Long-Chain Acyl CoA Dehydrogenase Deficiency 

  • Author: Fernando Scaglia, MD, FACMG; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Jul 22, 2009
 

Background

Long-chain 3-hydroxy acyl-coenzyme A dehydrogenase (LCHAD) is 1 of 3 enzymatic activities that make up the trifunctional protein of the inner mitochondrial membrane. The other 2 activities of the protein are 2-enoyl coenzyme A (CoA) hydratase (LCEH) and long-chain 3-ketoacyl CoA thiolase (LCKT). The protein is an octamer composed of 4 alpha subunits that contain the LCEH and long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activities, and 4 beta subunits that contain the LCKT activity. This enzyme complex metabolizes long-chain fatty acids, and the long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity is specific for compounds of C12-C16 chain length. The genes for the alpha and beta subunits have been localized to chromosome 2.

Affected infants with long-chain 3-hydroxy acyl-coenzyme A dehydrogenase deficiency, which is inherited as an autosomal recessive trait, present in infancy with acute hypoketotic hypoglycemia. These episodes typically appear for the first time after a fast, which usually occurs in the context of intercurrent illness with vomiting.

Next

Pathophysiology

The molecular defect occurs in the mitochondrial trifunctional protein (MTP). Some patients who are deficient in all 3 enzymatic activities of the protein have been described, although most have an isolated long-chain 3-hydroxy acyl-coenzyme A dehydrogenase deficiency, which results in the inability to metabolize long-chain fatty acids. Thus, the clinical features may result from either toxicity due to long-chain acyl-CoA esters that cause cardiomyopathy and cardiac arrhythmias or from a block in long-chain fatty acid oxidation that leads to an inability to synthesize ketone bodies and/or adenosine triphosphate from long-chain fatty acids.

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

Increased rates of lipolysis after fasting has been observed. The increased lipolysis may represent a compensatory mechanism to meet energy demands after few hours of fasting. However, this effect may be achieved at the cost of fatty acid infiltration and of toxic effects of β-oxidation intermediates on organ functions. Patients with long-chain 3-hydroxy acyl-coenzyme A dehydrogenase deficiency may develop a profound CNS deficiency of docosahexanoic acid ethyl ester (DHA), 22:6n-3. An association between retinopathy and DHA deficiency has been demonstrated. The etiology of the severe peripheral neuropathy of trifunctional protein deficiency may result from the unique metabolite, 3-keto-acyl-CoA, after conversion to a methylketone via spontaneous decarboxylation. The gene for the protein has been cloned and a common mutation, G1528C, has been identified in 87% of mutant alleles.

The fatty acid oxidation defect results in adverse effects on numerous organ systems, including the CNS, secondary to the hypoketotic hypoglycemia. Hypotonia and cardiomyopathy are also usually present, reflecting the underlying energy deficiency. In addition, hepatomegaly is usually evident, and biopsy of the liver reveals fat accumulation and fibrosis. Chorioretinopathy may also develop over time.

Previous
Next

Epidemiology

Frequency

United States

Occurrence frequency of either isolated long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity deficiency or trifunctional protein deficiency is unknown in the United States.

International

Analysis of the frequency of the most common mutation (G1528C) revealed a carrier frequency of 1:240 in Finland.

Mortality/Morbidity

In most cases, the disease is severe and may lead to death during the first few months of life. The disease may also be a cause of sudden infant death, even neonatal. For those infants that are diagnosed and treated, a risk for psychomotor retardation is still noted.

Race

Patients from all ethnic groups have been reported.

Sex

No gender predilection is observed because this is an autosomal recessive disorder.

Age

Patients with long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity deficiency usually present with hypoketotic hypoglycemia, cardiomyopathy, hypotonia, and hepatomegaly at a median age of 6 months. In childhood, the presentation is myopathic. A minority of patients (up to 15%) may present during the neonatal period. A late-onset neuromuscular disease has been reported in MTP deficiency.

Previous
Proceed to Clinical Presentation
 
 
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, American Society of Human Genetics, Society for Inherited Metabolic Disorders, and Society for the Study of Inborn Errors of Metabolism

Disclosure: Nothing to disclose.

Specialty Editor Board

Karl S Roth, MD  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 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

Disclosure: MDS Pharma Salary Employment

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Pharmacy Editor, eMedicine

Disclosure: Nothing to disclose.

Margaret M McGovern, MD, PhD  Professor and Chair of Pediatrics, Stony Brook University, New York

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

Disclosure: Genzyme Grant/research funds PI

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References

  1. Spiekerkoetter U, Lindner M, Santer R, et al. Management and outcome in 75 individuals with long-chain fatty acid oxidation defects: results from a workshop. J Inherit Metab Dis. Apr 29 2009;[Medline].

  2. [Guideline] Cunniff C. Prenatal screening and diagnosis for pediatricians. Pediatrics. Sep 2004;114(3):889-94. [Medline].

  3. Stopek D, Gitteau Lala E, Labarthe F, et al. [Long-chain 3-hydroxyacyl CoA dehydrogenase deficiency and choroidal neovascularization]. J Fr Ophtalmol. Dec 2008;31(10):993-8. [Medline].

  4. Dyke PC 2nd, Konczal L, Bartholomew D, McBride KL, Hoffman TM. Acute dilated cardiomyopathy in a patient with deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase. Pediatr Cardiol. May 2009;30(4):523-6. [Medline].

  5. Amirkhan RH, Timmons CF, Brown KO, Weinberger MJ, Bennett MJ. Clinical, biochemical, and morphologic investigations of a case of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Arch Pathol Lab Med. Jul 1997;121(7):730-4. [Medline].

  6. Bertini E, Dionisi-Vici C, Garavaglia B, et al. Peripheral sensory-motor polyneuropathy, pigmentary retinopathy, and fatal cardiomyopathy in long-chain 3-hydroxy-acyl-CoA dehydrogenase deficiency. Eur J Pediatr. Feb 1992;151(2):121-6. [Medline].

  7. den Boer ME, Wanders RJ, Morris AA, IJlst L, Heymans HS, Wijburg FA. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: clinical presentation and follow-up of 50 patients. Pediatrics. Jan 2002;109(1):99-104. [Medline]. [Full Text].

  8. Gillingham MB, Connor WE, Matern D, et al. Optimal dietary therapy of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Mol Genet Metab. Jun 2003;79(2):114-23. [Medline].

  9. Gillingham MB, Purnell JQ, Jordan J, Stadler D, Haqq AM, Harding CO. Effects of higher dietary protein intake on energy balance and metabolic control in children with long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiency. Mol Genet Metab. Jan 2007;90(1):64-9. [Medline].

  10. Gillingham MB, Scott B, Elliott D, Harding CO. Metabolic control during exercise with and without medium-chain triglycerides (MCT) in children with long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiency. Mol Genet Metab. Sep-Oct 2006;89(1-2):58-63. [Medline].

  11. IJlst L, Wanders RJ, Ushikubo S, Kamijo T, Hashimoto T. Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of the major disease-causing mutation in the alpha-subunit of the mitochondrial trifunctional protein. Biochim Biophys Acta. Dec 8 1994;1215(3):347-50. [Medline].

  12. Jackson S, Bartlett K, Land J, et al. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Pediatr Res. Apr 1991;29(4 Pt 1):406-11. [Medline].

  13. Lawlor DP, Kalina RE. Pigmentary retinopathy in long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Am J Ophthalmol. Jun 1997;123(6):846-8. [Medline].

  14. Olpin SE, Clark S, Andresen BS, et al. Biochemical, clinical and molecular findings in LCHAD and general mitochondrial trifunctional protein deficiency. J Inherit Metab Dis. 2005;28(4):533-44. [Medline].

  15. Pons R, De Vivo DC. Primary and secondary carnitine deficiency syndromes. J Child Neurol. Nov 1995;10 Suppl 2:S8-24. [Medline].

  16. Pons R, Roig M, Riudor E, et al. The clinical spectrum of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Pediatr Neurol. Apr 1996;14(3):236-43. [Medline].

  17. Rocchiccioli F, Wanders RJ, Aubourg P, et al. Deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase: a cause of lethal myopathy and cardiomyopathy in early childhood. Pediatr Res. Dec 1990;28(6):657-62. [Medline].

  18. Roe CR, Roe DS, Wallace M, Garritson B. Choice of oils for essential fat supplements can enhance production of abnormal metabolites in fat oxidation disorders. Mol Genet Metab. Dec 2007;92(4):346-50. [Medline].

  19. Sewell AC, Bender SW, Wirth S, Munterfering H, Ijlist L, Wanders RJ. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: a severe fatty acid oxidation disorder. Eur J Pediatr. Oct 1994;153(10):745-50. [Medline].

  20. Spiekerkoetter U, Sun B, Zytkovicz T, Wanders R, Strauss AW, Wendel U. MS/MS-based newborn and family screening detects asymptomatic patients with very-long-chain acyl-CoA dehydrogenase deficiency. J Pediatr. Sep 2003;143(3):335-42. [Medline].

  21. Treem WR, Rinaldo P, Hale DE, et al. Acute fatty liver of pregnancy and long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Hepatology. Feb 1994;19(2):339-45. [Medline].

  22. Tyni T, Majander A, Kalimo H, Rapola J, Pihko H. Pathology of skeletal muscle and impaired respiratory chain function in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency with the G1528C mutation. Neuromuscul Disord. Oct 1996;6(5):327-37. [Medline].

  23. Tyni T, Pihko H. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Acta Paediatr. Mar 1999;88(3):237-45. [Medline].

  24. Wanders RJ, IJlst L, van Gennip AH, et al. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of a new inborn error of mitochondrial fatty acid beta-oxidation. J Inherit Metab Dis. 1990;13(3):311-4. [Medline].

  25. Wilcken B, Leung KC, Hammond J, Kamath R, Leonard JV. Pregnancy and fetal long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency. Lancet. Feb 13 1993;341(8842):407-8. [Medline].

 
Previous
Next
 
Schematic demonstrating mitochondrial fatty acid beta-oxidation and effects of long-chain acyl CoA dehydrogenase deficiency (LCHAD) deficiency.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.