AUTHOR INFORMATION

Section 1 of 10

Authored by Karl S Roth, MD, Chair, Professor, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD, is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Association for the Advancement of Science, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research

Edited by Edward Kaye, MD, Vice President of Clinical Research, Genzyme Corporation; Robert Konop, PharmD, Director, Clinical Account Management, Ancillary Care Management, Inc; Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Karl S Roth, MD
Editor's Email:	Edward Kaye, MD

eMedicine Journal, October 4 2005, VOLUME 6, Number 10

INTRODUCTION

Section 2 of 10

Background: The study of fatty acid metabolism gained importance during the 1970s as investigators and clinicians recognized patients who seemed to have genetic defects in this area. The first of these conditions to be defined was carnitine palmitoyltransferase (CPT) deficiency, described in 1973. With attention focused on the definition of additional disorders, researchers reported case descriptions of patients with a Reye syndrome–like presentation who excreted dicarboxylic acids of chain lengths C6-C10 in their urine.

Beginning in 1976, when Gregersen and colleagues reported a patient with such findings in whom they proposed a beta-oxidation defect, expectations were raised that a defect of this type soon would be identified. By 1982, at least 2 reports involved patients who were thought to suffer from defects in beta-oxidation. In 1983, Gregersen's group demonstrated a deficiency of medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) in a patient with hypoketotic hypoglycemia. Stanley and colleagues, who reported on several children with similar clinical presentations who were MCAD deficient, confirmed the demonstration in the same year. The clinical entity known today as MCAD deficiency was defined biochemically fewer than 20 years ago, yet is thought by some to be at least as common in newborns as phenylketonuria, with an incidence approximating 1 in every 12,000 live births. A recent report from Europe indicates an incidence in Bavaria of 1:8456 in more than 500,000 newborns screened.

Pathophysiology: The beta-oxidation cycle permits the cell to extract energy from the breakdown of fatty acids with linkage to an accessory pathway for the formation of acetoacetate. Beta-oxidation is a complex mitochondrial pathway that is dependent upon the presence of adequate cytosolic carnitine and 2 mitochondrial membrane-bound enzymes, CPT I and CPT II.

In the cytosol, a saturated, straight-chain fatty acid molecule with no double bonds is activated by the action of fatty acyl-CoA synthetase to form its corresponding acyl-CoA. This acyl-CoA is linked to carnitine by the action of CPT I, with simultaneous transport across the mitochondrial membrane barrier. Once inside the mitochondrion, the action of CPT II at the inner surface of the membrane releases free carnitine, which exits to the cytosol and leaves behind the acyl-CoA molecule.

Beta-oxidation cycle

Entry into the beta-oxidation cycle requires the action of acyl-CoA dehydrogenase, the first enzyme in the sequence, which removes electrons from the alpha-carbon and the beta-carbon, introducing a double bond. The electrons are transferred to the flavin cofactor essential for normal enzyme activity. These are, in turn, transferred to the electron transport chain with the production of ATP.

The next step is the introduction of a water molecule and resaturation of the double bond to form fatty enoyl-CoA.

Oxidation of the hydroxyl substituent group on the beta-carbon creates an inherently unstable beta-ketoacyl-CoA compound. In the process, another electron transfer occurs, this time to nicotinamide-adenine dinucleotide (NAD), and more ATP is produced by passage down the electron transport chain.

Cleavage of the 3-keto compound at the now unstable alpha-beta carbon bond and transfer of another CoA moiety to the new fragment results in 2 products: acetyl-CoA, composed of the carbonyl and original alpha-carbon from the starting molecule, and a new fatty acyl-CoA that is 2 carbons shorter than the original molecule.

In addition to its intrinsic importance in the use of alternative fuels, the process of beta-oxidation clearly illustrates the role of vitamin cofactors in metabolism. Both riboflavin and nicotinamide are key to the ferrying of electrons to the cytochromes for production of ATP, without which the breakdown of fatty acid would be utterly useless to the cell's energy economy.

The following 2 additional points are noteworthy regarding beta-oxidation:

• Fatty acids shorter than C12 do not require CPT activity for mitochondrial entry.

• At least 3 separate acyl-CoA dehydrogenases are known to exist; they are described in Table 1.

Note that fatty acids longer than C12 can be oxidized by beta-oxidation down to a 12-carbon fatty acyl-CoA; those shorter than C6 also are oxidized normally.

The pathophysiology of MCAD deficiency results from the inability to carry out the first step of beta-oxidation. Any clinical situation in which fatty acid oxidation is required, such as fasting or metabolic stress due to illness, results in continued glucose consumption and a markedly reduced or absent corresponding increase in ketone body production.

The ultimate clinical result is severe hypoglycemia and hypoketonuria with accumulation of monocarboxylic fatty acids and dicarboxylic organic acids, which are structural analogues of the fatty acids that cannot pass through the MCAD step. These dicarboxylic acids include adipic (C6), suberic (C8), sebacic (C10), and dodecanedioic (C12). Each is formed by an alternative metabolic pathway called w-oxidation that attempts, without success, to begin oxidation at the opposite end of the fatty acid. These w-oxidation products appear in urine; an appropriately equipped laboratory can identify them and a diagnosis can be made expeditiously. As in propionic acidemia, the cell attempts to conserve free CoA by substitution with carnitine, with a resultant urinary excretion of acyl-carnitine compounds.

That octanoic acid (a C8 fatty acid), which accumulates during an impending metabolic decompensation in an affected patient, is a mitochondrial toxin is well known; this may account for the disruption of ammonia metabolism that often accompanies the clinical presentation of MCAD deficiency. In addition, octanoate has also been shown to reduce oxidation of glucose by rat cerebral homogenates by 70%, which might contribute significantly to the neurological abnormalities seen clinically. The hypoglycemia and hyperammonemia combine to account for the lethargy and coma that culminate in cerebral edema if left untreated.

Finally, note that gluconeogenesis is disabled effectively in MCAD deficiency because it depends on the activity of pyruvate carboxylase to produce oxaloacetate, a reaction that is downregulated by diminished mitochondrial acetyl-CoA. Consequently, gluconeogenesis cannot compensate for the continuing consumption of existing glucose and the inability to shift to oxidation of alternative fuels, specifically fatty acids.

Frequency:

• In the US: Inherited as an autosomal recessive trait, MCAD deficiency was found in at least one series, which used a population-screening technique, to occur in approximately 1 in every 8500 live births. This figure seems somewhat high, but the true incidence is almost certainly among the highest of the inborn errors of metabolism, rivaling that of phenylketonuria. In part due to the supposed frequency of the disorder, nationwide debate has resulted in many states adding MCAD to their existing newborn metabolic screening programs. Although screening is feasible, each of the available methodologies has drawbacks: tandem mass spectrometry requires a very large capital investment in instrumentation, while molecular probes are not yet available commercially for all mutations that result in clinical disease. Many additional states are likely to add MCAD deficiency soon to their routine newborn metabolic screening program, so that the true incidence of the disease in the United States will be revealed.

Mortality/Morbidity:

• Some authors note the potential for MCAD deficiency as a cause for sudden infant death syndrome (SIDS), a concept that largely has been discredited by extensive postmortem study over the past decade.

• The tendency for development of very severe hypoglycemia brings with it the risk of serious damage to the CNS and other organs.

• The possibility of cerebral edema and coma leading to death is a cause of legitimate concern.

Sex: Because the mutation is an autosomal recessive trait, equal gender distribution is anticipated.

Age: Because it is a genetically transmitted disorder, MCAD deficiency is present from conception. Clinical onset can occur at any time during infancy; however, the tendency is for onset in infants aged 3 months and older, when overnight feedings begin to diminish in frequency. The increase in fasting time exposes the underlying defect, which leads to the clinical presentation.

As in many other inherited metabolic disorders, MCAD has been reported as an adult-onset disease as well. The individuals reported have been previously well, normal adults. Given the rather high incidence of the disease, it is not surprising that affected adults are present in the population; what is surprising, however, is the absence of symptoms until clinical onset.

CLINICAL

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History:

• Because MCAD deficiency is transmitted in an autosomal recessive fashion, other affected members of a family pedigree are unlikely to be available to assist diagnosis.



• The naturally frequent feeding of a very young infant tends to offset the need for reliance on alternative fuel for fasting; however, as the infant begins to extend the interval between feeds, the need for fatty acid catabolism increases correspondingly. This need, historically, may correlate with increased preprandial irritability, lethargy, jitteriness, sweating, and, possibly, seizures, which are all symptomatic of hypoglycemia.



• Exaggerated lethargy accompanied by vomiting and acidosis with previous viral illness, often requiring intravenous fluid replacement therapy, frequently can be elicited on history.



• Although early development is usually normal, growth may be somewhat slow.

Physical:

• Prior to acute clinical presentation, physical examination findings may be entirely normal or may be remarkable only for a growth rate that is below the norm.



• At acute presentation, the infant is likely to be tachypneic, somnolent, and have a mildly enlarged liver, which is due to fatty infiltration.



• Neurological examination is nonspecific, without localizing signs.



• If the infant has experienced a hypoglycemic seizure, distinguishing a postictal state from coma due to cerebral edema is vital.



• The adult presentation may be characterized by headaches and vomiting, probably referable to hyperammonemia, as well as to the cerebral metabolic effects of accumulated octanoate.

Causes:

• The gene has been mapped to locus 1p31; several allelic variations have been reported. The most common mutation by far is called G985, referring to a substitution of a guanine for an adenine nucleotide at the 985th residue.



• Phenotype-genotype relationships have been sought, with little success. As an example, while the common G985 mutation is frequently responsible for an infantile onset, an adult-onset patient with the same mutation has been reported.

WORKUP

Section 4 of 10

Lab Studies:

• Serum electrolytes may show depressed bicarbonate and an anion gap.



• Blood ammonia may be mildly to moderately elevated.



• Urinalysis is helpful in ruling out ketonuria; urine should be submitted for organic acid profile and acylcarnitine excretion pattern.

Other Tests:

• Molecular genetic testing can identify the nature of the mutation for purposes of prenatal diagnosis.

TREATMENT

Section 5 of 10

Medical Care:

• A major component of the medical treatment of this disorder is a diet that permits adequate nutrition while avoiding any fasting period longer than 4-5 hours.



• Administration of carnitine has been advocated on the basis of recognition of the biochemical role of carnitine in permitting conjugation and excretion of toxic intermediates. However, the evidence for any therapeutic effect is sparse and mostly anecdotal.

Consultations:

• Biochemical genetics



• Nutrition

Diet:

• Diet should be adjusted to supply requisite nutrition for normal growth, while avoiding fasting periods greater than 4-5 hours.



• Because the fundamental biochemical defect is in fatty acid oxidation, it stands to reason that the composition of the diet should be adjusted to provide greater caloric density in carbohydrates and proteins, while minimizing lipids.

MEDICATION

Section 6 of 10

The only appropriate medication is carnitine, although this remains controversial among specialists of inherited biochemical diseases.

FOLLOW-UP

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Further Inpatient Care:

• Given the tendency for development of severe hypoglycemia during fasts, any intercurrent illness that reduces or interrupts food intake may require admission for intravenous glucose support.

Further Outpatient Care:

• The affected child requires close monitoring of growth to make appropriate dietary changes. A skilled nutritionist should direct such changes.



• If the child's condition remains stable, blood studies beyond those required in routine pediatric care are not needed.

In/Out Patient Meds:

• Other than daily carnitine administration, no medication has been proven effective.

Transfer:

• Transfer is indicated when severe ketoacidosis, coma, seizures, or cerebral edema is present.

Deterrence/Prevention:

• Avoidance of fatty foods



• Early treatment and blood glucose support during intercurrent illness

Complications:

• Frequent episodes of severe hypoglycemia carry a great risk of adverse effects on CNS integrity.



• Hypoglycemia and hyperammonemia may cause cerebral edema and prolonged coma.

Prognosis:

• Prognosis is difficult because of the broad clinical spectrum among affected patients.



• When appropriately treated, the majority of children do well.



• Experience is too limited to prognosticate about life span.

Patient Education:

• Genetic counseling should be provided for family members.



• The frequency of the homozygous state suggests the wisdom of testing for the gene in first-degree relatives of the affected child.

MISCELLANEOUS

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Special Concerns:

• Retrieval of DNA from preserved specimens or screening samples may provide a diagnosis in deceased siblings.

TEST QUESTIONS

Section 9 of 10

CME Question 1: Which of the following conditions is not a part of the clinical presentation of medium-chain acyl-CoA dehydrogenase deficiency?

A: Hypoglycemia
B: Ketoacidosis
C: Anemia
D: Hyperammonemia
E: Lethargy

The correct answer is C: Anemia is typically not part of the clinical presentation of medium-chain acyl-CoA dehydrogenase deficiency.

CME Question 2: Which of the following is the most effective treatment for medium-chain acyl-CoA dehydrogenase deficiency?

A: High-calorie, low-protein diet
B: Oral carnitine
C: Frequent feeding of normal diet
D: Regular meal schedule with a low-fat diet
E: High-fat, ketogenic diet

The correct answer is C: A diet that provides adequate nutrition while avoiding fasting periods longer than 4-5 hours is a major factor in the treatment of this disorder.

Pearl Question 1 (T/F): Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency usually becomes apparent in the first week of life.

The correct answer is False: MCAD deficiency usually becomes apparent in infants aged 3-5 months. The major factor in clinically uncovering the presence of the disease is prolonged fasting. Most infants younger than 3 months are fed frequently enough to suppress significant lipolysis. After 5 months, however, most infants have begun to fast overnight, so that lipid catabolism is used to sustain blood glucose. It is this need that causes development of the clinical disease.

Pearl Question 2 (T/F): Carnitine is required for transport of the medium-chain acyl-CoA compounds into the mitochondria.

The correct answer is False: Carnitine is not required for transport of the medium-chain acyl-CoA compounds into the mitochondria. Cellular conservation of CoA for other reactions requires transfer of the acyl moiety to carnitine, with subsequent transfer out of the cell and urinary excretion. This fact forms the basis for diagnosis of the disease by examination of the urinary acyl-carnitine pattern.

Pearl Question 3 (T/F): Hypoglycemia without ketonuria typically is the basis of suspicion of the diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in a seriously ill baby.

The correct answer is True: The single most valuable test, once hypoglycemia is documented, is urinalysis, which indicates little or no ketonuria. Lack of ketone production is abnormal in hypoglycemia. In MCAD deficiency, the inability to metabolize medium-chain-length fatty acids, either from dietary sources or from sequential breakdown via the beta-oxidation cycle, prevents ketone formation.

Pearl Question 4 (T/F): The hyperammonemia that frequently accompanies the hypoglycemia of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is caused by the accelerated breakdown of endogenous proteins.

The correct answer is True: The inability to utilize fatty acids to support blood glucose during fasting in MCAD deficiency accelerates the breakdown of endogenous protein. Catabolism of the constituent amino acids leads to the release of free ammonia. Concomitantly, the dicarboxylic acids produced by w-oxidation impair the N-acetylglutamate synthase reaction, which in turn causes deactivation of the carbamoyl phosphate synthase I reaction of the urea cycle. The net effect is a slowdown in the disposition of free ammonia and a resultant hyperammonemia.

BIBLIOGRAPHY

Section 10 of 10

• DiMauro S, DiMauro PM: Muscle carnitine palmityltransferase deficiency and myoglobinuria. Science 1973 Nov 20; 182(115): 929-31[Medline].
• Divry P, David M, Gregersen N, et al: Dicarboxylic aciduria due to medium chain acyl CoA dehydrogenase defect. A cause of hypoglycemia in childhood. Acta Paediatr Scand 1983 Nov; 72(6): 943-9[Medline].
• Ensenauer R, Winters JL, Parton PA, et al: Genotypic differences of MCAD deficiency in the Asian population: novel genotype and clinical symptoms preceding newborn screening notification. Genet Med 2005 May-Jun; 7(5): 339-43[Medline].
• Feillet F, Steinmann G, Vianey-Saban C, et al: Adult presentation of MCAD deficiency revealed by coma and severe arrythmias. Intensive Care Med 2003 Sep; 29(9): 1594-7[Medline].
• Gregersen N, Lauritzen R, Rasmussen K: Suberylglycine excretion in the urine from a patient with dicarboxylic aciduria. Clin Chim Acta 1976 Aug 2; 70(3): 417-25[Medline].
• Gregersen N, Wintzensen H, Christensen SK, et al: C6-C10-dicarboxylic aciduria: investigations of a patient with riboflavin responsive multiple acyl-CoA dehydrogenation defects. Pediatr Res 1982 Oct; 16(10): 861-8[Medline].
• Maier EM, Liebl B, Roschinger W, et al: Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency. Hum Mutat 2005 May; 25(5): 443-52[Medline].
• Nennstiel-Ratzel U, Arenz S, Maier EM, et al: Reduced incidence of severe metabolic crisis or death in children with medium chain acyl-CoA dehydrogenase deficiency homozygous for c.985A>G identified by neonatal screening. Mol Genet Metab 2005 Jun; 85(2): 157-9[Medline].
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• Reis de Assis D, Maria Rde C, Borba Rosa R, et al: Inhibition of energy metabolism in cerebral cortex of young rats by the medium-chain fatty acids accumulating in MCAD deficiency. Brain Res 2004 Dec 24; 1030(1): 141-51[Medline].
• Stanley CA, Hale DE, Coates PM, et al: Medium-chain acyl-CoA dehydrogenase deficiency in children with non- ketotic hypoglycemia and low carnitine levels. Pediatr Res 1983 Nov; 17(11): 877-84[Medline].
• Tajima G, Sakura N, Yofune H, et al: Enzymatic diagnosis of medium-chain acyl-CoA dehydrogenase deficiency by detecting 2-octenoyl-CoA production using high-performance liquid chromatography: a practical confirmatory test for tandem mass spectrometry newborn screening in Japan. J Chromatogr B Analyt Technol Biomed Life Sci 2005 Sep 5; 823(2): 122-30[Medline].
• Van Hove JL, Zhang W, Kahler SG, et al: Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: diagnosis by acylcarnitine analysis in blood. Am J Hum Genet 1993 May; 52(5): 958-66[Medline].
• Walter JH: L-carnitine in inborn errors of metabolism: what is the evidence? J Inherit Metab Dis 2003; 26(2-3): 181-8[Medline].
• Wang SS, Fernhoff PM, Hannon WH, Khoury MJ: Medium chain acyl-CoA dehydrogenase deficiency human genome epidemiology review. Genet Med 1999 Nov-Dec; 1(7): 332-9[Medline].
• Yang W, Roth KS, Coates PM: Hypoglycemic, hypoketotic dicarboxylic aciduria--a possible defect in fatty acid oxidation (Abstract). Pediatr Res 1982; 16(4): 267A.
• Ziadeh R, Hoffman EP, Finegold DN, et al: Medium chain acyl-CoA dehydrogenase deficiency in Pennsylvania: neonatal screening shows high incidence and unexpected mutation frequencies. Pediatr Res 1995 May; 37(5): 675-8[Medline].

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