Myoclonus epilepsy with ragged-red fibers
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This article includes discussion of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency and fatty acid oxidation disorder. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Medium-chain acyl-CoA dehydrogenase deficiency is the most common inborn error of metabolism in the United States Caucasian population. Diagnosed symptomatically, the morbidity and mortality are high, but outcome is significantly improved if patients are identified before the onset of symptoms. It is now included on newborn screening in the United States and many other developed nations. The author highlights the new technologies that have made it possible to diagnose this condition in the newborn period in a cost-effective fashion. As a result, more patients will ultimately find their way into adult medicine and neurology clinics in the coming years.
• Medium-chain acyl-CoA dehydrogenase deficiency can be asymptomatic for many years and present suddenly during periods of metabolic stress.
• Treatment during acute illnesses consists of maintaining caloric intake with sugar-containing oral or parenteral fluids.
• Medium-chain acyl-CoA dehydrogenase deficiency is now reliably identified in newborn screening in all states in the U.S. and many countries.
• Carnitine is rarely, if ever, needed to treat medium-chain acyl-CoA dehydrogenase deficiency.
Medium-chain acyl-CoA dehydrogenase deficiency is an autosomal recessive inborn error of mitochondrial fatty acid beta-oxidation (11; 16). The disorder was not identified until the early 1980s (50), but is now recognized as the most common of the genetic defects in fatty acid oxidation (05). It is the most frequent inborn error of metabolism in Caucasians, especially those of Western European descent. The medical literature prior to 1980 contains a number of references to patients who either were later proved to have medium-chain acyl-CoA dehydrogenase deficiency or probably had this disorder. The possibility of medium-chain acyl-CoA dehydrogenase deficiency should be considered in this older literature in patients described as having dicarboxylic aciduria, infantile Reye syndrome, and, particularly, either "systemic carnitine deficiency" or "primary carnitine deficiency." For example, 4 patients originally published as having "primary systemic carnitine deficiency" were later shown to have medium-chain acyl-CoA dehydrogenase deficiency (13). The reason for this confusion is that medium-chain acyl-CoA dehydrogenase deficiency and several other genetic defects in acyl-CoA oxidation are associated with secondary carnitine deficiency. Caution must be taken in reviewing discussions of carnitine deficiency that were published between 1970 and 1982 because they may be outdated and can be misleading.
Patients with medium-chain acyl-CoA dehydrogenase deficiency present with acute episodes of life-threatening hypoketotic coma that are induced by fasting stress (18; 59; 60; 66). The age at first attack is most often between 6 months and 2 years of age, with a mean of 12 months. Onset, however, has been reported as early as the first few days of life, especially when the baby is breast-feeding, and as late as in a 45-year-old woman who died of hypoglycemia following surgery for colon cancer. Patients are usually asymptomatic and appear normal between attacks. The initial episode of illness occurs without warning, and the presence of an underlying metabolic defect may not be suspected. Episodes of illness are triggered by prolonged fasts of more than 12 to 16 hours (ie, the time that fatty acids become the predominant metabolic fuel). Attacks may be associated with a longer than usual overnight period of fasting or, more commonly, with poor feeding that accompanies a febrile illness or gastroenteritis. Instances of neonatal onset have occurred in association with attempted breast-feeding that produced excessive duration of fasting in the first days after birth.
Sudden death, possibly due to acute cardiac failure or arrhythmia, may occur (22). The life-threatening nature of the illness is emphasized by the fact that 20% to 25% of patients with medium-chain acyl-CoA dehydrogenase deficiency die during their first attack of illness (18). Physical examination may reveal mild enlargement of the liver, or hepatomegaly may develop during the first 24 hours of treatment as fat is deposited in the liver. Laboratory studies typically reveal hypoglycemia, inappropriately low urinary and plasma ketones, and abnormal liver function tests (18). It must be emphasized that toxic effects of fatty acids or other factors probably contribute to the illness because patients may become ill before they develop frank hypoglycemia. Urinary ketones are usually "trace" or less but may be as high as "moderate." Blood ammonium levels in the range of 150 to 200 µmol/L are common, and serum uric acid and urea concentrations are also increased, perhaps reflecting increased protein catabolism. Serum AST and ALT levels are commonly elevated 5 to 10 times normal or greater, and prothrombin and partial thromboplastin times may be prolonged, but serum bilirubin is usually normal. Muscle involvement at times of acute illness is not usually apparent; however, creatine phosphokinase levels up to 12,000 U/L have been reported (47). Liver biopsy at times of illness reveals increased triglyceride accumulation, which may have both a microvesicular and a macrovesicular pattern, but mitochondrial morphology is relatively normal. Pulmonary hemorrhage and cardiac arrest without hypoglycemia has been reported (29).
Once treatment with intravenous glucose is started, most patients recover fully within a few days (43). Irreversible cerebral edema leading to death or permanent brain damage may occur (18). Patients who survive an acute episode of illness may have significant neurologic sequelae, including cerebral palsy, seizures, and developmental disabilities; however, those diagnosed presymptomatically almost always remain without significant clinical problems (71; 67; 05).
Apart from the risk of episodes of illness with excessive fasting stress, the medium-chain acyl-CoA dehydrogenase defect is essentially silent. Patients appear to be normal and have no noticeable impairment in skeletal or cardiac muscle function. Sudden death due to metabolic decompensation can still occur if appropriate treatment is not obtained during illnesses. Through investigations of family members of patients with medium-chain acyl-CoA dehydrogenase deficiency, several instances have been recognized of affected individuals who have never become symptomatic even into adult life (18; 07). Because fasting tolerance normally increases with age, the risk of illness due to medium-chain acyl-CoA dehydrogenase deficiency decreases in older children and adults. One case report has emphasized the need to consider medium-chain acyl-CoA dehydrogenase deficiency in a patient with mental status changes suspected of drug toxicity (35).
Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency has significantly altered the clinical picture of this disorder in many countries. Screening is accomplished by examination of the acylcarnitine profile by tandem mass spectroscopy in blood samples from blood spots taken for more traditional newborn screening (39). Except on rare occasions, a definitive and cost-effective diagnosis can now be made prior to the onset of symptoms. Once identified, affected individuals have fewer episodes of metabolic decompensation and a reduced risk of death (67; 05). Cord blood has been shown to be of limited value for screening newborns (62). Pre-term infants can rarely present with a false-positive newborn screen (31).
As long as excessive periods of fasting are avoided, it is possible for medium-chain acyl-CoA dehydrogenase deficiency to be well tolerated with little or no impact on health or long-term survival (43; 71; 67; 05). Because fasting tolerance improves with age, the risk of episodes of coma decreases in later childhood and adult life. However, fasting can still provoke illness in older patients. Chronic effects on cardiac muscle, such as cardiomyopathy, or skeletal muscle, such as weakness or reduced exercise tolerance, have not been observed, although these are common in other fatty acid oxidation disorders. Prolonged QTc interval has been reported in a 3-day-old infant (70). Recurrent rhabdomyolysis has been reported (41), as have episodes of encephalopathy, emesis, and acute liver failure (44). Several investigators have noted that the number of known patients with medium-chain acyl-CoA dehydrogenase deficiency is considerably lower than would be predicted from the frequency of the mutation. This might reflect a failure to diagnose the disorder in a large proportion of symptomatic patients. However, it is also possible that a significant number of patients never become symptomatic because they happen to escape ever being exposed to a sufficiently prolonged period of fasting stress.
Despite the fact that the medium-chain acyl-CoA dehydrogenase defect can be essentially silent, there is a high frequency of morbidity and mortality if the disease is not previously diagnosed due to episodes of fasting coma (18; 68). Without presymptomatic diagnosis (including newborn screening), 20% to 25% of patients may die during their first attack of coma, before the diagnosis of medium-chain acyl-CoA dehydrogenase deficiency has been made, emphasizing the need for early detection by newborn screening. As many as 40% of patients who have survived episodes of coma may suffer from chronic neurologic disabilities ranging from mild developmental delay to seizures and cerebral palsy. Sudden death has been reported even in infants identified through newborn screening, so vigilance in the face of this disorder remains appropriate (72).
A 19-month-old, previously well girl developed vomiting at bedtime and awoke twice more during the night with dry heaves. Later that night, the family heard an unusual cry from the room and found the child unresponsive on the floor with jerking movements of all extremities. An ambulance was called, and emergency medicine personnel arrived to find the child having a grand mal seizure. Vital signs were stable, and the child was afebrile. Normal saline followed by diazepam was administered intravenously and the seizure stopped, but by the time the ambulance arrived in the emergency room, the patient had begun seizing again. The physical exam showed a temperature of 98.2°F, pulse of 118, respirations rate of 32, blood pressure of 92/50, and oxygen saturation of 99% on room air by pulse oximetry. The exam was remarkable only for altered mental status with minimal response to pain and low tone. Dextrostix in the emergency room was read as <30, prompting immediate administration of IV 10% glucose at maximum rate. A repeat Dextrostix reading was 70 and the measured glucose level was 75 mg/dl (normal 70 to 120). Serum electrolytes measured at the same time showed a sodium level of 143 meq/L, potassium 4.8 meq/L, chloride 108 meq/L, and bicarbonate of 18 meq/L (all within the lab’s normal range). The patient remained lethargic and was admitted to the intensive care unit. There the plasma ammonium level was 350 µmol/L (normal < 35), the lactate was 2.8 µmol/L (normal < 2), and the liver function tests were normal. A CT scan of the head was normal with no signs of increased intracranial pressure, and a lumbar puncture showed normal CSF glucose and protein levels with no cells observed. Over the course of the next 6 hours, the patient gradually regained consciousness. A repeat blood ammonium level was 85 mmol/L. The next morning, the patient was described by her parents as being back to normal, and she was discharged to home with instructions to feed frequently. The acylcarnitine profile of blood taken during the initial presentation was notable for elevations of C6-10 saturated and C10:1 unsaturated species. Urine organic acids showed elevations of hexanoylglycine, suberylglycine, octanoate, and C6-10 dicarboxylic acids. A diagnosis of medium-chain acyl-CoA dehydrogenase deficiency was made, and molecular testing confirmed the presence of 2 copies of the 985 A>G mutation in the medium-chain acyl-CoA dehydrogenase gene.
The basis for the intermittent nature of illness in medium-chain acyl-CoA dehydrogenase deficiency relates to the impairment in the later stages of fasting adaptation when fatty acid oxidation normally increases from less than 10% to greater than 80% of total oxygen consumption. The switch to fatty acid oxidation and ketogenesis begins after 12 to 20 hours of fasting in infants and young children and somewhat later in older children and adults. Fasting studies in medium-chain acyl-CoA dehydrogenase deficiency and other defects in fatty acid oxidation illustrate their pathophysiology (57; 43). During fasting in these patients, the plasma levels of free fatty acids begin to rise due to acceleration of adipose tissue lipolysis at a normal time. However, synthesis of ketones from fatty acids by the liver is impaired and plasma levels of ketones fail to rise appropriately. The inability to utilize fat and to produce ketones as an alternative fuel for the brain results in excessive reliance on glucose as a metabolic fuel and the development of hypoglycemia by 16 to 20 hours of fasting. At the point of hypoglycemia, plasma free fatty acid concentrations may reach 3 to 4 mmol/L, whereas concentrations of beta-hydroxybutyrate, the major ketone, usually remain below 1 mmol/L. Typical values in normal fasted children are approximately 2 mmol/L for free fatty acids and 3 mmol/L for beta-hydroxybutyrate.
Patients with medium-chain acyl-CoA dehydrogenase deficiency may develop symptoms of lethargy, nausea, and vomiting a few hours before frank hypoglycemia occurs. This appears to correlate with the time when plasma free fatty acid levels become elevated, suggesting that some of the illness in medium-chain acyl-CoA dehydrogenase deficiency may reflect toxic effects of excessive free fatty acids or their metabolites (60). Hyperammonemia, when present, appears to be related to depletion of intracellular acetyl-CoA and reduced production of N-acetylglutamate. This in turn leads to secondary reduction in the urea cycle (52). The neurologic manifestations may also be enhanced by direct inhibition of neuronal respiratory chain function by the metabolites that accumulate in medium-chain acyl-CoA dehydrogenase deficiency (36) or by loss of critical functions related to specific acylcarnitines (20).
Mitochondrial fatty acid oxidation is predominantly responsible for the oxidation of fatty acids of carbon length 20 or less, whereas the peroxisomal pathway is physiologically more relevant for longer chain fatty acids (38). Mitochondrial beta-oxidation is a complex process involving transport of activated acyl-CoA moieties into the mitochondria and sequential removal of 2 carbon acetyl-CoA units. The pathway of mitochondrial fatty acid oxidation is initiated by activation of free fatty acids to acyl-CoA esters in the cytosol. The fatty acids are then transferred across the mitochondrial membrane bound to carnitine. Within the mitochondrial matrix, the fatty acids are converted back to acyl-CoA. The 4 steps of the beta-oxidation cycle then sequentially remove 2 carbons until the acyl-CoA (n carbons) is fully converted to n/2 acetyl-CoA molecules.
In peripheral tissues, the acetyl-CoA is terminally oxidized in the Krebs cycle for ATP production. In the liver, the acetyl-CoA from fatty acid oxidation is used via the beta-hydroxy-beta-methylglutaryl-CoA pathway for synthesis of ketones, beta-hydroxybutyrate, and acetoacetate, which are then exported for final oxidation by brain and other tissues.
At least 25 enzymes and specific transport proteins are responsible for carrying out the steps of mitochondrial fatty acid metabolism (04; 63). Medium-chain acyl-CoA dehydrogenase is 1 of 4 chain-length specific enzymes that catalyze the first step of the intramitochondrial beta-oxidation cycle. The acyl-CoA dehydrogenase step in beta-oxidation dehydrogenates fatty acyl-CoA substrates, leading to the insertion of a double bond at the beta-carbon to form an enoyl-CoA.. The enoyl-CoA is further processed by 3 other steps of the beta-oxidation cycle to form acetyl-CoA and an acyl-CoA that is 2 carbons shorter and can enter another cycle of beta-oxidation. The acyl-CoA dehydrogenase reaction also yields 1 electron, which is transferred via electron transfer flavoprotein to the electron transport chain for ATP production. The medium-chain acyl-CoA dehydrogenase enzyme shows specificity for fatty acyl-CoA's containing 6 to 10 carbons. Because longer-chain fatty acids must pass through the medium-chain acyl-CoA dehydrogenase step for complete oxidation, deficiency of medium-chain acyl-CoA dehydrogenase blocks the utilization of the typical 16- to 18-carbon long-chain fatty acids that make up the majority of endogenous fat stores. Fatty acid oxidation is now recognized as functionally and physically interacting with the mitochondrial respiratory chain in a macromolecular complex (65). Primary defects in medium-chain acyl-CoA dehydrogenase have been shown to disrupt this interaction in patient fibroblasts, with the presence of secondary defects in oxidative phosphorylation (27). The clinical relevance of this finding is unclear, as patients do not exhibit any overt signs of respiratory chain deficiency.
Medium-chain acyl-CoA dehydrogenase is synthesized in a larger precursor form in the cytoplasm from nuclear encoded transcripts, and then transported into mitochondria (19). Once inside the mitochondrial matrix, the leader peptide is removed by a specific protease, and the mature subunits assemble into the active homotetramer. One molecule of FAD is noncovalently attached to each ACD subunit. cDNAs for each of these proteins have been cloned, and sequence analysis shows that they are approximately 30% to 35% conserved, suggesting evolution from a common primordial gene (53). Active enzyme is a homotetramer containing 1 mole of riboflavin/subunit.
The vast majority of patients with medium-chain acyl-CoA dehydrogenase deficiency have a single common missense mutation: an A-to-G transition at cDNA position 985, which changes a lysine residue to glutamate at amino acid 329 of the medium-chain acyl-CoA dehydrogenase precursor protein (54; 02). The mutated amino acid is far removed from the catalytic site of the enzyme but appears to make the protein unstable by interfering with intramitochondrial folding and assembly of the nascent peptide (30). Preventing this misfolding offers an opportunity for development of new therapeutic agents for medium-chain acyl-CoA dehydrogenase deficiency (15; 24).
The A985G mutation accounts for approximately 90% of the mutant alleles in medium-chain acyl-CoA dehydrogenase deficiency. Approximately 70% of patients are homozygous for the A985G mutation (54; 02). Most of the remaining patients are compound heterozygotes for the 985A>G allele in combination with 1 of several rarer mutations. Thus, only a few percent of medium-chain acyl-CoA dehydrogenase patients do not have at least 1 A985G allele. The unusually high frequency of a single common mutation has made molecular diagnosis especially valuable in medium-chain acyl-CoA dehydrogenase deficiency. As more information accumulates from patients identified through newborn screening, correlation of phenotype with genotype is becoming clearer. Patients with the common mutation accumulate the highest levels of metabolites in the newborn period and are probably at risk for more severe disease than are many other mutations (06; 61). However, genotype-phenotype correlations are not consistent (03). The development of a knock out mouse model will greatly enhance studies of pathogenesis and therapeutic options (56). In babies identified by newborn screening in New York State, outcome was correlated to levels of octanoylcarnitine in the screening blood spot, which, in turn, was less tightly correlated to genotype (03). Analysis of urine acylglycine levels may provide additional insight into risk for symptoms in infants identified through newborn screening, with elevated hexanoylglycine correlated to more severe phenotype (45). Of note, it has been shown that the elevated levels of acylcarnitines in patients with medium-chain acyl-CoA dehydrogenase deficiency correlate to levels of acyl-ghrelin, highlighting the potential for unexpected secondary effects remote from the primary defect (01).
Medium-chain acyl-CoA dehydrogenase deficiency has been identified almost exclusively in patients of northwestern European background, particularly the British Isles and Germany (54; 02). This, together with the observation that a single common mutation accounts for 90% of all mutant alleles, indicates an unusually strong founder effect for the disease. Based on screenings of newborn blood spot cards for the A985G mutation, estimates of carrier frequency range from 1 in 40 in England, 1 in 70 in Australia, and 1 in 100 in the United States, to less than 1 in 500 in Japan. These data predict a disease frequency as high as 1 in 6400 in England, similar to that for phenylketonuria. A review reports a rate of 4.1 homozygotes per 100,000 individuals overall in Western Europe compared to 0.9 and one half per 100,000 in Eastern and Southern Europe, respectively (25). The frequency in the mid-Atlantic region of the United States is 1 in 10,000 live births, based on data from screening of more than 85,000 newborn blood spot cards for octanoyl and decanoylcarnitine by tandem mass spectrometry (73; 28). The reported rate in Ontario, Canada, is 1 in 14,000 births (21), and the incidence in New South Wales, Australia, in a study of 360,000 newborns was 4.7 per 10,000 (69). Qatar has a reported incidence of 1 in 4000, the highest rate yet identified (28). An article describes the significant differences between the genotype and screening allele frequency of the c.985A>G (25).
Once the diagnosis of medium-chain acyl-CoA dehydrogenase deficiency is known, attacks of coma can be avoided by preventing exposure to prolonged fasting (67; 05). This is accomplished by limiting periods of fasting to less than 8 hours for infants under 1 year of age and less than 12 hours for children over 1 year of age (12). It is important to note that symptoms may occur before hypoglycemia is observed. During intercurrent illnesses, extra carbohydrate feeding should be provided every 4 to 6 hours. With gastroenteritis or the development of early signs of illness such as unusual lethargy, it is necessary to intervene promptly with intravenous dextrose infusion. Deaths may occur but are uncommon after the diagnosis of medium-chain acyl-CoA dehydrogenase deficiency has been made. The diagnosis of medium-chain acyl-CoA dehydrogenase deficiency can be made presymptomatically either by testing at-risk siblings or through newborn screening.
The presentation of acute life-threatening coma in medium-chain acyl-CoA dehydrogenase deficiency may resemble a wide range of acquired and congenital disorders. This presentation is typical of most of the dozen known genetic defects in the fatty acid oxidation pathway, and specific testing is required to differentiate among these disorders: plasma membrane carnitine transporter defect, carnitine palmitoyltransferase I deficiency, carnitine and acylcarnitine translocase deficiency, carnitine palmitoyltransferase II deficiency, very long-chain acyl-CoA dehydrogenase deficiency, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, short-chain acyl-CoA dehydrogenase deficiency, HMG synthase deficiency, HMG lyase deficiency, electron transfer flavoprotein deficiency, and electron transfer flavoprotein dehydrogenase deficiency (04; 60). The clinical features mimic those originally described as Reye syndrome, and indeed, most such cases are now found to be due to an inborn error of metabolism. The hypoglycemia found in medium-chain acyl-CoA dehydrogenase deficiency is also seen in a wide range of disorders. The relatively long period of fasting required to induce illness, the mild degree of acidemia, and modest hepatomegaly help to distinguish medium-chain acyl-CoA dehydrogenase deficiency from glycogen storage disorders and gluconeogenic defects. The duration of prior fasting and age of onset are similar to ketotic hypoglycemia of infancy and hypopituitarism, and specific tests may be necessary to distinguish these from medium-chain acyl-CoA dehydrogenase deficiency. Hypoglycemia and coma may accompany genetic defects in amino acid oxidation, such as isovaleric academia (58). These are usually associated with more severe acidemia than medium-chain acyl-CoA dehydrogenase deficiency and can be distinguished by their distinctive abnormalities on urine organic acid profiles. The hyperammonemia seen with acute illness in medium-chain acyl-CoA dehydrogenase deficiency may suggest a urea cycle disorder, but the elevation of blood ammonia is usually milder and attacks of illness in the urea cycle defects are often provoked by protein feeding rather than prolonged fasting. Similar degrees of hyperammonemia with hypoketotic hypoglycemia also occur in patients with hyperinsulinism due to mutations of glutamate dehydrogenase (hyperinsulinism and hyperammonemia syndrome) (51). Hypoketotic hypoglycemia may be induced by ingestion of oral hypoglycemic drugs or surreptitious insulin administration. Jamaican vomiting illness is a Reye-like illness induced by hypoglycin A, a toxic amino acid present in unripe Akee fruit, which inhibits medium-chain acyl-CoA dehydrogenase and other acyl-CoA dehydrogenase enzymes (55).
During an acute attack of medium-chain acyl-CoA dehydrogenase deficiency, the critical blood and urine samples, obtained immediately as treatment is begun, are most useful in making the diagnosis (38; 04; 59). As indicators of the presence of a defect in fatty acid oxidation, these critical samples may show hypoglycemia; minimal acidemia; elevated blood urea nitrogen, ammonium, uric acid, and liver transaminases; abnormal coagulation tests; possible elevation of creatine phosphokinase; and, especially, inappropriately low urine ketones. The demonstration of elevated levels of free fatty acid and low beta-hydroxybutyrate concentrations in plasma is especially helpful in establishing that ketogenesis is impaired. These same markers are useful in following the clinical course in known patients. Portions of the critical plasma and urine samples should be preserved for some of the tests described below that can specifically diagnose medium-chain acyl-CoA dehydrogenase deficiency because abnormalities are often most apparent during fasting stress.
Measurement of plasma free and total carnitine in the nonfasted state provides a useful clue to the presence of an underlying defect in acyl-CoA oxidation, such as medium-chain acyl-CoA dehydrogenase deficiency. These disorders are commonly associated with secondary carnitine deficiency with total carnitine levels 25% to 50% of normal and reduction in percent free carnitine below the values of 80% to 90% seen in well-fed normal individuals (38). The test is less useful during times of illness, when total carnitine levels can rise acutely to normal or greater than normal values. The pattern of secondary carnitine deficiency can also occur in other acyl-CoA oxidation defects involving fatty acid oxidation (deficiencies of carnitine and acylcarnitine translocase deficiency, carnitine palmitoyltransferase II, long-chain and very long-chain acyl-CoA dehydrogenase, long-chain 3-hydroxyacyl-CoA dehydrogenase, short-chain acyl-CoA dehydrogenase, electron transfer flavoprotein, electron transfer flavoprotein dehydrogenase, or HMG-CoA lyase) or organic acid oxidation (isovaleric acidemia, methylmalonic aciduria, propionic acidemia).
Several special methods for the specific diagnosis of medium-chain acyl-CoA dehydrogenase deficiency based on metabolite analysis are available. For plasma, these include assay of the acylcarnitine profile by tandem mass spectrometry (octanoylcarnitine, decenoylcarnitine) and of the fatty acid profile by gas chromatography and mass spectrometry (octanoate, cis-dec-4-enoate) (10; 38). Care must be taken to avoid mischaracterization of other medium-chain acyl-CoA dehydrogenase deficiency-related metabolites as glutarylcarnitine because the presence of this compound would suggest instead a diagnosis of glutaric aciduria (33). Both of these methods can also be used with newborn blood spot cards, eg, for postmortem retrospective diagnosis or for neonatal screening. Tandem mass spectrometry can detect abnormal acylcarnitine profiles in a variety of metabolic defects, including medium-chain acyl-CoA dehydrogenase deficiency. The ratio of C8/C8:1 carnitine species appears to be more specific for disease than the C8 level alone (17). For urine, specific diagnostic tests include assay of the organic acid profile by gas chromatography and mass spectrometry, especially if quantitated using isotope dilution methods (hexanoylglycine, phenylpropionylglycine, suberylglycine) (37). The organic acid profile of the critical urine specimen will also show elevations of medium-chain dicarboxylic acids (adipic, suberic, sebacic) out of proportion for the levels of ketones (38). This is a nonspecific finding of impaired fatty acid oxidation that is common to all of the fatty acid oxidation disorders. Diagnosis can also be made postmortem on tissue extracts (08).
The diagnosis of medium-chain acyl-CoA dehydrogenase deficiency can be conveniently established in many instances using molecular techniques to identify the common 985A>G mutation (54; 02). Molecular diagnosis can be done on genomic DNA specimens from peripheral blood samples, Guthrie card blood spots, cultured fibroblasts or lymphoblasts, as well as postmortem tissue samples. Molecular diagnosis is highly likely to be successful in medium-chain acyl-CoA dehydrogenase deficiency, because 70% of patients are homozygous for the common 985A>G mutation.
Diagnosis by demonstration of deficient medium-chain acyl-CoA dehydrogenase enzyme activity can be carried out using cultured fibroblasts or lymphoblasts and freshly isolated leukocytes but is not necessary if molecular confirmation is definitive (14). With the development of highly specific metabolite tests and molecular diagnosis methods, direct assay of enzyme activity is rarely necessary. Cultured fibroblasts and lymphoblasts can be used to test the integrity of the fatty acid oxidation pathway using radio-labeled or stable isotope labeled fatty acid substrates (23; 32).
The diagnosis of a beta-oxidation defect, including medium-chain acyl-CoA dehydrogenase deficiency should be considered in anyone who dies suddenly and unexpectedly or has an acute life-threatening event, especially suspected sudden infant death syndrome. This includes collection and storage of blood and urine samples at the time of presentation, and harvesting of liver, muscle, and bile as rapidly as possible after death with rapid freezing of all samples without fixation (40). A fibroblast tissue culture should be established for later analysis. This maximizes the chance that a specific diagnosis can be made postmortem.
Treatment of acute episodes of coma in medium-chain acyl-CoA dehydrogenase deficiency is primarily supportive and aimed at quickly reversing the catabolic state that is responsible for stimulating the pathways of lipolysis and fatty acid oxidation (04; 59). Hypoglycemia should be corrected with bolus administration of intravenous dextrose. Continuous infusion of dextrose should then be given at a rate that maintains plasma glucose levels at, or slightly above, the normal range in order to stimulate insulin secretion and suppress adipose tissue lipolysis. This usually requires 10% dextrose solutions at maintenance rates or higher, if dehydration exists. Specific therapy for the mild hyperammonemia that may be present during acute illness has not usually been required. Cerebral edema has occurred during treatment in some patients with severe coma, possibly as a late reflection of acute brain injury from hypoglycemia, toxic effects of fatty acids, or ischemia. Recovery from the acute metabolic derangements associated with coma may require more than a few hours, but is usually complete within 12 to 24 hours except where serious injury to the brain has occurred.
Long-term management consists of dietary therapy to prevent excessive periods of fasting that can lead to coma. However, there is considerable variation across metabolic centers (34). Overnight fasting should be limited to no more than 10 to 12 hours by providing a high-carbohydrate snack at bedtime and ensuring that breakfast is not skipped or delayed (59). More frequent feedings of carbohydrates should be offered during times of intercurrent illness because appetite may be reduced. Episodes of gastroenteritis are especially dangerous, and early intervention with intravenous dextrose is advisable to prevent coma from developing. Home blood glucose monitoring is not useful because symptomatic illness can begin before hypoglycemia has occurred. Although it is reasonable to modestly reduce dietary fat, because this fuel cannot be used efficiently in medium-chain acyl-CoA dehydrogenase deficiency, patients appear to tolerate normal diets without difficulty, and severe restriction of fat intake may be unnecessary.
Formulas containing medium-chain triglycerides oil should be avoided. Special attention should be paid to premature infants who may have started on such formulas before the return of a newborn screening result.
Although patients with medium-chain acyl-CoA dehydrogenase deficiency and other acyl-CoA oxidation defects have secondary carnitine deficiency, the use of carnitine supplementation in these disorders is controversial (46). The mechanism of carnitine deficiency appears to be reduced transport of free carnitine in the kidney and other tissues (13; 49), possibly secondary to inhibition of the plasma membrane carnitine transporter by increased levels of medium and long-chain acylcarnitines (49). It has been speculated that carnitine might help to remove potentially toxic acyl-CoA intermediates and serve either as an adjunct to treatment of acute illness or to prevent attacks of coma. However, the amounts of abnormal acylcarnitines excreted in the urine are rather modest even with carnitine supplementation, and there is no clear evidence that carnitine is beneficial either during acute crises or in long-term management (48). Some investigators suggest 50 to 100 mg/day of oral carnitine. The present authors do not recommend using carnitine in medium-chain acyl-CoA dehydrogenase-deficient patients except for investigational purposes. Use of bezafibrate to induce fatty acid oxidation enzymes has been proposed as a therapy for long-chain fatty acid oxidation defects (09). Success appears to depend on the presence of partially stable but enzymatically impaired protein. A similar approach may be useful in medium-chain acyl-CoA dehydrogenase deficiency in some circumstances, but it has not yet been tested (26).
Issues that need to be considered with pregnancy in medium-chain acyl-CoA dehydrogenase deficiency include the health of an affected mother, prenatal diagnosis of an affected fetus, and management of an affected newborn. Minimal experience has been reported formally, but the author has personal experience with successful uneventful pregnancies in affected women and knows of similar experiences at numerous metabolic clinics worldwide. It can be anticipated that pregnancy in a mother affected with medium-chain acyl-CoA dehydrogenase deficiency might be associated with increased risk of coma both because of morning sickness and because of the usual decrease in fasting tolerance during later stages of pregnancy. One woman who was subsequently shown to have medium-chain acyl-CoA dehydrogenase deficiency has been reported to develop fatty liver of pregnancy at 39 weeks gestation (42). Extra care should be taken for the affected mother to avoid fasting stress of more than 10 to 12 hours by providing extra carbohydrate feeds. During labor and delivery, intravenous dextrose should be given to maintain high normal levels of plasma glucose and ensure that lipolysis and fatty acid oxidation are suppressed.
With the availability of molecular and other diagnostic techniques, prenatal testing for medium-chain acyl-CoA dehydrogenase deficiency is feasible, although it may be unnecessary in view of the good prognosis for affected patients. In addition, routine early feeding practices in most nurseries will usually be sufficient to prevent a period of fasting that would induce coma in the newborn period. Nevertheless, as noted above, several case reports have made it clear that newborn infants with medium-chain acyl-CoA dehydrogenase deficiency can develop coma in the neonatal period if excessively fasted. In these reports, coma occurred during the first days after birth in association with attempted breast-feeding. This may be explained by the fact that milk production is often poor during this time. Breast-feeding for the affected newborn should be possible as long as care is taken to provide supplemental feedings until milk production is well established.
Patients with medium-chain acyl-CoA dehydrogenase deficiency have undergone routine anesthesia and surgery without difficulty though this is rarely reported (64). Precautions should be taken to ensure that preoperative fasting does not exceed 8 hours and that intravenous dextrose infusions are started beyond this time limit in order to prevent activation of fatty acid oxidation. Drugs that stimulate lipolysis and fatty acid oxidation, such as epinephrine and other beta-agonists, theoretically might pose a hazard for patients with medium-chain acyl-CoA dehydrogenase deficiency and other fatty acid oxidation disorders. If these agents are unavoidable, the simultaneous administration of dextrose to minimize fatty acid utilization might be considered.
Jerry Vockley MD PhD
Dr. Vockley of the University of Pittsburgh School of Medicine has no relevant financial relationships to disclose.See Profile
Jennifer Friedman MD
Dr. Friedman of the University of California San Diego has no relevant financial relationships to disclose.See Profile
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