Long-Chain Acyl CoA Dehydrogenase Deficiency Clinical Presentation

  • Author: Fernando Scaglia, MD, FACMG; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Apr 16, 2012
 

History

  • Acute metabolic crises precipitated by intercurrent infections usually present with hypoketotic hypoglycemia that may be accompanied by cardiomyopathy, hypotonia, and hepatomegaly. These metabolic crises occur more frequently in infancy and early childhood.
  • Careful analysis of patients who presented with hypoglycemia revealed that most of them had a constellation of easily missed, nonspecific symptoms before the hypoglycemic episode.
  • Many patients may present with myopathy characterized by profound weakness, which may also be accompanied by cardiomyopathy. According to a more recent retrospective study, three fourths of patients studied with trifunctional protein deficiency, including long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity (LCHAD) deficiency had long term myopathic symptoms.[1]
  • Some patients may present in infancy or childhood with myoglobinuria or as adults with exercise-induced muscle pains and rhabdomyolysis.
  • Some patients present with peripheral sensorimotor polyneuropathy.
  • Progressive visual loss has been documented in over 70% of cases with long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity deficiency.
  • Rarely, affected infants can present with acute cholestatic jaundice or massive total hepatic necrosis in infancy.
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Physical

  • Neurological examination
    • The acute episode of hypoketotic hypoglycemic encephalopathy may begin with a seizure.
    • Most patients are hypotonic, at least in infancy.
    • Examination may reveal profound weakness, decreased movements, and a frog-leg position.
    • Deep tendon reflexes may be absent in infancy.
    • The patient may toe-walk and display an equinus deformity.
    • Extensor plantar responses have been reported.
  • Cardiac: Examination of the heart may reveal cardiomegaly, poor heart sounds, and gallop rhythm.
  • Abdomen
    • Most patients have hepatomegaly.
    • Jaundice may develop in infancy along with elevation of the transaminases.
  • Ophthalmological examination
    • In the youngest patients, the fundus may be pale. Thereafter, aggregation of pigment has been detected in the posterior pole and macular region.
    • Progressive atrophy of the retinal pigment epithelium, choroid, neural retina, and retinal vessels follow initial pigment abnormalities. This may lead to a completely bare sclera in the central fundus.
    • Posterior staphylomas and delicate lens opacities also may be observed. Cataracts have also been reported.
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Causes

  • A molecular defect that affects the mitochondrial trifunctional protein (MTP) causes long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity deficiency.
  • Molecular defects are responsible for the 2 types of defect of MTP (ie, long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity deficiencies, MTP deficiencies).
    • The molecular defect affects the function of the MTP, which contains the activity of long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity, 2-enoyl-CoA hydratase, and 3-oxoacyl CoA hydratase.
    • In most patients, the deficiency is isolated to long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity; yet, in some patients, defective activity of all 3 enzymes of the protein is observed.
    • In isolated long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity deficiency, most of the patients are homozygous for a guanine-to-cytosine transversion at position 1528, involving the alpha subunit of the MTP in the active site domain of the long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity encoding region. The nicotinamide adenine dinucleotide (NAD) cofactor-binding sequence resides in this region.
    • Other mutations have been described, usually in compound with G1528C.
    • MTP deficiency is caused by several mutations in either alpha or beta subunit DNA encoding regions with resulting decreased functioning of all 3 enzyme activities of long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity.
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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, 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: Nothing to disclose.

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, 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

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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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