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Long-Chain Acyl CoA Dehydrogenase Deficiency Workup

  • Author: Fernando Scaglia, MD, FACMG; Chief Editor: Luis O Rohena, MD  more...
 
Updated: Nov 14, 2014
 

Laboratory Studies

The following studies may be indicated in long-chain 3-hydroxy acyl-coenzyme A dehydrogenase (LCHAD) deficiency:

  • Blood glucose and urine ketones
    • The hallmark biochemical feature of this condition is acute hypoketotic hypoglycemia.
    • Collect urine ketones in the acute episode.
  • Creatine phosphokinase, ammonia, uric acid, liver enzymes, lactic acid
    • During acute episodes, elevated levels of creatine phosphokinase are observed.
    • Hyperammonemia may be observed in acute episodes.
    • Elevation of liver transaminases is also observed.
    • A high incidence of lactic acidemia accompanies the metabolic decompensation or acute episode.
  • Urine organic acids
    • Test for 3-hydroxylated dicarboxylic acids and nonhydroxylated dicarboxylic acids.
    • Nonhydroxylated dicarboxylic acids are nonspecific changes found in other beta-oxidation defects and in association with liver failure.
  • Plasma carnitine levels and acylcarnitine profile
    • Plasma carnitine levels are low.
    • Long-chain acylcarnitine levels are increased with 3-hydroxydicarboxylic derivatives of the C16:0, C18:1, and C18:2 species.
    • The profile may be completely normal during asymptomatic periods.
  • Serum fatty acid analyses
    • Serum fatty acid analysis may be diagnostic.
    • Look for 3-hydroxylated compounds even between exacerbations.
  • Fatty acid oxidation studies and enzyme assay
    • Diagnosis may be made by study of the oxidation of the 14C-labeled myristic (C14:0) and palmitic (C16:0) acids in fibroblasts.
    • The deficient activity of long-chain 3-hydroxy acyl-coenzyme A dehydrogenase may be diagnosed in fibroblasts, as well as the other enzyme activities of the trifunctional protein.
    • The enzyme usually is measured in fibroblasts in the reverse direction, with 3-oxopalmitoyl CoA as substrate and measurement of the decrease in absorbance at 340 nm of the nicotinamide adenine dinucleotide-reduced form (NADH) electron donor.
  • Fasting: In patients in whom the diagnosis has been difficult, an induced fast under strict medical supervision in a facility with expertise in the diagnosis of the inborn errors of metabolism may be considered.
  • Molecular studies: Molecular studies (sequencing) to identify the common mutation, G1528C, are available. In addition, if only one mutation is identified in one allele, the presence of deletions can be checked on the other allele by oligonucleotide-based array comparative genomic hybridization (CGH).
  • Prenatal diagnosis: Prenatal diagnosis using biochemical studies has been attempted. In appropriate families in whom the molecular defect is known, prenatal diagnosis is also possible by mutation analysis. Guidelines for prenatal screening have been established.[2]
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Imaging Studies

See the list below:

  • Chest roentgenography may reveal enlargement of the cardiac silhouette if cardiomyopathy is present.
  • Echocardiography may reveal cardiac enlargement, poor contractility with decreased ejection fraction, and pericardial effusion in some cases.
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Other Tests

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  • Abnormal nerve conduction velocities have been recorded in patients with long-chain 3-hydroxy acyl-coenzyme A dehydrogenase deficiency and peripheral neuropathy.
  • ECG may reveal left ventricular hypertrophy and cardiac arrhythmias.
  • Electroretinography may reveal progression of chorioretinopathy.[3]
  • Mitochondrial enzyme studies may reveal abnormal respiratory chain function in skeletal muscle specimens. A more generalized deficiency of mitochondrial enzymes or a more selective reduction of complex I may be noted.
  • If elevated C16-OH ± C18:1-OH and other long chain acylcarnitines are present on newborn screening, the pediatrician should do the following:
    • Contact the family to inform them of newborn screening results and determine clinical status and whether poor feeding, vomiting, and lethargy are present
    • Contact pediatric metabolic specialist
    • Evaluate infant for hepatomegaly, signs of hypoglycemia and metabolic acidosis and cardiomyopathy
    • Evaluate family history to determine whether a history of sudden death in a sibling and whether maternal liver disease was noted during pregnancy
    • Educate family about signs and symptoms of hypoglycemia and metabolic acidosis
  • A metabolic specialist needs to confirm or exclude diagnosis of long-chain 3-hydroxy acyl-coenzyme A dehydrogenase deficiency by requesting an acylcarnitine profile and urine organic acid analysis. If carnitine levels are low, consider carnitine supplementation. In addition, an evaluation should be done to exclude hypoglycemia, elevated liver transaminases, bilirubin, lactate, ammonia, and creatine phosphokinase, which could be suggestive of long-chain 3-hydroxy acyl-coenzyme A dehydrogenase and trifunctional protein deficiencies. In addition, sequencing of the gene that encodes long-chain 3-hydroxy acyl-coenzyme A dehydrogenase is clinically available for molecular confirmation. If only one mutation is found in one allele, a possible deletion should be screened in the other allele by using oligonucleotide-based array CGH.
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Procedures

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  • Skin biopsy to obtain cultures of skin fibroblasts for fatty acid oxidation studies or specific enzyme assay is necessary for confirmation of diagnosis.
  • Muscle biopsy, although not necessary for diagnosis, may be performed because lactic acidosis present in this condition may suggest a respiratory chain defect.
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Histologic Findings

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  • Pathological evaluation has revealed microvesicular and macrovesicular accumulation of fat in skeletal muscle, heart, and liver. Necrotic myopathy without steatosis has been described, as well as degeneration of muscle fibers. Hepatic cirrhosis has also been observed.
  • Ultrastructurally, the mitochondria appear to be increased in size and number with swollen appearance. Condensation of the mitochondrial matrix and irregular cristae is noted.
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Contributor Information and Disclosures
Author

Fernando Scaglia, MD, FACMG Associate Professor of Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital

Fernando Scaglia, MD, FACMG is a member of the following medical societies: American College of Medical Genetics and Genomics, Society for Inherited Metabolic Disorders, Society for the Study of Inborn Errors of Metabolism, American Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Margaret M McGovern, MD, PhD Professor and Chair of Pediatrics, Stony Brook University School of Medicine

Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Chief Editor

Luis O Rohena, MD Chief, Medical Genetics, San Antonio Military Medical Center; Assistant Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Assistant Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Additional Contributors

Karl S Roth, MD Retired Professor and Chair, 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 College of Nutrition, American Pediatric Society, American Society for 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, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

References
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Schematic demonstrating mitochondrial fatty acid beta-oxidation and effects of long-chain acyl CoA dehydrogenase deficiency (LCHAD) deficiency.
 
 
 
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