disorders raises both ethical and medical issues. On one hand, parents face the option of abortion for a treatable disorder like MCAD deficiency or carnitine uptake defect, having experienced the sudden death of one or more children. At the other end of the clinical spectrum are disorders like glutaric acidemia type 2 with congenital anomalies and neonatal CPT II deficiency, characterized by very poor prognosis and outcome, and obvious candidates for prenatal diagnosis. Another unique aspect of prenatal diagnosis for FATMO disorders is the associated risk of maternal