Anesthetic Considerations for a Patient with Compound Heterozygous Medium-Chain Acyl-CoA Dehydrogenase Deficiency (2002)

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common disorder of the β oxidation of fatty acids (1,2). When present, up to 80% of patients are homozygous for a single mutation of an A-to-G nucleotide at the position of 985, with the remaining 20% being either carriers of the single mutation or compound heterozygotes (1,2). Since the first case of MCAD deficiency was described in 1982 (3), three patients with MCAD deficiency between 3 and 8 yr of age have been reported to have undergone uneventful minor surgery with general anesthesia (4,5). However, no reports have described the anesthetic management of adult patients with either homozygous or heterozygous MCAD deficiency. MCAD deficiency results in considerable childhood mortality and morbidity. Affected homozygotes are at high risk for metabolic decompensations during childhood (e.g., hypoglycemia, metabolic acidosis, and encephalopathy), whereas heterozygous carriers and compound heterozygotes usually have less severe clinical courses because of the presence of intermediate levels of MCAD activity. Enhanced recognition of the compound heterozygosity and more effective treatment of the homozygote in childhood are likely to result in an increase in the prevalence of MCAD deficiency in the adult population. In the present study, we describe a parturient with compound heterozygous MCAD deficiency who presented for labor and delivery. Case Report A 20-yr-old nulliparous woman at 20 gestational wk of pregnancy presented to Antenatal Diagnostic Center for Genetic Counseling at the Brigham and Women’s Hospital. She reported that her paternal first cousin died suddenly at 18 mo of age, and was later determined to have MCAD deficiency. Her father was subsequently found to be a carrier of the G799A mutation, thus placing the patient at 50% risk for being a carrier. A molecular diagnostic study was immediately arranged and unexpectedly found two MCAD mutations, G799A, and a more common mutation, A985G. This confirmed that the patient was a compound heterozygote. Her parents were unrelated and of English origin. She was asymptomatic and denied history of syncope, exercise intolerance, and muscle weakness. Her blood glucose and carnitine levels were in the normal ranges. Subsequent amniocentesis testing demonstrated that the fetus carried an A985G mutation but had normal levels of medium-chain fatty acid-derived acylcarnitines. The patient was placed on oral regime of carnitine, was followed at the prenatal care center, and had an uneventful pregnancy. At 40 gestational wk, she was admitted for an elective induction of labor. Her blood pressure was 112/70 mm Hg; heart rate 70-80 bpm; respiratory rate 15-25 breaths/min. Her weight and height were 75 kg and 64 in., respectively, and physical examination was normal. Blood glucose level was 87 mg/dL and liver function tests, coagulation profile, complete blood count, thromboelastographic values, and electrocardiogram were within normal ranges. The fetus was in the vertex presentation with a heart rate at the range of 130-140 bpm. Two hours after admission, an IV oxytocin induction was commenced and lactated Ringer’s infusion was administered. As labor progressed, a combined spinal-epidural analgesia was performed with 0.25% bupivacaine (1 mL) and fentanyl (25 μg), followed by a continuous epidural infusion of 0.125% bupivacaine and fentanyl (2 μg/mL) at rate of 10 mL/h. As per our oral intake policy at the time, the patient was only allowed ice chips as spinal-epidural anesthesia was administered. One hour after initiation of spinal-epidural analgesia, a vaginal delivery of a female infant with Apgar scores of 9 and 9 at 1 and 5 min, respectively, occurred. The postpartum course for mother and infant was uncomplicated and both were discharged home on the fourth postpartum day. Discussion MCAD deficiency is an autosomal recessive disorder of the mitochondrial fatty acid oxidation. It occurs primarily in Caucasians of Northern European background with an approximate frequency of 1 in 20,000 live births (2). DNA analysis is sufficient to diagnose MCAD deficiency if two identical (i.e., homozygote) or different (i.e., compound heterozygote) mutations are found. Prospective molecular analysis has identified a more frequent incidence (56%) of compound heterozygosity as compared with the incidence (20%) reported in retrospective clinical studies (6). One major consequence of MCAD deficiency is a substantially impaired ability to oxidize fatty acids beyond the medium chain length. The enzymatic deficiency present in MCAD is related to one of four mitochondrial acyl-CoA dehydrogenases that perform the initial dehydrogenation step in the β oxidation cycle. As such, ketone bodies cannot be produced in quantities sufficient to meet tissue energy demands under conditions of fasting or stress. Hypoketotic hypoglycemia develops shortly thereafter because of excessive glucose utilization resulting from an inability to switch to fat as a fuel. Patients generally present initially at the mean age of 15 months with vomiting, lethargy, encephalopathy, metabolic acidosis and cardiovascular arrest or sudden unexplained death sometimes resembling Reye’s syndrome or sudden infant death syndrome. Twenty-five percent of affected children die with their initial occurrence of symptoms. Although clinical manifestations of MCAD deficiency have been described in children, limited information is available in adult patients. This is likely attributable to increased mortality of the disorder in childhood as well as the fact that attacks become less frequent in the adult because fasting tolerance improves with increasing body mass (2). However, a previous report demonstrated that an asymptomatic 30-year-old man with MCAD deficiency presented with acute encephalopathy after a strenuous exposure to cold environment without adequate food intake (7). Therefore, the ability to compensate during severe metabolic distress in adult patients with MCAD deficiency remains unclear. The present study is the first case report of a patient with MCAD deficiency who underwent labor and delivery. The pregnancy represents a state of dramatic metabolic changes with the increase in glucose consumption resulting in an accelerated starvation state (8). As a result, the levels of free fatty acids are increased to meet maternal energy requirements during the late trimester. Although a normal labor and delivery may not impose high energy demands on the parturient, a prolonged labor and delivery with fasting may lead to maternal metabolic disturbances (9). The patient in the present report appeared to be clinically and biochemically unaffected, however, the penetrance of the MCAD genotype is unknown and uncertainty exists as to which individuals will manifest symptoms (10). Therefore, caution should be exercised when extrapolating clinical presentation and outcome of our patient to others with MCAD deficiency. Preoperative assessment of the patient with MCAD deficiency should include evaluations of medical history, neurological status, and blood glucose levels. Coagulation profiles should be examined, especially when regional anesthesia is considered, as marked accumulation of fat in the liver during recurrent episodes may occur. Although MCAD deficiency is almost exclusively a “hepatic” type of presentation, an extra-hepatic defect in the enzymes may be present. Thus, appropriate cardiac and skeletal muscle evaluations should be undertaken. Fasting in children with MCAD deficiency should last no more than 12 hours. IV infusion of 10% glucose should be started preoperatively and continued intraoperatively in children with MCAD deficiency as well as in adult patients with a history of fasting intolerance. In our patient, an IV administration of glucose was not started because of a negative history of fasting intolerance and a short duration of fasting (approximately 1 hour). During a prolonged labor and delivery, however, frequent evaluations of blood glucose levels should be performed in these patients and an IV infusion of glucose should be initiated if hypoglycemia occurs. It may be advisable to avoid the use of succinylcholine in these patients because the interaction of succinylcholine in the presence of potential myopathy is unpredictable (11). IV infusion of carnitine may be considered if deterioration in neurologic symptoms occurs (e.g., vomiting, lethargy, or coma) in the presence of IV infusion of glucose (2). The rationale for carnitine supplementation includes the conjunction and excretion of potentially toxic intermediates of medium-chain fatty acids that accumulate under conditions of fasting stress or infection in these patients. In summary, we report a case of a parturient with a compound heterozygous MCAD deficiency. Anesthesiologists may encounter more adult patients with MCAD deficiency, as childhood mortality has significantly decreased because of widespread neonatal screening in susceptible families and an understanding that catastrophic episodes can be prevented through relatively simple dietary means. With careful preoperative evaluation of hepatic function, coagulation profile, cardiac and skeletal muscle function, and the frequent monitoring of blood glucose levels during prolonged fasting, a normal anesthetic course can be expected.